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https://f1000research.com/articles/12-1341/v1
|
16 Oct 23
|
{
"type": "Study Protocol",
"title": "Exploring the experiences of family caregivers of stroke survivors in Burkina Faso: A qualitative study protocol",
"authors": [
"Fatimata Ouédraogo",
"Gbètogo Maxime Kiki",
"Orthelo Léonel Gbètoho Atigossou",
"Fatimata Ouédraogo",
"Gbètogo Maxime Kiki"
],
"abstract": "Background: Stroke survivors in sub-Saharan Africa frequently require continuous assistance from their relatives for daily activities and personal hygiene care. In Burkina Faso, the experiences of these caregivers are not documented.\nPurpose: This protocol describes a study that aims to explore in-depth the experiences of the family caregivers of stroke survivors in this region in order to better understanding the real impacts of caregiving on their overall lives.\nMethods: A convenience sample of twenty family caregivers recruited from both urban and semi-urban regions will be used to conduct a qualitative study. Participants will take part in individual semi-structured online interviews using an interview guide pre-designed by the authors. The interviews will be recorded and transcribed verbatim. The data will then undergo abductive thematic analysis guided by the International Classification of Functioning, Disability, and Health (ICF) framework.\nExpected results: Four main potential themes could eventually emerge. 1) Health and well-being of family caregivers (e.g., physical, psychological, and social impacts, health management, conflicts, and priorities); 2) Balancing caregiving responsibilities and personal life (e.g., daily caregiving management and the impact of caregiving role on social participation); 3) Impact of environment on the caregiving role (e.g., social and physical environment factors); 4) Personal experience and perceptions of the caregiving role (e.g., self-assessment as a caregiver, expectations and needs).\nConclusions: To the best of our knowledge, this will be the first study of its kind conducted in this country. Therefore, it will make a substantial contribution to stroke research in sub-Saharan Africa, specifically in Burkina Faso.\nEthical approval: This study was approved by the Research Ethics Committee of the Burkina Faso Ministry of Health (No: 2023-07-183). It will be conducted following the prescribed guidelines respecting the confidentiality of participants.",
"keywords": [
"Experiences of family caregivers",
"Stroke survivors",
"Burkina Faso"
],
"content": "Introduction\n\nIn developing countries, stroke is more prone to occur at an earlier age than in developed countries. And this could lead to major long-term consequences, particularly in sub-Saharan Africa.1,2 Recent statistics indicate that the incidence rate of stroke is highest in Africa, with an estimated 316 cases per 100,000 individuals per year, and a prevalence of up to 1,460 per 100,000.1,3 Moreover, stroke patients in Africa experience high mortality rates, with over 80% of them passing away within three years.1,3 Sub-Saharan Africa is significantly challenged in managing the consequences of stroke,1,4 despite the efforts of national governments, and the institutional support of the World Health Organization (WHO).1 Stroke consequences range from physical5–7 and psychological disorders2,8 to post-stroke environmental barriers,9 and stroke impact on caregivers in both developed and developing countries.10 Indeed, in this context where individuals after a stroke have suddenly become dependent due to multiple functional limitations, their families and/or relatives are required to take on new responsibilities for them, such as assistance with mobility, feeding and body hygiene care, thus creating the notion of caregiving.10 A relevant systematic review conducted by Mackenzie and Greenwood in 2012, which included nine qualitative and quantitative studies, highlighted the main positive effects of caregiving.11 These effects referred to the improvement in the health status of stroke survivors and strengthening connections with their caregivers, resulting in better social integration of stroke survivors within their communities.11 However, caregiving can be seen as a burden on them and can have a negative impact on their lives.12 For example, a recent scoping review of fifty-eight studies showed that stroke survivors caregivers experienced a decline in their quality of life and increased levels of psychological disorders (i.e., depression and anxiety), as well as a lack of resources they need to efficiently carry out their duties.13\n\nIn addition, post-stroke sequelae, such as cognitive impairments or communication difficulties encountered by stroke survivors, are likely to complicate the assistance provided by family caregivers.14 Caregivers could therefore be severely and permanently affected or unable to assume their family, social, and personal or professional responsibilities.15 In summary, despite the benefits of caregiving, caregivers could face several difficulties that deserve special attention to prevent physical and emotional exertion in performing their duties. Due to the lack of institutional or governmental support services, including residential facilities or long-stay institutions, in Burkina Faso, a developing country in sub-Saharan Africa, family members of stroke patients systematically assume responsibility for supporting stroke survivors from hospital admission to their return to the community, sometimes indefinitely. As far as we know, there is currently no available data on experiences of family caregivers of stroke survivors in this country. Therefore, this intended study aims to explore in-depth the determinants and extent of the experiences of family caregivers of stroke survivors.\n\n\nMethods\n\nThis study will use a descriptive qualitative design that enables accurate data analysis of participants’ experiences and perceptions. To ensure transparency of the methodology, this study will follow the requirements of the Consolidated Criteria for Reporting Qualitative Research checklist (COREQ).16 Thus, we will provide demographic information about the members of the research team (e.g., profession, gender, experience, education, and responsibility in the study), as well as a description of the qualitative approach and conceptual framework used, the sampling and sample size. All these details will help to demonstrate the rigour with which the study will be carried out but will also add transparency to the results that will be provided.\n\nAdditionally, the International Classification of Functioning, Disability, and Health (ICF) framework17,18 will be used to guide the qualitative data analysis. ICF encompasses several health-related aspects about functioning, activity, participation, and personal and environmental factors. It applies to all individuals, whether they have a disability or not.18 ICF will facilitate the widespread documentation of the experiences of family caregivers of stroke survivors, each with their own unique experiences.\n\nThe study aims to recruit twenty family caregivers of stroke survivors in Burkina Faso through a convenience sample. Potential participants will be recruited from the rehabilitation unit registers of three hospitals: the “Centre Hospitalier Universitaire de Bogodogo”, the “Centre Hospitalier Universitaire Sourou Sanou”, and the “Centre Hospitalier Régional de Tenkodogo” in Burkina Faso. Once the stroke patients’ files have been identified, contact details (phone numbers, addresses, or email addresses) will be collected. Their caregivers will then be contacted via the patients to request their participation in the study after we have provided them with a brief overview of our research. Family caregivers interested in participating in the study will be contacted again to plan an initial appointment during which, they will receive a comprehensive information letter detailing the aspects of the study. All participants included in the study will be required to sign a consent form prior to participating in semi-structured interviews. To be eligible for this study, individuals should meet the following inclusion criteria: 1) providing continuous and non-remunerated assistance to a stroke survivor, including personal hygiene care, and feeding; 2) be a family member of the stroke survivor and be 18 years of age or older; 3) be able to communicate effectively in French and participate in an interview. Family caregivers will be excluded when a) they have a history of psychological disorders before their parent’s stroke, which could impact the interview procedure; b) they assist stroke survivors on a discontinuous or infrequent basis.\n\nIn July 2023, the research team submitted the protocol to the Research Ethics Committee of the Health Ministry of Burkina Faso and obtained ethical approval (N°: 2023-07-183) for conducting this study. Moreover, before starting data collection, the research team will request research authorization from the three hospitals mentioned above to access the data of stroke patients.\n\nSociodemographic characteristics\n\nSociodemographic data such as age, sex, level of education, occupation, time since stroke, and monthly income, will be collected using a survey.\n\nQualitative data\n\nOnline interviews will be conducted with the participants by one member of our research team (FO), who has expertise in qualitative research methods. The interview guide in Table 1 comprises six open-ended key questions that align with the ICF model domains. In order to explore more fully family caregivers’ experiences, between three and seven booster questions depending on these open-ended key questions will also be used during the semi-structured interviews. In addition, to improve relevance, suitability, and cohesiveness of the interview guide with the objective of the study, pre-tests will be conducted among members of the research team. The aim is to refine this support and test its effectiveness in an iterative process. These procedures illustrate the research team’s commitment to using an impartial, unbiased interview guide that corresponds closely with the study objective, thereby enhancing research reliability. Each semi-structured interview is expected to last between 30 and 45 minutes and will be scheduled at the participant’s convenience. Interview audio recordings will be transcribed verbatim to assist with thematic analysis.19 To preserve participants’ anonymity, pseudonyms will be used in the transcripts.\n\n\n\n‐ How have you been feeling since you started caring for your loved one who experienced a stroke?\n\n\n\n‐ What does your daily life look like as a family caregiver?\n\n‐ How does your role as a family caregiver impact your social participation?\n\n\n\n‐ How do the individuals around you contribute to your role as a family caregiver?\n\n‐ Describe the living environment in which you assist the stroke patient.\n\n\n\n‐ How do you perceive your skills as a family caregiver?\n\nSociodemographic data will be analyzed using descriptive statistics (frequency, percentage, mean and standard deviation - SD) with IBM SPSS Statistics 26 software. As for qualitative data, we will adhere to the Lincoln and Guba standards (as described in Table 2),20 ensuring the highest scientific value of the study. The verbatim transcripts will be uploaded to the Mixed Method Solution for Qualitative Analysis (QDA Miner software) to facilitate organization and coding. Two members of the research team (FO and GMK) will then verify the transcripts. Subsequently, an abductive thematic analysis21 will be conducted. By adopting this approach, the research team can generate new ideas through a dynamic interaction between theory and data. A predefined coding scheme will be developed based on the ICF categories. Next, the research team carefully will examine the transcription text to identify which meaning unit reflected one of the predetermined codes. The codes and assemblies will be frequently revised, and new relevant codes will be assigned to meaning units that could not be coded or categorized within the initial scheme codes. Finally, the new codes will be reviewed and represented as themes or sub-themes related to the ICF model or as an emerging category. Furthermore, the thematic analysis will be submitted to a specialist in analysing qualitative data, who will provide his expertise to enhance our analysis methodology and optimize the relevance of our research. Direct quotes to be provided in the article will be translated from French into English by a bilingual researcher.\n\n\n\n• Research team members received training in qualitative research.\n\n• Use of a conceptual framework (ICF)\n\n• Triangulation: Cross-checking of transcripts by two members of the research team, coding of data by at least two members of the research team, and inter-judge validation were performed to reach a consensus on the interpretations obtained. This multidimensional approach aims to mitigate potential biases and reinforce the robustness of the conclusions drawn from the analysis.\n\n• Participant feedback: After analysing the data, a feedback process will be conducted with family caregivers to confirm the accuracy and reliability of the collected data.\n\n\n\n• Information about the research context and participants will be provided anonymously to help readers evaluate the potential application of the findings in different settings.\n\n\n\n• The use of COREQ shall enable a meticulous and comprehensive description of the employed methods.\n\n• Comprehensive audit records documenting the process of data collection and analysis will be available upon request.\n\n\n\n• A reflective research journal shall be maintained during this study to facilitate the researcher's critical self-evaluation regarding potential subjective influences on the interpretation and direction of findings. Priority shall be given to objective evaluations.\n\n• An authenticity log, using the QDA Miner tool, will note all decisions and interpretations concerning the data throughout the thematic analysis phase. This log will be kept and provided upon request.\n\nExpected results: On the basis of the developed interview guide, up to four potential key themes were distinguished relating to the ICF domains (see Figure 1). These themes could be the focus of our future results:\n\n(1) Health and well-being of family caregivers: This main theme and its sub-themes may explore the health challenges experienced by family caregivers in their role, encompassing physical, psychological, and social aspects. It could highlight how caregivers handle these challenges while caring for stroke patients and address the complex dilemmas caregivers face when balancing their own well-being with that of the individuals they support.\n\n(2) Balancing caregiving responsibilities and personal life: This main theme and its sub-themes could investigate the connection between the family caregivers’ duties and maintaining an enjoyable social life. For example, it could examine how family caregivers schedule their time to accommodate the needs of stroke survivors, along with the difficulties and strategies for achieving equilibrium between caregiving and maintaining a fulfilling social life.\n\n(3) Impact of environment on the caregiving role: This main theme and its sub-themes could explore the influence of the environment on family caregivers, considering the social and physical aspects for both caregivers and stroke survivors. It could emphasise the crucial function of social support in caregiver well-being and fulfilment of their duties, as well as how the physical environment can impact caregiving.\n\n(4) Personal experience and perceptions of the caregiving role: This main theme and its sub-themes would examine the personal, emotional, and psychological aspects of family caregivers’ experiences, focusing on their perception of their skills, expectations, and the influencing factors. The analysis would use the participants’ sociodemographic information to gain a deeper understanding of how personal factors interact with their role as family caregivers.\n\nThe four key themes are aligned with the ICF domains. Theme 1 and its sub-themes relate to the domain of ‘functioning’, while theme 2 relates to the domain of ‘activities and participation’. Theme 3 and its sub-themes cover the sub-domain of ‘environmental factors’, and theme 4 and its sub-themes address the sub-domain of ‘personal factors’.\n\n\nDiscussion\n\nThis qualitative study aims to enhance our understanding of the experiences of family caregivers of stroke survivors in Burkina Faso. By including a variety of viewpoints, the study will provide accurate information about the challenges and issues that these caregivers face in their day-to-day lives. Previous research on this topic in the sub-Saharan African context has been limited,22–24 with minimal emphasis on exploring the various aspects covered by the ICF domains. This restricted approach failed to capture the extent of the experiences of family caregivers.\n\nUsing the ICF model as a conceptual framework will enable a comprehensive exploration of family caregivers’ lived experiences, investigating the various limitations they encounter in their caregiving role, and the personal and environmental factors that may act as barriers or facilitators in fulfilling their caregiving responsibilities. By considering the physical, psychological, and social dimensions of family caregivers’ experiences according to the ICF components, the study will adopt a holistic and nuanced approach, facilitating a comprehensive understanding of their daily concerns. Consequently, the results of the study are expected to be more exhaustive, reliable, and better suited to inform policies and potential support programs for family caregivers caring for stroke survivors in Burkina Faso.\n\nThis study presents methodological strengths that will bolster the credibility of its findings. Using ICF framework for classifying data will enhance the accuracy of our future results. To ensure transparency and consistency in our approach, we will adhere to the COREQ criteria and the Lincoln and Guba standards. Moreover, this study represents the first qualitative exploration of the experiences of stroke survivors’ caregivers in Burkina Faso. The results will therefore contribute to advancing knowledge in the field of stroke research. Nevertheless, it is essential to recognize a limitation to this coming study. Being a qualitative approach, the impact of researchers’ subjectivity on data analysis should not be overlooked. However, all the objective strategies planned for this study should minimise this impact.\n\n\nConclusion\n\nThis qualitative study has the potential to shed light on the various problems encountered by family caregivers of stroke survivors in Burkina Faso. By exploring different facets of their experiences, this study aims to provide novel insights on the management of stroke-related repercussions in this country, and fill gaps in stroke research in sub-Saharan Africa.\n\nIdentification of potential participants began on 11 August 2023, and interviews are scheduled to start in October 2023.\n\nOnce the study is completed, the results will be published in a peer-reviewed scientific article.\n\n\nAuthors contributions\n\nConceptualization, F.O., G.M.K., O.L.G.A.; Methodology, F.O., G.M.K., O.L.G.A.; Validation, F.O., G.M.K., O.L.G.A.; Writing—Original draft preparation, F.O., G.M.K., O.L.G.A.; Review and Editing, F.O., G.M.K., O.L.G.A.; Visualization, F.O., G.M.K., O.L.G.A.; Supervision, O.L.G.A. All authors have read and approved the final version of the manuscript.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nAcknowledgments\n\nThe research team would like to thank Dr Boukaré Ouédraogo for his help with the administrative procedures required to obtain approval for this research.\n\n\nReferences\n\nAkinyemi RO, et al.: Stroke in Africa: profile, progress, prospects and priorities. Nat. Rev. Neurol. 2021; 17(10): 634–656. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAtigossou OLG, Ouédraogo F, Honado AS, et al.: Association between post-stroke psychological disorders, activity limitations and health-related quality of life in chronic stroke survivors in Benin. Disabil. Rehabil. 2022; 45: 2087–2094. Publisher Full Text\n\nOkekunle A, et al.: Stroke in Africa: a systematic review and meta-analysis of the incidence and case-fatality rates. Int. J. Stroke. 2022; 17474930221147164.\n\nAdoukonou T, et al.: Stroke case fatality in sub-Saharan Africa: systematic review and meta-analysis. Int. J. Stroke. 2021; 16(8): 902–916. PubMed Abstract | Publisher Full Text\n\nHonado AS, Atigossou OLG, Daneault J-F, et al.: Relationships between overall physical activity and step counts in able-bodied adults and stroke survivors in developing countries: a cross-sectional study. Disabil. Rehabil. 2022; 45: 997–1004. Publisher Full Text\n\nHonado AS, Atigossou OLG, Roy J-S, et al.: Relationships between Self-Efficacy and Post-Stroke Activity Limitations, Locomotor Ability, Physical Activity, and Community Reintegration in Sub-Saharan Africa: A Cross-Sectional Study. Int. J. Environ. Res. Public Health. 2023; 20(3): 2286. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDefebvre L, Krystkowiak P: Movement disorders and stroke. Rev. Neurol. 2016; 172(8-9): 483–487. Publisher Full Text\n\nvan Dijk MJ , de Man-van Ginkel JM , Hafsteinsdóttir TB, et al.: Identifying depression post-stroke in patients with aphasia: a systematic review of the reliability, validity and feasibility of available instruments. Clin. Rehabil. 2016; 30(8): 795–810. PubMed Abstract | Publisher Full Text\n\nFoley E, Connor L, Nicholas M, et al.: Influence of environmental factors on social participation poststroke. Am. J. Occup. Ther. 2019; 73(4_Supplement_1): 7311505189p1. Publisher Full Text\n\nSee Toh WXS, Lim WHJ, Yobas P, et al.: The experiences of spousal and adult child caregivers of stroke survivors in transitional care: A qualitative systematic review. J. Adv. Nurs. 2022; 78(12): 3897–3929. PubMed Abstract | Publisher Full Text\n\nMackenzie A, Greenwood N: Positive experiences of caregiving in stroke: a systematic review. Disabil. Rehabil. 2012; 34(17): 1413–1422. PubMed Abstract | Publisher Full Text\n\nDenham AM, et al.: The long-term unmet needs of informal carers of stroke survivors at home: a systematic review of qualitative and quantitative studies. Disabil. Rehabil. 2022; 44(1): 1–12. Publisher Full Text\n\nMoura A, Teixeira F, Amorim M, et al.: A scoping review on studies about the quality of life of informal caregivers of stroke survivors. Qual. Life Res. 2022: 1–20.\n\nAïach P, Baumann M: L’aphasie, principal facteur aggravant du vécu d’un AVC par les proches. Médecine. 2007; 3(3): 130–135.\n\nBaumann M, Aïach P: L’« AIDANT PRINCIPAL » FACE A L’AVC D’UN PROCHE. Médecine. 2009; 5(4): 184–188.\n\nAllison Tong PS, Craig J: Consolidated criteria for reporting qualitative research (COREQ): a 32-item checklist for interviews and focus groups. Int. J. Qual. Health Care. 2007; 19(6): 349–357. PubMed Abstract | Publisher Full Text\n\nChan F, Gelman JS, Ditchman N, et al.: The World Health Organization ICF model as a conceptual framework of disability.2009.\n\nWorld Health Organization: International classification of functioning, disability and health: ICF. World Health Organization; 2001. Reference Source\n\nBraun V, Clarke V: Using thematic analysis in psychology. Qual. Res. Psychol. 2006; 3(2): 77–101. Publisher Full Text\n\nLincoln YS, Guba EG: Naturalistic Inquiry. Newbury Park, CA: Sage Publications; 1985.\n\nCoffey AJ, Atkinson PA: Making Sense of Qualitative Data: Complementary Research Strategies. Thousand Oaks, CA, USA: Sage Publications; 1996.\n\nScheffler E, Mash R: Figuring it out by yourself: Perceptions of home-based care of stroke survivors, family caregivers and community health workers in a low-resourced setting, South Africa. Afr. J. Prim. Health Care Fam. Med. Oct 8 2020; 12(1): e1–e12. PubMed Abstract | Publisher Full Text | Free Full Text\n\nElmberg Sjoholm M, Eriksson G, Bii A, et al.: Living with consequences of stroke and risk factors for unhealthy diet- experiences among stroke survivors and caregivers in Nairobi, Kenya. BMC Public Health. Mar 16 2021; 21(1): 511. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKalavina R, Chisati E, Mlenzana N, et al.: The challenges and experiences of stroke patients and their spouses in Blantyre, Malawi. Malawi Med. J. Jun 2019; 31(2): 112–117. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "223559",
"date": "18 Dec 2023",
"name": "Mohd Azmi Bin Suliman",
"expertise": [
"Reviewer Expertise Public Health",
"Non-communicable Diseases",
"Research Methodology."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall: The proposed qualitative study on stroke caregiver burden appears well-designed and appropriate for investigating the research question. The protocol is clearly written, easy to follow, and the methodology aligns well with the intended research.\nStrengths:\nThe research question is clearly defined and significant, addressing a gap in the existing literature. The proposed qualitative methods (e.g., interviews, focus groups) are well-suited to capturing the lived experiences of stroke caregivers. The sampling strategy is appropriate and likely to yield diverse and informative data. The data analysis plan is comprehensive and rigorous, ensuring the validity and reliability of the findings.\nAreas for Potential Improvement:\nConsider elaborating on potential challenges and mitigation strategies. Provide additional details on ethical consideration, especially on the respondent autonomy to respond and care of patient (e.g. the patient care won't be affected by the decision to participate or not participate in this study)\nOverall Assessment: This proposal presents a well-conceived study with the potential to generate valuable insights into the challenges and experiences of stroke caregivers. With minor revisions to address the suggested areas for improvement, this proposal demonstrates a strong foundation for conducting impactful research.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1341
|
https://f1000research.com/articles/12-1338/v1
|
16 Oct 23
|
{
"type": "Systematic Review",
"title": "PERMA well-being and innovative work behaviour : A systematic literature review",
"authors": [
"Nor Fauziana Ibrahim",
"Sabri Mohamad Sharif",
"Hasan Saleh",
"Nor Hasliza Mat Hasan",
"Nur Faezah Jayiddin",
"Sabri Mohamad Sharif",
"Hasan Saleh",
"Nor Hasliza Mat Hasan",
"Nur Faezah Jayiddin"
],
"abstract": "Background: The purpose of this research is to examine at how the literature measures the relationship between PERMA (positive emotion, engagement, relationships, meaning, and accomplishments) well-being and innovative work behaviour (IWB).\nMethods: This systematic literature review examines peer-reviewed English research papers published in 2012 that investigate the relationship between PERMA well-being and IWB. A total of 37 publications were discovered in 32 journals.\nResults: A total of 220 articles were initially retrieved from the database. 37 studies out of 220 satisfied the inclusion criteria and were thoroughly examined. Our findings present a comprehensive overview of the types of PERMA well-being related to IWB in different countries and industries. Literature-based research approaches are also discussed. Research methods from the previous literature are also discussed.\nConclusions: This study is one of the first to conduct a systematic literature review (PRISMA) method on the relationship between PERMA well-being and IWB. This review suggests constructive future research directions.",
"keywords": [
"Systematic Literature Review",
"Innovative Work Behaviour",
"PERMA",
"Well-being"
],
"content": "Introduction\n\nInnovation is vital to stay competitive in the global market. At the core of every innovation are creative ideas, and it is the individual employees who, either independently or collaboratively, create, promote, discuss, refine, and realise ideas.1 Therefore, it is no surprise that innovative work behaviour (IWB) employees are vital for modern contemporary organizations. The management must be able continuously to enable IWB among their employees especially as the business environment becomes more dynamic. To better understand IWB, both academics and corporate managers have focused on the antecedents of employees’ IWB and how to promote and support employees’ innovativeness.2\n\nSome of the proposed antecedents of IWB include leadership styles and organisation citizenship behaviours,3,4 job characteristics, job design, organisational support,5,6 personality, trust, and justice.7,8 Other studies view the human resource (HR) system and organizational structure as important determinants of IWB.9 Moreover, recent research has highlighted work engagement in shaping employee IWB.10–13\n\nAlthough existing research has explored various factors that contribute to IWB, it is necessary to explore the underlying psychological factors involved in positive well-being especially specifying how individual positive well-being impacts IWB.14 Focusing on the positive aspects of employee well-being is likely to result in increased work engagement, which is particularly beneficial for fostering innovation within organizations.15 Employees who are happy and possess a positive mindset tend to demonstrate greater competence, creativity, and actively generating innovative ideas.16,17\n\nGaining an understanding of the relationship between employee well-being and IWB is crucial in order to determine the appropriate ways to support and nurture innovative employees. Past studies have focused on examining the influence of individual well-being on the IWB.18,19\n\nWhile scholars in the social sciences have increasingly focused on employee well-being, it has been acknowledged that the dimension of employee well-being has been limited to one or two models or approaches18,19 which cannot represent overall employee well-being.20 Therefore, the main aim of this review is to examine how positive well-being factors influence IWB based workers on the selected literature which covers various model and approaches.\n\nWell-being encompasses an individual's holistic experience of their physical, mental, emotional and their level of happiness. At work, well-being is crucial because it greatly influences an individual's physical, mental, and emotional health.21 According to Ogbonnaya and Messersmith,22 if an employee's well-being is compromised, it can lead to reduced productivity, higher absenteeism, increased stress, and negatively affect their work performance and the organisation's overall success. Indeed, positive well-being among employee provides positive impact towards innovative work behaviour. An employee who is physically and mentally healthy and satisfied with their work are more likely to be engaged and motivated to create up creative ideas and solutions.23\n\nIWB refers to creative and unconventional ways of thinking and approaching work tasks and challenges.24 Encouraging employees to engage in innovative work behaviour can lead to increased productivity and improved problem-solving skills, which can in turn contribute to the success of the organization. Following Onne Janssen,25 our understanding of IWB in the workplace involves recognizing it as a multifaceted behaviour comprising three distinct behavioural tasks: generating ideas, promoting ideas, and implementing ideas. Idea generation is the process of creating, developing, and generating new ideas, concepts, or solutions to problems.9 The following step in the innovation process involves promoting ideas to a potential group. Idea promotion occurs once an employee has generated an idea, involving the process of presenting and persuading allies to gain their support and approval for the idea.26 Idea generation and idea promotion can be critical to the success of innovation, as it involves persuading others to invest in or implement the idea, which can help to bring it to market or bring it to life. The last stage will be idea realization by bringing an idea to fruition, from conception to implementation.15,27,28\n\nMany research has shown that well-being is connected to IWB.4,17,29–32 However, many studies pointed out that well-being cannot be defined by a dimension measurement.1,18,33,34 Seligman34 argued that well-being cannot be defined by a single measurement dimension, but rather encompasses multiple aspects that can be more easily measured. Emotion, relationship, meaningfulness, achievement and life satisfaction are all highly influenced by an employee’s current mood and situation. In reality, research has demonstrated that only multidimensional measurements of well-being are effective.35 Furthermore, reducing measurement of well-being dimension to single dimension obscures potential vital information according to Morgan and Simmons.36 Psychology experts believe that well-being is best understood as comprehensive set of indicators by covering multiple dimensions rather than as a single element.1,18 Ascenso20 emphasises heavily on research efforts directed to the development of creative, innovative, valid, reliable, and affordable survey questions for measuring the multiple dimensions of positive well-being.\n\nSeligman34 introduced the PERMA model with five core elements of psychological well-being knowing as “positive emotion” (happiness, joy, pleasure, satisfaction), “engagement” (involvement in a particular task, activity, or relationship), “relationships” (having positive connection, association, or bond with others), “meaning” (sense of purpose, mindful, significance, and coherence in one's life.), and “accomplishment” (regularly achieving successes.18,37 The PERMA model is widely recognized as a prominent framework for well-being, leading to the rapid adoption of the PERMA Profiler since its publication in 2016.38 In fact, it has been identified that there are five pathways that are considered the most effective in determining what individuals seek for their own well-being, serving as indicators of positive emotions and optimal functioning.39\n\nThe PERMA encompasses both hedonic and eudaimonic perspectives of well-being, has been developed. One of the primary critiques levelled against the PERMA model pertains to the limited empirical evidence supporting its claims.35,39 Recent efforts aimed at bridging this gap supported PERMA's proposed facets of well-being, by using a study sample of over 15,000 individuals from various regions worldwide.18,35 Current authors consider PERMA model to compliment other unidimensional well-being theories to provide a deeper level of understanding in employee positive well-being. Hence, the aim of this study is to investigate the possibility of measuring the individual constructs of PERMA as distinct dimensions to measure well-being and measure relationship between IWB.\n\nThe current systematic literature review aims to answer the following question:\n\nHow is the relationship between PERMA and IWB measured?\n\nSpecifically, within the broader research question, there were six guiding questions that directed the review:\n\nQ1. What specific methods have been employed in previous studies?\n\nQ2. Which countries/regions have been examined or included in the existing literature?\n\nQ3. Which academic journals are scholars publishing those articles?\n\nQ4. What is the pattern observed or trend of this line of research?\n\nQ5. What are the research samples included in the existing literature?\n\nQ6. What is PERMA well-being? Which specific PERMA factors have been identified as predictors of IWB in the literature? Conversely, which PERMA factors have received comparatively less research attention? What are the reasons for this disparity?\n\n\nMethods\n\nThis systematic literature review had a specific objective of determining how multidimension PERMA well-being affects IWB by examining the current body of literature. This review follows the reporting criteria of Preferred Reporting Items for Systematic Reviews and Meta Analysis (PRISMA) guidelines.\n\nEligibility criteria\n\nSince the objective of this study was to measure PERMA well-being constructs that includes significant relationship with the IWB, we performed a systematic literature review. This technique allows for in-depth analysis of all important publications on this topic, thus improving the quality of the review process and findings.9 We reviewed current theoretical and empirical studies related to well-being and IWB in various industries. Only papers published in peer-reviewed publications beginning in 2012 and written in English were evaluated for inclusion in the review. Studies classified as editorials, comments, opinion articles, or without an abstract were not considered further.\n\nSearch strategy\n\nWe selected five major social sciences databases which were Science Direct, Emerald, ProQuest, Scopus and Springer. Next, with the research focusing on the relationship between well-being and IWB, we employed the Boolean approach and selected the terms 'well-being,' 'innovative work behavior,' and 'PERMA' as the primary keywords for our initial article search. The search process was continued until no new studies meeting the selection criteria were identified.\n\nExtracting and synthesising data\n\nInitially, a search in the first trial database yielded a total of 220 results. After removing 15 duplicate and non-English articles, 205 articles remained. The titles and abstracts of these 205 papers underwent screening, leading to the exclusion of 152 papers. This was based on the initial exclusion criteria such as lack of relevant abstracts or irrelevance to PERMA dimensions. A total of 53 papers were selected to underwent a thorough review to assess the eligibility. In order to obtain the final set of papers, further selection and refinement processes were carried out. We excluded 16 papers for the following reasons: they were literature reviews, not solely focused on IWB, and lacked a direct discussion on the significant relationship between PERMA well-being and IWB. Finally, 37 papers were used in a qualitative synthesis. To answer our main research question about the relationship between PERMA well-being and IWB, we analysed 37 articles and extracted relevant information such as publication details, authors, methodology, PERMA well-being dimensions, instruments used, and the findings. This helped us to understand the types of PERMA well-being associated with IWB and how scholars examined them. Figure 1 depicts the PRISMA selection flow process.\n\n\nResults\n\nUpon thorough review and analysis of the articles, the results section of this study has been structured into six categories based on the research questions. It encompassed research design, journal titles, publication volume, research samples, geographical distribution of publications, and the PERMA factors of well-being as stated in Table 2.\n\nAmong the 37 articles reviewed, 35 articles opted for quantitative research methodologies, while only two articles employed a mixed-methods approach in their study designs. It is a norm when looking for relationships, or correlations between two or more variables, positivist researchers typically use quantitative methods.40 From Figure 5, we can conclude that positive emotion, positive relationship, engagement, meaningful and accomplishment constructs were measured with various instruments. For positive emotion construct, most of the studies adopted instruments from Porath et al.41 Meanwhile, the most widely used measure for assessing work engagement was UWES–Utrecht Work Engagement Scale by42 (Schaufeli et al., 2002) (n = 6).\n\nNext, for the positive relationship construct, the majority of researchers used Multi-Factor Leadership Questionnaire (MLQ-5X) by Avolioa et al.43 The second commonly most used instrument was the Supportive Relationship Leader from Liden et al.44 and Relational Leadership Questionnaire (RLQ) by Carifio.44 On the other hand, Multidimensional Work Motivation Scale was used by Gagné et al.45 and direct-consensus, a composition model was used by Chan46 to assess the meaningful factor. Finally, the item used to measure the accomplishment construct was adopted from Reward and Recognition by Spector.46 Structural equation modelling was the most popular technique to analyse the relationship between constructs (n =17). Figure 2 illustrates this highly disproportional distribution of research methodology among the reviewed articles.\n\nThere were 37 articles related to PERMA and innovative work behaviour found in 32 journals in various fields as stated in Table 1. There are four articles published in the journal of sustainability between the year 2017 and 2022.47–50 The authors in these articles discuss the relationship between work engagement and innovative work behaviour. There are two articles published in RAUSP Management Journal. The article written by Dixit and Upadhyay13 has discussed the importance of employee engagement and the significant effect of award and recognition to employee engagement. However, Kundu, Kumar and Lata51 has conducted research on the relationship between intrinsic motivation and innovative work behaviour. There were two articles published by Heliyon.52,53 The article published in 2020 by Gemeda and Lee52 discussed the effect of engagement and relationship with innovative work behaviour. Sudibjo and Prameswari53 also discussed about the leadership relationship.\n\nFigure 3 shows an obvious ascending research trend from 2013 to 2022 for PERMA factors and IWB. The number of papers spiked up from one paper in 2013 to eight papers in 2019. The earliest empirical study about the PERMA factor positive emotion and IWB was conducted in 2013 by Yesil and Sozbilir.54 Previous scholars have contributed eight papers about PERMA factors in the year 2019 and year 2022. In both years, the most PERMA factors explored by scholars is the relationship factor with a total of 11 papers.48,49,55–63 This is in line with earlier predictions by Anderson et al.64 who suggested the need for future research to examine the impact of relationships in the process of creativity and innovation at various levels of analysis. The pattern shows a growing scholarly interest in PERMA factors such as relationships towards IWB.\n\nThe large geographic distribution in the matrix table shows that PERMA factors are well-known among researchers all around the world. In total, 37 empirical research studies have been published using samples from 13 different countries with China and European Union countries leading the ranking with seven articles, followed by Turkey with four articles, and Pakistan, India and South Korea, each with three articles (see Figure 4 below).\n\nResearch scholars from different countries tend to focus on the relationship factor in the PERMA factors. It is the most widely studied PERMA factor as 23 research studies have been published using samples from 12 countries. Engagement is the second most popular PERMA factor being researched with 10 research studies and scholars using samples from seven countries (i.e. European Union countries, India, Iran, South Korea, Thailand and Turkey). The number of research studies performed on the remaining PERMA factor is seven studies for the positive emotion factor, two studies for the meaningful factor, and one study for the accomplishment factor.\n\nWhat is interesting in Figure 3 is the growth of articles in 2019 to 2020 are contributed by scholars from European Union countries with seven articles altogether.47,58,61,62,65–67 The increasing number of papers from European Union countries is contributed by the objective of EU2020 strategy which is to develop the European economy based on research and development (R&D), knowledge and innovation.68\n\nScholars have shown a significant research interest in the field of PERMA indicating IWB in different types of organisations. For research samples, we found two major industries were surveyed by most of the scholars with eight studies targeted at organisations in the education industries and eight studies targeted at organisations in the service industries. In the education industry, five studies examined the relationship and IWB in an educational setting53,56,60,62,69: with three studies confirmed that relationship factor has a positive impact on IWB.60,62,69 Another three studies in the education industries confirmed a positive relationship between engagement and IWB.13,56,70\n\nA total of eight out of 37 papers chose the service sector as their research sample. Among these eight studies, four articles provide empirical evidence regarding the relationship factor and IWB and found a positive relationship between the two variables.55,57,66,71 Two articles provided evidence that IWB in the service sector is positively impacted by engagement.47,72 Additionally, scholars did not discover a significant link between the positive emotion factor and IWB in the service industry, particularly in the hotel industry.3,54,67\n\nWith four papers for each, the technology and information technology (IT) industries are the second most researched by scholars. The least surveyed industries for PERMA factors and IWB from 2013 to 2022 were mixed industry, manufacturing industry and other industries. Few scholars did not specify the type of industries that the organisation reside in. For example, Laguna et al.61 administered a survey to employees of a small firm that provide private employment and Pukkeeree et al.73 chose a human resource officer who was a member of the Personnel Management Association of Thailand as the analysing unit in the study.\n\nPositive emotion\n\nThe PERMA model of flourishing, introduced by Seligman,34 comprises of five fundamental elements that contribute to psychological well-being such as positive emotions, engagement, relationships, meaning, and accomplishment. The first element of the PERMA well-being model is positive emotions. Emotions are commonly defined as an individual's appraisal of meaning following an experience.74 Positive emotion corresponds to hedonic happiness feelings like pleasure, fun and joy.75–77 It is good that we feel, and it becomes a primary goal of individuals. Positive emotion helps us to be positive and perceive the environment in a positive manner.75 It also contributes to the expansion of one's horizons and the accumulation of resources. As a result, people can create social and emotional capital by cultivating an open mindset.\n\nPositive emotion also relates to the concept of mental health in that it shows the positive functioning of personal and social life. Some scholars regard positive emotions to be a critical component of psychological well-being.78 Positive emotion is perhaps the only aspect of well-being that has received an extensive study from psychophysiology experts. Numerous research suggest that positive emotions are a main indicator of well-being. It is positively related to life satisfaction, resilience, mindfulness, social rewards, work outcomes and physical health.79\n\nEngagement\n\nSeligman34 includes engagement as one of the domains that make up psychological well-being based on the PERMA framework. Engagement is a psychological state in which people report being thoroughly engaged and focused on what they are doing.77 Work engagement can be defined as a positive, fulfilling, work-related state of mind that encompasses vigour, dedication and absorption.42 When it comes to working, vigour refers to a high level of motivation and mental strength and a readiness to put out the effort and persevere in the face of obstacles. Dedication is defined as a solid commitment to one's job and a sense of purpose and enthusiasm, and absorption refers to being completely and pleasantly engaged in one's job to the point where time passes without notice. Various works have used constructs such as employee engagement, work engagement, and role engagement to define work engagement in line with Kahn's conceptualization.80,81\n\nRelationship\n\nWith the emerging organization performance trends, the positive work relationships factor between IWB have been explored.82 Positive work relationships factor such as acts of support, kindness, caring, as well as cooperation contribute to well-being of an employee.19,83 Researchers have started finding out such work relationships that focused on the leader’s ability to attain higher level of performance from their employees. Among several leadership styles, servant leader has a significant impact on the positive workplace which contribute to well-being and IWB. Servant leader prioritise beyond their self-interest and focus on opportunities to help followers grow and develop.69 Opoku et al.48 stated that servant leaders focus on the interest and well-being of others and also enhance the motivation of IWB among employees. It shown that those with servant leadership also are able to contribute to the positive work relationship through providing support, direction, opportunity and care which will motivate them to engage in innovative behaviour.84 Indeed, when employees receive support from their organization, it contributes to their positive well-being, which engenders innovativeness in work.82 On the other hand, many scholars cited transformational leadership also in favour of positive work relationships and IWB.3,59,85 Transformational leadership clarifies as a strong influencer of employee well-being and IWB because of its motivational impacts by positive relationship between the leader and the subordinates.53 Besides, transformational leaders encourage employees to engage in innovative thinking, problem-solving, and fostering creative behaviour.86 Moreover, transformational leadership promotes a supportive environment where employees are encouraged to take risks, even when there may be negative consequences.87 Therefore, transformational leaders empower employees to build a positive work relationship that support IWB between supervisors and subordinates. Further, inclusive leadership, known as relational leadership, always concern the employees needs and well-being.88 This type of leader always project as supportive behaviour which motivate their employee’s engagement in IWB as they receive emotional and cognition resources.60 The servant leadership, transformational leadership and inclusive leadership confirms that leaders build positive work relationship between employees which foster their well-being. Employees shows high level of energy and commitment to their leaders and thus are more likely to pay back by exhibiting IWB when they received support, care, love, availability and opportunity.89 Thus, a leader is the one who can create positive workplace by flourishing care, support and love of the employees regardless type of leadership styles.76\n\nMeaningful\n\nMeaning is a part of the PERMA domain which is considered as a direction to achieve well-being.34 In the literature, meaning tends to refer to believing that a person's life is valuable and that there is a sense of purpose in life that is greater than oneself.34 When people have meaning in life, they will have a purpose that generates passion and motivation.90 Meaning is a superordinate term that encompasses two main dimensions which are comprehension and purpose.91 The first dimension is comprehension, which is the ability to make sense of and comprehend one's life, including one's own self, the external environment, and how one fits into and acts within it. The second dimension is purpose, which is long-term life goals that are self-congruent and inspire relevant action.91 Meaningful refers to engaging in work for the sake of living, not just for a living.92 Cohen-Meitar et al.93 posit that meaningfulness in the workplace has a positively related with the employee creativity. As meaning is a crucial component of creative activity, employees who feel their work meaningful (e.g., those who exhibit higher identified motivation in regard to their work) are more likely to engage in IWB.93 Based on theory of motivation which is self-determination theory (SDT), there are three types of autonomous motivation which are intrinsic motivation, identified motivation and integrated motivation.94 Identified motivation occurs when a person identifies and internalize the perceived value and meaning of behaviour due to its instrumental value.45,94 Identified motivation is probably connected to IWB.95 Employees who find their work is meaningful will express a higher identified motivation and they are likely to engage in IWB as meaning is an important element of creative behaviour.93\n\nAccomplishment\n\nAccomplishment is another PERMA domain that is important for psychological well-being. Accomplishment can be broadly defined as a person's perception of progress toward goals and a sense of accomplishment in their live.47 In order to achieve the goals of task completion, a person needs the ability of competence and efficacy.34 A sense of accomplishment comes from working toward and achieving goals and mastery and efficacy in completing specific tasks.18 Self-efficacy relates to subjective assessments of one's capacity to plan and carry out actions in given conditions,96 while competence refers to accomplishing a specific task to a predetermined standard.97 The accomplishment also can be defined as one's achievement and performance.98 Employee motivation to perform can be increased by intrinsic and extrinsic motivation.99 Examples of extrinsic motivation-enhancing practices are incentives such as economic rewards.100 Janssen25 suggests that employees are willing to be involved in innovative activities beyond contractually stipulated job objectives when their efforts are fairly rewarded in such a social exchange relationship.\n\n\nDiscussion\n\nIn this study, there were seven articles have been identified discussing positive emotion and IWB.54,65,67,73,101–103 Saether, E. A.67 and González-González, T., and García-Almeida, D. J67 have discussed the intrinsic motivation as a factor for positive emotion under PERMA. The finding of Saether, E. A.65 showed that intrinsic work motivation is positively related to research and development employees’ IWB. However, the research conducted by González-González, T., and García-Almeida, D. J67 found no significant influence between employees’ intrinsic motivation to innovate with innovative suggestions in hospitality firms. Previous research also found that thriving at work has been associated with IWB.101,103 Thriving at work is a form of positive emotion. The research conducted by Abid, G., Zahra, I., and Ahmed, A.103 has put thriving at work as a mediating mechanism between perceived organization support and innovative work behaviour. The study found that thriving at work is positively related to IWB. Riaz, S., Xu, Y., and Hussain, S.54 discovered that employee thriving was positively associated to organisational support for innovation, which in turn was favourably related to IWB. However, extraversion which was discussed by Yesil, S., and Sozbilir, F.54 in their research also found no significant relation to individual IWB. Research discovered that mindfulness had no direct effect on IWB.73 This link benefits considerably from the mediating role of eudaimonic well-being. The previous research discusses the attainment value as a moderation between engagement and IWB.73 The findings have shown that positive emotion promotes employee engagement which significantly increases IWB.\n\nA total of 10 papers have focused on engagement influence in IWB.13,47,50–52,56,61,70,72,73 While most papers measure the direct effect of engagement on IWB, several papers use engagement as a mediator in the study of work behaviour.13,50–52,61,72 All papers were selected based on the keyword chosen that depicts the engagement domain of the PERMA framework, and the keywords are “work engagement” and “employee engagement”.\n\nThis study has found that employee engagement13,51,56,70,73 and work engagement47,50,52,61,72 has shown to have a significant relationship with IWB. Ganji et al.70 explains the relationship between employee engagement with IWB based on Social Exchange Theory104 in public university in Iran. The study found that the employee engagement has a positive influence on IWB and able to forecast the idea generation, idea promotion and idea implementation in the institution. Dixit and Upadhyay13 investigated the influence of work engagement with IWB based on JD-R model and discovered the work engagement has a significant and positive relationship to IWB. The author found that work engagement mediates the relationship between reward and recognition to IWB. They emphasize on the importance of monetary and non-monetary incentives that will keep the staff engaged and perform innovatively at work. Gemeda and Lee52 suggested that employees who psychologically identify with their work, dedicating and experiencing an emotional connection to their work, seem to be more innovative and put extra effort into completing tasks. Managers also should initiate supporting motivational activities and provide training to their staff to build work engagement.73 Human resource practitioners should consider developing or improving the human resource related policy that supports staff work engagement. This will drive the employee IWB and contribute to a sustainable organisation economic performance.50 The research findings from the papers selected in this study show that the higher the engagement of staff in the work, the higher the staff’s IWB.\n\nHaving conceptualised positive work relationship practices based on the PERMA model, we structure the results on the relationship between positive work relationship able to influence IWB among employees as supportive organisation and positive relationship between the leaders and employees.3,62,63,71,82 As such, positive leadership style does influence relationship between leader and employees which influence positively towards IWB.49,59,66,105 Our analysis identified five main leadership styles that could be influence positive work relationship factor which able to encourage IWB among employees. A total of 16 papers have focused on leadership influence positive relationship factor with IWB, and among those 16, four papers confirmed that servant leadership able to promote employees IWB and intrinsic motivation.48,69,106,107 The transformational leadership style had significant positive relationship in employees work engagement and IWB.52,108 Sudibjo et al.53 argues that there is a negative effect on transformational leadership on IWB. On the other hand, two papers examined the role of inclusive leadership in positive relationship between leader and subordinates which positively influence on IWB.60,83 Only one paper mentioned on authentic leadership predicts the work engagement among employees and in return able to predict employees IWB.61 Hunsaker109 concluded employees IWB is positively influenced by the effects of spiritual leadership which embedded positive workplace relationship. As overall, much less known about how leadership styles influence positive work relationships factor and IWB. The literature calls for further investigation on other antecedents and mediator factors of IWB.60,63,66\n\nIn this present study, there are two papers that discuss the relationship between meaning and IWB.65,110 The papers are selected based on two keywords that represent the meaning domain in PERMA which are “identified motivation” and “spiritual climate”. One of the variables that represent spiritual climate is meaningful.111 Spiritual climate is defined as “the collective perception of the employee about the workplace that facilitates harmony with ‘self’ through meaningful work, transcendence from the limited ‘self’ and operates in harmony with social and natural environment having sense of interconnectedness within it.111 Through the systematic literature review, this study found that meaningful factors represent by a team’s spiritual climate have a positive relationship to team IWB.110 Individuals in business organisations look for the fulfilment of their spiritual needs especially the meaning and purpose of their job and the chance to improve the wider social and ecological environment apart from financial rewards.110 On top of that, a group of employees with a higher spirituality shows a higher propensity to learn and innovate.110 Saether65 who examines the motivational antecedent of employees’ IWB based on self-determination theory (SDT) found that there is a significant and positive relationship between identified motivation and IWB and the relationship is weaker compared to intrinsic motivation. Even though identified motivation has a weaker connection to IWB, Gagné et al.45 proposed that it is more practical for organisations to promote identified motivation as it is often easier to encourage employees to internalize the value of their work rather than make the work more fun. Managers may provide constructive and positive feedback to their employees, assign meaningful tasks and give employees the freedom of choice in completing the task to support autonomous motivation.112\n\nThis study has identified one paper that discuss the relationship between accomplishment and IWB.13 Dixit and Upadhyay13 investigate the effect of job resources such as rewards toward IWB. The paper is selected based on the keyword “reward” which explains the accomplishment domain in PERMA. Dixit and Upadhyay13 conducted a study based on JD-R model to identify the driver of IWB for teachers serving higher education in India. JD-R model was used to analyse how two components of the work environment namely demand, and resources contribute to employee burnout and engagement.13,113 IWB is an employee extra-role performance that results from work engagement.114,115 Dixit and Upadhyay13 choose two types of job resources which are job autonomy and reward and recognition in the study and found that rewards were insignificant to IWB. It was also found that rewards and recognition have an indirect impact on IWB through work engagement.13\n\nAll types of PERMA factors that have been studied in the literature are shown in Figure 5. Among the PERMA well-being dimension, positive relationship has been more frequently studied than other types of PERMA well-being from 2012 to 2022. A total of 23 articles studied the effect of positive relationship towards IWB. The least PERMA factors being researched are meaningful and accomplishment.\n\nMeaningful work as a motivating tool may influence people's motivation by allowing them to solve an issue or complete a task that represents their desire to make a difference, which may influence IWB.4,116 Although studies in intrinsic motivation have discovered a connection between meaningfulness at work and IWB, the relationship between them is not always significant in some studies.117 Latest findings by Wiener et al.118 revealed that there is a lack of empirical evidence about how meaningfulness in work influences employees’ IWB. Recent research has underexplored whether meaningful work increases employees' IWB since meaningful work is not vital for clarifying the intrinsic motivation to boost creativity at work.119\n\nHence, this review draws the same summary that meaningful at work is still an unresolved gap in the literature in terms of examining the relationship with IWB. Meanwhile, there are many research studies that have been conducted on accomplishment towards cooking behaviour, mental illness, well-being, life satisfaction, perfectionism, work environment, leadership and music.37–39,78,98,120–124 However, to our knowledge, there is limited previous literature on the relationship between accomplishment and IWB. This is in line with Wammerl et al.35 that PERMA well-being represents a quite new well-being model.\n\nImplications for future practice\n\nThe findings of this review indicate that the existing literature extensively addresses the relationship between five PERMA elements well-being dimensions towards IWB. Even though there is a growing trend of more research on how relationships, engagement, and positive emotions are linked to positive well-being and IWB, there is less research on how the meaningful factor and accomplishment factor are linked to positive well-being and IWB. Hence there is further investigation needed to explore PERMA well-being on IWB.124\n\nFurthermore, according to the empirically supported PERMA theory of positive well-being,34 positive well-being experienced by employees can have a positive organizational impact, including increased productivity, stronger work engagement, improved problem-solving skill and creativity, engaged on innovation and in the long term, more organizational thriving.28,125–127\n\nConcluding from the literature, a positive well-being that support IWB in the organisation involved should:\n\n• provide a supportive and cooperative work environment;\n\n• find ways to galvanize employees to feel cheerful and joyful;\n\n• embrace and encourage thriving at work;\n\n• focus on enhancing work engagement among employees;\n\n• be consistent in shaping inclusive and positive relationships at work;\n\n• be savvy at communicating values;\n\n• focus on employees’ intrinsic and extrinsic motivation; and\n\n• grant empowerment to flourish innovativeness.\n\nHowever, further investigation is still greatly necessary when it comes to the practical implications of positive well-being in a more inclusive and diverse working environment.\n\nResearchers and corporate managers should focus on factors that lead to IWB and explore ways to foster and facilitate employees' creativity. At the organisation level, management team can promote a culture of continuous learning and creativity by encourage employees to seek out new knowledge, embrace failure as a learning experience, and adopt a flexible and adaptive mindset that supports innovation.\n\nFor organizations that are determined to flourish employees well-being, the leaders must actively provide the five dimensions of PERMA well-being. Firstly, organizations can foster positivity by celebrating achievements and showing appreciation and care to the employees. This can encourage a positive work environment where employees experience positive emotions, such as happiness, joy, and contentment that boost their overall well-being. Secondly, organizations should create opportunities for employees to be fully engaged and immersed in their work by building positive relationships within the workplace. As sense of belonging and support, leading to higher levels of happiness and satisfaction. By integrating the PERMA theory into their practices, organizations can create a work environment that supports employee well-being and flourishing, leading to increased organisational performance such as higher productivity and innovativeness.\n\nRecommendation for future research\n\nThis systematic literature review highlights various directions for future research. Firstly, the existing literature reveals numerous aspects of positive well-being in relation to IWB that remain understudied within organizational contexts, including PERMA. This would involve measuring the PERMA elements and IWB over an extended period to understand how changes in well-being factors influence employees' IWB over time. Secondly, from a theoretical development standpoint, it is important to investigate the mediating and moderating factors that may influence the relationship between PERMA elements and IWB.117 For example, exploring the role of intrinsic motivation, such as work engagement in mediating or moderating the relationship can provide a deeper understanding of the mechanisms through which well-being factors promote innovation. Finally, this highlighted that there is an vital need for studies to examine the influence of contextual factors on the relationship between PERMA elements and IWB. Factors such as organizational climate, industry type, organizational size, and cultural differences may impact how the PERMA elements interact with IWB. Exploring these contextual factors can provide insights into the applicability and effectiveness of the PERMA theory across different organizational settings. By exploring these research areas, scholars can deepen their understanding of how the PERMA theory relates to IWB and provide practical insights for organizations seeking to foster innovation through employee well-being.\n\n\nConclusions\n\nThe findings of this systematic literature review indicate that between 2012 and 2022, a total of 37 studies focused on PERMA in relation to IWB, primarily conducted in European countries. The majority of these studies employed quantitative research methods (95%) and applied a cross-sectional design. This review utilised 37 articles that meet predefined criteria and constructs a framework exploring the impact of PERMA well-being dimensions on IWB within organizations. The review findings reveal the presence of three influential dimensions that affect employees in IWB, namely: 1) positive emotion, 2) positive relationship, and 3) engagement. However, 4) meaning and 5) accomplishment need further investigation as there are limited studies on those dimensions.\n\nThere are certain limitations in this research, including the restricted access to the complete texts of all articles, resulting in the exclusion of some relevant studies on PERMA and IWB within organizations. For future investigations, employing qualitative research methods can provide valuable insights into comprehending the influence of positive well-being on employees' IWB in diverse workplace scenarios.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nFigshare: PRISMA flow diagram and checklist for PERMA well-being and Innovative Work Behaviour: a systematic literature review. 10.6084/m9.figshare.24143619.\n\nThis project contains the following extended data:\n\n- PRISMA_2020_checklist 14_9_2023.docx\n\n- Figure 1 PRISMA flow diagram.jpg\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nLambriex-Schmitz P, Van der Klink MR, Beausaert S, et al.: Towards successful innovations in education: Development and validation of a multi-dimensional Innovative Work Behaviour Instrument. Vocat. Learn. 2020; 13(2): 313–340. Publisher Full Text\n\nSrirahayu DP, Ekowati D, Sridadi AR: Innovative work behavior in public organizations: A systematic literature review. Heliyon. 2023; 9: e13557. 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Publisher Full Text"
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[
{
"id": "217346",
"date": "14 Nov 2023",
"name": "Imran Saeed",
"expertise": [
"Reviewer Expertise Leadership/Human Resource Management/ Organizational Behavior"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for providing the opportunity to review the manuscript titled \"PERMA Well-being and Innovative Work Behaviour: A Systematic Literature Review.\" Overall, I found this manuscript to be of good quality. However, there is always room for improvement, and I would like to highlight the following points:\nIn the abstract section, the authors did not mention the implications.\n\nThe introduction lacks a proper rationale and research gap. It is essential to include the latest references in the rationale and research gap.\n\nThe theoretical background discussed in the manuscript is insufficient. Add some relevant theories and literature to support the theoretical background.\n\nIn the methods section, the authors mentioned the period from 1st November to 31 December. Why only this period? Is there any valid reason?\n\nThe rest of the methodology section seems good.\n\nImplications should cover practical implications, theoretical implications, and managerial implications.\n\nFuture recommendations and the conclusion are good.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? No\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
},
{
"id": "224902",
"date": "27 Nov 2023",
"name": "Shahrul Nizam Salahudin",
"expertise": [
"Reviewer Expertise Expert in behavioral sciences"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nWhile the abstract mentions a systematic literature review using the PRISMA method, it lacks details about the specific steps involved, such as search terms, databases used, and the inclusion/exclusion criteria. Adding a sentence or two to briefly outline these details would enhance the abstract.\n\nThe progression of ideas is logical and coherent, providing a smooth transition from the general importance of innovation to the specific focus on the relationship between well-being and innovative work behavior.\n\nThe conceptualization of well-being and innovative work behavior is clear and aligns with established perspectives. The distinction between hedonic and eudaimonic perspectives and the introduction of the PERMA model contribute to a comprehensive understanding.\n\nThe breakdown of research samples across industries is beneficial for understanding the scope of the literature. The detailed exploration of industries, such as education and service, and the number of studies within each provides a comprehensive view\n\nOverall this is a well written article\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
},
{
"id": "224899",
"date": "18 Dec 2023",
"name": "Ágota Kun",
"expertise": [
"Reviewer Expertise positive psychology",
"well-being",
"workplace happiness",
"character strengts interventions",
"mental health at work"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article has set an interesting objective, to examine one of the most popular models within the positive psychology movement, the PERMA model, in the context of innovative behavior within an organization. To improve the quality of the article, I suggest the authors to consider the following: - I suggest that the PERMA model should not be referred to as PERMA well-being, but as PERMA model of well-being - there is no such concept as positive well-being, since well-being is positive in itself so that the adjective 'positive' is superfluous (the opposite of well-being is not negative well-being, but ill-being or unwell) - the M factor in the PERMA model is Meaning and not meaningful. meaningful is an adjective, whereas meaning is a noun and this is the original name for the factor - this needs to be corrected in many places in the article - in terms of the structure of the paper, I suggest that the PERMA model and its dimensions be presented in detail at the beginning of the article before the literature analysis is presented, as this would be a more logical place - I suggest the authors present the relationship between the PERMA elements and IWB in a separate subsection after the literature analysis, because the discussion and presentation of this is presented in the PERMA well-being subsection and the Discussion section, and is therefore rather inconsistent, mixed in both sections and thus somewhat unintelligible and redundant, making the overall understanding of the whole study difficult - I would also recommend improving the English of the study\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Partly\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1338
|
https://f1000research.com/articles/12-1336/v1
|
16 Oct 23
|
{
"type": "Research Article",
"title": "Clinical profile of brain abscesses: ten-year retrospective single-center study",
"authors": [
"Ganesh Adhikari",
"Samit Lamichhane",
"Aashish Sapkota",
"Ajit Shrestha",
"Nidhi Bhatt",
"Nimish Raj Bastola",
"Ganesh Adhikari",
"Aashish Sapkota",
"Ajit Shrestha",
"Nidhi Bhatt",
"Nimish Raj Bastola"
],
"abstract": "Background: Brain abscess is a rare clinical entity of neurosurgery with poor outcomes. In this study, we aimed to develop clinical profiles of the cases of brain abscesses presented at Chitwan Medical College by reviewing hospital records.\n\nMethods: The hospital-based retrospective study includes 18 patients presented from April 2013 to April 2023 diagnosed with brain abscess. Data regarding their demographic profile and other factors were collected in well-structured proforma from hospital records, OT records, and ICU records of the neurosurgery department of Chitwan medical college teaching hospital. Data were analysed using SPSS software using frequencies, proportions, and means functions.\n\nResults: In our study, we reported 18 cases of brain abscess with a mean age of 24.6 years having male to female ratio of 3.5:1. Fever, headache, and focal neurological deficit (classic triad of brain abscess) were present in 16.67 % of the cases. The most common presenting complaint was fever in 61.1 % following headache in 50% of cases. The commonly involved part of the brain was temporal lobe 27.8%. Primary focus of lesion was identifiable in ten cases with CSOM being the most common focus in 44.4% of the case. Consciousness was clear (GCS = 15) in five patients (27.7%), mildly disturbed (GCS = 13 or 14) in 16.7% , moderately disturbed (GCS = 9-12) in 44.5%, and severely disturbed or comatose (GCS = 3-8) in 11.11% of patients. 72.2 % of the cases were managed by craniotomy and evacuation, 11.1% by burr hole and evacuation whereas 16.7% denied any form of treatment.\n\nConclusion: The advancement of imaging techniques and the use of IV antibiotics has exponentially improved outcome of the brain abscesses. Furthermore, with CSOM being the most common contagious focus, multidisciplinary management of the cases with brain abscess will benefit the patient.",
"keywords": [
"Brain abscess",
"Infections",
"Otogenic infection",
"Craniotomy",
"Antibiotics"
],
"content": "Introduction\n\nA focal suppurative process of the brain parenchyma is a brain abscess.1 Brain abscess is brought on by bacteria, mycobacteria, fungus, protozoa, or helminths in the parenchyma of the brain which can develop from contiguous (sinusitis, mastoiditis, odontogenic infection, dental infection) or from distant sources of infection like endocarditis, congenital heart disease, respiratory infections, etc.2 The clinical manifestations of brain abscess depend upon its size, location, number, and any secondary brain injury. Patients with brain abscesses commonly present with headache, neurological deficits, fever, and altered sensorium. Although serum markers can be detected in up to 75% of cases and raise a significant amount of clinical suspicion, the primary diagnostic techniques used today are imaging modalities.3 In developing countries, brain abscesses occur at a rate of about 8% of intracranial masses, compared to 1-2% in Western nations.4\n\n\nMethods\n\nThis study was ethically approved by the institutional review committee of Chitwan Medical College recognized by Nepal Health Research Council (Ref: CMC-IRC/070/080/16). This is a retrospective study achieved by reviewing medical records from ten years (April 2013 to April 2023). Data were searched from the electronic data record system of the neurosurgery ICU, operation records, and hospital records. Both electronic and record books were reviewed in the process of data collection. All cases admitted to our tertiary care center with the diagnosis of brain abscess were included in this study. We found 20 cases diagnosed in our tertiary care center upon reviewing the medical records. Among those 20 cases, 18 cases are included in this case series whereas two cases were excluded due to inadequate data on our records. For each case, information about the patient’s demographics, clinical presentation, initial neurological status (clinical signs associated with GCS, seizures, focal neurological deficits), risk factors, site of lesion, Source of infection, radiological and microbiological test results, and treatment modalities was reviewed. At the time of discharge, the result was evaluated using the GOS. Moderate disability (having an impairment but being independent) and good recovery were considered favorable outcomes. Death, chronic vegetative state, and severe disability (aware but disabled) were all considered unfavorable outcomes.\n\nAll the related data were filled in preformed proforma and entered in SPSS version 26.0 for analysis. Data were analyzed using frequency, mean, and proportion functions.\n\n\nResults\n\nBetween April 2013 to April 2023, 20 cases of brain abscesses were admitted and treated in our tertiary care centre. Among those 20 cases 18 cases are included in this case series, two cases were excluded due to inadequate data on our records. Among 20 cases of brain abscess, 14 were males and four were females with ratio of 3.5:1. The mean age is 24.6 years with a maximum age of 68 years and minimum age of ten months. Ten cases were of less than 18 years old, and eight cases were of more than 18 years. 50% of cases stayed in the hospital for <20 days.\n\nThe classical triad of brain abscess viz. fever, headache, and focal neurological deficit is present in 16.67% (n=3) of the cases. Fever (61.1%) and headache (50%) are the most common presentation followed by focal neurological symptoms (33.3%), ear discharge (33.3%), and vomiting (33.3%) whereas seizure was present in only 16.7 % of cases. Presenting symptoms of all cases are summarized in (Table 1). Consciousness was clear (GCS=15) in five patients (27.7%), mildly disturbed (GCS=13 or 14) in 3 (16.7%), moderately disturbed (GCS=9-12) in 8 (44.5%), and severely disturbed or comatose (GCS=3-8) in 2 (11.11%) patients.\n\nIn 88.8% of patients, the abscess was localized in a single location with the temporal region being the most commonly involved region in 27.8% of patients whereas 11.1% of patients had abscesses in multiple locations. Primary focus of lesion was identifiable in 55.56% (n=10) cases with CSOM being the most common focus of infection and in 44.4% of patients, the source of infection was unknown. One out of 18 cases was culture positive in which proteus mirabilis was isolated.\n\nIn 72.2% (n=13) patients craniotomy and evacuation was done and burr-hole and evacuation were performed in 11.1% (n=2) patients, whereas 16.7 % (n=3) patients denied treatment.\n\nOf the 18 patients in the study, 5.56% patient died (GOS=1), 11.1% had moderate disability (GOS=4) and 66.7% (GOS=5) had good outcomes whereas GOS cannot be designated to 16.7% of individuals who denied intervention.\n\n\nDiscussion\n\nIn this study, we included 18 cases of brain abscess which has fever as the most common presenting complaint and mostly involves the temporal lobe of the brain with chronic ear infection being the most common foci of infection.\n\nThe mean age of the patient is 24.6 years with male predominance with a ratio of 3.5:1. A case series from Nepal5 also suggests brain abscess had male predominance with a ratio of 2.1:1 and most of the other studies also report the same finding.3,6 whereas it is different in a developed country like Germany with an equal predisposition in both male and female populations.7 In a study, Landriel reported 59.3% of the female population in the study had brain abscesses.8 With a mean age of 24.4 years, our study has 55.5% of the younger population involvement (age less than 18 years). A previous study from Nepal also showed similar age group involvement with a mean age of 16.76 years.5 One of the reasons for the maximum involvement of the younger age group is the prevalence of predisposing factors like ear infections, odontogenic, and sinusitis in the younger population.9\n\nChronic suppurative otitis media (CSOM) is the most common contagious source of infection present in most of the studies.3,5,10 Whereas a study from Germany reported sinusitis and dental infections as the most common source of infection.7 The source of infection and location of the brain abscess was found to be closely related. The most common location of the brain abscess was found to be the temporal lobe or cerebellum if the source of infection is CSOM whereas frontal lobe involvement is most common where sinusitis and dental infections are most common.3,5,7,11,12 The classical triad of brain abscess viz. fever, headache, and focal neurological deficit is present in three patients. Fever is complained by 61.1 % of the patient followed by headache which was the chief complaint of 50 % of the patient. Previous studies suggest both headache3,5,7 and fever10 as the major presenting complaint whereas the triad of brain abscesses is present in only 20% of cases.6 One of our cases had an increase in head circumference as a chief complaint who was ten months old. There have been reports of increased head circumference as the presenting complaint in younger age groups.9,13\n\nThe use of intravenous antibiotics and drainage or excision of abscesses is the treatment of choice for brain abscesses.14 However, the treatment varies according to the size, location, and stage of the abscess. Surgical procedures used are burr hole and evacuation, craniotomy, craniectomy, evacuation or excision, and stereotactic CT/MRI-guided aspiration.14 Stereotactic CT-guided aspiration is one of the most effective minimally invasive methods available for the aspiration of abscesses. A study suggests this method of treatment can access the abscess located in inaccessible regions like the thalamus, and brain stem, and in case of multiple abscesses.15,16 Stereotactic aspiration has its own set of complications and drawbacks. Most of the cases need repeated aspiration and constant monitoring by repeated CT scans and there are risks of complications during the procedure like the risk of rupture of abscess into the ventricle, subarachnoid leakage of pus and ventriculitis, or meningitis.17,18 Whereas in open craniotomy since there is extensive resection and drainage of the abscess there is a rate of low recurrence.19 In the cases with subdural empyema open craniotomy and drainage is still the treatment of choice.20 However, aspiration has a higher mean survival rate compared with open excision of brain abscesses.21 In our study, 15 patients had surgical intervention which includes craniotomy and burr hole with the evacuation of the abscess, whereas three patients denied any form of intervention.\n\nIsolation of organisms causing brain abscesses is difficult and most of the reports were culture negative. In our study, only one case (5.5%) was found to be culture positive with Proteus mirabilis as the causative agent. Similar reports were reported by Kafle et al.5 with only 19.61% of the cases showing positive culture. The reason for these negative culture reports may be the preoperative use of antibiotics and limited lab facilities lacking an anaerobic culture medium.22 Decreased GCS at the time of presentation has been associated with poor outcomes in patients with brain abscesses.10 The mortality rate in our study was 5.55% whereas other studies from Nepal, China, Pakistan, and Germany showed mortality rates of 3.92%, 16.9%, 11.3%, and 23.4% respectively.3,5,7,10\n\n\nLimitations of this study\n\nThis study has a small sample size. It is a single-center study and cannot represent the profile of brain abscesses throughout the country and the result cannot be generalized for the whole population. In the future, multicentre prospective studies must be planned for determining the risk factors and outcome of the patient with brain abscess.\n\n\nConclusion\n\nBrain abscess is an uncommon but important clinical condition as the mortality rate is high if timely intervention is not done. In this series, we presented cases of brain abscesses in the past ten years who were treated in our tertiary care center. CSOM being one of the most common foci of infection, multidisciplinary management with an otorhinolaryngology team will be the way forward for better outcomes of cases with brain abscesses.",
"appendix": "Data availability\n\nFigshare: Clinical profile of brain abscesses: Ten year retrospective single-center study, DOI: 10.6084/m9.figshare.23739114.\n\nThe project contains following underlying data\n\n- sex, age, days of hospital stay, Symptoms, source, site of lesion, microbiology, method of treatment, GCS at the time of admission, GOS\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC BY 4.0 Public domain dedication).\n\n\nReferences\n\nBrook I: Microbiology and treatment of brain abscess. J. Clin. Neurosci. 2017; 38: 8–12. Publisher Full Text\n\nWaked R, Tarhini H, Mansour H, et al.: A case series of brain abscesses: An eleven-year retrospective single center study. J. Infect. Dev. Ctries. 2021; 15(6): 791–797. PubMed Abstract | Publisher Full Text\n\nManzar N, Manzar B, Kumar R, et al.: The study of etiologic and demographic characteristics of intracranial brain abscess: A consecutive case series study from Pakistan. World Neurosurg. 2011; 76(1-2): 195–200. PubMed Abstract | Publisher Full Text\n\nMuzumdar D, Jhawar S, Goel A: Brain abscess: An overview. Int. J. Surg. 2011; 9(2): 136–144. Publisher Full Text\n\nKafle P, Sharma MR, Shilpakar SK, et al.: Shifting paradigm in brain abscess management at tertiary care centre in Nepal. Neuroimmunol. Neuroinflammation. 2018; 5(6): 24. Publisher Full Text\n\nBrouwer MC, Coutinho JM, Van De Beek D: Clinical characteristics and outcome of brain abscess:Systematic review and meta-analysis. Neurology. 2014; 82(9): 806–813. PubMed Abstract | Publisher Full Text\n\nLange N, Berndt M, Jörger AK, et al.: Clinical Characteristics and Course of Brain Abscess. World Neurosurg. 2018; 120: e675–e683. PubMed Abstract | Publisher Full Text\n\nLandriel F, Ajler P, Hem S, et al.: Supratentorial and infratentorial brain abscesses: Surgical treatment, complications and outcomes-a 10-year single-center study. Acta Neurochir. 2012; 154(5): 903–911. PubMed Abstract | Publisher Full Text\n\nSahbudak Bal Z, Eraslan C, Bolat E, et al.: Brain Abscess in Children: A Rare but Serious Infection. Clin. Pediatr. (Phila). 2018; 57(5): 574–579. PubMed Abstract | Publisher Full Text\n\nTseng JH, Tseng MY: Brain abscess in 142 patients: factors influencing outcome and mortality. Surg. Neurol. 2006; 65(6): 557–562. PubMed Abstract | Publisher Full Text\n\nSáez-Llorens X, Nieto-Guevara J: Brain abscess. Handb. Clin. Neurol. 2013; 112: 1127–1134. Publisher Full Text\n\nRoche M, Humphreys H, Smyth E, et al.: A twelve-year review of central nervous system bacterial abscesses; presentation and aetiology. Clin. Microbiol. Infect. 2003; 9(8): 803–809. PubMed Abstract | Publisher Full Text\n\nLahat E, Livneh M, Schiffer J, et al.: Rapidly growing head circumference as an isolated presenting symptom of brain abscesses in an infant. Clin. Neurol. Neurosurg. 1987; 89(4): 269–270. PubMed Abstract | Publisher Full Text\n\nNathoo N, Nadvi SS, Narotam PK, et al.: Brain abscess: Management and outcome analysis of a computed tomography era experience with 973 patients. World Neurosurg. 2011; 75(5-6): 716–726. PubMed Abstract | Publisher Full Text\n\nBarlas O, Sencer A, Erkan K, et al.: Stereotactic surgery in the management of brain abscess. Surg. Neurol. 1999; 52(4): 404–411. Publisher Full Text\n\nKocherry XG, Hegde T, Sastry KVR, et al.: Efficacy of stereotactic aspiration in deep-seated and eloquent-region intracranial pyogenic abscesses. Neurosurg. Focus. 2008; 24(6): 1–5. PubMed Abstract | Publisher Full Text\n\nHall WA, Truwit CL: The surgical management of infections involving the cerebrum. Neurosurgery. 2008; 62 Suppl 2(SUPPL. 2): 519–531. PubMed Abstract | Publisher Full Text\n\nÇavuşoglu H, Kaya RA, Türkmenoglu ON, et al.: Brain abscess: Analysis of results in a series of 51 patients with a combined surgical and medical approach during an 11-year period. Neurosurg. Focus. 2008; 24(6). PubMed Abstract | Publisher Full Text\n\nGadgil N, Patel A, Gopinath S: Open craniotomy for brain abscess: A forgotten experience? Surg. Neurol. Int. 2013; 4(1): 34. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNathoo N, Nadvi SS, Gouws E, et al.: Craniotomy improves outcomes for cranial subdural empyemas: Computed tomography-era experience with 699 patients. Neurosurgery. 2001; 49(4): 872–878. PubMed Abstract | Publisher Full Text\n\nRatnaike TE, Das S, Gregson BA, et al.: A review of brain abscess surgical treatment - 78 years: Aspiration versus excision. World Neurosurg. 2011; 76(5): 431–436. PubMed Abstract | Publisher Full Text\n\nMampalam TJ, Rosenblum ML, Salcman M, et al.: Trends in the management of bacterial brain abscesses: A review of 102 cases over 17 years. Neurosurgery. 1988; 23(4): 451–458. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "216605",
"date": "20 Oct 2023",
"name": "Oshan Shrestha",
"expertise": [
"Reviewer Expertise general surgery"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI wish to congratulate the authors for completing their study.\nI have some comments that intend to improve the quality of the paper:\nIntroduction section: The introduction section should also include the objectives of the study or the hypotheses that are prespecified, along with the background of the study.\n\nMethod section: The authors have listed the variables that were reviewed in hospital records (patient’s demographics, clinical presentation, initial neurological status (clinical signs associated with GCS, seizures, focal neurological deficits), risk factors, site of lesion, source of infection, radiological and microbiological test results, and treatment modalities). But all of the mentioned headings are not presented in the result section (they are also not present in the supplementary file). Please specify the details of the analytical strategy/data handling, study tool, handling of missing data, and potential biases.\n\nMethod section: The authors have used the mean as a measure of central tendency. I suggest the authors to revisit this choice and confirm if the mean is a suitable measure of central tendency (max age is 68 and the minimum age is 10 months.)\n\nResult section: Just mentioning the number of cases that are of age less than or more than 18 years provides less information. It can be made more informative, for example, by mentioning the number of paediatric patients instead.\n\nResult section: Length of hospital stay is a continuous variable, and the authors are suggested to present it accordingly.\n\nResult section: Please mention the medical management also (e.g., use of antibiotics).\n\nResult section: It would be interesting if the authors could separate the outcomes for patients who underwent treatment and those who denied treatment.\n\nResult section: It would be great if the authors could include pictures with radiological findings.\n\nDescriptive studies help in the development of hypotheses. I suggest the authors give future prospects to the findings of this study.\n\nConclusion section: Please revisit the conclusion section and assess if it is right to mention that mortality is high with only one mortality case in the study. Also, please remove, \"In this series, we presented cases of brain abscesses in the past ten years who were treated in our tertiary care center\" from conclusion section.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "241353",
"date": "24 Feb 2024",
"name": "Mohammed Awad Elzain",
"expertise": [
"Reviewer Expertise Neurosurgery",
"pediatric neurosurgery"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper is nice and well written however there are some points the author should consider. First the study is on 18 patients not 20 so he should not say out of 20. second in results section the table is nice, but you cannot include all results in a single table. I suggest to be separated in different tables. The result section needs more elaboration like mentioning what why some operated with burr hole while others with craniotomy, the outcome and duration of hospital stay among both groups, that who died was operated with burr hole or craniotomy and what was the reason of his death, those who had deficit why and what kind of deficit. Finally, it is not clear that what the author means by denied treatment he should make this statement more clear. In discussion section there should be no mention for the numbers and percentages (this should be only in result section) For example instead of saying 60% presented with headache he can say the majority of patients, or more than half of the patients presented with headache and apply this to whole discussion section. There is no mention for antibiotics use in the paper. The imaging should be with contrast, and this should be clearly mentioned besides mentioning how many diagnosed with CT with contrast and how many with MRI with contrast. in the references the bulk of the references should be during the last 5 years, I found 2 ONLY out of the 22 references complying with that.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1336
|
https://f1000research.com/articles/12-1016/v1
|
21 Aug 23
|
{
"type": "Study Protocol",
"title": "Estimation of prevalence of risk factor of hypertension among population of Wardha district between age group of 35-60 years: a study protocol.",
"authors": [
"Amruta Dadmal",
"Gaurav Mude",
"Gaurav Mude"
],
"abstract": "A serious medical condition known as hypertension or elevated blood pressure significantly rises the risk of brain, heart, kidney, and other medical conditions. It is the most common cardiovascular disease globally and is now recognized as a major health issue that needs to be addressed. It serves as a warning sign for serious illnesses including myocardial infarction, stroke and renal failure. An estimated 46% of the population with hypertension are not aware of the condition they have. Only 42% of those diagnosed with hypertension receive a diagnosis and treatment. 21% (1/5) of the population who have hypertension have it under control. Around the world, high blood pressure (HBP) is a main cause of early death. Knowledge on the prevalence of risk factors for hypertension is needed because there are relatively few community-based research projects on the condition. The objective of this study is to assess the prevalence of hypertension risk factor in the Wardha district in the state of Maharashtra in western India. A cross-sectional study will be performed. The study’s strength lies in the use of a standardized risk factor check list, which will ensure consistency in data collection and minimize bias. The use of a large sample size (165 patients) will also improve the precision of study and increase the generalization of the result.",
"keywords": [
"Hypertension",
"Risk factors",
"Prevalence",
"Blood pressure",
"Cardiovascular-disease"
],
"content": "Introduction\n\nBlood pressure (BP) is the force of the blood exerted on the walls of arteries as a result of the left ventricle contracting against the resistance provided by the arteries and arterioles, which is necessary for the best possible functioning of the body.1 HBP is the medical term for elevated BP. The BP is addressed as two numbers. The Systolic pressure, which is the first number, is the blood vessel pressure produced when the heart contract or beats. The Diastolic pressure which is the second number indicates the pressure in the arteries between heartbeats.2\n\nHBP is regarded as the third most crucial element of danger for the associated burden of illness in South Asia. In India, the impact of hypertension (HTN) on the cardiovascular healthcare system and health status is significant. In India, hypertension is mainly accountable for more than 50% of all deaths from stroke and more than 20% of all fatalities from CDH (coronary heart disease) and according to World Health Organization (WHO), one of the main global elements of risk for early death is hypertension.3\n\nThe principal factor adding to cardiovascular mortality and morbidity is hypertension.4 Experts on hypertension continue to disagree on the HBP threshold that constitute abnormality, based on epidemiological and intervention research, the generally recognized criteria is systolic blood pressure (SBP) > or = 140 mmHg and/or diastolic blood pressure (DBP) > or = 90 mmHg.5 Adult blood pressure is divided into stages. Health and physical risks increase with each stage. These stages vary from normal, elevated (SBP 130-139mm Hg and DBP 80-89 mmHg), stage 2 Hypertension (SBP 140 mmHg and up and 90 mmHg and up), and hypertension crisis (SBP 180 mmHg and up and DBP 120 mmHg and up), a hypertension crisis is a sudden rise in blood pressure rise in blood pressure that can result in a stroke and is recorded at 180/120.6\n\nBP by age and gender also vary from; 18–39-year male (119/70 mmHg) and female (110/68 mmHg), 40-59 years male (124/77 mmHg) and female (122/74 mmHg), 60 + years male (133/69 mmHg), and female (139/68 mmHg).6\n\nAccording to epidemiological research, in India the prevalence of hypertension has been continuously rising over the past 40 years, with urban areas experiencing this trend more than rural ones.5 Based on The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) standard which was published 2003 and the American College of Cardiology/American Heart Association (ACC/AHA) guideline, Hypertension prevalence based on sex and age was 22.3% (95% CI: 20.6, 24.1) and 36.5% (31.1, 41.8), respectively.7\n\nPrimary hypertension & Secondary hypertension are the two main assortments of hypertension.\n\nEssential hypertension, which is commonly called as primary hypertension, is a multifactorial form of HBP that has multiple causing factors. It is often referred to as essential or idiopathic hypertension, anything above 120/80 mmHg is normally considered to be above normal, indicating that arteries are under more pressure than they should be. You are more likely to develop essential primary hypertension if you engage in unhealthy behaviours and certain situations.8 Other forms of hypertension have a unique root cause, including a medical condition or drug side effects. Secondary hypertension is the term used when there is a clear direct cause. Primary and secondary hypertension can coexist, and when there is an instant deterioration of BP, a new secondary cause should be considered.8\n\nSecondary hypertension may frequently be cured effectively in order to minimize both the HBP & the disorder that causes it. The risk of major consequences, such as kidney failure, heart disease and stroke are decreased by effective therapy. Even if BP has risen to risky levels, secondary BP typically exhibits no particular symptoms, similar to primary hypertension. Secondary hypertension can result from many medical problems also secondary hypertension may be caused by a number of renal disorders, including: Polycystic kidney disease, Diabetes compilation (diabetic nephropathy), Renovascular hypertension, Glomerular disease, etc.9\n\nAnother type of hypertension is pregnancy-induced hypertension. Pregnancy-induced hypertension can be characterized as a disorder of conditions that happens following 20 weeks of pregnancy described by an expansion in circulatory strain to more than 140/90 mmHg regardless of proteinuria.10\n\nA vital causal factor for stroke, long-term heart disease and coronary heart disease is high BP unhealthy diets, use of cigarettes and alcohol, inactivity, excessive salt consumption, being overweight or obese, diet high in saturated and trans fats, are some of the modifiable risk factors that may be altered.2 Non-modifiable risk factor of hypertension includes being older than 64 years, having a heredity of hypertension, and having other diseased condition like diabetes or renal disease; these risk factors cannot be altered.2 The aim of the proposed study is to estimate the prevalence of risk factor of hypertension among population of age group 35-60-years in Wardha district.\n\n\nObjective\n\nTo assess the prevalence of risk factor of hypertension\n\nTo state the risk factor of hypertension\n\n\nProtocol\n\nType of study – Observational study (Cross-sectional)\n\nDuration of study – 4 months\n\n• The study will be a cross-sectional observational study, and will be carried out over a period of four months\n\n• Conceptual research on hypertension will be done\n\n• Prior to the initiation of the study permission will be obtained from the ethics committee\n\n• The subject will be assigned, with the help of simple random sampling method\n\n• The evaluation of prevalence of risk factor of hypertension will be done through face-to-face interview by using standardized risk factor check list\n\n• Subjects will be provided Informed Consent, which will be filled after explaining the purpose of study\n\n• Standardized risk factor check list will be given to the subject and will be filled by them\n\n• The data collected will be tabulated and analysed\n\nThe study is about the prevalence of risk factor oh high BP. The study will be conducted among the hypertensive population of Wardha district. The recruitment of the subjects will be done independently, and the evaluation will be observed through a risk factor check list.\n\nThe subjects will be recruited using simple random sampling from various private and government hospitals in Wardha district.\n\nSample size11 – 165\n\nDaniel formula for sample size:\n\nWhere’s\n\nZα/2 is the level of satisfaction at 5% i.e. 95%\n\nConfidence interval = 1.96\n\nP = Prevalence = 29.8% = 0.298\n\nn = 165\n\nhence, 165 subjects will be needed in the study.\n\nInclusion criteria:\n\n1. Males or Females with hypertension\n\n2. population between 35-60 years age group\n\nExclusion criteria:\n\n1. Age below 35 and above 60 years\n\n2. Clinical diagnosis of malignant tumour\n\n3. Pregnant/lactating women\n\nInstrument – Risk factor check list (see extended data)\n\nThe check list will include details of the subject such as Name of the subject, Age, Gender, blood pressure of the subject.\n\nThe check list will also include different risk factors of hypertension such as Age, Obesity, Genetic and Family history, Alcohol Consumption, Physical inactivity, etc.\n\nStep 1: Permission will be obtained prior from the Ethics Committee for the data collection\n\nStep 2: Introduction between the participants and the researcher\n\nStep 3: The participants will be assigned by using random sampling method\n\nStep 4: Written, informed consent will be taken from all the participants who are willing to participate, after explaining the study purpose\n\nStep 5: Standardized risk factor check list will be filled out by the subjects with the help Of face-to-face interview\n\nStep 6: The data collected will be tabulated and analyzed\n\nTo state the risk factors of hypertension among hypertensive population of Wardha district.\n\n\nMethod of data analysis\n\nStatistical analysis including standard deviation, mean, proportion, frequency, and percentage and inferential statistics comprising χ2 test, discriminants analysis and factor analysis will be used to analyse the data using Statistical Package for Social Sciences (SPSS)12 and Excel.\n\nIt will be published in an indexed journal.\n\nYet to be started.\n\n\nDiscussion\n\nHBP is a notable cause of element of danger for stroke, chronic heart disease and coronary heart disease. Unhealthy diet (diets heavy in saturated and trans fats, excessive salt intake, insufficient intake of vegetables and fruits), use of tobacco and alcohol, inactivity, and being obese or overweight are some of the modifiable risk factors that can be changed. Family history of hypertension, having additional illness like diabetes or kidney disease and being over 65 years are all non-modifiable risk factors that cannot be changed.2\n\nCardiovascular morbidity and mortality are increased by hypertension by a factor of two to four. Atherosclerosis and coronary disease are now the main risks. The degree of diastolic or systolic BP elevation in either sex, at any age, is inversely correlated with risk of hypertension. Patients with hypertension who also have an impaired glucose tolerance, high-density/high total lipoprotein (HDL) - cholesterol ratio, abnormal electrocardiographic (ECG) results, high fibrinogen levels and who smoke cigarette are at a higher chance to develop coronary heart disease.13\n\nHBP is a prime element of danger for heart attack and stroke and affects almost 30% of adults. Due to hypertension, the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS) are affected and that are also associated with the regulation of salt-water balance and cardiovascular function.14\n\nHypertension a condition that can be controlled. It has been claimed that targeted reductions in the number of persons with hypertension are projected to result in significant decreases in the burden of cardiovascular disease. The acceptance of healthy lifestyle by every individual is essential for the prohibition of high BP, according to the JNC-7. Therefore, accurate estimates of hypertension are required to develop effective control strategies.15\n\nA two-dimensional methodology is utilized for the underlying treatment of hypertension, with an emphasis on way of life changes and extra pharmacological administration. Lifestyle management, also known as non-pharmacological treatment, is essential for both individual with hypertension and individual without hypertension. Non-hypertensive individual, including those with pre-hypertension, can reduce their risk of BP-related clinical consequences and lower their blood pressure through lifestyle modifications. If the patient is able to maintain lifestyle changes, these interventions may enable drug step-down in hypertensive patients whose blood pressure is controlled by medication. The therapy is successful when a various aspects of the subject’s life are considered because essential hypertension is thought to be the result of interactions between genes and the environment. In the treatment of high blood pressure, it is crucial to control environmental factors considering they are powerful and cause the majority of variations in BP across individuals and communities. Consumption of inactivity, psychosocial stress, alcohol, and a diet deficient in fibre and potassium are all important lifestyle or environmental factors. Obesity, particularly truncal obesity, is a strong proximate determinant of high blood pressure in Indians as well. It is well known that lifestyle factors contribute to their onset.16\n\nAll individuals with hypertension should start non-pharmacologic therapies. Changing one’s lifestyle early on can lessen the likelihood of developing other diseases and even eliminate the need for pharmaceutical treatment. However, maintaining a healthy lifestyle is insufficient or However, majority of subjects will require pharmaceutical therapies to manage their blood pressure, and leading a healthy lifestyle is inadequate or difficult to adhere to.17\n\nThe following drugs are used to treat high blood pressure18:\n\nDiuretics (Water pills): The elimination of salt and water from the body is aided by these medications. These are frequently the 1st medications used to treat high BP. Depending on the measurements of blood pressure and other medical conditions, such as kidney disease or heart failure, diuretics can be grouped into a number of different categories, such as potassium sparing, loop, and thiazide.\n\nAngiotensin-converting enzyme (ACE) inhibitors: By causing the secretion of a natural chemicals that narrows the blood vessels, ACE inhibitors assist in blood vessel relaxation. Benazepril (Lotensin), lisinopril (Prinivil, Zestril), captopril, and others are examples of angiotensin-converting enzyme inhibitors.\n\nAngiotensin II receptor blockers (ARBs): Additionally, angiotensin II receptor antagonists relax blood vessels. They prevent the natural chemical that dilates blood vessels from acting, not from developing. Losartan (Cozaar), candesartan (Atacand), and other Angiotensin II receptor blockers include.\n\nAlpha blockers, Alpha-beta blockers, Beta Blockers, Aldosterone antagonists, Renin inhibitor, Vasodilators, and Central acting agents are other medications that can be used to treat high blood pressure.\n\nAyurvedic medications have also been shown to help with conditions like hypertension and improve heart function for a long time. To ensure that the patient’s health is a primary concern, various principles and guidelines are described in Ayurvedic texts. Jatamamsi, Sarpagandha, Rason, and Arjuna are some of the therapeutic plants used to treat hypertension.19\n\nShamak Yoga is the type of yoga which also helps to treat hypertension. “Shamak Yoga” is a polyherbal combination of 10 Ayurvedic plants. In individuals with moderate hypertension, Shamak Yoga was shown to be statistically significant and equivalent to Atenolol for systolic and diastolic blood pressure.20\n\nThis observational study will highlight the prevalence of risk factors of hypertension among population of Wardha district between age group of 35-60 years.\n\nBased on The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) standard which was published 2003 and the American College of Cardiology/American Heart Association (ACC/AHA) guideline, Hypertension prevalence based on sex and age was 22.3% (95% CI: 20.6, 24.1) and 36.5% (31.1, 41.8), respectively.7\n\nThis study is limited to Hypertensive population of Wardha district between age group 35-60 years.\n\nCompared to males, older women had a greater risk of developing hypertension (AOR, 4.24; 95% CI, 3.94-4.57 for men aged 50–54 and AOR, 5.58; 95% CI, 5.16–6.03 for women aged 40–49). Other than age, it has been shown that drinking alcohol, having diabetes, and not working are the main risk factors for this condition in women. In order to prevent the early onset of hypertension, teenagers and adults in India should be encouraged to adopt new lifestyle habits including eating a diet high in fruits and vegetables and getting regular blood pressure checks.21\n\n19.1% of people worldwide had hypertension. Adults were 3.6 times more likely to develop hypertension if they had known diabetes mellitus. Risk factors for hypertension include a family history of HT (OR:1.82), cigarette use (OR:1.94), and alcohol use (OR:1.54 for men). With a BMI of 25 to 29.9 and below 30 correspondingly, it was shown that the risk of hypertension increased to 1.45 times and 2.27 times, respectively. Age, family history of hypertension, known history of diabetes mellitus, and body mass index were the factors of hypertension in multiple logistic regression analysis.22\n\nAs similar study is not conducted in Wardha district the result from this study will add data to the data base related to prevalence of risk factors of hypertension.\n\n\nEthical approval\n\nApproval by the Institutional Ethics Committee Ref. No. DMIHER (DU)/IEC/2023/594.\n\nDatta Meghe Institute of Higher Education and Research Sawangi (M) Wardha- 442107 Maharashtra, India.",
"appendix": "Data availability\n\nNo underlying data are associated with this article.\n\nZenodo: Check list Hypertension, https://zenodo.org/record/7997228 (Amruta Dadmal, 2023).\n\nThis project contains the following extended data:\n\nCheck list hypertension.doc\n\nData are available under the terms of the Creative Commons Attribution 4.0 International (CC-BY 4.0)\n\n\nReferences\n\nAshraf M, Irshad M, Parry NA: Pediatric hypertension: an update review. Clinical Hypertension. 01 December 2020.\n\nPandey S, Shrestha N, Thakur UK, et al.: Lifestyle Modifications in the Management of Hypertensive Patients in a Secondary Care Center: A Descriptive Cross-sectional Study.Reference Source\n\nAnchala R, Kannuri NK, Pant H, et al.: Hypertension in India: a systematic review and meta-analysis of prevalence, awareness, and control of hypertension. J. Hypertens. 2014 Apr 30; 32: 1170–1177. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKota V, Kumar S, Wanjari A, et al.: Lifestyle modification and nutrition in preventing prehypertension and hypertension — Narrative review. International Journal of Nutrition, Pharmacology, Neurological Diseases. 2023 Mar; 13(1): 9.\n\nGupta R: Hypertension in India— definition, prevalence and evaluation. J. Indian Med. Assoc. 01 Mar 1999; 97(3): 74–80. PubMed Abstract\n\nHassanein F, Masoud IM, Awwad ZM, et al.: Microbial bowel infections-induced biochemical and biological abnormalities and their effects on young Egyptian swimmers. Sci. Rep. 2023 Mar 21; 13(1): 4597. Reference Source\n\nSepanlou S, Najafi F, Poustchi H, et al.: Prevalence, awareness, treatment, and control of hypertension based on ACC/AHA versus JNC7 guidelines in the PERSIAN cohort study. Sci. Rep. 08 March 2022; 12: 4057. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPrimary Hypertension (Formerly Known as Essential Hypertension) .Reference Source\n\nSecondary hypertension. Reference Source\n\nDhingra G, Jungari ML, Shrivastava D: Study of Management of Pregnancy Induced Hypertension by Magnesium Sulfate and a Calcium Channel Blocker in Central India. IJCRR. 2020; 12(15): 140–144. Publisher Full Text\n\nAnchala R, Kannuri NK, Pant H, et al.: Hypertension in India: a systematic review and meta-analysis of prevalence, awareness, and control of hypertension. J. Hypertens. 2014 Apr 30; 32: 1170–1177. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSPSS Statistics Version 22: A Practical Guide - Murdoch University.cited 2023 Jun. Reference Source\n\nKannel WB: Risk factors in hypertension. J. Cardiovasc. Pharmacol. 01 Jan 1989; 13(Suppl 1): S4–S10. Publisher Full Text\n\nDrummond GR, Vinh A, Guzik TJ, et al.: Immune mechanism of hypertension. World J. Meta-Anal. 16 Apr 2019; 19: 517–532. Publisher Full Text\n\nMidha T, Nath B, Kumari R, et al.: Prevalence of hypertension in India: A meta-analysis. World Journal of Meta Analysis. Aug 26, 2013; 1: 83. Publisher Full Text\n\nGupta R, Gupta S: Strategies for initial management of hypertension. Indian J. Med. Res. November 2010; 132(5): 531–542. PubMed Abstract\n\nNguyen Q, Dominguez J, Nguyen L, et al.: Hypertension Management: An Update. National Library.\n\nHigh blood pressure (hypertension). Reference Source\n\nBhokardankar P: CRITICAL REVIEW ON POTENTIAL AYURVEDIC DRUGS FUNCTIONAL IN HYPERTENSION. JMPAS. 2021 Jul 15; 10(3): 3007–3010. Publisher Full Text\n\nSharma M, Sharma HR, Takalkar K, et al.: Effectiveness of Shamak Yoga on Essential Hypertension in comparison with Atenolol: A Randomized Controlled Trial. Res. J. Pharm. Technol. 2021 Sep 14; 14(9): 4925–4928. Publisher Full Text\n\nKuma K, Misra S: Sex differences in prevalence and risk factors of hypertension in India: Evidence from the National Family Health Survey-4.April 13, 2021. Publisher Full Text\n\nRajasekar VD, Krishnagopal L, Mittal A, et al.: Prevalence and risk factors for hypertension in a rural area of Tamil Nadu, South India. India J. Med. Specialities. 2012; 3(1): 12–17. 6p. 4 Charts. Publisher Full Text"
}
|
[
{
"id": "206364",
"date": "03 Oct 2023",
"name": "Jelina Basnet",
"expertise": [
"Reviewer Expertise Endocrinology",
"Cell and Molecular Biology",
"Hypertension",
"Phamacology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe overall approach of study is convincing. The rationale and aim of the study can be strengthened by providing a more detailed overview of why you chose to do the study on the prevalence of hypertension risk factor in Wardha district in particular (why not other state or region), or how this study could also benefit the people from other regions/parts of India.\nThe authors have a good understanding of the relevant literature and have cited their sources appropriately.\n\nThe paper could be made better by referring to either HBP or HTN exclusively throughout; doing so makes the document a less confusing.\nOther than that, I feel this will be a great study, good luck.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Partly",
"responses": [
{
"c_id": "10341",
"date": "06 Oct 2023",
"name": "Amruta Dadmal",
"role": "Author Response",
"response": "Thank you for your response, and for the valuable time that you have given for my article. As I am PG student of Clinical Research from Datta Meghe Institute of Higher Education and Research, Sawangi (Meghe), Wardha. it is feasible for me to conduct study in Wardha district and according to literature search there were no similar studies conducted in Wardha district. Because of these reasons, I have chosen to conduct the study in Wardha district. As per your suggestion I will make the changes in my article and will submit it as soon as possible. Thanking you!"
}
]
}
] | 1
|
https://f1000research.com/articles/12-1016
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https://f1000research.com/articles/12-1335/v1
|
16 Oct 23
|
{
"type": "Study Protocol",
"title": "The role of transvaginal sonography in diagnosis of female infertility: a study protocol",
"authors": [
"Nirja Thaker",
"Rajasbala Dhande",
"Rajasbala Dhande"
],
"abstract": "Infertility has an increased incidence in today’s world. It has a negative impact on both the psychological and physical aspects of a person. In order to tackle this issue, it is necessary to know the cause of infertility. Transvaginal ultrasound is an accurate, cost-effective and rapid method in diagnosing the causes of infertility which can reduce the need of invasive procedures like hysteroscopy. The main aim of this study is to describe the role of transvaginal ultrasonography in diagnosing various causes of female infertility.",
"keywords": [
"INFERTILITY",
"TRANSVAGINAL ULTRASONOGRAPHY",
"DIAGNOSIS"
],
"content": "Introduction\n\nInfertility is the inability to conceive after one year of unprotected intercourse. Approximately 15.5% of women globally are afflicted with infertility.1 In India, the prevalence ranges from 3.9 to 16.8% (according to the Government website). The standard workup for female infertility includes assessing ovarian reserve, tubal and uterine examination, hormonal issues such as thyroid disorders and prolactin abnormalities, and confirmation of polycystic ovarian syndrome/disorder (PCOS).2\n\nFemale infertility causes are difficult to pinpoint. Although there are numerous therapies available, the treatment will be determined on the basis of cause of infertility. The most significant gains in assisted reproductive technology (ART) have resulted from advancements in pelvic structure evaluation tools.3 Infertility evaluation necessitates histo-pathological testing as well as visualization using several imaging modalities. There are many causes of infertility, including ovarian (such as ovarian dysgenesis or agenesis, premature ovarian failure, oophoritis, chocolate cyst, and polycystic ovarian syndrome), uterine (such as fibroid, adenomyosis, mullerian duct anomalies, endometrial polyp, endometriosis, endometritis, and intra-uterine adhesions caused by infectious causes such as tuberculosis), cervical aetiology (such as cervical stenosis), tubal aetiology (such as tubal occlusion, hydrosalpinx, pelvic inflammatory illness, and endometriosis).4\n\nBecause it is inexpensive, convenient, and gives basic information about the morphology of the uterus, cervix, endometrium, adnexa, and ovaries, ultrasound is the chosen initial modality of study for evaluating possible causes of female infertility.5\n\nTransvaginal ultrasonography (TVS) is a relatively new diagnostic method for the female pelvic region. A high frequency transducer is implanted endo-vaginally to evaluate pelvic organs in detail. But other investigations are needed to confirm TVS's role and to know how accurate it is in diagnosing various causes of primary and secondary infertility.5\n\nInfertility has a negative physical and psychological impact on the individual, and the causes can be difficult to identify. Although there are numerous therapies available, the treatment of choice will be determined by the cause of infertility. Transvaginal ultrasonography is a relatively new diagnostic method for the female pelvic region. It is a low-cost, rapid, safe (no ionising radiation), and precise technique for determining the reasons of various gynecological problems. The goal of this study is to re-evaluate the role of TVS in diagnosing various causes of infertility. It reduces the need for invasive diagnostic procedures such as hysteroscopy.\n\nWhat are the common causes of infertility and its various imaging findings when diagnosed with transvaginal ultrasound?\n\nThe aim of this study is to describe the role of transvaginal ultrasonography in diagnosing various causes of female infertility.\n\n\n\n1. To describe the role of transvaginal ultrasonography in evaluating various adnexal, uterine and cervical pathologies as a cause of female infertility.\n\n2. To find the ovarian causes of infertility by measuring the ovarian volume, follicular size, and ovarian reserve assessment in form of antral follicular count.\n\n3. To compare the accuracy in diagnosis of female infertility by TVS in comparison with other diagnostic modalities like hysteroscopy, MRI, histopathology etc. wherever possible.\n\nThe institute will begin data collection after the project has been ethically cleared.\n\nOnce a patient passes the eligibility requirements for the study, the process will be described to them and written agreement will be obtained.\n\nA female attendant/nurse will be present throughout the process.\n\nProper sanitary conditions will be maintained – Gloves will be worn by the health professionals, and a condom will be used to cover the transvaginal probe.\n\nBefore the scan, the patient will be instructed to empty her bladder, and she will be scanned in the lithotomy position. TVS is performed with a 5-12 MHz endovaginal probe on ALOKA HITACHI ARIETTA S-70 and WIPRO GE LOGIQ P5 PRO ultrasound equipment during the follicular phase of the menstrual cycle (the 5th-13th day following menstruation).\n\nThe TVS probe will be first covered with ultrasound gel, then with a condom, and finally with ultrasound gel again over the covered transducer. A female nurse will inject it inside the patient.\n\nThe uterus will be examined in both saggital and transverse views to examine the entire uterine anatomy, including the cervix, ovaries, adnexa, myometrium, and endometrium (thickness and consistency). The measurement of uterine dimensions (length and height) is taken in the saggital plane, whereas the width is assessed in the transverse plane (at the level of the tubal ostia). The mid-saggital plane is used to evaluate endometrial thickness. Ovarian length, height, and width will be measured, as well as the baseline AFC (antral follicle count of follicles measuring 2-10mm and >10mm).6 AFC is calculated by adding the total follicles of both ovaries (AFC5 is regarded low, AFC>=20 is called ovarian hyperstimulation syndrome, and AFC=4 indicates a chance of menopause within the next 7 years).7–9\n\nFree fluid and sliding sign (to see adhesion) are seen in examination of the culdesac- This involves applying gentle pressure through probe on the lower abdomen to assess the gliding of anterior rectum and sigmoid colon along the posterior aspect of the upper portion of uterus, cervix, and vaginal wall. When sliding sign is “Negative”, it indicates the obliteration of pouch of Douglas which can be due to endometriosis.\n\nThus data will be collected regarding the various causes of infertility relating to adnexal, uterine and cervical pathologies, and ovarian causes (by measuring the ovarian volume, follicular size, and ovarian reserve assessment in form of antral follicular count). Also data regarding causes of infertility will be collected from different modalities like Magnetic resonance imaging of pelvis and hysterosalpingography and results of other modalitity will be compared with results from transvaginal ultrasound.\n\nAs this is mainly a descriptive study, the data(causes) will be enumerated in a tabular form. And wherever possible accuracy of transvaginal sonography in diagnosing infertility will be mentioned in percentage (as compared to different modalities).\n\nA written consent will be obtained in either Marathi or English from all the patients included in this study.\n\nEthical approval was obtained from the Institutional Ethics Committee (Datta Meghe Institute Of Higher Education And Research) Re-regd. No.: ECR/440/Inst/MH/2013/RR-2019)-Dated- 21/03/2023.\n\n\nMethods\n\nThis study will be a descriptive prospective cross-sectional study conducted on patients visiting the OPD department as well as the IPD patients of Hospital from January 2023 to January 2025. The population will consist of married women in the age group of 18-40 years with the inability to conceive for one year despite being sexually active, who present to the gynecology department.\n\nWe will use purposive sampling to recruit the participants.\n\nSample size:\n\nFormula with prevalence with proportion\n\nTopic: female infertility.\n\nPrevalence= 3.9 to 16.6% (average -10.25%) (website)\n\nFormula\n\nα: type I error = 0.05\n\nEstimated proportion (p) = 0.10\n\nEstimation of error (d) = 0.05\n\nMinimum sample size needed = 139\n\nDuration of study: 2023 – 2025\n\n\n\n▪ All married female patients between the ages of 18 and 40 who present to ABVRH with a provisional clinical diagnosis of infertility (including primary and secondary).\n\n\n\n• Female patients under the age of 18.\n\n• Female patients above the age of 40.\n\n• Married female patients who refuse to give consent.\n\n• Married female patients with suspected infertility caused by medication, radiation, or pituitary, adrenal, or thyroid gland issues.\n\n• Female patients who are married and have a uterine congenital abnormality.\n\nStudy Status:\n\nRecruitment.\n\n\nDiscussion\n\nA study ‘Role of transvaginal ultrasonography and diagnostic hysteroscopy in assessing endometrial cavity of women presenting with infertility’ was conducted by K. Sarala et al. in 2018. This study concluded that hysteroscopy can be regarded as the gold standard in the diagnosis of infertility. The study compared the transvaginal findings with hysteroscopic findings. The transvaginal findings and hysteroscopic findings were similar. The various causes of infertility were endometrial hyperplasia, submucous fibroids, endometrial polyps, adhesions and congenital malformations in decreasing order of frequency respectively. Thus it was concluded that although hysteroscopy is considered gold-standard, transvaginal sonography can be used as an initial investigation in the infertility work.10\n\nIn the study conducted by Maysa S. Elkerdawy et al. on role of ultra-sonography (USG) in management of primary infertility, it was found that 60% of patients had uterine abnormalities (mainly subseptate and bicornuate uterus) while approximately 23% of patients had ovarian pathology (mainly polycystic ovaries). Only a small percentage of patients had tubal and cervical pathologies (like hydrosalpinx, cervical mass etc.). It was further found that USG can be used as a primary tool for investigation.4\n\nIn the study carried out by Salaam AJ et al. on the topic of evaluation of infertile women using transvaginal USG, primary fertility constituted about 42% of total subjects while secondary infertility constituted about 58%, and about 54% had normal TVS findings and rest (46%) had abnormal findings like uterine fibroid, free fluid in Pouch of Douglas (POD), endometritis, and hydrosalpinx in the decreasing order of frequency. It was also found that there was a significant difference in volume between the right and left ovaries in infertile women with Polycystic ovaries (PCO). This study found that a high yield of sonographic anomalies were observed on transvaginal sonography in infertile subjects, bolstering TVS's essential function as a useful diagnostic tool for evaluating infertility.11\n\nIn the study conducted on transvaginal sonographical findings by Nafeesa Binti Hussain et al. on women presenting with inability to conceive, they inferred the following: 75%of cases were of primary infertility while 25% of cases were of secondary infertility, and the most common pathological findings were polycystic ovarian syndrome (69%), followed by chronic pelvic inflammatory disorder, fibroid, anatomical disorders, endometrial or cervical polyps, and endometritis in decreasing order of frequency. The study concluded that PCO was the most frequent finding in women with infertility, which was easily diagnosed by transvaginal sonography.5\n\nTransvaginal ultrasonography is a highly accurate method for detecting various disorders in the female reproductive system. The goal of this study is to identify the many diseases of primary and secondary infertility and to demonstrate the diagnostic accuracy of TVS as a main inquiry in infertility.\n\nThis study will enumerate the various causes of infertility in today’s scenario in India that will be educational and helpful in future planning of focus areas for further studies. This study will establish the importance of Transvaginal sonography as a first line in diagnosis of infertility.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nExpert Panel on Women’s ImagingWall DJ, Reinhold C, et al.: ACR Appropriateness Criteria® Female Infertility. J. Am. Coll. Radiol. 2020 May; 17(5S): S113–S124. PubMed Abstract | Publisher Full Text\n\nKondagari L, Kahn J, Singh M; Sonography Gynecology Infertility Assessment, Protocols, And Interpretation.\n\nAflatoonian A, Mashayekhy M: Transvaginal Ultrasonography in Female Infertility Evaluation.\n\nElkerdawy MS, Ali MA, Nermeen N: Keriakos, Ultrasound Role in Management of Female Infertility, 1523-1530.2020.\n\nHussain NB, Das RR: Transvaginal Ultrasound Findings Among the Women Presenting with Infertility.2017.\n\nAIUM Practice Parameter for the Performance of a Focused Ultrasound Examination in Reproductive Endocrinology and Female Infertility. J. Ultrasound Med. 2019 Mar; 38(3): E1E3. PubMed Abstract | Publisher Full Text\n\nCoelho Neto MA, Ludwin A, Borrell A, et al.: Counting ovarian antral follicles by ultrasound: a practical guide. Ultrasound Obstet. Gynecol. 2018 Jan; 51(1): 10–20. PubMed Abstract | Publisher Full Text\n\nDepmann M, Broer SL, van der Schouw YT , et al.: Can we predict age at natural menopause using ovarian reserve tests or mother's age at menopause? A systematic literature review. Menopause. 2016 Feb; 23(2): 224–232. PubMed Abstract | Publisher Full Text\n\nWellons MF, Bates GW, Schreiner PJ, et al.: Antral follicle count predicts natural menopause in a population-based sample: the Coronary Artery Risk Development in Young Adults Women's Study. Menopause. 2013 Aug; 20(8): 825–830. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSarala K, Misra K: Role of Transvaginal Sonography and Diagnostic Hysteroscopy in Evaluation of Endometrial Cavity in Infertile Women.2018.\n\nKolade-Yunusa HO, Abdullahi HI, Salaam AJ: Evaluation of infertile women using transvaginal ultrasound in a tertiary health facility.2019."
}
|
[
{
"id": "223667",
"date": "30 Nov 2023",
"name": "Elias Tsakos",
"expertise": [
"Reviewer Expertise Obstetrics & Gynaecology",
"Fertility",
"Gynaecological Surgery",
"Robotic Surgery",
"Minimally Invasive Surgery"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a protocol for a prospective, cross-sectional study with the reported aim of assessing the role of transvaginal ultrasound in the diagnosis of female infertility. I unfortunately have located several issues with the proposed protocol, which I will divide into subcategories.\nBackground/introduction: The breakdown of infertility and the causes is quite adequate. However, I find issue with the description of the role of transvaginal ultrasound (TVUS) as a relatively new method of assessment. TVUS is by no means a new method, but a well-established diagnostic tool, which has become an indispensable part of gynecological examination and its value has been already demonstrated repeatedly by many published studies.\n\nRationale: Once more, the value of TVUS in the assessment of pelvic anatomy is well-known and has been described long ago, take for instance the articles by Gratton et al1, which describes the assessment of normal pelvic anatomy via the use of TVUS over 30 years ago. Likewise, its value in the infertile patient has also been demonstrated long ago and repeatedly, for example by Ubaldi et al. in 19982. Overall, your rationale, in my opinion, does not demonstrate a gap in medical knowledge, or a lack of sufficient data in order to justify this research (at least in its present form, see also “research question”).\n\nResearch question: This is the most problematic part of this protocol in my opinion. The research question is very broad and vague. The “role” is not a quantifiable outcome, to use, it is a subjective metric. Outcomes such as diagnostic accuracy, cost, safety, tolerability, diagnostic efficacy compared to alternative diagnostic methods, complications, reproducibility of results, values of ultrasonographic measurements etc are more appropriate for medical research, as they evaluate specific aspects of the performance of this diagnostic method (continued in the next point).\n\nIn your “Objectives”, the most important section of the research protocol, you introduce the potential of comparing to other methods (point 3), but again, this is too vague, it is not clear which specific methods will be used and whether they will apply to all patients. In point 2 of the “Objectives”, you also introduce the interesting potential of specific measurements, however, you do not explain what is to be done with these measurements. Will they be compared to a health control? Will they be utilized as prognosis factors of fertility, based on whether the woman achieves pregnancy? Simple collection and presentation of data does not suffice, analysis and evidence-based interpretation is necessary.\n\nRelated to the above, you need to define your research question and your outcomes/objectives more clearly and using quantifiable measures. I suggest using the PICO format, or one of its alternatives3.\n\nSample size: the website you cite demonstrated that the average rate of infertility was 12.6 per cent (n = 113; 95% CI: 10.5-15.0%), so you should use this percentage, unless there were other sources as well. Additionally, please provide the statistical software that you used to conduct the sample size calculation.\n\nIn your exclusion criteria, since you wish to assess female fertility only, you should exclude cases of male factor infertility as well. Therefore, some screening of the husbands’ reproductive health may also be necessary to achieve homogeneity.\n\nIn your “Scope”, you introduce the additional, different objective of quantifying the various causes of infertility, thus introducing an epidemiological surveillance angle. Right after that, you mention that the goal is also to demonstrate the diagnostic accuracy of TVUS. However, diagnostic accuracy studies require a reference standard in order to determine sensitivity, specificity and other parameters, which is something not mentioned in your protocol.\n\nReferences: most references are not accessible, please provide links or DOI.\nOverall, if I had to summarize my recommendations, they would be to apply a narrower focus on your research question. Define specific, quantifiable outcomes and use comparators when and if necessary. If diagnostic accuracy is the outcome, then a reference standard, such as hysteroscopy will be required. Even if your ultimate aim is to simply collect and present epidemiological data, confirmation of the diagnoses made by ultrasound will be required by a reference standard. Additionally, infertility is frequently caused by multiple factors, so you will need to address that as well. In any case, major revision are required.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? No\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
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https://f1000research.com/articles/12-1335
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https://f1000research.com/articles/12-478/v1
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10 May 23
|
{
"type": "Research Article",
"title": "Evaluation of paraoxonase I and hemoglobin levels in farmers and agricultural workers in relation to pesticide levels in their blood and urine samples: A cross sectional study",
"authors": [
"Vinutha Bhat",
"Pragati Nayak",
"Shankar Bakkannavar",
"Padmanabha Udupa",
"Vinutha Bhat",
"Pragati Nayak",
"Padmanabha Udupa"
],
"abstract": "Background: Pesticides are chemicals that have become common household products in developing countries. The purpose of pesticides is to manage agricultural work. The majority of pesticides for indoor and agricultural use are carbamate and organophosphorus. Toxicity is caused due to excess and improper use or disposal of these chemical agents. Slow exposure to pesticides causes chronic poisoning whereas rapid exposure causes acute poisoning. The paraoxonase I (PON 1) enzyme has a role in detoxifying some of the oxon derivatives which thereby inhibit acetylcholinesterase and butyrylcholinesterase. Methods: This study analyzed farmers who were exposed intermittently to organophosphorus and carbamates pesticides during farming for more than five years. Serum paraoxonase I was evaluated by colorimetry method, and hemoglobin levels were evaluated using portable Fresenius Kabi haemoglobinometer. Results: The study showed that the pesticides were found in the blood and urine samples of farmers and there was an alteration of paraoxonase I and hemoglobin levels in them due to the exposure of pesticides in large quantities over some time. The present study showed around 81% of the participants who were intermittently exposed to pesticides for more than five years were detected with pesticide toxicity. The paraoxonase I level was altered in farmers who were positive for organophosphorus and carbamate pesticides. The hemoglobin level did not show much variation among the farmers exposed to pesticides. This may be due to the lifestyle of the subjects, climatic variations and also their eating habits. Conclusions: The study suggested that there was alteration in the levels of PON1 and hemoglobin in farmers and agricultural workers with positive organophosphorus and carbamates in their blood and urine samples. As our study was done without quantifying the amount of pesticides, further studies can be done by quantifying the pesticide level and comparing it with the paraoxonase I level.",
"keywords": [
"Pesticides",
"toxicity",
"organophosphorous poisoning",
"carbamate poisoning",
"paraoxanase I (PONI)",
"haemoglobin"
],
"content": "Introduction\n\nPesticides are synthetic chemical compounds that are used to destroy pests including insects and unwanted plants. As a result of its easy availability, it has become a commonly used agricultural product in rural areas of developing countries.1 Pesticide poisoning is a major challenging problem all over the world.2 Acute pesticide poisoning is an important cause of morbidity and mortality in India.3 According to World Health Organization (WHO) in 1990, all together around three million pesticide poisoning cases occur annually around the world (WHO 1990).4\n\nOrganophosphorus (OP) and carbamate pesticides are common household insecticides used commonly for agricultural purposes in developing countries.5,6 In India, organophosphorus, carbamate, organochlorine, and pyrethroids are the commonly used pesticides.4 Most of these pesticides are sold directly from shops due to the lack of special rules and regulations regarding the use and sale of pesticides in countries like India.2\n\nChronic and acute exposure is mainly through residue of pesticides sprayed to crops and vegetables.7 According to a recent study, the various food commodities such as cereals and vegetables contain pesticide residues.8 Hence the farmers and agricultural workers exposed to pesticides are at risk of acute or chronic poisoning.\n\nPON1, an Esterase, can detoxify pesticide derivatives in human serum.9 The primary function of the PON1 enzyme is likely to be related to its antioxidant properties.10 However, it plays an important role in the pesticide toxicity pathway by helping in hydrolyzing several oxon derivatives.11 PON1 activity of an individual can vary to a large extent. It is reported that paraoxanase I levels can vary by at least 13-fold and the activity up to 40-fold.7 This implies that the ability of individuals to detoxify OP would depend on their PON1 activity. Pesticide poisoning inhibits the PON1 enzyme which in turn inhibits acetylcholinesterase in synapse and on red blood cell (RBC) membrane and butyrylcholinesterase in plasma.12 Accumulation of cholinesterases causes central nervous system depression or seizures, and respiratory failure.13\n\nThe PON1 has a role in prevention of oxidative stress and inflammation, the level of which is affected in poisoning cases.14 The lifespan of red blood cells can be shortened through oxidative damage and toxic mechanisms resulting in anaemia. Hemoglobin is also subjected to oxidative damage resulting the formation of methemoglobin which is nonfunctioning resulting in tissue hypoxia.14\n\nThe present study shows the pesticide toxicity in farmers and agricultural workers who were exposed to pesticides for more than 5 years. Exposure was confirmed by asking the participants about their use/contact with pesticides, and toxicity was determined via the paraoxonase I and hemoglobin levels measured.\n\n\nMethods\n\nEthical approval was obtained from Institutional Ethics Committee (Kasturba Hospital, Manipal, which is a part of Kasturba Medical College, Manipal; No: IEC143/2017 dated 15.02.2017) before starting the study. The detailed plan of the study was explained to the 100 farmers and agricultural workers through the Participant Information Sheet (PIS) and on willingness to participate in the study, written informed consent in a printed form was obtained from the study participants. After agreeing to participate in the study, the participants voluntarily signed the form. The consent form was pre-validated and approved from the ethics committee. The consent was obtained for both participation and for academic publication purposes.\n\nThis cross-sectional prospective observational study was conducted between October 2017 to April 2018 in the poison information center, part of the Kasturba tertiary care teaching hospital in South India. Both male and female agricultural workers were included in the study belonging to the age group 25–75 years. 100 farmers and agricultural workers (50 males and 50 females) of the native district (Udupi district of Karnataka) were included in the study and the blood and urine samples were collected from them in the hospital by the postgraduate medical students (interns) and faculty members. These farmers and agricultural workers were part of the health checkup camp arranged for them in the native district. A total of 240 agricultural workers were the part of health checkup camp. Out of them based on inclusion criteria i.e. those with minimum 5 years of work in the field and more than 25 years of age were included in the study. Those farmers and agricultural workers were identified based on their identity card and initial information collected. The effects of chronic toxicity can be seen in individuals in several months to years after the exposure.15 Hence, only the farmers and agricultural workers who were involved in agriculture for a period of at least 5 years (and who confirmed their exposure to pesticides) were included in the study.\n\nDuring the study, the antecubital fossa was cleaned with antiseptic solution and through venipuncture by puncturing medial cutaneous vein or cubital vein or brachial vein, 2 ml of the blood was collected. The urine was collected in the labelled plastic container of 20 ml capacity.\n\nHaemoglobin levels of each participant was evaluated using portable Fresenius Kabi haemoglobinometer. It is essentially photometer which allows measurement of color intensity of solutions. The disposable micro cuvette acts as reaction vessel in which measurements are made. The reagents necessary for both release of Hb from erythrocytes and conversion of Hb to a stable colored product are present in dried form on the walls of the cuvette. A small sample (typically 10 μL) of venous blood to the micro cuvette is introduced and micro cuvette is introduced into the instrument. The instrument is factory precalibrated using HiCN standard, and absorbance of the test solution is automatically converted to ctHb. The result is displayed in less than a minute. The displayed results were recorded.\n\nA total of 2 ml of each extracted blood and urine sample were processed qualitatively by performing thin-layer chromatography (TLC) by running against organophosphorus (Cypermethrin, Thimet and Chlorpyrifos) and carbamate (Anuferon) standards.\n\nTo one portion of the sample, two portions of the diethyl ether was added and vortexed. The upper layer was collected and considered as the treated sample. The extraction process was repeated two to three times.\n\nThe thin layer silica sheets were cut according to the number of the samples and the size of the chamber. Linea were cut 1 cm away from the top and bottom cut ends of TLC sheets. The line below was for the sample application and the line above was considered as the solvent front. Simultaneously the glass chamber with the solvent system consisting of cyclohexane:acetone:chloroform [70:25:5] in it, was kept for saturation (at least for 10–15 min).\n\nSpotting the standards and treated sample was done using the capillary tubes. Capillary tube was placed vertically on the TLC sheet repeatedly so that the solution was applied in several portions with intermediate drying (blow with cold or hot air). The organophosphorus and carbamate standards were spotted 5-6 times to increase the concentration and the treated samples are spotted 16–18 times for the same reason at the base line drawn. Then the TLC plates were kept in the saturated TLC chamber carefully without disturbing the solvent and allowed the solvent to run till the solvent front.\n\nThe solvent ascends through the layer by capillary action and causes the substances to separate. Once the solvent reaches the solvent front (near the top line) the TLC plates are taken out and kept for drying. The dried TLC plates are carefully placed in the visualizing chamber (iodine chamber) for 5–10 min till brown spots are visible.\n\nThe plates were then taken out and the spots were marked immediately. Localization of a substance was done with parallel runs with reference substances. The value used for evaluation was Rf value (retention factor). Rf values of samples were calculated, and comparison was done with the Rf value of the standards. Rf value was defined as follows: Rf = Distance from starting point to middle of spot/Distance from starting point to solvent front.\n\nThe farmers and agricultural workers were categorized depending on the presence or absence of pesticides in their blood or urine samples into following 4 groups; carbamate toxicity, organophosphorus toxicity, both carbamate and organophosphorus toxicity and no pesticide toxicity.\n\n250 μl of diluted serum was added in 2 ml of tris HCl buffer containing 0.5 ml of 1 mmol of CaCl2, 0.5 ml of 2.5% methanol, and 0.5 ml of p-nitrophenyl acetate. The absorbance of the solution is measured at 405 nm. The intensity of the color developed is directly proportional to the amount of Paraoxanase present in the serum.\n\nThe data obtained were tabulated and analyzed using Statistical Package for Social Sciences (SPSS) version 21. Data was expressed as Mean ± SD. The significance value was set to p > 0.05. Inter comparison of data between the groups was assessed by ANOVA (One Way Analysis of Variance).\n\n\nResults\n\n100 samples were collected from 100 farmers and agricultural workers belonging to the age group of 18 to 75 years involving both males and females. All the samples were divided into four groups based on the presence of the type of pesticide as; Group 1: Carbamate toxicity which was detected as positive in 60 farmers; Group 2: Organophosphorus toxicity, positive in 13 farmers; Group 3: Absence of pesticide which was seen in 19 participants and Group 4: Both carbamate and Organophosphorus toxicity, positive in 8 farmers, as mentioned in Table 1 and Underlying data.30\n\nThe four groups were analyzed statistically but did not show any significant relation with a p-value (p < 0.005). Paraoxonase I level was comparatively low in participants positive for carbamate, organophosphorus, and both carbamate and organophosphorus toxicity when compared with participants who were detected negative for pesticide toxicity (Table 2).\n\nHemoglobin level was considerably low in participants containing both carbamate and organophosphorus toxicity.\n\nWhen the levels of haemoglobin and PON1, were compared between the groups, the statistically significant results were not shown (Table 3). F value was 1.856 for intergroup comparison for hemoglobin and 1.780 for Paraoxanase which were statistically unsignificant with p value. We had outliers in the study. As a result, the data of one participant was not included in the analysis of intergroup comparison as shown in Table 3. We are confining our study to only adjusted estimates since we have no regression analysis included in our study.\n\n\nDiscussion\n\nPesticides poisoning is the major global issue all over the world.16 In rural areas of developing countries like India, pesticidal poisoning causes a greater number of deaths than rest of other diseases or infections.17 Lack of regulatory control to the use and distribution of pesticides is one of the major reasons for these poisoning cases.18 Organophosphorus and carbamate toxicity are the most common cases seen in agriculturally rich areas.19\n\nManagement of pesticide poisoning cases is a greater challenge in developing countries. Though there are specific management protocols available,20,21 research is still being performed around the world in view of their early diagnosis and more effective management. A number of biomarkers and bedside diagnostic tools are being developed for easy detection of pesticide exposure.22 The levels of biomarkers of pesticide exposures in human invasive samples such as blood and non-invasive samples such as urine have been studied.3,23,24\n\nParaoxonase 1 (PON1) is a high-density lipoprotein-associated enzyme that plays a critical role in the metabolism and detoxification of Organophosphorus pesticides as shown in many studies.8,10 In the present study, the PON1 level is comparatively less in Organophosphorus poisoning than in the other poisoning groups. Similar observations were mentioned by Vilanova and Sogorb, 1999; Sogorb and Vilanova, 2002.25–27 A low level of PON1 enzyme will increase the susceptibility to pesticides causing respiratory and neurological problems.28 The higher levels of PON activity in the patients may have substantially better detoxifying capacity against OP compounds as shown in research done by Hettagowdanahally V Rahul et al.29 However, previous researchers have shown that the organophosphorus compounds directly inactivate the PON1 affecting neither their synthesis nor clearance of the enzyme.1\n\nIn cases with both organophosphorous and carbamate toxicity, there is a considerably lower hemoglobin level. Cholinesterase inhibition due to pesticide poisoning leads to cellular dysfunction leading to oxidative damage of the RBC membrane. This leads to a lower level of hemoglobin levels in pesticide poisoning cases. In these cases, there is no statistical significance in hemoglobin levels may be due to environmental factors or due to the food habits of the patients.\n\nIn the present study, around 85% of the participants were evaluated positively to various pesticides like Organophosphorous and carbamate. This concludes that there is no proper management for the use and disposal of pesticides. The studies have shown that PON1 levels to a larger extent and detoxification of pesticides majorly Organophosphorus would depend on Paraoxanase I.7\n\nThe study had no statistical significance since it had certain limitations. The quantification of organophosphorus and carbamates was not done in our study. Only the samples were analysed qualitatively for presence of organophosphorus and carbamates. Hence the considerable proportionate of lowering of PON1 level probably was not statistically significant.\n\n\nConclusions\n\nOur study suggests that around 85% of the participants who were exposed to pesticides for more than 5 years were detected with pesticide toxicity. The Paraoxanase I level was low in participants who were positive for presence of pesticide than in the participants who were normal. Further studies can be done by quantifying the pesticide level and comparing it with the Paraoxanase level.\n\nEarly identification followed by effective management in the initial stages increases the rate of survival among pesticide toxic patients.",
"appendix": "Data availability\n\nFigshare: Evaluation of paraoxonase I and hemoglobin levels in farmers and agricultural workers in relation to pesticide levels in their blood and urine samples: A cross sectional study. https://doi.org/10.6084/m9.figshare.22595113.v3. 30\n\nThis project contains the following underlying data:\n\n- FARMERS LIST - ALL.xlsx.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgments\n\nWe gratefully acknowledge for supporting this work by the Department of Biochemistry, Manipal University and Manipal University, Manipal.\n\n\nReferences\n\nSözmen EY, Mackness B, Sözmen B, et al.: Effect of organophosphate intoxication on human serum paraoxonase. Hum. Exp. Toxicol. 2002; 21: 247–252. PubMed Abstract | Publisher Full Text\n\nHarley KG, Huen K, Aguilar Schall R, et al.: Association of organophosphate pesticide exposure and paraoxonase with birth outcome in Mexican-American women. PLoS One. 2011; 6(8): e23923. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEsteban M, Castaño A: Non-invasive matrices in human biomonitoring: A review. Environ. Int. 2009; 35(2): 438–449. PubMed Abstract | Publisher Full Text\n\nSrinivas Rao C, Venkateswarlu V, Surender T, et al.: Pesticide poisoning in south India: opportunities for prevention and improved medical management. Tropical Med. Int. Health. 2005 Jun; 10(6): 581–588. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVale JA, Bradberry SM: Organophosphorus and Carbamate Insecticides.Brent J, Burkhart K, Dargan P, et al., editors. Critical Care Toxicology. Cham: Springer; 2016. Publisher Full Text\n\nMeerdink C: Organophosphorus and Carbamate Insecticide Poisoning in Large Animals. Vet. Clin. N. Am. Food Anim. Pract. 1989; 5: 375–389. PubMed Abstract | Publisher Full Text\n\nRichard SA, Frank EA, D’Souza CJ: Correlation between Cholinesterase and Paraoxanase 1 Activities: Case Series of Pesticide Poisoning Subjects. Bioimpacts. 2013; 3: 119–122. PubMed Abstract | Publisher Full Text\n\nLi WF, Costa LG, Richter RJ, et al.: Catalytic efficiency determines the in-vivo efficacy of PON1 for detoxifying organophosphorus compounds. Pharmacogenetics. 2000; 10: 767–779. PubMed Abstract | Publisher Full Text\n\nFonnum F, Sterri SH: Chapter 19 - Tolerance Development to Toxicity Of Cholinesterase Inhibitors.Gupta RC, editor. Toxicology Of Organophosphate & Carbamate Compounds. Academic Press; 2006; pp. 257–267. Publisher Full Text\n\nShunmoogam N, Naidoo P, Chilton R: Paraoxonase (PON)-1: a brief overview on genetics, structure, polymorphisms and clinical relevance. Vasc. Health Risk Manag. 2018 Jun 18; 14: 137–143. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCosta LG, Li WF, Richter RJ, et al.: The role of paraoxonase (PON1) in the detoxication of organophosphates and its human polymorphism. Chem. Biol. Interact. 1999; 119-120: 429–438. PubMed Abstract | Publisher Full Text\n\nGonzalez V, Huen K, Venkat S, et al.: Cholinesterase and paraoxonase (PON1) enzyme activities in Mexican-American mothers and children from an agricultural community. J. Expo. Sci. Environ. Epidemiol. 2012 Nov; 22(6): 641–648. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGonzalez V, Huen K, Venkat S, et al.: Cholinesterase and paraoxonase (PON1) enzyme activities in Mexican–American mothers and children from an agricultural community. J. Expo. Sci. Environ. Epidemiol. 2012; 22: 641–648. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBates N: Poisons affecting the blood. accessed on 04.03.2023. Reference Source\n\nShah R: Pesticides and Human Health. Emerging Contaminants. 2021 May 27. Publisher Full Text\n\nJeyaratnam J: Acute pesticide poisoning: a major global health problem. World Health Stat. Q. 1990; 43(3): 139–144. PubMed Abstract\n\nEddleston M, Karalliedde L, Buckley N, et al.: Pesticide poisoning in the developing world--a minimum pesticides list. Lancet. 2002 Oct 12; 360(9340): 1163–1167. PubMed Abstract | Publisher Full Text\n\nSrinivas Rao C, Venkateswarlu V, Surender T, et al.: Pesticide poisoning in south India: opportunities for prevention and improved medical management. Tropical Med. Int. Health. 2005 Jun; 10(6): 581–588. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGupta RC, Doss RB, Begum Y-D, et al.: Organophosphates and carbamates.Gupta RC, editor. Reproductive and Developmental Toxicology. 3rd ed.Academic Press; 2022; pp. 617–639. Publisher Full Text\n\nRoberts DM, Aaron CK: Management of acute organophosphorus pesticide poisoning. BMJ. 2007 Mar 24; 334(7594): 629–634. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBird S: Organophosphates and Carbamate poisoning. Uptodate accessed on 06.03.2023. Reference Source\n\nCampion S, Aubrecht J, Boekelheide K, et al.: The current status of biomarkers for predicting toxicity. Expert Opin. Drug Metab. Toxicol. 2013 Nov; 9(11): 1391–1408. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYusa V, Millet M, Coscolla C, et al.: Occurrence of biomarkers of pesticide exposure in non-invasive human specimens. Chemosphere. 2015 Nov; 139: 91–108. PubMed Abstract | Publisher Full Text\n\nKapka-Skrzypczak L, Cyranka M, Skrzypczak M, et al.: Biomonitoring and biomarkers of organophosphate pesticides exposure - state of the art. Ann. Agric. Environ. Med. 2011; 18(2): 294–303. PubMed Abstract\n\nSogorb MA, Estévez J, Vilanova E: Chapter 57 - Biomarkers in biomonitoring of xenobiotics.Gupta RC, editor. Biomarkers in Toxicology. San Diago: Academic Press; 2014; pp. 965–973. Publisher Full Text\n\nCeja-Gálvez HR, Torres-Sánchez ED, Torres-Jasso JH, et al.: Effect of structure and function of paraoxonase-1 (PON-1) on organophosphate pesticides metabolism. Biocell. 2020; 44(3): 363–370. Publisher Full Text\n\nLincy Juliet K, Adole PS, Pandit VR, et al.: Serum Paraoxonase 1 Activity in Patients with Organophosphate Poisoning: A Potential Indicator of Prognosis. Asia Pac. J. Med. Toxicol. 2018; 8: 50–55.\n\nManthripragada AD, Costello S, Cockburn MG, et al.: Paraoxonase 1, agricultural organophosphate exposure, and Parkinson disease. Epidemiology. 2010 Jan; 21(1): 87–94. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRahul HV, Asha Rani N, Nusrath A: Utility of Serum Paraoxonase Levels with reference to Severity of Organophosphorus Poisoning. Indian J. Med. Biochem. July-December 2017; 21(2): 101–105. Publisher Full Text\n\nBakkannavar S, Bhat V, Udupa P, et al.: Evaluation of paraoxonase I and hemoglobin levels in farmers and agricultural workers in relation to pesticide levels in their blood and urine samples: A cross sectional study. [Dataset]. figshare. 2023. Publisher Full Text"
}
|
[
{
"id": "195014",
"date": "22 Aug 2023",
"name": "Eugenio Vilanova",
"expertise": [
"Reviewer Expertise Toxicology of organophosporus compounds"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this paper, blood and urine of farmers working 5 years potentially exposed to pesticides were qualitatively detected organophosphorus (OP) and carbamates (CBM) and measured paraoxonase 1 (PON1) and hemoglobin in serum.\nI consider this is an interesting study that does warrant to be published. It is not easy to get direct information about pesticide exposure in humans, therefore any available information is very convenient to be reported, including in studies in which like this, the reported information is very limited.\nHowever, there are some concerns about the lack of some information, and the interpretation of the observations. Therefore, I suggest authors to consider my comment in order to improve the manuscript.\nSorry, I apologise that I have done a long series of comments but it reflects my interest in the topic and my willingness to help for improving the manuscript.\n(0). ONE GENERAL CONCERN\nThe study is studying 100 people, all them farmers with potential exposure to pesticides. The study is lacking of stabilizing a control group with a clear absence of potential exposure. I understand that author is comparing several groups, and may be considered that the equivalent to a control is the group with negative detection by the qualitative procedures. However, the negative detection by such weak procedure does not means absence of exposure. As I consider that any observed data in humans are convenient to be reported, I still consider of interest its publication beside of this deficiency. In any case authors had to include a short comment about this limitation in the Discussion section.\n(1).-SOME MINOR GENERAL ISSUES:\n(1.1).-As the wording organophosphorus and carbamates are used many times along the manuscript (and more if you consider my next suggestion), I recommend define an abbreviation first time mentioned and use the abbreviation along the manuscript. I suggest to use the most usual abbreviation of OP and CbM or CBM.\n(1.2).-There are several inconsistencies. Note that the word “organophosphorus” is a common name, therefore, it should be named in lower case always (except when initiating a paragraph, or using an abbreviation).\n(1.3).-You are not studying “pesticides” in general, but only OPs and CB, then please delete most of the expression of “pesticides” along the manuscript for the specific kind of evaluated compounds (OP, CB, or OP and CB).\n(1.4).-The number of decimal digits (four) in Table 2 for the values of PON and hemoglobin levels has no meaning as the Standard error are in the level of decimals or units, therefore I suggest to show only a maximum of 2 decimal digits which mean up to 4 total significant digits. The same for the PON1 values in the complementary raw data in the Excel table.\n(2).-A MAIN CONCERN about interpretations:\nIn abstract and in several points of the manuscript, it is mentioned that paraoxonase (PON) is altered in worker with positive detection of OP and carbamates. It seems that authors suggest that the change of PON1 is due to the exposure to pesticides, but the interpretation might be just the reverse as I am commenting as follows:\nParaoxonase is well known that is able to hydrolyze organophosphorus compounds (OPs) (biodegradation and detoxification) but not inhibited by them. Authors could consider the interpretation that just those people with low level of paraoxonase have lower capacity of detoxication, and consequently, higher level may be detected in their blood.\nActually, for example, in the reference 1, have in the title the same mistake with a inconsistency, as in that paper in the last sentence in abstract, the author concluded with the reverse line of cause-effect relationship: that the level and polymorphism of PON1 is a risk factor affecting to the susceptibility to the exposure to OPs. In your Discussion, I agree with your comment in which you confirm this interpretation. However, at the end of 3rd paragraph you mention this reference (1); I consider that that paper of Sozmen, Mackness et al (2002) did not concluded that OP are directly affecting PON1, although they mentioned this possibility. No confirmation of inhibition of PON1 by OPs have been demonstrated. They actually observed a reduction of level, that could be interpreted by a reduction of liver synthesis.\nSo, I strongly suggest author to change the rational interpretation, changing the direction of the correlation PON<> (OP LEVEL AND TOXICITY). PON level is a cause (risk factor), not the effect. PON1 level and polymorphism, is affecting the capacity of detoxication and so the level of OP in blood may be higher as they are hydrolyzed and eliminated at lower rate.\nTherefore, it is not true that OP exposure is strongly altering PON (what is mainly genetically conditioned), while it should be considered that the level of PON1 in the individual is affecting the level of OPs remaining in blood and the possibility of toxic effects.\nThis comment does not invalidate the value of the paper and that in my opinion the recorded data is of interest to be published. My concern is with the interpretation.\n(3).-OTHER MINOR ISSUES\n(3.1).-The difference in the levels of paraoxonase and hemoglobin, seems not be statistically significant, therefore author should be more prudent describing the differences in the level of the different groups and indicated in results and abstract expressions as “lower values were observed for OP positive workers, although no statically significant.\n(3.2).-Under my point of view the relationship with PON1 level has actual sense in relationship with OPs. Consequently, it should be of interest comparing all positive OP (group 2+4) with all negative OP (group 1 + 3) cases.\n(3.3).-For hemoglobin, I have more difficult to give an interpretation of why OP positives (group 2 and 4) seems to show lower level . The suggested interpretation of an effects in the cells producing hemoglobin seems a reasonable interesting speculation, although there is not published data supporting it, but perhaps it worth to be investigated in future.\n(4).-ABSTRACT\n(4.1).-Abstract is a very important section of the paper as may reader only read it, and it should reflect clearly and objectively the content of the manuscript. I consider that it needs to be improved significantly.\n(4.2).-In Method in abstract should be mentioned that OP and CB pesticides were detected by a qualitative method with thin layer chromatography, and assigned a positive or negative to OP or carbamates.\n(4.3).-In method in abstract, please indicate the kind of epidemiological study (cross-sectional, longitudinal, other). In title you say “cross sectional”. However, in the abstract you are mentioning 5 years. Have you been studying these workers continually or periodically during this time, or on the contrary, in a specific time but to workers that had been working during the las 5 years?\n(4.4).-Taking into consideration my main concern, please modify abstract to show more objective and precise description of the observations. Some examples as follows:\nThe sentence: “The study showed that the pesticides were found in the blood and urine samples of farmers and there was an alteration of paraoxonase I and hemoglobin levels in them due to the exposure of pesticides in large quantities over some time.”\nFor something like: “Farmers were classified as a function of positive/negative detection of OP and CB and the level of PON1 and hemoglobin were compared in the different groups.”\nThe sentence: “The present study showed around 81% of the participants who were intermittently exposed to pesticides for more than five years were detected with pesticide toxicity.”\nFor: “The 81% of the participants showed positive detection for OPs, CB or both”\n(4.5).-You also indicated in abstract that 81% workers “were detected with pesticide toxicity”. What you want to mean with “toxicity”? Are you wanting to say that all they suffer illness or disease and some symptoms and signs of health alteration compatible with toxicity OP/carbamate? In that case, please be more precise and specific, indicating the specific sign of toxicity. I understand that you are not evaluating clinically toxicological effects, therefore delete the wording “toxicity” in all related comments along the manuscript. I understand that you are using as criteria the positive detection with the qualitative methods you have used.\n(4.6) Also, you say that “alteration in the levels of PON1 and hemoglobin in farmers and agricultural workers with positive organophosphorus and carbamates in their blood”, however later you say that “done without quantifying the amount of pesticides” Therefore it is no clear how you could consider “positive in OP and CBM in blood? For this reason is needed my suggestion (1.3)\n(5).-please, consider my previous comments before for abstract, also in those place in the section of Methods, Results and Discussion, related with the same topic.\n\n(6).-INTRODUCTION INITIAL SENTENCE AND LAST SENTENCE IN DISCUSSION\n(6.1).-I disagree and suggest delete or modify your first sentence in Discussion, in which you say: “Pesticides poisoning is the major global issue all over the world”. This an absurd exaggeration, compare with many other severe issues in the world (cancer, tobacco, COVID, wars, hunger). Therefore, I suggest to change by something like as: “Pesticide poisoning is an important toxicological issue”.\nThe reference (16) says “a major”, while you say “the major”. This reference is not good evidence, because it is just a statement with no information about the studies that demonstrate the figures they show. Therefore may be better to delete as it is not needed for the purpose of you paper.\n(6.2).-Related with the previous comment, I also strongly disagree and I suggest deleting the sentence in the introduction that say “According to World Health Organization (WHO) in 1990, all together around three million pesticide poisoning cases occur annually around the world (WHO 1990)”. This and similar sentences are written in many publications but if you think that it is true, please show an appropriate reference of the original objective study demonstrating such statement. Please do not give an indirect reference of reference of reference. It is also common to state that 300.000 fatalities due to OPs intoxication is occurring every year. There are some reports (not official from WHO but supported by WHO) in which, based of some few data were suggesting such kind of figures. These statements are coming from reports in 1990, from data coming from 1970s, without appropriate sufficient data obtained from regions that are not representing the world. It has been assumed that data from a few situations with special incidence due to special social circumstances, can be extrapolated to all the world, and that today is still occurring the same situation. In those statements, 3 million of cases are also suggested from which 2 million by suicides and the other 1 M by occupational and other unintentional intoxication. In India it was officially recorded about 400,000 suicides during 11 years (1995-2015) by pesticides (around 35,000 `per year) with about 20% fatalities, 90 % by OPs and with a strong tendency to decrease after 2014. If in India with not very good situation with 1.4 thousand million inhabitants, assuming all the world with 8 thousand million people in the same bad situation than India, the extrapolation would be about 300,000 cases (very far from the 2 million in those reports). Assuming about 20% fatalities as described in India, they would be not more than 60.000. Indeed, this extrapolated number would be a very high exaggeration, because the tendency since 2010s is a clear decrease, OPs is strongly decreasing their use in all the world. For example, in my country (40 million population) zero lethal cases by pesticides have been registered during last 5 years.\nCan you suggest an original objective study demonstrating that 3 million pesticide acute intoxication? Probably not, therefore it may be better to delete it to avoid something not sure and discussable, and what is not needed for the purpose of your paper. Probably a more simple and neutral statement as “Exposure to pesticides and specially of OPs is an important toxicological issue of concern, in India” This problem is still a big problem in some countries, and may be better to give reference about the specific situation in your country with objective data. If you have not such appropriate reference, better not to give not validated data. You do not need for the purpose of your paper that I still consider of interest its publication.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "10306",
"date": "29 Nov 2023",
"name": "Shankar Bakkannavar",
"role": "Author Response",
"response": "Dear Reviewer, Thanks a lot for detailed review and letting us know the points to be added/modified in our manuscript. Accordingly we have modified the manuscript pointwise as per your suggestions which are attached below for your perusal. The study is lacking of stabilizing a control group with a clear absence of potential exposure. I understand that author is comparing several groups, and may be considered that the equivalent to a control is the group with negative detection by the qualitative procedures. In our study the control group was comprised of participants who were non farmers. The estimation of samples did not reveal the presence of OP and CBM in these samples. I suggest to use the most usual abbreviation of OP and CbM or CBM. Changed You are not studying “pesticides” in general, but only OPs and CB, then please delete most of the expression of “pesticides” along the manuscript for the specific kind of evaluated compounds (OP, CB, or OP and CB) Changes done. However at few places we have kept pesticides as we are introducing the topic and wherever necessary we have removed pesticides and and change to organophosphorus and carbamates. Table 2 for the values of PON and hemoglobin levels has no meaning as the Standard error are in the level of decimals or units, therefore I suggest to show only a maximum of 2 decimal digits which mean up to 4 total significant digits. The same for the PON1 values in the complementary raw data in the Excel table. Changes done and only 2 decimal points included. ON<> (OP LEVEL AND TOXICITY). PON level is a cause (risk factor), not the effect. PON1 level and polymorphism, is affecting the capacity of detoxication and so the level of OP in blood may be higher as they are hydrolyzed and eliminated at lower rate. Your statement if highly appreciated and we have added the same thing in the discussion part of our manuscript. Therefore, it is not true that OP exposure is strongly altering PON (what is mainly genetically conditioned), while it should be considered that the level of PON1 in the individual is affecting the level of OPs remaining in blood and the possibility of toxic effects. PON level is a risk factor, not the effect. Its level and polymorphism is affecting the capacity of detoxication and so the level of OP in blood may be higher as they are hydrolysed and eliminated at lower rate. Therefore, it should be considered that the level of PON1 in the individual is affecting the level of OPs remaining in blood and the possibility of toxic effects. The difference in the levels of paraoxonase and hemoglobin, seems not be statistically significant, therefore author should be more prudent describing the differences in the level of the different groups and indicated in results and abstract expressions as “lower values were observed for OP positive workers, although no statically significant. When the difference in the levels of paraoxonase and hemoglobin was considered, the lower values were observed for OP and CBM positive workers, although it was not statically significant. Under my point of view the relationship with PON1 level has actual sense in relationship with OPs. Consequently, it should be of interest comparing all positive OP (group 2+4) with all negative OP (group 1 + 3) cases. Values were compared between groups 2 & 4. Group N Mean Median SD SE df P Paroxanase 2 13 29.3 29.3 0.976 0.271 19 <0.001 4 8 35.6 35.5 1.16 0.411 Abstract is a very important section of the paper as may reader only read it, and it should reflect clearly and objectively the content of the manuscript. I consider that it needs to be improved significantly. It is improved by changing the statements as we have a word limit to structure the abstract. In Method in abstract should be mentioned that OP and CB pesticides were detected by a qualitative method with thin layer chromatography and assigned a positive or negative to OP or carbamates. Included the suggested point in the manuscript. In method in abstract, please indicate the kind of epidemiological study (cross-sectional, longitudinal, other). In title you say “cross sectional”. However, in the abstract you are mentioning 5 years. Have you been studying these workers continually or periodically during this time, or on the contrary, in a specific time but to workers that had been working during the las 5 years? Cross sectional study was included. “The study showed that the pesticides were found in the blood and urine samples of farmers and there was an alteration of paraoxonase I and hemoglobin levels in them due to the exposure of pesticides in large quantities over some time.” Changes done in the manuscript. Farmers were classified as a function of positive/negative detection of OP and CB and the level of PON1 and hemoglobin were compared in the different groups. Values were compared between groups 1 & 3 and 2 & 4. The present study showed around 81% of the participants who were intermittently exposed to pesticides for more than five years were detected with pesticide toxicity. Changes done The 81% of the participants showed positive detection for OPs, CB or both Changes done delete the wording “toxicity” in all related comments along the manuscript. Toxicity word deleted wherever it was appropriate. in their blood”, however later you say that “done without quantifying the amount of pesticides” Therefore it is no clear how you could consider “positive in OP and CBM in blood? Positive or negative was decided by qualitative method (TLC). “Pesticides poisoning is the major global issue all over the world”. This an absurd exaggeration, compare with many other severe issues in the world (cancer, tobacco, COVID, wars, hunger). Therefore, I suggest to change by something like as: “Pesticide poisoning is an important toxicological issue”. This Statement is considered and added The reference (16) says “a major”, while you say “the major”. Reference 16 is deleted as suggested. “Exposure to pesticides and specially of OPs is an important toxicological issue of concern, in India” Statement was considered in the manuscript."
}
]
}
] | 1
|
https://f1000research.com/articles/12-478
|
https://f1000research.com/articles/12-1334/v1
|
16 Oct 23
|
{
"type": "Research Article",
"title": "Knowledge, attitudes, and practices regarding male infertility: A cross-sectional study among infertile couples visiting fertility clinics in Indonesia’s urban areas",
"authors": [
"Yusuf Mushlih",
"Imam Adli",
"Leo Alfath Araysi",
"Kemal Akbar Suryoadji",
"Rinaldo Indra Rachman",
"Ghifari Nurullah",
"Roberto Bagaskara Indy Christanto",
"Missy Savira",
"Rupin Shah",
"Ashok Agarwal",
"Indah Suci Widyahening",
"Gita Pratama",
"Gede Wirya Kusuma Duarsa",
"Ricky Adriansjah",
"Dyandra Parikesit",
"Widi Atmoko",
"Nur Rasyid",
"Ponco Birowo",
"Yusuf Mushlih",
"Imam Adli",
"Leo Alfath Araysi",
"Kemal Akbar Suryoadji",
"Rinaldo Indra Rachman",
"Ghifari Nurullah",
"Roberto Bagaskara Indy Christanto",
"Missy Savira",
"Rupin Shah",
"Ashok Agarwal",
"Indah Suci Widyahening",
"Gita Pratama",
"Gede Wirya Kusuma Duarsa",
"Ricky Adriansjah",
"Dyandra Parikesit",
"Widi Atmoko",
"Nur Rasyid"
],
"abstract": "Background:\nIn many countries, the stereotype that women are to blame for infertility in relationships remains prevalent, even though approximately half of the cases are caused by male factors. This study aimed to determine the knowledge, attitudes, and practices of infertile couples in urban areas with regard to male infertility.\nMethods:\nA web-based survey was conducted among infertile couples who visited fertility clinics in three cities in Indonesia. Sociodemographic information and knowledge, attitudes, and practices regarding male infertility were obtained through self-reported questionnaires.\nResults:\nA total of 378 participants completed the questionnaire (210 men and 177 women); 66.9% had good knowledge, 72.5% had positive attitudes, and 70.1% had good practices related to male infertility. Knowledge moderately correlated with attitudes (r = 0.280, p = 0.016), whereas the correlation with practices was not significant (r = 0.140, p = 0.186). The correlation between attitudes and practices was moderate (r = 0.251, p = 0.031). Among all participants, 82% visited an obstetrician-gynecologist first. A total of 39.9% of fertility examinations were conducted first on the wife, 11.4% on the husband, and 48.7% on both.\nConclusion:\nMost participants in our study at fertility clinics in urban areas visited an obstetrician-gynecologist first rather than a urologist, despite having good knowledge, attitudes, and practices regarding male infertility. The government needs to conduct health education and further public health efforts regarding male infertility to reduce the negative stigma and misperceptions about infertility in society.",
"keywords": [
"male infertility",
"infertile couples",
"infertility knowledge",
"fertility",
"stigma",
"misperception"
],
"content": "Introduction\n\nInfertility is defined as the absence of pregnancy for one year or more after regular unprotected sexual intercourse.1 Male infertility is a common health concern globally. It affects 15% of couples worldwide.2 About 40–50% of infertility cases are caused by male factor infertility.3 One in eight couples encounter problems attempting to conceive their first child, and one in six couples encounter difficulties trying to conceive subsequently.4 In 40–50% of infertility cases, abnormalities in the semen parameter were found.5\n\nThe stereotype that women are to blame for infertility in a relationship remains prevalent worldwide. This stigma causes many women to be depressed and self-deprecating.6 In the United States, women continue to be the focus of infertility workups even though male factors contribute to 50% of infertility cases.7 In Pakistan, women are often blamed for infertility despite the fertility status of their partner being unknown,6 because the public lacks an accurate understanding of infertility. Male infertility is not given enough attention, as evidenced by the lack of mainstream literature and media on the subject. Infertility as a social construct focuses on women because they are considered the carriers of conception and pregnancy; men are considered secondary participants.8 A survey conducted in Indonesia revealed that 93.4% of participants living in an urban area (Jakarta) indicated both the husband and wife should be evaluated for infertility, whereas only 55.4% of participants living in a rural are (East Sumba) indicated both husband and wife should be evaluated.9\n\nA lack of knowledge about what can contribute to infertility can lead to incorrect perceptions of male infertility, which could have an effect on clinical presentations at the first clinic visit. The Andrology Research Consortium recently conducted a North American survey on the characteristics of 4335 men seeking an infertility consultation.10 The average age of men seeking consultation was 37, and 74% had no previous male fertility evaluation. Interestingly, 6% of couples underwent intrauterine insemination (IUI), and 10.9% of couples underwent in vitro fertilization (IVF) before evaluation for possible male factor infertility.\n\nAmong infertile males who presented at an andro-urology clinic in an urban hospital, 53% exhibited azoospermia.11 In contrast, the European Association of Urology guidelines indicated that approximately 10% of male infertile patients were diagnosed with azoospermia.12 This difference in percentages suggests the possibility of misdiagnosis and that non-azoospermic causes may have been underdiagnosed, which could result in undertreated cases. Male patients with a more severe spectrum of infertility may require surgical sperm retrieval and assisted reproductive technology (ART) to obtain offspring. These are expensive procedures, and the success rate varies between 21.6% and 94%.13\n\nFew studies have examined the knowledge, attitudes, and practices of married couples in Indonesia regarding male infertility. Societal and cultural norms and attitudes, and medical treatment and stereotypes regarding male infertility, can affect help-seeking and the treatment couples receive. In this regard, the aim of the present study was to determine the knowledge, attitudes, and practices regarding male infertility in infertile couples in urban areas of Indonesia.\n\n\nMethods\n\nEthical approval was obtained from the Health Research Ethics Committee, Faculty of Medicine, Universitas Indonesia and Cipto Mangunkusumo National General Hospital (40/UN2.F1/ETIK/PPM.00.02/2022) on January 17th, 2022. Informed consent was obtained from the participants through an online informed consent form before completing the questionnaire.\n\nThis cross-sectional study was conducted in Indonesia with couples who visited fertility clinics in Jakarta, Bandung in West Java, and Denpasar in Bali between May and August 2022. Participants were recruited using a consecutive sampling technique, and all data were collected using a self-reported questionnaire through Google Forms. The sample size of 375 participants was determined using a Raosoft sample size calculator with a 5% margin of error, a 95% confidence interval, and a response distribution of 50%.14 The questionnaire was completed voluntarily and anonymously. The inclusion criteria were heterosexual couples who could not conceive after one year of unprotected sexual intercourse, visited a fertility clinic, and indicated their consent to participate in this study. The exclusion criteria were those with low cognitive function and those who did not understand Indonesian or English. The participants provided written informed consent to participate in the study. To avoid duplicate data, participants were asked whether they had already participated in the study. Participants’ personal data (including full name, email address, and telephone number) were not recorded so as to maintain confidentiality. The study was conducted and reported based on STROBE guidelines for cross-sectional studies.\n\nThe questionnaire was developed through a literature search and previously validated questionnaire,9,15–17 which was modified and translated into Indonesian (backward and forward translation) by three of the authors. Validity was assessed in two stages: face validity and a pilot test. Face validity was assessed by two experts to determine the adequacy and appropriateness of the questionnaire. A pilot study was conducted with 30 participants to improve item comprehension and assess validity. Cronbach's alpha test was conducted on the variables of knowledge, attitude, and behavior, resulting in values of 0.607 for knowledge, 0.669 for attitude, and 0.774 for behavior. No changes were made to the questionnaire after conducting the pilot survey.\n\nThe questionnaire was divided into four parts: (1) sociodemographic characteristics, (2) knowledge of male infertility, (3) attitudes toward male infertility, and (4) practices regarding male infertility. Sociodemographic data included gender, age, education, monthly income, health insurance, first clinic visited to treat infertility, first to be tested for infertility, and history of IVF. Gender on the survey exclusively denote the biological sex assigned at birth. The participants' sex was determined based on self-reported information provided in the questionnaire. Participants’ ages were grouped into two categories, ≥ 35 years and < 35 years, based on the effect of age on male and female infertility.18,19 Education was classified into middle school, high school, and higher education (academic, diploma, and vocational degrees). Education and occupation were categorized according to the Central Bureau of Statistics of Indonesia (BPS) classification.20 Monthly income was divided into three categories: low (<Rp 5 million), middle (Rp 5–10 million), and high (>Rp 10 million).21 Health insurance was divided into four categories: no insurance, national health insurance, private insurance, and national and private insurance.\n\nAll study questions were required to be answered before the questionnaire could be submitted to reduce the potential for missing or incomplete data. Participants’ knowledge was assessed using 14 questions regarding the risk factors for male infertility. Responses included “true” or “false.” Each question had a score of zero or one point, with a total possible score of 14. Participants’ attitudes were assessed using 21 questions that included their views on the effects of male infertility, treatment, quality of life, and divorce. The attitude assessment used a five-point Likert scale ranging from “strongly agree” to “strongly disagree”, with a maximum score of 105 points. Ten questions were used to assess practices. The questions were divided into two sections: six about the husbands’ practices and four about the couples’ practices related to male infertility. Questions included drug usage, smoking, alcohol cessation, lifestyle changes, first clinic visit, IVF history, and whether the couple had ever adopted a child. We used only the men’s practices section for scoring. Each question had a score of zero or one point, with a total possible score of 6 points for men’s practices. Any mention of the word “practices” in this study referred to the men.\n\nData storage and processing were done using MS Excel® for Office 365 MSO ver. 2018 (Microsoft Corporation, Redmond, WA, 2018),22 and data analysis was conducted using SPSS 25.0 (IBM, Armonk, NY).23 Analysis was conducted by taking into account factors that can affect the level of knowledge, attitudes, and practices. Demographic data were calculated in a tabular form as frequency and percentage. Subsequently, the data were subjected to a bivariate analysis based on the measurement scale and assessed variables.\n\nParticipants’ knowledge, attitudes, and practice levels were classified as poor, moderate, and good using Bloom’s cutoff ratio (<60% = poor, 60–79% = moderate, 80–100% = good);24 a “good” score indicated adequate knowledge, positive attitudes, and good practices. The Goodman-Kruskal gamma bivariate correlation test was used to determine the correlation between knowledge, attitudes, and practices. Logistic regression analysis was used to examine the relationships between sociodemographic factors (gender, age, education, income, occupation, and health insurance) and knowledge, attitudes, and practices. Correlations (r-values) were assessed based on the 1992 Rea and Parker classification, and a p-value < 0.05 indicated statistical significance.25\n\n\nResults\n\nThe characteristics of the participants are summarized in Table 1. Of the 378 participants, 210 (53.2%) were male. Most participants were over 35 years of age (70.9%). Approximately 91% had a higher level of education. The highest proportion of participants had an occupation in the private sector (37.3%), with the most significant proportion having a monthly income of more than 10 million rupiah (45.2%), or approximately 666 USD (1 USD = Rp 15,000). In addition, most of the participants had national health insurance (BPJS [Badan Penyelenggara Jaminan Sosial/Social Security Administrator for Health]).\n\nThe adequacy of knowledge of male infertility was between 55.8% and 97.1% for each question, as shown in Table 2. More than 80% of the participants knew that hormonal imbalance, smoking, excessive alcohol consumption, psychological stress, and recreational drugs were relevant to male infertility; however, age, high temperature, and urinary tract infections were less known. We found no significant differences between men and women in the statements regarding knowledge of male infertility.\n\nResponses indicative of positive attitudes toward male infertility varied between 12.2% and 96.3% as shown in Table 3. Among the items, infertility as a disability was the least endorsed attitude (12.2%). Less than half of the participants (45%) agreed that male infertility was a disease. However, most participants agreed that couples experiencing infertility needed to be treated and were given treatment (96.3%). There were no significant differences between men and women regarding attitudes toward male infertility.\n\nMany male participants tried to quit smoking (89.2%) or drinking alcohol (94.7%) to have children (Table 4). In addition, most men had a healthy lifestyle, including nutritious food consumption (86.8%). More than half of the men (58.5%) had not tried traditional or alternative medicine. Most men tried to change their lifestyle to be healthier and have children (89.7%).\n\nTable 5 shows that approximately 82% of participants visited an obstetrician-gynecologist before visiting a urologist. Approximately 48% of participants underwent fertility checks simultaneously with their partner. Most participants had a history of IVF (67%) and no history of child adoption (96.6%).\n\nThe results on level of insight into the knowledge, attitudes, and (men’s) practices are presented in Table 6. Scores were divided into good, moderate, and poor categories, with a \"good\" score indicating adequate knowledge, positive attitudes, and good practices. The results indicated that the majority of the participants had good knowledge (66.9%), attitudes (72.5%), and practices (70.1%) regarding male infertility.\n\nTable 7 shows that moderate correlations were observed between knowledge and attitudes (r = 0.280, p = 0.016), and attitudes and practices (r = 0.251, p = 0.031). No significant correlation was found between knowledge and practices.\n\nThe logistic regression analysis on the relationship between the sociodemographic factors and knowledge, attitudes, and practices is presented in Table 8. The primary factor significantly associated with good knowledge was a monthly income of ≥ 10 million rupiah (OR = 1.93, 95% CI = 1.21–3.06). In addition, the higher-income groups had more positive attitudes (OR = 1.611, 95% CI = 0.99–2.63), and a higher level of education was associated with better practices compared to a lower level of education (OR = 1.91, 95% CI = 0.92–3.98).\n\n† indicates used as reference.\n\n\nDiscussion\n\nThe findings of this study indicated that infertile couples who visited fertility clinics in urban areas in Indonesia usually first consulted with an obstetrician-gynecologist and had good knowledge, attitudes, and practices regarding male infertility. Furthermore, a higher level of income and education was associated with better knowledge, more positive attitudes, and better practices by men related to infertility. These findings were supported by a positive correlation between knowledge and attitudes toward male infertility.\n\nIn Indonesia, few studies have examined knowledge, attitudes, and practices regarding male infertility. Several studies have explored infertility in general and female infertility; however, none have focused on measuring people’s understanding of male infertility.9,26 Furthermore, despite the fact that approximately half of infertility cases are due to male factors, women are often prioritized in discussions related to the cause, diagnosis, and treatment of the condition.6–8 About 50% of infertile male patients who visited the fertility clinic at Dr. Cipto Mangunkusumo Hospital in Jakarta had azoospermia; however, azoospermia occurs in just 10% of all infertile patients,11,12 implying many cases of male infertility may be misdiagnosed and undertreated. Additionally, the issue of male infertility and azoospermia have received increasing attention, with the findings of meta-analyses and recent studies indicating that progressive sperm and semen quality is decreasing globally.27–30 This may contribute to high rates of azoospermia as a diagnosis. To add to its urgency, a global survey on mostly childbearing-aged women of almost 17,500 participants from 10 countries revealed poor fertility and reproductive biology knowledge.31 Government and health regulations, especially in Indonesia, have several policies regarding infertility, though none directly focus on male infertility.32,33 Moreover, despite the increasing prevalence, infertility problems have not yet been included in national insurance coverage.34 These issues increase our concerns about the need to measure people’s understanding of male infertility in Indonesia, especially in couples who visit fertility clinics.\n\nThe findings of this study suggest that level of education plays a significant role in having knowledge regarding male infertility, which can reduce the social stigma related to infertility, particularly in women. It is noteworthy that a vast majority (90.7%) of participants had a diploma or higher degree, suggesting that individuals with higher levels of education possess better knowledge about infertility treatment and are more likely to seek treatment at a fertility clinic. These results are consistent with those of Swift et al.35 who demonstrated a relationship between education and fertility awareness. Similarly, a study in Pakistan revealed 80% of participants with higher education tended to seek gynecologists as the primary reference for treatment.6 Lastly, we also found that higher education was a positive predictor of men’s fertility practices.\n\nMost participants went to an obstetrician-gynecologist first (82%) rather than a urologist (18%), although almost all of the participants (95.8%) agreed that both partners should be tested for infertility simultaneously. Approximately 39.9% chose to test the wife first for infertility, while only 11.4% opted to test the husband first. These findings are surprising, considering the high level of education, adequate knowledge, positive attitudes, and good practices that characterize the sample in this study. The high percentage of participants choosing to seek help from an obstetrician-gynecologist and test the wife suggests that the belief that women are the primary cause of infertility remains prevalent, similar to earlier findings.6–8,19 This belief may lead to women being blamed, depressed, or even subjected to violence from their partners. A meta-analysis by Sharifi et al.36 revealed that 14–88% of infertile women experienced domestic violence. Nevertheless, we can conclude that knowledge, attitudes, and men’s practices regarding male infertility did not necessarily affect a couple’s decision on which type of doctor to see or who should get examined first. Multiple factors, such as knowledge of infertility as a whole, knowledge about female infertility, lack of awareness among health care providers, and lack of male infertility health services, could be the catalysts for why most participants went to an obstetrician-gynecologist first. Therefore, further studies are required to compare these factors. Along these lines, education remains a powerful tool for combating infertility stigma. A study suggested that education, peer support, and self-help could be used to reduce stigma.37 The government must implement public education initiatives and policy changes related to infertility because they can increase knowledge and minimize stigma, particularly regarding the pressure and violence experienced by women in infertile couples.\n\nMost of the participants had good knowledge (66.9%), attitudes (72.5%), and practices (70.1%). This could be attributed to the study setting, an urban fertility clinic, where more than 90% of the participants had higher education and are generally more knowledgeable and aware of health problems than rural residents, especially regarding infertility.9,38 In addition, participants with higher monthly incomes showed better results, which is consistent with Almeida-Santos et al.’s39 study indicating that higher-income individuals had better knowledge of infertility. The income disparity may lead to different infertility treatment options and facilities. An equitable distribution of health workers, health facilities, and wider national health insurance coverage must be implemented to overcome the effect of the disparity between urban and rural areas. Education on male infertility that focuses on lower-income populations should also be implemented to increase their level of knowledge.\n\nFertility plays a significant role in marital and sexual satisfaction. The pressure to have children, complicated pregnancy programs, and infertility treatment can negatively affect the marital relationship and sexual functioning of married couples. Although infertility could be a factor in divorce, most studies suggest that infertility is not the primary cause of divorce in married couples.40–42 Our results support this statement, with only 9.8% of participants considering divorce as a solution for their husbands’ or wives’ infertility problem, which is lower than that reported in studies from Chennai, India and Jeddah, Saudi Arabia where 64.4% and 57.6% of the participants saw divorce as a solution to infertility, respectively.15,17\n\nThe results indicated that more than half of the husbands had not used traditional or alternative medicine for the problem with fertility. This finding was surprising considering their level of education, good knowledge, and positive attitudes. However, it was in line with a previous study in Pakistan in which 28% of the participants sought alternative treatment for infertility as their first choice, and 75% sought it as their second choice.6 The common reasons for utilizing alternative medicine are dissatisfaction with conventional medicine, favorable past experiences, and belief in the advantages of alternative medicine.33 Commonly used herbal medicines in Indonesia, such as bee pollen, royal jelly, cinnamon, and ginger, have limited or inconclusive evidence in treating infertility.43–48 This could lead to the misuse of herbal remedies and pose a danger to the patient.\n\nThe results of this study indicated a moderate correlation between knowledge and attitudes, as well as attitudes and practices regarding male infertility. No significant correlation was found between knowledge and practices. It is possible that confounding variables, such as cultural and economic differences among participants, could restrict the strength of the relationship. No previous studies have demonstrated a direct correlation among knowledge, attitudes, and practices related to male infertility. However, a systematic review49 revealed that awareness of male infertility was related to education level. This awareness can be explained from the observation that individuals with a high level of education are more likely to have general knowledge of male infertility and informed attitudes toward infertility conditions in men. These findings further reinforce our statement that individuals who have a low level of education are most in need of interventions to increase knowledge and raise awareness about infertility and reduce social stigma around infertility. It is suggested that teaching the public about male infertility has the potential to positively impact attitudes and practices related to infertility within the community, including among couples who seek treatment at clinics for infertility issues.\n\nThis study has several strengths and limitations. First, there was an imbalance in the number of participants based on sampling location. The majority of the participants were from Jakarta (over three-quarters of the participants), and those from Bandung accounted for less than 5%, limiting the generalizability of our results. Further research must assess the knowledge, attitudes, and practices regarding male infertility in more diverse Indonesian populations. Second, this research was conducted in urban areas and included only clinically infertile couples. However, other studies have demonstrated differences in knowledge and attitudes toward infertility between urban and rural populations,9 and the insights of the general population could not be assessed. Third, this study did not explore the psychological aspects of male infertility, as multiple studies have revealed a connection between male infertility and mental disorders.50,51 Moreover, additional uncontrolled confounding variables could have affected our results.\n\nNevertheless, a strength of this study is that it is the first to evaluate knowledge, attitudes, and practices regarding male infertility in urban couples in Indonesia. Consequently, it offers a knowledge base and reference for institutions, clinicians, and policymakers to develop effective strategies to address male infertility. In addition, it raises public awareness about male infertility and reduces the negative stigma associated with female infertility.\n\n\nConclusion\n\nOur study revealed that most participants at fertility clinics in urban areas visited an obstetrician-gynecologist first rather than a urologist, despite having good knowledge, attitudes, and practices regarding male infertility. In addition, we found that having knowledge about male infertility was associated with positive attitudes, and that positive attitudes related to the husband’s practices regarding male infertility. However, the results suggest that social stigma about infertility may (still) exist, especially for women. Health education on reproduction and further public health efforts regarding infertility that focus on low-income populations need to be implemented by the government to reduce the negative stigma and misperceptions about infertility.\n\n\nData availability\n\nOpen Science Framework: DATA - Knowledge, Attitudes, and Practices Regarding Male Infertility; A Cross-Sectional Study Among Infertile Couples Visiting Fertility Clinics in Indonesia’s Urban Areas. https://doi.org/10.17605/OSF.IO/AS6Y3.52\n\nThis project contains the de-identified underlying data of the survey (Raw Data – Knowledge Attitudes and Practice Regarding Male Infertility.xlsx).\n\nOpen Science Framework: DATA - Knowledge, Attitudes, and Practices Regarding Male Infertility; A Cross-Sectional Study Among Infertile Couples Visiting Fertility Clinics in Indonesia’s Urban Areas. https://doi.org/10.17605/OSF.IO/AS6Y3.52\n\nThis project contains the following extended data:\n\n- STROBE checklist\n\n- Blank questionnaire\n\n- Descriptive table\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "References\n\nZegers-Hochschild F, Adamson GD, de Mouzon J , et al.: International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009. Fertil. Steril. 2009; 92(5): 1520–1524. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization: International Classification of Diseases, 11th Revision (ICD-11). Geneva: WHO; 2019.\n\nKumar N, Singh AK: Trends of male factor infertility, an important cause of infertility: a review of literature. Journal of human reproductive sciences. 2015; 8(4): 191–196. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGreenhall E, Vessey M: The prevalence of subfertility: a review of the current confusion and a report of two new studies. Fertil. Steril. 1990; 54(6): 978–983. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization: WHO Manual for the Standardized Investigation and Diagnosis of the Infertile Couple. Cambridge: Cambridge University Press; 2000.\n\nAli S, Sophie R, Imam AM, et al.: Knowledge, perceptions and myths regarding infertility among selected adult population in Pakistan: a cross-sectional study. BMC Public Health. 2011; 11: 760. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMumtaz Z, Shahid U, Levay A: Understanding the impact of gendered roles on the experiences of infertility amongst men and women in Punjab. Reprod. Health. 2013; 10: 3. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChu KY, Patel P, Ramasamy R: Consideration of gender differences in infertility evaluation. Curr. Opin. Urol. 2019; 29(3): 267–271. PubMed Abstract | Publisher Full Text\n\nHarzif AK, Santawi VPA, Wijaya S: Discrepancy in perception of infertility and attitude towards treatment options: Indonesian urban and rural area. Reprod. Health. 2019; 16(1): 126. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJarvi K, Lau S, Lo K, et al.: MP19-09: results of a North American survey on the characteristics of men presenting for infertility investigations: The Andrology Research Consortium. J. Urol. 2018; 199(4S): e247. Publisher Full Text\n\nBirowo P: Semen parameter profile of infertile men visiting andro-urology clinic. eJournal Kedokteran Indonesia. 2020; 8(2): 88–92. Publisher Full Text\n\nNieschlag E, Behre HM, Nieschlag S, editors. Andrology: Male reproductive health and dysfunction. Berlin: Springer Verlag; 2010. Publisher Full Text\n\nChiba K, Enatsu N, Fujisawa M: Management of non-obstructive azoospermia. Reproductive medicine and biology. 2016; 15(3): 165–173. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRaosoft, Inc: Sample size calculator.2004. Reference Source\n\nChinnaiyan S, Babu B: Knowledge, attitude, and practices about male infertility among men and women in slums of Chennai, Tamil Nadu: a cross-sectional study. International journal of community medicine and public health. 2020; 7(10): 3996–4000. Publisher Full Text\n\nGerhard RS, Ritenour CW, Goodman M, et al.: Awareness of and attitudes towards infertility and its treatment: a cross-sectional survey of men in a United States primary care population. Asian J. Androl. 2014; 16(6): 858–863. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAbolfotouh MA, Alabdrabalnabi AA, Albacker RB, et al.: Knowledge, attitude, and practices of infertility among Saudi couples. International journal of general medicine. 2013; 6: 563–573. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHarris ID, Fronczak C, Roth L, et al.: Fertility and the aging male. Rev. Urol. 2011; 13(4): e184–e190.\n\nGeorge K, Kamath MS: Fertility and age. Journal of human reproductive sciences. 2010; 3(3): 121–123. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKementerian Kesehatan Republik Indonesia: Hasil utama riskesdas 2018.2022. Reference Source\n\nSugiharto E: Tingkat kesejahteraan masyarakat nelayan desa benua baru ilir berdasarkan indikator badan pusat statistik. EPP. 2007; 4(2): 32–36. Reference Source\n\nMicrosoft Corporation: Microsoft Excel.2018. Reference Source\n\nIBM Corporation: IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM; 2017.\n\nFeleke BT, Wale MZ, Yirsaw MT: Knowledge, attitude and preventive practice towards COVID-19 and associated factors among outpatient service visitors at Debre Markos compressive specialized hospital, north-west Ethiopia, 2020. PLoS One. 2021; 16(7): e0251708. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRea LM, Parker RA: Designing and conducting survey research: a comprehensive guide. 2nd ed.Hoboken, New Jersey: Jossey-Bass; 1992.\n\nBennett LR, Wiweko B, Bell L, et al.: Reproductive knowledge and patient education needs among Indonesian women infertility patients attending three fertility clinics. Patient Educ. Couns. 2015; 98(3): 364–369. PubMed Abstract | Publisher Full Text\n\nCarlsen E, Giwercman A, Keiding N, et al.: Evidence for decreasing quality of semen during past 50 years. BMJ (Clinical research ed.). 1992; 305(6854): 609–613. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSwan SH, Elkin EP, Fenster L: The question of declining sperm density revisited: an analysis of 101 studies published 1934-1996. Environ. Health Perspect. 2000; 108(10): 961–966. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJørgensen N, Vierula M, Jacobsen R, et al.: Recent adverse trends in semen quality and testis cancer incidence among Finnish men. Int. J. Androl. 2011; 34(4 Pt 2): e37–e48. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFeki NC, Abid N, Rebai A, et al.: Semen quality decline among men in infertile relationships: experience over 12 years in the South of Tunisia. J. Androl. 2009; 30(5): 541–547. PubMed Abstract | Publisher Full Text\n\nFido A: Emotional distress in infertile women in Kuwait. Int. J. Fertil. Womens Med. 2004; 49(1): 24–28. PubMed Abstract\n\nJDIH BPK Republic of Indonesia: Peraturan Pernerintah Republik Indonesia Nomor 61 Tahun 2014 tentang Kesehatan Reproduksi. 2014.Reference Source\n\nMenteri Kesehatan Republik Indonesia: Peraturan Menteri Kesehatan Republik Indonesia Nomor 43 Tahun 2015 Tentang Penyelenggaraan Pelayanan Reproduksi dengan Bantuan atau Kehamilan di Luar Cara Alamiah.2015.Reference Source\n\nKesehatan BPJS: Panduan layanan bagi peserta BPJS kesehatan.2020. Reference Source\n\nSwift BE, Liu KE: The effect of age, ethnicity, and level of education on fertility awareness and duration of infertility. J. Obstet. Gynaecol. Can. 2014; 36(11): 990–996. Publisher Full Text\n\nSharifi F, Jamali J, Larki M, et al.: Domestic violence against infertile women: a systematic review and meta-analysis. Sultan Qaboos Univ. Med. J. 2022; 22(1): 14–27. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOfasu-Budu D, Hänninen V: Ways of reducing the stigma of infertility: views of infertile women and their herbalists. Afr. J. Reprod. Health. 2021; 25(2): 110. Publisher Full Text\n\nAljassim N, Ostini R: Health literacy in rural and urban populations: a systematic review. Patient Educ. Couns. 2020; 103(10): 2142–2154. PubMed Abstract | Publisher Full Text\n\nAlmeida-Santos T, Melo C, Macedo A, et al.: Are women and men well informed about fertility? childbearing intentions, fertility knowledge and information-gathering sources in Portugal. Reprod. Health. 2017; 14(1): 91. PubMed Abstract | Publisher Full Text | Free Full Text\n\nValsangkar S, Bodhare T, Bele S, et al.: An evaluation of the effect of infertility on marital, sexual satisfaction indices and health-related quality of life in women. Journal of human reproductive sciences. 2011; 4(2): 80–85. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNyarko SH, Amu H: Self-reported effects of infertility on marital relationships among fertility clients at a public health facility in Accra, Ghana. Fertility research and practice. 2015; 1: 10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHawkins AJ, Willoughby BJ, Doherty WJ: Reasons for divorce and openness to marital reconciliation. Journal of divorce & remarriage. 2012; 53(6): 453–463. Publisher Full Text\n\nWelz AN, Emberger-Klein A, Menrad K: Why people use herbal medicine: insights from a focus-group study in Germany. BMC Complement. Altern. Med. 2018; 18(1): 92. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAkbaribazm M, Goodarzi N, Rahimi M: Female infertility and herbal medicine: an overview of the new findings. Food Sci. Nutr. 2021; 9(10): 5869–5882. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKashani L, Akhondzadeh S: Female infertility and herbal medicine. Journal of medicinal plants. 2017; 16(61): 3–7.\n\nAnh NH, Kim SJ, Long NP, et al.: Ginger on human health: A comprehensive systematic review of 109 randomized controlled trials. Nutrients. 2020; 12(1): 157. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAhmad S, Campos MG, Fratini F, et al.: New insights into the biological and pharmaceutical properties of royal jelly. Int. J. Mol. Sci. 2020; 21(2): 382. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSuleiman JB, Bakar ABA, Mohamed M: Review on bee products as potential protective and therapeutic agents in male reproductive impairment. Molecules. 2021; 26(11): 3421. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPedro J, Brandão T, Schmidt L, et al.: What do people know about fertility? a systematic review on fertility awareness and its associated factors. Ups. J. Med. Sci. 2018; 123(2): 71–81. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAhmadi H, Montaser-Kouhsari L, Nowroozi MR, et al.: Male infertility and depression: a neglected problem in the Middle East. J. Sex. Med. 2011; 8(3): 824–830. PubMed Abstract | Publisher Full Text\n\nFisher JR, Hammarberg K: Psychological and social aspects of infertility in men: an overview of the evidence and implications for psychologically informed clinical care and future research. Asian J. Androl. 2012; 14(1): 121–129. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBirowo P, Mushlih Y, Adli, et al.: Knowledge, Attitudes, and Practices Regarding Male Infertility; A Cross-Sectional Study Among Infertile Couples Visiting Fertility Clinics in Indonesia’s Urban Areas. [Dataset]. 2023, July 28. Publisher Full Text"
}
|
[
{
"id": "216784",
"date": "24 Oct 2023",
"name": "Hong-Jun Li",
"expertise": [
"Reviewer Expertise Male infertility"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article aims to determine the knowledge, attitudes, and practices of infertile couples by a web-based survey in urban areas regarding male infertility through self-reported questionnaires. The authors found that most participants in their study at fertility clinics in urban areas visited an obstetrician-gynecologist first rather than a urologist, despite having good knowledge, attitudes, and practices regarding male infertility. Overall, this work is well designed and completed, but still have some defects:\nThis research included 378 participants (210 men and 177 women). Compared to the more prevalence of infertility, the sample size was limited. Due to the limited sample size, this made the heterogeneity large, and subgroup analysis impossible.\n\nLast sentence of conclusion in abstract (The government needs to conduct health education and further public health efforts regarding male infertility to reduce the negative stigma and misperceptions about infertility in society) can be deleted. This is only a suggestion or discussion content, and not based on research outcomes of the paper.\n\nHow to definite the good knowledge, positive attitudes, and good practices were an important problem. The questionnaires should be carefully designed and validating. The authors should give more discussion in discussion part.\n\nOf course, the stigma (women are to blame for infertility in a relationship remains prevalent worldwide) causes many women to be depressed and self-deprecating. From other view, male infertility is not given enough attention, and this may also a reflection that the ability (diagnosis and treatment of male infertility) and attitude towards male infertility are not good enough. The authors can discuss about the serious situation for management of male fertility in discussion part.\n\nSome of references might not be proper and should be changed or deleted, including references number 14, 20, 22, 32, 33, 34.\nAll in all, this work was well done, had some value, and could be published as data or information, but some revision needs to be done before it can be approved for indexing.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
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https://f1000research.com/articles/12-1334
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https://f1000research.com/articles/11-696/v1
|
23 Jun 22
|
{
"type": "Case Report",
"title": "Case Report: Fortuitous discovery of primary peritoneal psammocarcinoma",
"authors": [
"Imen Helal",
"Fatma Khanchel",
"Raja Jouini",
"Maissa Ben Thayer",
"Chaouki Mbarki",
"Hajer Bettaieb",
"Saber Rebii",
"Imen Ben Ismail",
"Ehsen Ben Brahim",
"Aschraf Chedli-Debbiche",
"Imen Helal",
"Fatma Khanchel",
"Raja Jouini",
"Chaouki Mbarki",
"Hajer Bettaieb",
"Saber Rebii",
"Imen Ben Ismail",
"Ehsen Ben Brahim",
"Aschraf Chedli-Debbiche"
],
"abstract": "Psammocarcinoma is an uncommon subtype of low-grade serous carcinoma. It is characterized by the presence of extensive psammoma bodies and can have either an ovarian or peritoneal origin. To our knowledge fewer than 30 cases of primary peritoneal psammocarcinoma (PPP) have been reported in the English literature. We report a rare case of PPP in a 74-year-old female, discovered fortuitously within a laparotomy for gallbladder lithiasis. At laparotomy, multiple nodular implants involving the omentum, the peritoneum and a magma of intestinal loops in the right iliac fossa were noted. A biopsy from nodules was performed. Gross examination showed multiple nodules of different sizes in the fat tissue. Pathologic examination showed massive psammoma bodies representing more than 75% of the tumor. The final diagnosis was psammocarcinoma. Our patient was referred to the gynecologic department for further investigation and to ascertain whether the tumor arose from the ovaries or peritoneum. Hysterectomy, bilateral adnexectomy and omentectomy were performed. Macroscopic examination showed that both ovaries were intact having a normal size. No invasion of ovarian stroma was shown in microscopic examination. The patient died of SARS-CoV-2 (COVID-19) six days after the surgery. PPP is a rare type of low-grade serous carcinoma. The behavior of this tumor is unclear, and the treatment is not standardized because of its rarity and lack of long-term follow-up. More cases need to be studied for better understanding and improvement of the management protocols.",
"keywords": [
"Primary peritoneal psammocarcinoma",
"psammocarcinoma",
"serous carcinoma",
"psammomatous bodies",
"case report"
],
"content": "Introduction\n\nPsammocarcinoma, firstly reported by Kettle et al in 1916, is an extremely rare low-grade serous carcinoma.1,2 Its diagnostic criteria have been clearly established, 74 years later, by Gilks et al.1 Psammocarcinoma can arise from either the ovary or peritoneum. Primary peritoneal psammocarcinomas (PPP) are less common than ovarian psammocarcinomas, since fewer than 30 cases of PPP have been reported in the English literature.3–6 In the majority of cases, PPP has a favorable prognosis, although some may show recurrences and metastases.7 We report a rare case of primary peritoneal psammocarcinoma (PPP) in a 74-years-old female, discovered fortuitously within a laparotomy for gallbladder lithiasis.\n\n\nCase presentation\n\nA 74-year-old postmenopausal woman, presented to the emergency department with fever and right upper abdominal pain. The patient, a Caucasian housewife, had no significant personal or family medical history. Physical examination on admission revealed tenderness and guarding of the right hypochondrium and a fever with a temperature of 38.2 degrees. Routine laboratory tests were normal except for a leucocytosis and an increased C-reactive protein (CRP) level. Abdominal ultrasonography showed a lithiasic gallbladder with thickened walls (see Figure 1). The patient was referred to the surgery department for cholecystectomy for acute lithiasic cholecystitis.\n\nThe walls of the gallbladder (GB) are thickened, hyperechoic with a mobile gallstone.\n\nAt coelioscopy, multiple nodular implants involving the omentum, the peritoneum and a magma of intestinal loops in the right iliac fossa were noted. A biopsy from nodules was performed. Gross examination showed multiple nodules of different sizes in the fat tissue. Pathologic examination showed massive psammoma bodies representing more than 75% of the tumor (see Figure 2). The epithelial cells had low to moderate grade nuclear features including small nuclei, inconspicuous nucleoli and rare mitoses. We haven’t identified any solid area of epithelial proliferation. No vascular emboli have been identified. The final diagnosis was psammocarcinoma.\n\nNumerous psammoma bodies with small epithelial nests (see arrows) invading the peritoneum.\n\nThe patient was referred to gynecologic department for further investigation and to ascertain whether the tumor arose from ovaries or peritoneum. A computerized tomography scan was undergone and revealed: an uncomplicated sigmoid diverticulosis, an agglutination of the last ileal loops in contact with the anterior abdominal wall, an infiltration of the mesenteric fat and multiple mesenteric lymphadenopathies (see Figure 3). Hysterectomy, bilateral adnexectomy and omentectomy were performed. Macroscopic examination showed that both ovaries were intact having a normal size (see Figure 4). No invasion of ovarian stroma was shown in microscopic examination. No lymph node invasion or distant metastasis had been identified. The final diagnosis was primary peritoneal psammocarcinoma (PPP). It was classified as stage III C carcinoma according to the International Federation of Gynecology and Obstetrics’ (FIGO) classification.\n\nAgglutination of the last ileal loops in contact with the anterior abdominal wall, infiltration of the mesenteric fat and multiple mesenteric lymphadenopathies.\n\nAfter a multidisciplinary meeting, the decision was made to complete the treatment by adjuvant chemotherapy. The patient died of SARS-CoV-2 (COVID-19), six days after the surgery. The diagnosis of COVID-19 was confirmed by a PCR test and a Computed Tomography.\n\n\nDiscussion\n\nPsammocarcinomas of the peritoneum and the ovary are rare serous carcinomas sharing the same histologic characteristics, natural history, and treatment modalities.8 PPP is an extremely rare peritoneal carcinoma. To the best of our knowledge, less than 30 cases of PPP have been reported in the literature.3–6\n\nThe mean age for diagnosis in PPP is 52.1 years, ranging from 27 to 83 years.9 Clinically, patients usually present with nonspecific symptoms, such as abdominal discomfort, increase in abdominal girth, nausea, or vomiting.10 In 40% of cases, PPP is asymptomatic and is discovered incidentally,11 similar to our case and the case described by Grinaldi et al.3\n\nThe diagnosis of PPP is based on histopathological findings. Microscopically, Gilks et al define psammocarcinoma by four specific histologic criteria: (i) a destructive invasion of ovarian stroma, a vascular invasion, or, in the extraovarian cases, an invasion of intraperitoneal viscera; (ii) a mild to moderate nuclear atypia; (iii) an absence of area of solid epithelial proliferation, except for occasional nests with no more than 15 cells in diameter; (iv) at least 75% of papillae associated with or totally replaced by psammoma bodies.1,3\n\nIn 1994, Chen et al adapted the diagnostic criteria established by Gilks et al and had added the presence of an invasive pattern of the peritoneum, as a criterion for the diagnosis of PPP.12 Our case fulfilled all the criteria defined by Gilks and updated by Chen et al.\n\nIt is sometimes arduous to specify whether the psammocarcinoma is of peritoneal or ovarian origin. In such cases, only histologic examination can differentiate PPP from ovarian psammocarcinoma. The most important feature is ovarian stromal invasion seen in ovarian psammocarcinoma.1,13,14 In PPP, psammoma bodies and nests of tumor cells may be seen in the serosal surface of ovaries but without any invasion of ovarian stroma.\n\nWe have faced such difficulties in the case we present. For our patient, both ovaries were of normal size, small nests and psammoma bodies were present in serosal surface of ovaries but ovarian stroma was intact. The peritoneal involvement was greater than the involvement on the ovarian surface. Therefore, the diagnosis of PPP was confirmed.\n\nThe main differential diagnoses of PPP include the other epithelial serous neoplasms, such as cystadenofibromas and serous borderline tumors.9 These tumors may present abundant psammoma bodies, but the invasion of surrounding structures excludes these diagnoses. Low-grade serous carcinoma with numerous psammomatous bodies is another differential diagnosis. The presence of several nests of more than 15 cells precludes the diagnosis of psammocarcinoma. The presence of marked nuclear atypia and numerous figures of mitosis distinguishes high-grade serous carcinoma from PPP.\n\nMesothelioma with massive psammoma bodies may simulate PPP but negativity of D2-40, calretinin and CK5/6 excludes the diagnosis of mesothelioma.15\n\nCalcified leiomyomatosis peritonealis disseminata (LPD), an infrequent subtype of leiomyomatosis occurring amongst young women with history of myomectomy, is another differential diagnosis of PPP.16 We could rule out this diagnosis since our patient was 74 years-old with no history of myomectomy.\n\nManagement protocols are not standardized due to the rarity of these tumors.17 However, the majority of institutions recommend optimal debulking followed by adjuvant chemotherapy, as a basis of treatment.1,18–20 For young women, conservative surgery can be discussed to preserve fertility.3\n\nChemotherapy is thought to have a poor efficiency in PPP.16 However, follow-up adjuvant chemotherapy is required, at least for residual diseases and for PPP with aggressive behavior like in the case reported by Akbulut et al.7,21\n\nGiven their rarity, we do not dispose enough elements to judge the scalability of PPPs. However, PPP is likely to have a high potential towards peritoneal recurrence, even after suitable treatment.22 Some of the reported cases had developed several recurrences with a period of more than 5 or 10 years between those recurrences.8\n\nAlthough most of PPP seem to display an indolent clinical course, some may be very aggressive, with distant metastases.7\n\nOne of the strengths of our study is that we were able to demonstrate with certainty that the primary origin of the psammocarcinoma was peritoneal and not ovarian. However, its major limitation consists in the lack of follow-up. In fact, since our patient had died of COVID-19 six days after the second surgery, we were not able to assess the response to treatment, the risk of recurrence and metastases and the prognosis of this tumor.\n\n\nConclusions\n\nPPP is a rare type of low-grade serous carcinoma. The behavior of this tumor is unclear, and the treatment is not standardized because of its rarity and lack of long-term follow-up. More cases need to be studied for better understanding and improvement of the management protocols.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nConsent\n\nWritten informed consent for publication of their clinical details and clinical images was obtained from the patient.\n\n\nCompeting interests\n\nNo competing interests were disclosed.\n\n\nGrant information\n\nThe author(s) declared that no grants were involved in supporting this work.",
"appendix": "References\n\nGilks CB, Bell DA, Scully RE: Serous Psammocarcinoma of the Ovary and Peritoneum. Int. J. Gynecol. Pathol. 1990 Apr; 9(2): 110–121. Publisher Full Text\n\nThe Pathology of Tumours. Nature. 1916 Aug; 97(2440): 460–460. Publisher Full Text\n\nGrimaldi L, Danzi M, Reggio S, et al.: Decision making in borderline ovarian tumors: report of a rare case of mesosigma psammocarcinoma. Ann. Ital. Chir. 2013 Sep 3; 84(ePub): S2239253X13021609.\n\nZhen-Zhong D, Zheng N, Liu H, et al.: Elevated CA125 in primary peritoneal serous psammocarcinoma: a case report and review of the literature. Case Rep. 2009 May 26; 2009(May26 1): bcr1020081063–bcr1020081063.\n\nBodnar L, Wcislo G, Górnas M, et al.: Serous peritoneal psammocarcinoma with an aggressive course: a case and review of the literature. Ginekol. Pol. 2009 Aug; 80(8): 632–636. PubMed Abstract\n\nAsotra S, Gupta S, Gupta N: Primary psammocarcinoma of peritoneum. Indian J. Pathol. Microbiol. 2009; 52(2): 280–281. PubMed Abstract | Publisher Full Text\n\nTakahashi R, Ueda Y, Shioji M, et al.: Enormous Cystic Tumor of Peritoneal Psammocarcinoma Exhibiting Complete Response to Cisplatin and Cyclophosphamide after Suboptimal Cytoreduction: Case Report and Review of the Literature. Gynecol. Obstet. Invest. 2012; 74(2): 165–170. PubMed Abstract | Publisher Full Text\n\nPoujade O, Uzan C, Gouy S, et al.: Primary Psammocarcinoma of the Ovary or Peritoneum. Int. J. Gynecol. Cancer. 2009 Jul; 19(5): 844–846. Publisher Full Text\n\nAlanbay İ, Dede M, Üstün Y, et al.: Serous psammocarcinoma of the ovary and peritoneum: two case reports and review of the literature. Arch. Gynecol. Obstet. 2009 Jun; 279(6): 931–936. PubMed Abstract | Publisher Full Text\n\nJena SK, Mishra P, Mohapatra V, et al.: Bilateral Serous Psammocarcinoma of Ovary: Rare Variant Low Grade Serous Carcinoma. Case Rep. Obstet. Gynecol. 2015; 2015: 1–4. PubMed Abstract | Publisher Full Text\n\nKurman BA, Robert J, Ellenson LH, et al.: Springer Nature. Blaustein’s pathology of the female genital tract. Cham: Springer; 2019.\n\nChen KTK: Psammocarcinoma of the peritoneum. Diagn. Cytopathol. 1994 May; 10(3): 224–228. Publisher Full Text\n\nMunkarah AR, Jacques SM, Qureshi F, et al.: Conservative Surgery in a Young Patient with Peritoneal Psammocarcinoma. Gynecol. Oncol. 1999 May; 73(2): 312–314.\n\nWeir MM, Bell DA, Young RH: Grade 1 Peritoneal Serous Carcinomas: A Report of 14 Cases and Comparison With 7 Peritoneal Serous Psammocarcinomas and 19 Peritoneal Serous Borderline Tumors. Am. J. Surg. Pathol. 1998 Jul; 22(7): 849–862.\n\nOrdóñez NG: Value of Immunohistochemistry in Distinguishing Peritoneal Mesothelioma From Serous Carcinoma of the Ovary and Peritoneum: A Review and Update. Adv. Anat. Pathol. 2006 Jan; 13(1): 16–25. Publisher Full Text\n\nArole VC, Deshpande KA, Jadhav DB, et al.: Primary peritoneal psammocarcinoma. J. Obstet. Gynaecol. Res. 2017 Aug; 43(8): 1366–1372. Publisher Full Text\n\nColonval P, Boven C, Oana M: Aggressive Serous Peritoneal Psammocarcinoma: a Case Report. Acta Chir. Belg. 2015 Jan; 115(6): 426–428. PubMed Abstract | Publisher Full Text\n\nBi̇Lgi̇N T, Özuysal S, Cankiliç H: Primary psammocarcinoma of the peritoneum. Int. J. Gynecol. Cancer. 2006 Feb; 16(S1): 129–131. Publisher Full Text\n\nPiura B, Rabinovich A, Yanai-Inbar I: Psammomacarcinoma of the peritoneum. Eur. J. Obstet. Gynecol. Reprod. Biol. 2001 Aug; 97(2): 231–234. Publisher Full Text\n\nPoggi S: Psammocarcinoma with an aggressive course. Obstet. Gynecol. 1998 Oct; 92(4): 659–661. Publisher Full Text\n\nAkbulut M, Kelten C, Bir F, et al.: Primary peritoneal serous psammocarcinoma with recurrent disease and metastasis: A case report and review of the literature☆. Gynecol. Oncol. 2007 Apr; 105(1): 248–251. PubMed Abstract | Publisher Full Text\n\nDelhorme J-B, Ohayon J, Gouy S, et al.: Ovarian and peritoneal psammocarcinoma: Results of a multicenter study on 25 patients. Eur. J. Surg. Oncol. 2020 May; 46(5): 862–867. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "144608",
"date": "22 Aug 2022",
"name": "Marouen Braham",
"expertise": [
"Reviewer Expertise Reproductive Medicine / Gynecology Surgery / Fertility preservation"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis case report shows the approach in front of a suspicion of peritoneal psammocarcinoma, diagonostic difficulty and etiological research, the subject is interesting because primary peritoneal psammocarcinoma is a very rare pathology and the diagnosis is not obvious.\nRecommendations:\nCould you add pictures from the 1st or 2nd surgery?\n\nCould you elaborate on the anatomopathological examination with more detailed description?\n\nRegarding the discussion, could you note the prognosis in the literature and chemotherapy used in theses cases?\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "10361",
"date": "16 Oct 2023",
"name": "Maissa Ben Thayer",
"role": "Author Response",
"response": "We are very grateful for your precious time and effort in reviewing our paper and providing valuable comments. The authors have carefully considered the comments and tried our best to address every one of them. We have incorporated most of the suggestions. We hope the manuscript after careful revisions will meet your high standards. The authors welcome further constructive comments and feedback. Point-by-point response to the reviewer’s comments and concerns are provided below. The adjustments were highlighted in yellow in the revised manuscript. Could you add pictures from the first and second surgery? Authors’ response: Unfortunately, no intraoperative images were available. We had to make do with the photos taken during the gross examination. Could you elaborate on the anatomopathological examination with a more detailed description? Authors’ response: A more detailed description of the histological lesions was provided in the revised version of the manuscript. Regarding the discussion, could you note the prognosis in the literature and chemotherapy used in this case? Prognosis, therapeutic strategies, and indications for adjuvant treatment, including chemotherapy, were discussed in detail in the revised version."
}
]
},
{
"id": "195525",
"date": "29 Aug 2023",
"name": "Isao Otsuka",
"expertise": [
"Reviewer Expertise gynecologic oncology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors report a case of primary peritoneal psammocarcinoma (PPP) incidentally discovered during a laparotomy (written in Abstract) for gallbladder lithiasis. After the coelioscopy (written in Case Presentation), the patient underwent surgical staging consisting of hysterectomy, bilateral adnexectomy, and omentectomy. The patient died six days after the surgery.\nThis manuscript reports a rare case of stage IIIC PPP. Some flaws need to be revised.\nMajor comments\nThe authors wrote, \"Macroscopic examination showed that both ovaries were intact having a normal size (see Figure 4).\" However, \"small nests and psammoma bodies were present in serosal surface of ovaries.\" Papillary excrescences may be seen on the surface of both ovaries (Figure 4). Were both ovaries truly intact on macroscopic examination?\n\nWas the surgery for gallbladder lithiasis a laparotomy or a laparoscopy? (see above)\n\nThe authors wrote, \"No lymph node invasion.\" Was lymphadenectomy performed?\n\nThe authors need to explain factors associated with early post-operative death due to COVID-19 infection. What was her body mass index (Figure 3 may indicate the patient was obese)?\n\nThe title of this case report is \"Fortuitous discovery of PPP\". However, the patient died six days after the surgical staging for stage IIIC PPP. As the word fortuitous implies \"advantage [Cambridge Dictionary]\", the title might be changed.\nMinor comments\nCase presentation. a temperature of 38.2 degrees \"Celsius\".\n\nFigure 2. Where is the arrow?\n\nFigure 3. The figures should carry an arrow pointing to \"agglutination of the last ileal loops.\"\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": [
{
"c_id": "10360",
"date": "16 Oct 2023",
"name": "Maissa Ben Thayer",
"role": "Author Response",
"response": "We are very grateful for your precious time and effort in reviewing our paper and providing valuable comments. The authors have carefully considered the comments and tried our best to address every one of them. We have incorporated most of the suggestions. We hope the manuscript after careful revisions will meet your high standards. The authors welcome further constructive comments and feedback. Point-by-point response to the reviewer’s comments and concerns are provided below. The adjustments were highlighted in yellow in the revised manuscript. The authors wrote “Macroscopic examination showed that both ovaries were intact having a normal size. However, “small nests and psammoma bodies were present in serosal surface of ovaries”. Were both ovaries truly intact on macroscopic examination? Authors’ response: As shown in Figure 4, there were no macroscopically detectable abnormalities in either ovary. The psammomas observed on the surface of the ovaries on microscopic examination are sub-millimetric and cannot be visualized with the naked eye. Was the surgery for gallbladder lithiasis a laparotomy or a laparoscopy? Authors’ response: The cholecystectomy was performed laparoscopically. The authors wrote “No lymph node invasion. Was lymphadenectomy performed? Authors’ response: A lymph node dissection was performed. We added this detail in the case presentation’s description in the revised version. The authors need to explain factors associated with early post-operative death due to the COVID-19 infection. What was her body mass index? Authors’ response: We discussed factors favoring the early post-operative death due to the COVID-19 infection. Indeed, the patient was obese with a BMI of 32. The title of this report is “Fortuitous discovery of PPP”. However, the patient died six days after the surgical staging for PPP. As the word fortuitous implies ‘advantage’, the title might be changed. Authors’ response: We replaced the title in the revised version by “Case Report: Incidental discovery of primary peritoneal psammocarcinoma” Case presentation: a temperature of 38.2 degrees “Celsius” Authors’ response: The term “Celsius” was added in the revised manuscript. Figure 2: where is the arrow? Authors’ response: the arrow was added in Figure 2 Figure 3: the figure should carry out an arrow pointing the agglutination of the last ileal loops. Authors’ response: The arrow pointing the agglutination of the last ileal loops was added in Figure 3."
}
]
}
] | 1
|
https://f1000research.com/articles/11-696
|
https://f1000research.com/articles/11-1063/v1
|
16 Sep 22
|
{
"type": "Research Article",
"title": "Prevalence and determinants of obesity among individuals with diabetes in Indonesia",
"authors": [
"Mahalul Azam",
"Luluk Fadhoh Sakinah",
"Martha Irene Kartasurya",
"Arulita Ika Fibriana",
"Tania Tedjo Minuljo",
"Syed Mohamed Aljunid",
"Luluk Fadhoh Sakinah",
"Martha Irene Kartasurya",
"Arulita Ika Fibriana",
"Tania Tedjo Minuljo",
"Syed Mohamed Aljunid"
],
"abstract": "Background: Obesity and diabetes mellitus (DM), both individually or simultaneously, increase the risk of morbidity and mortality. The present study aimed to determine the prevalence and determinants of obesity among diabetic individuals in Indonesia. Methods: Data were extracted based on 2018 Indonesian Basic Health Survey (Riset Kesehatan Dasar=RISKESDAS). This study involved all individuals with DM and categorized obesity based on body mass index. After data clearing, this study analyzed 3911 DM subjects of the 33.905 subjects acquired from the 2018 RISKESDAS. The study also observed demographic data, diabetes control parameters, history of hypertension, lipid profiles, and food consumption patterns. These variables were involved in a Chi-square test, and related variables were then involved in the Binary logistic regression to define the independent determinants of obesity among DM subjects. Results: Of the 3911DM subjects included, the study found an obesity prevalence of 32.9%. This study found that female (prevalence odds ratio [POR]=2.15; 95% CI: 1.76-2.62), age 15-44 years (POR=2.46; 95% CI: 1.83-3.33), urban residence (POR=1.49; 95% CI: 1.25-1.77), history of hypertension (POR=1.25; 95% CI: 1.04-1.51), high diastolic blood pressure (POR=1.90; 95% CI: 1.58-2.29), high LDL (POR=1.44; 95% CI: 1.13-1.84), and high triglycerides (POR=1.27; 95% CI: 1.07-1.50) were the risk factor of obesity among DM subjects; while high HDL (POR=0.60; 95% CI: 0.46-0.78 higher education (POR=0.64; 95% CI: 0.53-0.78) and married (POR=0.73; 95% CI: 0.59-0.90) were protective factors of obesity among DM subjects. Conclusions:. The study concluded that almost one-third of DM subjects in Indonesia were obese. Female, age, urban residence, education level, history of hypertension, diastolic blood pressure, and lipid profiles were all associated with obesity among DM subjects in Indonesia. These findings suggest that monitoring and controlling of related determinants is needed to prevent complications caused by the doubled burden of diabetes and obesity.",
"keywords": [
"prevalence",
"determinant",
"diabetes mellitus",
"obesity",
"Indonesia"
],
"content": "Introduction\n\nNon-communicable (NCD) diseases are the most contributed cause of death worldwide.1 Obesity is related to NCD’s increased morbidity and mortality, including diabetes mellitus (DM).1 The global prevalence of obesity in adults has nearly doubled since 1980.2 In 2015, the prevalence of obesity, classified as a body mass index (BMI) ≥ 27 kg/m2 in Indonesia, was 30.4%.3\n\nThe prevalence of DM globally was estimated at 9.3% (463 million) in 2019. It is predicted to increase to 10.2% (578 million) in 2030.4 The prevalence of DM in Indonesia in 2014 was 6.7%5 and has increased over the last six years6,7 placing Indonesia in the 9th rank in the world.8 Based on the Indonesian Basic Health Survey (Riset Kesehatan Dasar=RISKESDAS), the DM prevalence rate significantly increased from 6.9% in 2013 to 8.5% in 2018.9 DM accounts for 3% of the causes of death in Indonesia.10\n\nObesity increases the risk of DM, hypertension, dyslipidemia, stroke, cancer, coronary heart disease, and obstructive sleep apnea.2,11–13 Obesity contributes to insulin resistance, which is associated with DM conditions.14 Obesity increased the release of non-esterified fatty acids, glycerol, hormones, and pro-inflammatory cytokines in adipose tissue, affecting insulin resistance conditions.15 Severe obesity in childhood and adolescence is associated with the increased risk of DM in youth and young adults.16 Obesity is related to the high increase in carbohydrate intake that causes insulin resistance in genetically predisposed individuals.16 The obese-year describes the severity and the duration of obesity, and the age of onset was the independent predictor for type 2 DM.17 Overweight and obesity have been associated with the poor control of blood glucose levels, blood pressure, and cholesterol among DM subjects.18 Indeed, obesity is well known as a major modifiable risk factor for type 2 DM.11,19\n\nA study in Saudi Arabia revealed that the prevalence of obesity among DM was 38.3%, and non-smoker homemakers were the most affected.20 A previous study in Tanzania observed that the majority of type 2 DM patients (85%) were overweight (44.9%) or obese (40.1%).21 Among them, 33.7% were overweight/obese after being diagnosed with type 2 DM, and the prevalence was significantly higher in women.21 In Turkey, the prevalence of obesity among DM individuals in 1999 was 35.6%, which increased with age.22 In the US, the prevalence of obesity among adults with diagnosed DM in 2004 was 54.8%,23 while among young aged less than 20 years old with type 2 DM, most of them were obese (79.4%).24 Previous studies had reported the prevalence of obesity among DM and its related factors ─ which had a pivotal role in the comprehensive management of diabetes subjects as well as describing the risk factors and the poor control of diabetes. However, to our knowledge, no study has reported the prevalence of obesity among DM patients, especially in an extensive national survey in Indonesia. The present study aimed to explore the prevalence and independent determinants of obesity among DM subjects in Indonesia using national survey data.\n\n\nMethods\n\nData were extracted from 2018 RISKESDAS, a five-annual national health cross-sectional survey managed by the National Institute of Health Research and Development (NIHRD), Ministry of Health, Republic of Indonesia. RISKESDAS survey was approved by the Ethics Committee of the National Institute of Health Research and Development (NIHRD), Ministry of Health, Republic of Indonesia. At this time, this 2018 survey was the latest RISKESDAS survey conducted. The target sample subjects of RISKESDAS 2018 were the same as the other national surveys conducted by the Indonesian Central Bureau of Statistics. To minimize the selection bias, the sampling was done using the census block system with the target of 300,000 households visited from 30,000 census blocks. The RISKESDAS’ respondents were selected from all household members. The detailed study protocol was published in the official RISKESDAS report25 and other publications.26,27 In total, respondents in the RISKESDAS were 1,017,290 subjects from 416 districts and 98 cities in 34 provinces.\n\nThe study population was all individuals with diabetes mellitus, those who were previously diagnosed by a doctor with/without medication, and those who were tested using a rapid plasma glucose test. Fasting plasma glucose ≥ 126 mg/dL or 2 hours postprandial and random plasma glucose levels≥ 200 mg/dL.25 For the subjects aged ≥19 years old, BMI ≥ 27 kg/m2 was categorized as obese, while among the subjects aged 15-18 years old, the z score of BMI for age > 2 were categorized as obese.25 We categorized educational level as high for the subjects who graduated from senior high school or higher and low for those who completed their junior high school or lower. Age was categorized as young adults for subjects aged 15-44 years, middle-aged adults for 45-64 years and senior adults for subjects aged 65 years and over. The detailed food frequency and physical activity questionnaires were published previously in the study protocol.25 The physical activity questionnaire was modified from the WHO Global Physical Activity Questionnaire (GPAQ). The subjects were categorized as “lack of physical activity” if the subjects met the sedentary or low physical activity criteria and “adequate” if the subjects met moderate to vigorous physical activity, which reached ≥ 1500 metabolic equivalent (MET).25 The consumption of sugary food and drinks, salty food, fatty food, burnt food, food with preservatives, food flavoring, carbonated drinks, energy drinks, and instant noodles consumption were categorized as ‘frequent’ if the frequency was 1-2 times a week or more and classified as ‘rare’ if the frequency was less than 1-2 times a week.25\n\nWe performed the chi-square tests, to find the association between each factor and the obesity status. Then, the factors with p-values < 0.1 were included in the multiple logistic regression models, with Enter method, to obtain the independent determinants of obesity among DM subjects. A p-value < 0.05 was considered statistically significant. The factors which were associated with obesity, by Chi-square tests with the p-value <0.1, were demographical characteristics (age, sex, occupation, residence status, educational level, marital status), lifestyle factors (physical activity, smoking, medication compliance, fatty food consumption, food flavoring consumption, instant noodles consumption) and biomedical characteristics (fasting plasma glucose level, previous history of hypertension, systolic and diastolic blood pressure, level of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides). All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) software (version 23.0 for Windows, IBM SPSS Inc., Chicago, IL).\n\nThe prevalence of DM among RISKESDAS subjects was 8.5% meaning that the number of DM subjects was 86,469 of 1,017,290 RISKESDAS respondents.25 However, after considering the data completeness, consistency, and outliers, this study only analyzed 33,905 total subjects acquired from RISKESDAS 2018 data; of them 3,911 subjects were categorized as having DM (11.5% DM subjects among the total population aged ≥ 15 years acquired data; the original dataset is provided as Underlying data.68\n\n\nResults\n\nOf the 3,911 DM subjects analyzed in this study, 1,287 (32.9%) subjects were obese. Table 1 shows the characteristics of the study population based on socio-demographic characteristics, i.e., age, sex, occupational status, type of residence, education level, and marital status. Most of the subjects were 45-64 years (57.4%) and 67% were women. Most of the subjects were employed (52.0%), 56.9% had a low education level (<12 education years) and 78.5% were married.\n\nFactors of obesity among DM subjects are shown in Table 2. This table shows the results of the chi-square tests. We observed subjects’ characteristics, physical activity, smoking status, DM duration, and previous history of hypertension. We found that the age category of 15-44 years had the prevalence odds ratio (POR) of 3.02 with a 95% confidence interval (CI) of 2.39-3.80, and the age category of 45-64 years had a POR of 2.16, with a 95% CI: 1.75-2.68 for obese compared to the age group of ≥ 65 years (as reference), respectively. The proportion of women was significantly higher in the obesity group compared to the non-obesity, with the POR of 2.26; 95% CI: 1.94-2.64. The unemployed group also had a higher risk for obesity with the POR of 1.43 and 95% CI: 1.25-1.64.\n\n* Chi square test.\n\nTable 3 showed that high fasting plasma glucose (POR=1.21, 95% CI: 1.06-1.39), high systolic blood pressure (POR=1.49, 95% CI: 1.30-1.70), high diastolic blood pressure (POR=2.46, 95% CI: 2.15-2.82), high total cholesterol level (POR=1.44, 95% CI: 1.26-1.64), high low-density lipoprotein (LDL) cholesterol level (POR=1.83, 95% CI: 1.50-2.24), and high triglycerides level (POR=1.72, 95% CI: 1.50-1.97) were related to the obesity among DM subjects as risk factors with POR>1, while high high-density lipoprotein (HDL) cholesterol level (POR=0.58, 95% CI: 0.47-0.73) was related as a protective factor. The study also reported that the result of the chi-square test for the parameters of dietary patterns and expressed that frequent fatty food consumption (POR=1.26, 95% CI: 1.09-1.45), food flavoring consumption (POR=1.23, 95% CI: 1.02-1.49), and instant noodle consumption (POR=0.81, 95% CI: 0.68-0.96) were correlated to the obesity among DM subjects (Table 4).\n\n* Chi square test; HDL: high-density lipoprotein; LDL: low density lipoprotein cholesterol; TG: triglyserides.\n\n* Chi-square test.\n\nThe final model of the binary logistic regression is shown at Table 5. Of the 20 variables that had been analyzed, ten parameters had statistically significant POR. Female sex (adjusted (a)POR=2.15; 95% CI: 1.76-2.62), urban residence (aPOR=1.87; 95% CI: 1.629-2.155), higher education level (aPOR=0.64; 95% CI: 0.53-0.78), married (aPOR=0.73; 95% CI: 0.59-0.90), history of hypertension (aPOR=1.25; 95% CI: 1.04-1.51), high diastolic blood pressure (aPOR=1.90; 95% CI: 1.58-2.29), high triglycerides level (aPOR=1.27; 95% CI: 1.07-1.50), high LDL cholesterol level (aPOR=1.44; 95% CI: 1.13-1.84), high HDL cholesterol level (aPOR=0.60; 95% CI: 0.46-0.78), and younger age (aPOR=0.63; 95% CI: 0.54-0.73) altogether were related to the obesity among DM subjects (R=0.39).\n\n* Binary logistic regression test.\n\n\nDiscussion\n\nOur cross-sectional study revealed that the prevalence of obesity among DM subjects in Indonesia was 32.9%. The current study had a national scope, using community-based data representing the figure of obesity among DM subjects in Indonesia. A study based on diabetes clinics data in Tanzania reported that the prevalence of obesity among DM subjects was 40.1%, and the prevalence of overweight was 44.9%.21 A study based on diabetes clinic data in Ghana revealed that the prevalence of overweight and obesity among DM subjects was 32%.28 The prevalence of obesity among DM subjects is higher than in the general adult population. The prevalence in the general adult population in Indonesia (2015), Tanzania (2020), and Ghana (2017) were: 30.4%,3 37.8%,29 and 29.9%,30 respectively. Previous studies have concluded that obesity is associated with the incidence of diabetes mellitus and strongly correlates with the duration and onset of obesity.17,31,32 The difference in the prevalence of obesity among DM subjects and the general population in the three countries is consistent. Unfortunately, the data is not supported by prevalence data according to the onset and duration of obesity.\n\nThis study also found that female diabetes subjects were more likely to be obese than males, with an adjusted-POR of 2.15; 95% CI: 1.76-2.62. This relationship aligns with the study conducted in the diabetic clinic in Tanzania,21 which concluded that women are five times more likely to be obese than men.21 A cohort study in the US33 also indicated that women were more at risk of obesity in diabetes than men and tended to have more medical expenditure. The prevalence of obesity continues to increase yearly, and women have increased faster than men.34 A previous study in a rural population in India35 also revealed that the prevalence of overweight and obesity was higher in women than in men. This study35 also concluded that abdominal and central obesity was more prevalent in women with diabetes subjects. A study in Thailand36 observed diabetes subjects with chronic kidney disease (CKD), and disclosed that the prevalence of obesity in this entire study population was 51.5% (68.2% in women and 31.8% in men, p = 0.01). This study also concluded that the prevalence of obesity was lower in CKD than in non-CKD diabetes subjects (46.5% vs. 54.1%, p<0.001), and there was no difference based on the stages of CKD.36 Previous studies have shown consistent results that the prevalence of obesity in women with diabetes is higher than in men; this might be influenced by the pre-menopause/menopause status as the dominant study population being observed (56.8%), i.e., 45-64 years of age (Table 1), of which the median age of menopause in Indonesia is 51 years.37–39 Decreasing estrogen levels at menopause causes shifting the gynoid to android fat, which makes fat distribution dominant to abdominal fat; furthermore, the basal metabolic rate will also be very low.37\n\nThe current study concluded that age category 45-64 years significantly had a higher risk to get obese among DM subjects (a-POR=1.53; 95% CI: 1.19-1.96) than the age category ≥ 65 years, so did the age category 15-44 years which had an almost twofold odds ratio (a-POR=2.46; 95% CI: 1.83-3.33). Previous studies reported that prevalence of overweight and obesity was highest in the age category 41-60 years,21,40 The previous studies coincided with the current study finding that revealed a high prevalence of obesity was observed in the age category ≤ 60 years. However, the current study found that the highest prevalence was in the 15-44 years group, while previous studies found the highest prevalence was in the 41-60 years group.21,40 Age category on young and middle adults had a high risk to get obese among DM subjects. The younger age groups tend to be obese in this study; it can be associated with an increased prevalence of obesity in children41 and might be related to the onset and duration of diabetes mellitus.17,31,32\n\nThis study also found that living in urban residences was more likely to get obese among diabetic subjects. The urban area is a complex area where environmental, social, cultural, and economic factors significantly impact the health of the area’s population—both positive and negative impacts on the health sector.42 While living in urban areas has a positive role in education and the economy, living in an urban area often causes greater risk factors that threaten health damage due to greater exposure to all sectors.42 Our study found that living in urban areas has 1.49 times (95% CI: 1.25-.177) the risk of obesity in diabetes subjects than living in rural areas. This study is in accordance with the study in Tanzania21 that deduced diabetes subjects who live in urban areas were 1.3 times more likely to have obesity than diabetes subjects who live in rural areas. The study in Peru43 revealed similar findings in the general population. The subjects living in urban areas were more likely to get obese; more detail, this study also found that longer residing in urban areas for the rural-to-urban migrants tended to be obese.\n\nThe relationship between education and obesity in the general population and diabetes subjects consistently concluded that lower education tends to get obese.44–46 Our study also found that lower education levels in diabetes subjects tend to be obese. High-level education related to the understanding and healthier lifestyle that influence obesity status.45 A cross-sectional study in Saudi Arabia conducted the subgroup analysis and concluded that the highest risk of obesity was in the population with high income and low education levels.46 Another study47 observed that the Chinese twins concluded that education positively correlated with obesity, marital status, age, and sex confounders. Higher education will relate to knowledgeable persons. Furthermore, this knowledge and lifestyle are closely related to the incidence of obesity among DM subjects.48 Poor knowledge will affect the poor lifestyle,48 i.e., taking more snacks outside of regular meals, eating late at night, physical inactivity, excessive fast food intake, and alcoholic beverage intake, which were associated with increased obesity among DM subjects.48\n\nIt is known as common knowledge that obesity has been firmly associated with profound health consequences and metabolic disorders, including hypertension, diabetes, cardiovascular diseases and dyslipidemia.21,49 Hypertension was reported as a common co-morbidity of diabetes affecting around 20-60 % of diabetes subjects and twice as prevalence in diabetes subjects.28 Our study found that previous history of hypertension was more likely to get obesity among DM subjects than subjects without a history of hypertension with the a-POR = 1.25; 95% CI: 1.04-1.51. The prevalence of hypertension among diabetes was two-three-fold higher than in non-diabetes subjects.22 Similarly, the prevalence of obesity among diabetes was also increasing. The increasing prevalence of obesity is followed by a rising prevalence of type 2 diabetes and other compounds’ health risk.50 These conditions reflect the poor lifestyle of the general population.50\n\nWe also noticed that DM subjects that were married significantly had lower odds risk of being obese; a-POR=0.73; 95% CI: 0.59-0.90. This finding was in accordance with the study involving the general population in Malaysia ─ which concluded that never married individuals had a higher risk of being obese.51 However, our finding contradicted a previous study, which concluded that individuals with married status had a higher risk of being obese in the general population.52 In the general population of ever-married women in Bangladesh, a study reported that obesity among them was influenced by oldest age, higher wealth and higher education.53 Similarly, a study in Kuwait that included the general population found that obesity is related to smoking, hypertension, higher income, being women, greater age, and being married.54 A study in the US involving Asian subjects revealed that married or living with a partner was associated with obesity among general populations.55 Marital status describes a general condition that is difficult to be associated with the incidence of obesity; marital status should be described and detailed of their marital quality. A study in the US disclosed that low marital quality was related to diabetes and other health problems.56 Our study also found that a higher proportion of DM subjects with married status had the habit of frequent fatty foods consumption (Figure 1).\n\nIt is firmly known that obesity in DM subjects is associated with poor control of blood glucose levels, blood pressure, and cholesterol.48,57 The current study found that high diastolic blood pressure (a-POR=1.90; 95% CI: 1.58-2.29), high LDL cholesterol (a-POR=1.44; 95% CI: 1.13-1.84), high HDL cholesterol (a-POR=0.60; 95% CI: 0.46-0.78), and high triglycerides (a-POR=1.27; 95% CI: 1.07-1.50) were related to the occurrence of obesity among DM subjects in this setting. High diastolic blood pressure, high LDL cholesterol, and high triglycerides increase the risk of obesity, while high HDL cholesterol decreases the risk. Obesity itself was the most important modifiable risk factor for DM; obesity also interferes with the treatment and control of dyslipidemia, hyperglycemia, hypertension, and cardiovascular diseases.28 Obesity is also intimately associated with dyslipidemia and hypertension.58,59 The current study consistently revealed that lipid profiles included LDL cholesterol, HDL cholesterol, and triglycerides related to obesity among DM subjects. Total cholesterol was also associated with obesity among DM in the chi-Square test; however, this association was not statistically significant in the binary logistic regression. Unfortunately, novel lipid biomarkers in obesity, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) and other biomarkers of obesity-associated dyslipidemia were not evaluated in the RISKESDAS 2018 survey.58 Pathophysiology of dyslipidemia observed in obesity was also well known and involved multifactorial parameters, including hepatic overproduction of very low-density lipoprotein, decreased circulating triglycerides lipolysis, and impaired peripheral free fatty acids trapping.60 Adequate exercise and reduce saturated fatty acids intake will be the first choice for treatment of dyslipidemia and simultaneously with obesity. However, medical therapy can be considered if these lifestyle changes could not be sufficiently undertaken. The current study showed the high diastolic blood pressure category has a high proportion of fasting plasma glucose levels (Figure 2).\n\nBP: blood pressure, FPG: fasting plasma glucose.\n\nPlasma glucose parameters with obesity simultaneously represent the control treatment results for DM subjects.58 However, our study reported that both fasting and 2 hours of postprandial plasma glucose were not related to obesity among DM subjects. Fasting plasma glucose in the chi-square was associated with obesity (POR= 1.21; 95% CI: 1.06-1.39) (Table 3). However, it was not involved in the final binary logistic regression model. Previous studies reported that glycaemic control was proportionate with the body weight and body composition in the diabetes population.61 Another study reported that a lower glycaemic index diet was related to reducing glycaemic control parameters, i.e., glycated hemoglobin (HbA1C), fasting, and postprandial plasma glucose, which was in line with lowering body weight.62 The high postprandial hyperglycemia is usually strongly influenced by carbohydrate intake. This might be why obesity is common in DM subjects with postprandial hyperglycemia.62 Two parameters of fasting and postprandial plasma glucose level were the standard parameters of glycaemic control. Unfortunately, this study did not provide glycated hemoglobin data, which will elucidate this relationship.\n\nRegarding the diet pattern, our study revealed that frequent fatty food consumption was related to obesity in the chi-square test with a POR of 1.26; 95% CI: 1.09– 1.45). We did not find any relationship between obesity in diabetic individuals with sugary food and drink, salty food, food with preservatives and flavoring, instant noodles, carbonated drinks, energy drinks, and alcohol consumption. A cohort study in the general population concluded a relationship between fatty and sugary food consumption and obesity.63 Another cross-sectional study observed the children and adolescents population in Korea revealed that dietary sugars from milk and fruit were inversely related to obesity, while sugar-sweetened beverages increase the risk of obesity in the boy population.64 High salt intake was also concluded as an independent risk factor of obesity in the general population,65 while there is no evidence in our study population. Soft drink consumption was concluded significantly with global overweight, obesity, and diabetes in the general population;65 however, our diabetes population in this study did not find any relationship. Instant noodle consumption in the general population was also reported to be related to the increased risk of obesity and cardiovascular diseases;66,67 however, as our finding, there was no relationship in our diabetes individuals population.\n\nOur cross-sectional study was conducted to analyze secondary data from RISKESDAS 2018 survey. The availability of parameters in RISKESDAS 2018 data limits our discussion to elucidate comprehensive determinants of obesity in diabetes individuals. Some diabetes therapy that may be used, like insulin and sulphonylurea, is weight gain, so further sub-analysis is also needed on whether this population includes DM subjects administered these drugs when data is provided in the following survey. RISKESDAS 2018 data determined diabetes status just on the determination of subjects’ statement of being previously diagnosed by a doctor or being determined from the measurement of fasting or postprandial plasma glucose, without differing type 1 or type 2 DM.\n\n\nConclusions\n\nThe prevalence of obesity among diabetic individuals based on Indonesian RISKESDAS 2018 data was 32.9%. Female sex, age categorized as 15-44 years, living in an urban residence, low education level, previous history of hypertension, high diastolic blood pressure, high LDL and triglycerides level, and low HDL cholesterol level all together were associated with obesity among diabetes individuals in Indonesia. These findings suggest that monitoring and controlling of related determinants is needed to prevent complications caused by the doubled burden of diabetes and obesity.\n\n\nData availability\n\nFigshare: Prevalence and Determinants of Obesity among Indonesian Diabetics. https://doi.org/10.6084/m9.figshare.20291934.68\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgments\n\nThe authors wish to thank the National Institute of Health Research and Development, Ministry of Health, the Republic of Indonesia for providing RISKESDAS 2018 data.\n\n\nReferences\n\nWorld Health Organization: World health statistics 2018: monitoring health for the SDGs, sustainable development goals. World Health Organization;2018; vol. viii. : 86.\n\nWorld Health Organization: Global Status Report On Noncommunicable Diseases.2014; 2014.\n\nPengpid S, Peltzer K: The Prevalence of Underweight, Overweight/Obesity and Their Related Lifestyle Factors in Indonesia, 2014–15. AIMS Public Heal. 2017; 4(6): 633–649. PubMed Abstract | Publisher Full Text\n\nSaeedi P, Petersohn I, Salpea P, et al.: Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res. Clin. Pract. 2019; 157: 107843. 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}
|
[
{
"id": "150740",
"date": "14 Dec 2022",
"name": "Laurentia K. Mihardja",
"expertise": [
"Reviewer Expertise Public Health about Non-Communicable Diseases"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article is good but needs revision.\nBased on the Indonesian Basic Health Survey (Riset Kesehatan Dasar= RISKESDAS), the DM prevalence rate significantly increased from 6.9% in 2013 to 10.9% in 2018 (as in the Riskesdas report which states 10.9% based on ADA 2015 and PERKENI 2015)1.\n\nDiabetes Mellitus was defined in Riskesdas 2018 (Basic Health Research in Indonesia 2018) as fasting blood glucose level ≥ 126 mg/dL or random blood glucose ≥ 200 mg/dL with classic symptoms of polyuria, polydipsia, polyphagia, and weight loss or blood glucose at 2 hours after a glucose load ≥ 200 mg/dl or the use of glucose-lowering drugs. If only random blood glucose > 200 mg/dl without classic symptoms, it is not stated as diabetes. I'm sure the authors knew about this statement.\n\nAll individuals with DM, not those who are pregnant. There must be a certainty that the analyzed individuals have DM without pregnancy. Chances of getting pregnant can be biased. This data must be excluded. The data on obesity needs to be checked again.\n\n\"DM subjects that were married significantly had lower odds risk of being obese\" - DM subjects that were unmarried significantly had lower odds risk of being obese. Obese in unmarried group 216/ (216 + 625) = 25.6% (Table 2) and obese in married group 1071/ (1071+ 1999) = 34.8%. Continue chi-square and log multivariate regression, we will find unmarried had lower OR than married. So 7th paragraph in the discussion should be revised.\n\nInside Table 5 is written urban residence 1.49 but, underneath the table in the description, is written 1.87.\nThank you for your attention.\nA little summary and opinion\nThe prevalence of Diabetes Mellitus in Indonesia has been rising more rapidly, e.g. the prevalence of Diabetes Mellitus in 2007 among those aged 15 years and over was 5.7% in urban, rising to 10.9% in urban-rural by 2018. Obesity is one of the most potent risk factors for type 2 diabetes. Research showed that the prevalence of overweight and obesity (BMI > 25) in Indonesia among those at the age of more than 18 years was, based on Riskesdas data, 28.9% in 2013 and 35.4% in 2018. The study aimed to determine the prevalence of obesity among diabetes patients. Some studies have been carried out, but there is no national data in Indonesia yet. The result shows a high prevalence of obesity was found in diabetic patients (32.9%) (make sure it doesn't include pregnant individuals). Diabesity will accelerate the occurrence of complications such as heart disease. The high prevalence of diabesity is a warning for program makers that they should increase public awareness to prevent obesity and diabetes.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "9316",
"date": "10 Feb 2023",
"name": "Mahalul Azam",
"role": "Author Response",
"response": "Thank you very much for the very precise and constructive reviews of our manuscript. We have revised it in line with the reviewer's comments as follows: Based on the Indonesian Basic Health Survey (Riset Kesehatan Dasar= RISKESDAS), the DM prevalence rate significantly increased from 6.9% in 2013 to 10.9% in 2018 (as in the Riskesdas report which states 10.9% based on ADA 2015 and PERKENI 2015)1. Thank you for the precise correction, we revised the prevalence rate in 2018 to 10.9%. Diabetes Mellitus was defined in Riskesdas 2018 (Basic Health Research in Indonesia 2018) as fasting blood glucose level ≥ 126 mg/dL or random blood glucose ≥ 200 mg/dL with classic symptoms of polyuria, polydipsia, polyphagia, and weight loss or blood glucose at 2 hours after a glucose load ≥ 200 mg/dl or the use of glucose-lowering drugs. If only random blood glucose > 200 mg/dl without classic symptoms, it is not stated as diabetes. I'm sure the authors knew about this statement. Thank you very much for the thorough correction; we revised the statement with the additional clause: with classic symptoms of polyuria, polydipsia, polyphagia, and weight loss or blood glucose at 2 hours after a glucose load ≥ 200 mg/dl or the use of glucose-lowering drugs. All individuals with DM, not those who are pregnant. There must be a certainty that the analyzed individuals have DM without pregnancy. Chances of getting pregnant can be biased. This data must be excluded. The data on obesity needs to be checked again. Thank you. We added the statement in the discussion section: “We recognize that our study did not address the incidence of pregnancy in reproductive-age women, which posed a risk of bias. The incidence of pregnancy among reproductive-age women in Indonesia was 7.48%, while the population of reproductive-age women was 1153 or 29.48% among the DM population in our dataset. Assuming the incidence of pregnancy of reproductive-age women is 7.48%, we ignored around 86 of our female respondents who may be pregnant.\" \"DM subjects that were married significantly had lower odds risk of being obese\" - DM subjects that were unmarried significantly had lower odds risk of being obese. Obese in unmarried group 216/ (216 + 625) = 25.6% (Table 2) and obese in married group 1071/ (1071+ 1999) = 34.8%. Continue chi-square and log multivariate regression, we will find unmarried had lower OR than married. So 7th paragraph in the discussion should be revised. Thank you very much for the correction. We revised as: “We also noticed that DM subjects that were unmarried significantly had lower odds risk of being obese; a-POR=0.73; 95% CI: 0.59-0.90” Inside Table 5 is written urban residence 1.49 but, underneath the table in the description, is written 1.87. Thank you very much for the correction. We revised as stated on Table 5: “urban residence (aPOR=1.49; 95% CI: 1.25-1.77)”"
}
]
}
] | 1
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https://f1000research.com/articles/11-1063
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https://f1000research.com/articles/12-452/v1
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28 Apr 23
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{
"type": "Data Note",
"title": "The identification of high-performing antibodies for Vacuolar protein sorting-associated protein 35 (hVPS35) for use in Western Blot, immunoprecipitation and immunofluorescence",
"authors": [
"Riham Ayoubi",
"Maryam Fotouhi",
"Kathleen Southern",
"Peter S. McPherson",
"Carl Laflamme",
"NeuroSGC/YCharOS/EDDU collaborative group",
"ABIF consortium",
"Riham Ayoubi",
"Maryam Fotouhi",
"Kathleen Southern",
"Peter S. McPherson"
],
"abstract": "Vacuolar protein sorting-associated protein 35 is a subunit of the retromer complex, a vital constituent of the endosomal protein sorting pathway. The D620N mutation in the VPS35 gene has been reported to be linked to type 17 Parkinson’s Disease progression, the exact molecular mechanism remains to be solved. The scientific community would benefit from the accessibility of validated and high-quality anti-hVPS35 antibodies. In this study, we characterized thirteen hVPS35 commercial antibodies for Western Blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.",
"keywords": [
"Uniprot ID Q96QK1",
"VPS35",
"hVPS35",
"Vacuolar protein sorting-associated protein 35",
"antibody characterization",
"antibody validation",
"Western Blot",
"immunoprecipitation",
"immunofluorescence"
],
"content": "Introduction\n\nVacuolar protein sorting-associated protein 35 (hVPS35) is a component of the retromer complex.1 The retromer complex is a multimeric protein complex responsible for sorting transmembrane cargo from the endosome to the trans-Golgi network or plasma membrane, a pathway which is conserved across all eukaryotes.1,2 Composed of two major subcomplexes, the cargo-selective complex and the membrane bound vacuolar protein sorting-associated protein (VPS) complex, hVPS35 serves as an essential component of the VPS complex where it mediates the recruitment of the retromer complex to the endosomal membrane.1\n\nVariants of the VPS35 gene, otherwise referred to as PARK17, have recently been associated with the development of type 17 of Parkinson’s Disease (PD), among other neurodegenerative diseases.3–5 A missense mutation in the gene, D620N, has been reported in numerous individuals and families with PD.6–12 Further research is required to investigate the molecular mechanisms in which VPS35 mutations induces neurodegeneration in PD.3\n\nMechanistic studies would be greatly facilitated with the availability of high-quality antibodies. Here, we compared the performance of a range of commercially-available antibodies for hVPS35 and identified high-performing antibodies for Western Blot, immunoprecipitation and immunofluorescence, enabling biochemical and cellular assessment of hVPS35 properties and function.\n\n\nResults and discussion\n\nOur standard protocol involves comparing readouts from wild-type (WT) and knockout (KO) cells.13–18 The first step was to identify a cell line(s) that expresses sufficient levels of hVPS35 to generate a measurable signal. To this end, we examined the DepMap transcriptomics database to identify all cell lines that express the target at levels greater than 2.5 log2 (transcripts per million “TPM” + 1), which we have found to be a suitable cut-off (Cancer Dependency Map Portal, RRID:SCR_017655). Commercially available HAP1 cells expressed the hVPS35 transcript at RNA levels above the average range of cancer cells analyzed. Parental and VPS35 KO HAP1 cells were obtained from Horizon Discovery (Table 1).\n\nFor Western Blot experiments, we resolved proteins from WT and VPS35 KO cell extracts and probed them side-by-side with all antibodies in parallel (Figure 1).14–18\n\nLysates of HAP1 (WT and VPS35 KO) were prepared and 20 μg of protein were processed for Western Blot with the indicated hVPS35 antibodies. The Ponceau stained transfers of each blot are presented to show equal loading of WT and KO lysates and protein transfer efficiency from the polyacrylamide gels to the nitrocellulose membrane. Antibody dilutions were chosen according to the recommendations of the antibody supplier. An exception was given for antibody 81453**, which was titrated to 1/500, as the signal was too weak when following the supplier’s recommendations. Antibody dilution used: GTX635821** at 1/1000, GTX108058 at 1/1000, GTX116260 at 1/1000, A9278** at 1/1000, MA5-34647** at 1/1000, PA5-21898 at 1/1000, PA5-30654 at 1/1000, ab157220** at 1/1000, ab57632* at 1/270, ab118838 at 1/900, 81453** at 1/500, 10236-1-AP at 1/500, NBP2-75710** at 1/1000. Predicted band size: 91 kDa. *=monoclonal antibody, **=recombinant antibody.\n\nFor immunoprecipitation experiments, we used the antibodies to immunopurify hVPS35 from HAP1 cell extracts. The performance of each antibody was evaluated by detecting the hVPS35 protein in extracts, in the immunodepleted extracts and in the immunoprecipitates (Figure 2).14–18\n\nHAP1 lysates were prepared, and IP was performed using 2.0 μg of the indicated hVPS35 antibodies pre-coupled to Dynabeads protein A or protein G. Samples were washed and processed for Western Blot with the indicated hVPS35 antibody. For Western Blot, GTX635821** and 81453** were used at 1/1000 and 1/500, respectively. The Ponceau stained transfers of each blot are shown. SM=2% starting material; UB=2% unbound fraction; IP=immunoprecipitate. *=monoclonal antibody, **=recombinant antibody.\n\nFor immunofluorescence, as described previously, antibodies were screened using a mosaic strategy.19 In brief, we plated WT and KO cells together in the same well and imaged both cell types in the same field of view to reduce staining, imaging and image analysis bias (Figure 3).\n\nHAP1 WT and VPS35 KO cells were labelled with a green or a far-red fluorescent dye, respectively. WT and KO cells were mixed and plated to a 1:1 ratio in a 96-well plate with a glass bottom. Cells were stained with the indicated hVPS35 antibodies and with the corresponding Alexa-fluor 555 coupled secondary antibody including DAPI. Acquisition of the blue (nucleus-DAPI), green (WT), red (antibody staining) and far-red (KO) channels was performed. Representative images of the merged blue and red (grayscale) channels are shown. WT and KO cells are outlined with green and magenta dashed line, respectively. Antibody dilutions were chosen according to the recommendations of the antibody supplier. When the concentration was not indicated by the supplier, which was the case for antibodies GTX116260, A9278**, MA5-34647**, PA5-30654, 81453** and NBP2-75710**, we tested the antibodies at 1/600, 1/400, 1/1000, 1/60, 1/60 and 1/500, respectively. At these concentrations, the signal from each antibody was in the range of detection of the microscope used. Antibody dilution used: GTX635821** at 1/1000, GTX108058 at 1/600, GTX116260 at 1/600, A9278** at 1/400, MA5-34647** at 1/1000, PA5-21898 at 1/100, PA5-30654 at 1/60, ab157220** at 1/500, ab57632* at 1/1000, ab118838 at 1/1000, 81453** at 1/60, 10236-1-AP at 1/50, NBP2-75710** at 1/500. Bars = 10 μm. *=monoclonal antibody, **=recombinant antibody.\n\nIn conclusion, we have screened hVPS35 commercial antibodies by Western Blot, immunoprecipitation and immunofluorescence and identified several high-quality antibodies under our standardized experimental conditions. The underlying data can be found of Zenodo.20,21\n\n\nMethods\n\nAll hVPS35 antibodies are listed in Table 2, together with their corresponding Research Resource Identifiers, or RRID, to ensure the antibodies are cited properly.22 Peroxidase-conjugated goat anti-rabbit and anti-mouse antibodies are from Thermo Fisher Scientific (cat. number 62-6120 and 65-6520). Alexa-555-conjugated goat anti-rabbit and anti-mouse secondary antibodies are from Thermo Fisher Scientific (cat. number A21429 and A21424).\n\n* = monoclonal antibody.\n\n** = recombinant antibody.\n\n1 refers to RRID recently added to the Antibody Registry (on February 2023), they will be available on their website in the coming weeks.\n\nBoth HAP1 WT and VPS35 KO cell lines used are listed in Table 1, together with their corresponding RRID, to ensure the cell lines are cited properly.23 Cells were cultured in DMEM high-glucose (GE Healthcare cat. number SH30081.01) containing 10% fetal bovine serum (Wisent, cat. number 080450), 2 mM L-glutamate (Wisent cat. number 609065), 100 IU penicillin and 100 μg/mL streptomycin (Wisent cat. number 450201).\n\nWestern Blots were performed as described in our standard operating procedure.24 HAP1 WT and VPS35 KO were collected in RIPA buffer (25mM Tris-HCl pH 7.6, 150mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS) (Thermo Fisher Scientific, cat. number 89901) supplemented with 1x protease inhibitor cocktail mix (MilliporeSigma, cat. number 78429). Lysates were sonicated briefly and incubated for 30 min on ice. Lysates were spun at ~110,000 x g for 15 min at 4°C and equal protein aliquots of the supernatants were analyzed by SDS-PAGE and Western Blot. BLUelf prestained protein ladder from GeneDireX (cat. number PM008-0500) was used.\n\nWestern Blots were performed with pre-cast mini 4-15% gradient polyacrylamide gels from Bio-Rad (cat. number 4561084) and transferred onto nitrocellulose membranes. Proteins on the blots were visualized with Ponceau S staining (Thermo Fisher Scientific, cat. number BP103-10) which is scanned to show together with individual Western Blot. Blots were blocked with 5% milk for 1 hr, and antibodies were incubated overnight at 4°C with 5% bovine serum albumin (BSA) (Wisent, cat. number 800-095) in TBS with 0,1% Tween 20 (TBST) (Cell Signaling Technology, cat. number 9997). Following three washes with TBST, the peroxidase conjugated secondary antibody was incubated at a dilution of ~0.2 μg/mL in TBST with 5% milk for 1 hr at room temperature followed by three washes with TBST. Membranes were incubated with Pierce ECL from Thermo Fisher Scientific (cat. number 32106) prior to detection with the HyBlot CL autoradiography films from Denville (cat. number 1159T41).\n\nImmunoprecipitation was performed as described in our standard operating procedure.25 Antibody-bead conjugates were prepared by adding 2 μg to 500 μL of Pierce IP Lysis Buffer from Thermo Fisher Scientific (cat. number 87788) in a 1.5 mL microcentrifuge tube, together with 30μL of Dynabeads protein A- (for rabbit antibodies) or protein G- (for mouse antibodies) from Thermo Fisher Scientific (cat. number 10002D and 10004D, respectively). Tubes were rocked for ~1 hr at 4°C followed by two washes to remove unbound antibodies.\n\nHAP1 WT were collected in Pierce IP buffer (25 mM Tris-HCl pH 7.4, 150 mM NaCl, 1 mM EDTA, 1% NP-40 and 5% glycerol) (Thermo Fisher Scientific, cat. number 87788) supplemented with protease inhibitor (MilliporeSigma, cat. number P8340). Lysates were rocked for 30 min at 4°C and spun at 110,000 x g for 15 min at 4°C. 0.5 mL aliquots at 2.0 mg/mL of lysate were incubated with an antibody-bead conjugate for ~2 hrs at 4°C. The unbound fractions were collected, and beads were subsequently washed three times with 1.0 mL of IP lysis buffer and processed for SDS-PAGE and Western Blot on a pre-cast mini 4-15% gradient polyacrylamide gels. Prot-A: HRP (MilliporeSigma, cat. number P8651) was used as a secondary detection system at a concentration of 0.3 μg/mL.\n\nImmunofluorescence was performed as described in our standard operating procedure.14–19 HAP1 WT and VPS35 KO were labelled with a green and a far-red fluorescence dye, respectively. The fluorescent dyes used are from Thermo Fisher Scientific (cat. number C2925 and C34565). The nuclei were labelled with DAPI (Thermo Fisher Scientific, cat. Number D3571) fluorescent stain. WT and KO cells were plated in 96 well glass plates (Perkin Elmer, cat. number 6055300) as a mosaic and incubated for 24 hrs in a cell culture incubator at 37oC, 5% CO2. Cells were fixed in paraformaldehyde (PFA) (Beantown chemical, cat. number 140770-10ml) in phosphate buffered saline (PBS) (Wisent, cat. number 311-010-CL) for 15 min at room temperature and then washed 3 times with PBS. Cells were permeabilized in PBS with 0,1% Triton X-100 (Thermo Fisher Scientific, cat. number BP151-500) for 10 min at room temperature and blocked with PBS with 5% BSA, 5% goat serum (Gibco, cat. number 16210-064) and 0.01% Triton X-100 for 30 min at room temperature. Cells were incubated with IF buffer (PBS, 5% BSA, 0,01% Triton X-100) containing the primary hVPS35 antibodies overnight at 4°C. Cells were then washed 3 × 10 min with IF buffer and incubated with corresponding Alexa Fluor 555-conjugated secondary antibodies in IF buffer at a dilution of 1.0 μg/mL for 1 hr at room temperature with DAPI. Cells were washed 3 × 10 min with IF buffer and once with PBS.\n\nImages were acquired on an ImageXpress micro widefield high-content microscopy system (Molecular Devices), using a 20x/0.95 NA water objective lens and scientific CMOS camera (16-bit, 1.97mm field of view), equipped with 395, 475, 555 and 635 nm solid state LED lights (Lumencor Aura III light engine) and bandpass emission filters (432/36 nm, 520/35 nm, 600/37 nm and 692/40 nm) to excite and capture fluorescence emission for DAPI, CellTrackerTM Green, Alexa fluor 555 and CellTrackerTM Red, respectively. Images had pixel sizes of 0.68 x 0.68 microns. Exposure time was set with maximal (relevant) pixel intensity ~80% of dynamic range and verified on multiple wells before acquisition. Since the IF staining varied depending on the primary antibody used, the exposure time was set using the most intensely stained well as reference. Frequently, the focal plane varied slightly within a single field of view. To remedy this issue, a stack of three images per channel was acquired at a z-interval of 4 microns per field and best focus projections were generated during the acquisition (MetaExpress v6.7.1, Molecular Devices). Segmentation was carried out on the projections of CellTrackerTM channels using CellPose v1.0 on green (WT) and far-red (KO) channels, using as parameters the ‘cyto’ model to detect whole cells, and using an estimated diameter tested for each cell type, between 15 and 20 microns.26 Masks were used to generate cell outlines for intensity quantification. Figures were assembled with Adobe Photoshop (version 24.1.2) to adjust contrast then assembled with Adobe Illustrator (version 27.3.1).",
"appendix": "Data availability\n\nZenodo: Antibody Characterization Report for hVPS35, https://doi.org/10.5281/zenodo.7671730. 20\n\nZenodo: Dataset for the hVPS35 antibody screening study, https://doi.org/10.5281/zenodo.7795779. 21\n\n\nAcknowledgment\n\nWe would like to thank the NeuroSGC/YCharOS/EDDU collaborative group for their important contribution to the creation of an open scientific ecosystem of antibody manufacturers and knockout cell line suppliers, for the development of community-agreed protocols, and for their shared ideas, resources and collaboration. We would also like to thank the Advanced BioImaging Facility (ABIF) consortium for their image analysis pipeline development and conduction (RRID:SCR_017697). Members of each group can be found below.\n\nNeuroSGC/YCharOS/EDDU collaborative group: Riham Ayoubi, Thomas M. Durcan, Aled M. Edwards, Carl Laflamme, Peter S. McPherson, Chetan Raina, Wolfgang Reintsch and Kathleen Southern.\n\nABIF consortium: Claire M. Brown and Joel Ryan.\n\nThank you to the Michael J. Fox Foundation for Parkinson’s Research for their contribution to the project, the Characterization of Antibody Reagents for 15 Diverse Protein Targets.\n\nAn earlier version of this of this article can be found on Zenodo (doi: 10.5281/zenodo.7671730)\n\n\nReferences\n\nSeaman MN: The retromer complex - endosomal protein recycling and beyond. J. Cell Sci. 2012; 125(Pt 20): 4693–4702. PubMed Abstract | Publisher Full Text\n\nMcGough IJ, de Groot REA , Jellett AP, et al.: SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion. Nat. Commun. 2018; 9(1): 3737. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWilliams ET, Chen X, Moore DJ: VPS35, the Retromer Complex and Parkinson's Disease. J. Parkinsons Dis. 2017; 7(2): 219–233. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZimprich A, Benet-Pagès A, Struhal W, et al.: A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am. J. Hum. Genet. 2011; 89(1): 168–175. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChiu CC, Weng YH, Huang YZ, et al.: (D620N) VPS35 causes the impairment of Wnt/β-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model. Cell Death Dis. 2020; 11(11): 1018. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDeng H, Gao K, Jankovic J: The VPS35 gene and Parkinson's disease. Mov. Disord. 2013; 28(5): 569–575. Publisher Full Text\n\nKumar KR, Weissbach A, Heldmann M, et al.: Frequency of the D620N mutation in VPS35 in Parkinson disease. Arch. Neurol. 2012; 69(10): 1360–1364. PubMed Abstract | Publisher Full Text\n\nSharma M, Ioannidis JP, Aasly JO, et al.: A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants. J. Med. Genet. 2012; 49(11): 721–726. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSheerin UM, Charlesworth G, Bras J, et al.: Screening for VPS35 mutations in Parkinson's disease. Neurobiol. Aging. 2012; 33(4): 838.e1–838.e5. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVerstraeten A, Wauters E, Crosiers D, et al.: Contribution of VPS35 genetic variability to LBD in the Flanders-Belgian population. Neurobiol. Aging. 2012; 33(8): 1844.e11–1844.e13. PubMed Abstract | Publisher Full Text\n\nBandrés-Ciga S, Mencacci NE, Durán R, et al.: Analysis of the genetic variability in Parkinson's disease from Southern Spain. Neurobiol. Aging. 2016; 37: 210.e1–e5. PubMed Abstract | Publisher Full Text\n\nGustavsson EK, Guella I, Trinh J, et al.: Genetic variability of the retromer cargo recognition complex in parkinsonism. Mov. Disord. 2015; 30(4): 580–584. PubMed Abstract | Publisher Full Text\n\nLaflamme C, McKeever PM, Kumar R, et al.: Implementation of an antibody characterization procedure and application to the major ALS/FTD disease gene C9ORF72. elife. 2019; 8: 8. Publisher Full Text\n\nAlshafie W, Fotouhi M, Shlaifer I, et al.: Identification of highly specific antibodies for Serine/threonine-protein kinase TBK1 for use in immunoblot, immunoprecipitation and immunofluorescence. F1000Res. 2022; 11: 977. Publisher Full Text\n\nAlshafie W, Ayoubi R, Fotouhi M, et al.: The identification of high-performing antibodies for Moesin for use in Western Blot, immunoprecipitation, and immunofluorescence [version 1; peer review: awaiting peer review]. F1000Res. 2023; 2023(12): 172.\n\nWorrall D, Ayoubi R, Fotouhi M, et al.: The identification of high-performing antibodies for TDP-43 for use in Western Blot, immunoprecipitation and immunofluorescence [version 1; peer review: 1 approved]. F1000Res. 2023; 12: 277. Publisher Full Text\n\nAyoubi R, Fotouhi M, Southern K, et al.: The identification of high-performing antibodies for transmembrane protein 106B (TMEM106B) for use in Western blot, immunoprecipitation, and immunofluorescence [version 1; peer review: awaiting peer review]. F1000Res. 2023; 12: 308. Publisher Full Text\n\nAyoubi R, Alshafie W, Shlaifer I, et al.: The identification of high-performing antibodies for Sequestosome-1 for use in Western blot, immunoprecipitation and immunofluorescence [version 1; peer review: awaiting peer review]. F1000Res. 2023; 12: 324. Publisher Full Text\n\nAlshafie W, McPherson P, Laflamme C: Antibody screening by Immunofluorescence.2021.\n\nAyoubi R, Fotouhi M, Ryan J, et al.: Antibody Characterization Report for hVPS35 (Vacuolar protein sorting-associated protein 35).2023.\n\nLaflamme C: Dataset for the hVPS35 antibody screening study. [Data set]. Zenodo. 2023.\n\nBandrowski A, Pairish M, Eckmann P, et al.: The Antibody Registry: ten years of registering antibodies. Nucleic Acids Res. 2022.\n\nBairoch A: The Cellosaurus, a Cell-Line Knowledge Resource. J. Biomol. Tech. 2018; 29(2): 25–38. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAyoubi R, McPherson PS, Laflamme C: Antibody Screening by Immunoblot.2021.\n\nAyoubi R, Fotouhi M, McPherson P, et al.: Antibody screening by Immunoprecitation.2021.\n\nStringer C, Wang T, Michaelos M, et al.: Cellpose: a generalist algorithm for cellular segmentation. Nat. Methods. 2021; 18(1): 100–106. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "191098",
"date": "07 Sep 2023",
"name": "Maria-Paz Marzolo",
"expertise": [
"Reviewer Expertise Cell Biology",
"neurobiology",
"membrane trafficking",
"cell polarity",
"signaling pathways."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article is a data note that evaluates different commercial antibodies for the human Vacuolar protein sorting-associated protein 35 (hVPS35),a. subunit of the Retromer complex, also composed of VPS26 and VPS29 subunits. Retromer is involved in several cargo sorting processes at the endosomes, regulating endosome to plasma membrane trafficking of cargoes and the endosome to Golgi apparatus retrograde transport of cargoes such as the mannose-6-phosphate receptors. Mutations in Retromer are associated with neurodegenerative conditions, such as Parkinson's Disease (PD). This article is particularly relevant as a data note for evaluating different commercial antibodies for VPS35 detection, but some mistakes should be addressed.\nIn the Abstract and the Introduction, it is mentioned a type 17 Parkinson's disease progression. The VPS35 gene is the PARK17, but there are not 17 types of PD. The authors could check the PARK genes that historically are the genes that have been linked to PD. Reference 1 can be complemented with other articles; I suggest including the articles:\nHaft, C. R., de la Luz Sierra, M., Bafford, R., Lesniak, M. A., Barr, V. A., & Taylor, S. I. (2000). Human orthologs of yeast vacuolar protein sorting proteins Vps 26, 29, and 35: Assembly into multimeric complexes. Molecular Biology of the Cell, 11, 4105–4116.\nSeaman, M. N. J., Marcusson, E. G., Cereghino, J. L., & Emr, S. D. (1997). Endosome to Golgi retrieval of the vacuolar protein sorting receptor, Vps10p requires the function of the VPS29, VPS30, and VPS35 gene products. Journal of Cell Biology, 137, 79–92.\nSeaman, M. N. J., McCaffery, J. M., & Emr, S. D. (1998). A membrane coat complex essential for endosome-to-Golgi retrograde transport in yeast. Journal of Cell Biology, 142, 665–681.\nSeaman, M. N. J. (2004). Cargo-selective endosomal sorting for retrieval to the Golgi requires a retromer. Journal of Cell Biology, 165, 111–122. https://doi.org/10.1083/jcb.20031 2034\nIs the rationale for creating the dataset(s) clearly described?\nThe study is relevant to the field. It is necessary to characterize and find reliable antibodies that can detect the VPS35, without false positives, for describing and ascribing different and eventually new retromer functions and cargoes. The authors established that the main AIM of the data note is to use it as a guide to select the appropriate antibody for the research. The guide could help scientists in the field to invest in quality antibodies, saving time, money, and other resources in the characterization of antibodies that, in the end, will be useless. This AIM is accomplished; as a guide, this article gives useful information. However, it could be improved by discussing the reliability of the antibodies tested and the pertinence of the results obtained.\nAre the protocols appropriate, and is the work technically sound?\nThe authors analyze the antibody's performance in three techniques widely utilized in cell biology: western blot, immunoprecipitation, and immunofluorescence. These are techniques often used in the field, including membrane trafficking studies and neurobiology studies. Nevertheless, the results could be improved.\nThe authors decided to test the antibodies in the carcinogenic cell line HAP1 should explore other non-carcinogenic cell lines as well as neuronal cell lines considering that many mutants of VPS35 are associated with neurodegenerative diseases, including PD. Moreover, even among cells of the same species, antibody performance also depends on the cellular type; therefore, it would be desirable to test the antibodies in a neuron-like cell line as H4, SH-Sy5Y, to mention some.\nIn the western blot experiments, there are unspecific bands in the WT and KO lines for GTX116260, PA5-30654, and ab57632*. This should be remarked in an additional table or Table 2 for scientists to evaluate the pertinence of these antibodies.\nIn the immunofluorescence, the signal shown does not correlate with an expected signal of Retromer following the VPS35 subunit. It should show a vesicular pattern with identifiable structures. This could be correlated with other endosome markers or cargos such as mannose-6-phosphate, the GTPase Rab7, or the expression of a GFP-tag VPS35. Besides, authors should consider testing other fixations as methanol and performing negative controls in non-permeabilized cells. I wonder if 20X is the ideal magnification for the analysis because the label is very diffused. However, comparing the WT and KO lines in the same field is a great idea.\nAre sufficient details of methods and materials provided to allow replication by others?\nThe methods are clear and detailed. However, the authors could explain why, for the western blots, they decided to block with milk and then incubate the primary antibody in BSA. For example. for some antibodies, the BSA is also required for blocking. A clarification on the concept of high-performing antibodies and what it entails should be included.\nAre the datasets presented in a usable and accessible format?\nThe datasets are clearly and accessibly presented, but Table 2 could include the performance of the antibodies in the different techniques and if the antibodies have been cited in other articles.\n\nIs the rationale for creating the dataset(s) clearly described? Partly\n\nAre the protocols appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and materials provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Partly",
"responses": [
{
"c_id": "10357",
"date": "16 Nov 2023",
"name": "Kathleen Southern",
"role": "Author Response",
"response": "Thank you for your review and feedback. We will be addressing your comments and submitting a new version of the article, with many of your suggestions included. To the abstract and introduction, we have removed the mention of type 17 Parkinson’s disease. Furthermore, in the introduction we have included information to mention other PARK genes that have been identified in research, including PARK17. We are always looking to improve on our articles and hope this satisfies your feedback! In regard to your comment on the rationale for creating the dataset, we understand that you believe it would enhance the quality of the article if we discussed the performance of the antibodies tested and reported their specificity or selectivity in regards to the results. In response to this feedback, it’s important to clarify that YCharOs does not engage in result analysis nor do we offer explicit antibody recommendations. We’re not experts of these proteins and prefer to remain impartial which is why we carry out the study without interpreting the results. The purpose of YCharOS is to deliver antibody characterization reports as a public good collection to benefit biomedical research as a whole. It is for this reason that we chose to publish our articles using the Data Note format, as it does not require result analysis but rather presents KO characterization data for experts of the individual targets to further their studies and projects. We have found that, for the most part, scientists viewing our articles have the expertise to the characterization data independently, enabling them to make informed choices regarding the most suitable antibodies for their specific experimental needs. We understand that this point has not been made clear within the article, which is why we have added a new paragraph to the Results and Discussion section, explaining our reasonings as to why we do not recommend or score the antibodies tested. In terms of cell lines, at this point, testing and validating the antibodies in various neuronal cell lines is outside the scope of our standard protocol and study. We utilize the Cancer Dependency Map (DepMap) as a guide to select a cell line with adequate levels of protein of interest. That being said, we hope to revisit all Parkinson’s disease- related protein targets in the future by quantifying the antibody performance on a larger scale and analyzing protein expression in various neuronal cell lines. In terms of evaluating the antibodies you mentioned in Western blot, as previously mentioned, we believe scientists viewing the article will have the expertise to see that the antibodies mentioned are non-selective using our current experimental set-up. The reason as to why different fixation methods were not used, is because with our current workflow we identified antibodies that specifically target hVPS35 by immunofluorescence (IF). It is only in the case that no successful antibodies were identified that we consider other fixation protocols such as methanol. Furthermore, our goal for the IF application is not to identify the subcellular distribution of hVPS35, but rather demonstrate to the scientific community which of the antibodies perform successfully in IF. Meaning, we look for antibodies that immunolocalizes the target protein by generating a fluorescence signal in WT cells that is at least 1.5-fold higher than the signal in KO cells (1). Using a 20X magnification allows us to evaluate the antibodies selectivity but does not have the resolution to dive into the subcellular distribution of the antibodies. With our reports, the experts now know which antibodies are successful in identifying VPS35, and can further their research by identifying subcellular distribution utilizing organelle markers. We intend on clarifying this factor in our FAQ section on our YCharOS gateway. After performing our standard operating procedure for around 80 protein targets and 800 antibodies, we haven’t seen a difference in results when blocking with milk or BSA. Furthermore, Milk was chosen as a blocking solution as it doesn’t get contaminated as easily, allowing us to repeat the experiment, if necessary. We agree that the definition of a high-performing antibody is not made evident in the first version of the article. In the introduction of the new article version to be submitted shortly, we have included a small description of what high-performing antibody signifies in each application. You can also visit an article written by Riham et al. which provides an in-depth description on what a successful antibody looks like in each application (Box 1) (1) We don’t look at antibody performance in individual reports, but we do in a separate study, looking at the overall performance of antibodies, compared to their use in literature (1). 1. Ayoubi R, Ryan J, Biddle MS, Alshafie W, Fotouhi M, Bolivar SG, et al. Scaling of an antibody validation procedure enables quantification of antibody performance in major research applications. eLife. 2023;12:RP91645."
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https://f1000research.com/articles/12-452
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https://f1000research.com/articles/12-1333/v1
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16 Oct 23
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{
"type": "Research Article",
"title": "Assessment of general population knowledge, attitude, and practice on safe unused and expired drugs disposal: a cross-sectional study",
"authors": [
"Abd-ul Munaf Mohammed",
"Fadya Al-Hamadani",
"Fadya Al-Hamadani"
],
"abstract": "Background The appropriate disposal of medication is a well-recognized issue that has convened growing recognition in several contexts. Insufficient awareness relating to appropriate methods for the disposal of unneeded medicine may result in notable consequences. The current research was conducted among the public in Iraq with the aim of examining their knowledge, attitude, and practices regarding the proper disposal of unused and expired medicines.\n\nMethods The present study used an observational cross-sectional design that was community-based. The data were obtained from using an online questionnaire. The study sample included people of diverse genders, regardless of their race or occupational status. The study mandated that all participants meet two criteria: firstly, they had to be a minimum of 18 years old, and secondly, they needed to have permanent residency status in Iraq.\n\nResults The research population consisted of 591 participants from general population. The majority of participants were men (64.8%) with average age of 33.5±9.1 years. The majority of participants (˃50%) answered four out of eight knowledge questions correctly. There were significant (P-value ˂0.05) differences in four knowledge items about disposing of unused/expired medications according to the educational level. Elder participants had significantly higher knowledge about the disposing of unused/expired medications compared to younger ones. More than 84% correctly agreed that improper disposal of unused and expired medication has adverse effects on environment. Although the majority of the participants had positive attitude toward the safe disposal of unused/expired medications, their actual practice was improper for these medications. Approximately 70% of the participants have disposed unused/expired medications into their home trash can.\n\nConclusion Despite increasing awareness from the general populace about the possible harm and substantial hazards linked to expired medicines, there is an absence of understanding concerning the proper techniques for disposing of and managing these prescriptions.",
"keywords": [
"Attitude",
"Drugs Disposal",
"Knowledge",
"Practice",
"Unused medicines."
],
"content": "Introduction\n\nThe proper disposal of medicine is a well-acknowledged challenge that has gained increasing attention in diverse settings.1,2 A lack of sufficient knowledge regarding the proper methods of disposing of unused medication can lead to significant consequences, such as the accumulation of chemical compounds and dangerous chemicals from the medication in the environment around it, unintentional events of overdose, and the possibility of prescription drug misuse.3,4 A number of countries have implemented legislation pertaining to the appropriate disposal of unwanted or expired medicine.5 Ensuring the effectiveness and safety of pharmaceutical items may be achieved by following the prescribed storage conditions specified on the label and using them prior to their designated expiry date.6,7 The disposal of pharmaceuticals is often advised by suppliers and certain healthcare organizations, taking into consideration their expiry date.8,9 This is primarily because outdated medicines could decompose, resulting in a loss of effectiveness or even the manifestation of harmful consequences.10 Prescribed drugs often remain unused owing to several circumstances, including changes in treatment plans, unpleasant responses, improvements in patients’ well-being, or other contributing factors.11–14 According to the World Health Organization (WHO), a considerable number of pharmaceuticals has been prescribed or made available for sale improperly, resulting in the buildup of enormous volumes of solid waste consisting of expired and unused medications, hence, there is a notable burden for the environment that is linked to the disposal of these pharmaceutical substances.15\n\nThe Food and Drug Administration (FDA) in the United States has issued guidelines to the general public pertaining to the proper disposal of leftover pharmaceuticals; as per the guidelines provided by the FDA, the optimal approach for disposing of unneeded or expired medications involves depositing them at certified drug take-back locations, these locations are often available at various medical institutions, including retail pharmacies and health centers.16 Properly disposing of expired, unwanted, or unused drugs by customers is a significant worldwide concern.17 Numerous developed countries have implemented initiatives to recycle unwanted medications properly. In Australia and Canada, the National Return and Disposal of Unwanted Medicines Project has been implemented with the respective governments and pharmaceutical industries.18 Drug take-back strategies are prevalent in both the United Kingdom and Sweden.19\n\nA study conducted in Africa examined the knowledge and perceptions of people regarding the disposal procedures for unused medications. The findings revealed that families lacked knowledge regarding proper disposal procedures. This poor knowledge can be attributed to insufficient public education and promotion campaigns and the failure of healthcare providers to deliver disposal advice at healthcare facilities and drug stores. Additionally, unclear disposal instructions on medicine packages and a disregard for reading these instructions were identified as contributing factors to this issue.20 Despite the existence of international guidelines regarding the appropriate disposal practices for expired and unused drugs,21 implementation of these guidelines is often inadequate, and the public has limited access to sometimes conflicting information on this matter.22,23\n\nFurthermore, it is important to acknowledge that certain medications may be appropriately discarded by flushing them down the toilet, as long as they are included in FDA roster of pharmaceuticals that are deemed safe for such disposal. The list provided includes various opiates such as buprenorphine, morphine, other derivatives of opioids, diazepam, and methylphenidate.24 In contrast, medicines that are not acceptable for disposal by flushing should be mixed with a less appealing substance, such as dirt, cat litter, or recently used coffee grounds; following this, it is recommended that they be securely sealed inside a hermetically sealed plastic bag and appropriately discarded in the designated waste receptacle.25\n\nThe existing body of research on the knowledge and attitudes of the general population regarding the disposal of expired and unused medicines has been conducted in various regions worldwide. However, the specific knowledge and attitudes of the Iraqi population regarding the safe removal of expired and unused drugs remain unknown. This lack of understanding is primarily due to the absence of a regulatory authority system in Iraq that addresses the proper handling of expired and unused medicines at the household level. Therefore, this study aimed to evaluate the general population’s knowledge, attitude, and practices about the disposal procedures for expired and unused medications.\n\n\nMethods\n\nThe research proposal obtained approval from the Central Scientific Committee of the College of Pharmacy at the University of Baghdad (approval number: RECAUBCP292023A on 29/1/2023). The ethical committee waived the requirement for obtaining written informed consent, as all participants voluntarily participated in the study. All the procedures were conducted in adherence to the appropriate guidelines and regulations.\n\nThis research utilized an observational cross-sectional design, community based, and was conducted from the 28th of Feb to the 11th of May 2023. The data were collected by an online questionnaire that was administered on a voluntary basis without offering any incentives to motivate participation. The researchers provided a detailed explanation of the study’s scope and objective in the introductory section of the questionnaire. Privacy and confidentiality were secured through the study items.\n\nThe estimation of the sample’s size was conducted with the Raosoft® online software calculator. The estimate was determined based on the need to achieve a minimum sample size, set a confidence level of 95%, and maintain a margin of error of 5%. A recommendation was made to use a sample size of 591 individuals. The online questionnaire portal was closed after it reached the above specified number.\n\nAdults who agree to participate, and are at least eighteen years old.\n\nAny healthcare workers, and participants under the age of eighteen.\n\nThe questionnaire included 23 questions and was divided into four distinct sections. The first section of the study collected socio-demographic data, such as age, gender, educational attainment, marital status, monthly income, and sources of information on drug disposal. The three remaining components consisted of a series of conceptual inquiries that assessed people’ knowledge (8 questions), attitudes (10 questions), and practices (5 questions) pertaining to the disposal of drugs. This study thoroughly analyzes the existing literature to identify relevant inquiries about knowledge, attitudes, and practices (KAP) in the context of unused drugs management. These questions were adopted from various studies7,13,26–31; furthermore, it was later modified to conform to the precise aims of the present study. We collected the accurate responses, awarding one point for each right answer, with the exception that selecting the “I do not know” option was considered an incorrect answer. The attitude score was measured using a 5-point Likert scale.\n\nThe content validity of each survey question was assessed by a panel of five experts who are affiliated with the Central Scientific Committee of the clinical department at the College of Pharmacy, University of Baghdad. An agreement was established by the experts about the importance and clarity of each item included in the question. Subsequently, the study proceeded to a preliminary phase, with a cohort of 48 individuals, with the aim of assessing its clarity and reliability. The reliability of the questionnaire was assessed by calculating the alpha-Cronbach’s coefficient, which yielded a value of 0.67.\n\nAn online questionnaire was developed using the Google Forms platform in order to assess the knowledge, attitudes, and practice of the general population about the disposal of drugs. Following this, the survey was distributed across several social media sites (Facebook, WhatsApp, Telegram). The data were collected through a convenient method of sampling. The participants were formally notified that their participation in the research endeavor was totally voluntary and that their replies would be handled with the utmost regard for anonymity and confidentiality. The survey included a combination of closed-ended and open-ended inquiries, with the objective of collecting information on the socio-demographic attributes, knowledge, attitudes, and behaviors of the participants. The completion of the questions normally necessitates a time range of probably 10 to 15 minutes.\n\nIn this type of research, sometimes certain individuals may have refrained from disclosing their improper medicine disposal practices in order to satisfy the investigators. This might potentially introduce social desirability bias or even recollection bias into the study findings. However, the potential bias was mitigated by ensuring that the research participants were guaranteed anonymity and were informed about the significance of providing honest responses.\n\nThe data was subjected to analysis using SPSS software, version 25. Descriptive statistics were conducted on all variables included in the study. Continuous data were expressed using means ± standard deviation (SD), whereas categorical variables were expressed using frequencies and percentages. The independent t-test was used to evaluate the differences in the means of continuous variables between men and women participants. The chi-square test was used to evaluate the discrepancy in the categorical variables, namely knowledge and practice, with respect to the genders of the participants. A P-value that falls below the predetermined threshold of 0.05 is considered to possess statistical significance. Moreover, the final study analysis omitted the involvement of 48 people who were part of the pilot phase.\n\n\nResults\n\nThe study recruited 591 participants. The majority of participants were men (64.8%) with average age of 33.5±9.1 years. More than two-thirds (72.9%) were married and 88.7% had university education. Approximately 65% had governmental work with income between 0.5-1.0 million Iraqi Dinars. Although 59.2% had healthcare worker relatives (HCW), 62.9% of them have not received information about how to dispose unused medications (Table 1).\n\nThe majority of participants (˃50%) answered four out of eight knowledge questions correctly. More than 84% correctly agreed that improper disposal of unused and expired medication has adverse effects on the environment. In contrast, only one-third (34-36%) answered correctly that the other three items related to the ways of proper/safe disposal of unused medications. In other words, more than two-thirds of the participants believed that disposal of solid and semi-solid medications into garbage is acceptable. In contrast, 68.2% believed that it is not acceptable to dispose needles and syringes into garbage (Table 2 and Figure 1).\n\nThe majority of participants (60-95%) had positive attitudes toward the necessity of proper disposal of unused medications and the pivotal roles of healthcare workers (HCWs) to raise awareness about the safe disposal methods. The majority of participants (60-95%) agreed with two items describing the HCW roles in counseling about improper ways of disposal. The attitude items indicated two suggested methods to enhance the safe disposal of unused medications including via community pharmacies and encouraging patients to return unused/expired medications to community pharmacies to be disposed safely (Table 3).\n\nAlthough the majority of the participants had a positive attitude toward the safe disposal of unused/expired medications, their actual practice is improper disposal for these medications (Table 4). Approximately 70% of the participants have disposed unused/expired medications into their home trash can. Additionally, 66.3% of them had unused medications in their homes (Table 4).\n\nAccording to the participants’ gender, there was significant (P-value˂0.05) differences in seven out of eight knowledge items related to disposing of unused/expired medications. In other words, men participants had significantly higher percentages of correct answers in almost all knowledge items compared to women participants (Table 5).\n\n* Significant (P-value˂0.05) according to Pearson Chi-Square.\n\nThere was significant (P-value˂0.05) difference in the participant attitude toward one item regarding the disposal of unused/expired medications according to the gender. In other words, men participants more likely to believe “if there is monetary incentive for customers to return unused medicines, they would be more likely to do so”. However, there was no other significant (P-value˃0.05) difference according to the participant gender with the other nine attitude items (Table 6).\n\n* Significant (P-value˂0.05) according to Independent T-test.\n\nThere were significant (P-value˂0.05) differences in four knowledge items about disposing of unused/expired medications according to the education level as presented in Table 7. In other words, participants with university education had a significantly higher percentage of correct answers to three of the knowledge questions. In contrast, the participants with primary school education had significantly higher percentage of correct answer to one knowledge item: “Incineration is proper environmental way to dispose unwanted medications.\n\n* Significant (P-value˂0.05) according to Chi-square or.\n\n‡ Fisher's Exact Test.\n\nThere were significant (P-value˂0.05) differences in three knowledge items about disposing of unused/expired medications according to participant age. In other words, older participants had significantly higher knowledge about the disposing of unused/expired medications compared to younger ones (Table 8).\n\n* Significant (P-value˂0.05) according to Independent T-test.\n\nAccording to the Chi-square test, the participants with higher income were more likely to have correct answers regarding four knowledge items compared to lower income participants (Table 9). In other words, higher income was associated with better knowledge about disposing unused/expired medications.\n\n* Significant (P-value˂0.05) according to Chi-square test.\n\n\nDiscussion\n\nThe increasing availability and use of medicines have resulted in accumulated and inadequate disposal of unwanted, expired drugs inside households, which may give rise to environmental and public health concerns.32,33 The reduction of this issue may be achieved by the implementation of policies and recommendations for medication disposal,34 as well as by enhancing public knowledge about suitable techniques and procedures for disposing of medicine.35 Hence, the primary objective of this research was to evaluate the general population’s knowledge, attitude, and behavior pertaining to the disposal of unused and expired home medications.\n\nThe findings of our study revealed a satisfactory level of knowledge among the general populace about the proper disposal of medications. A majority of the participants correctly answered four out of eight knowledge-based questions related to medicine disposal. Additionally, most of the respondents expressed the belief that it is unacceptable to dispose of needles and syringes in regular rubbish. The present results are consistent with the earlier findings published by A. Althagafi et al. in Saudi Arabi, which recruited 1100 participants,36 however they differ with the findings of research done in Lebanon, which emphasized the limited understanding of the general community about medicine disposal, and where the knowledge score were 24.5%.6\n\nPrevious research has shown that individuals with intermediate and higher education levels (secondary, university, or postgraduate) and higher incomes had a higher perceived knowledge score, as documented in previous study.37 One reasonable assumption is that those who have higher levels of education and have more financial stability are inclined to exhibit a more intuitive preference towards seeking knowledge and possess a heightened understanding of their environment. In contrast, in line with findings from previous studies, those with lower levels of education are more prone to encountering challenges when attempting to acquire new knowledge and may lack awareness of the potential repercussions of incorrectly disposing of medications.38 The aforementioned findings are consistent with the current study results, indicating that those with a university degree exhibited a statistically significant increase in the proportion of accurate responses to three of the knowledge-based questions.\n\nThere was a substantial association seen between gender and knowledge and attitudes, with men exhibiting considerably higher scores in both domains. The results exhibit inconsistency compared to prior research, which indicated that women showed a considerably higher inclination towards using medicine collecting facilities than men in a study conducted between Lebanese and Malaysian populations.6,39 Additionally, women were found to possess a greater sense of personal accountability towards the proper disposal of medication.40\n\nThe respondents expressed a belief in the need of consulting healthcare experts on appropriate means of disposal. This finding is consistent with the expectation that health care providers bear primary responsibility for managing medicines and hazardous waste.41\n\nThe present study reveals that 66.3% of the participants had leftover, unutilized, or unwanted medicines, a finding consistent with previous research done in India and Harar city in Ethiopia, where 68% and 66% of the respondents, respectively, retained unused medicines inside their households.17,42 Furthermore, the findings of research done in Northern Ethiopia by Halefom Kahsay et al. demonstrated a lesser value compared to the information presented in this study, approximately 52.4% of the participants said they had leftover medications stashed inside their households, with analgesics being the most prevalent category, accounting for 41.5% of the reported instances.43\n\nThe results from the study indicate that a significant proportion of respondents reported disposing of expired drugs in their home garbage (approximately 70%), in line with previous research that gave insight regarding a number of studies undertaken in different countries around the world.18 In Busan city, Korea, housewives were seen to dispose of unneeded drugs by using regular rubbish bags.44 It was believed that the appropriate approach for disposing of unneeded or expired prescriptions was to flush them down the toilet or drain rather than putting them in the garbage. This was based on the concern that if medications were thrown in the trash, there was a higher likelihood of animals or people coming into contact with them.45 A small proportion, about 4.2% of the survey participants, reported disposing of expired prescriptions by flushing them down the toilet or sink. This disposal method aligns with the patterns seen in Kuwait (2%), and much lower than what reported previously in the United States, as it was documented that 35.4% of participants flushed medications down the toilet or sink.21,46 Notably, this approach is considered the recommended practice for liquid pharmaceuticals.18 A small portion of the participants in the study engaged in the practice of returning drugs that were unused and had expired to drugstores, but only 1.35%. This behavior has similarities to comparable practices seen in the United States and Malaysia as reported in previous studies.46,47 The various methods used for the safe disposal of residual pharmaceuticals have a substantial impact on mitigating the entry of these substances into the environment since they have the potential to pose risks to both the environment and individuals.48,49\n\nIt is crucial to recognize that this research has experienced several limitations. The results were contingent upon the accuracy and sincerity of the participants’ responses, which may introduce a bias in the information obtained. There was no physical inspection conducted on the storage of medication. Moreover, while the existing sample size might consider enough for achieving statistical significance, it is recommended to use a bigger sample size to improve the applicability of the findings to the wider community. The last limitation of the research design is its cross-sectional character, which hinders our ability to establish causal relationships between the selected factors and outcome variables across time.\n\n\nConclusion\n\nThe present study conducted among the general population in Iraq provides insights into the actual practices and level of knowledge about the appropriate handling and disposal methods of unused and expired medications. Despite the widespread awareness among the general community of the potential damage and significant risks associated with expired pharmaceuticals, a lack of knowledge was observed on the appropriate methods for disposal and management of such medications. A significant proportion of the participants had positive attitudes about the necessity of appropriately disposing of unneeded drugs. Yet, their current practice involves poor disposal methods for these drugs. The healthcare system and its practitioners must play a pivotal role in providing education and guidance to the general population in this matter. It is recommended that authorities take proactive measures to develop and implement medication take-back campaigns, along with methods aimed at increasing public awareness on this issue. Lastly, all community members must take up the duty and responsibility of protecting the environment and preventing the unethical discharge of chemical substances, such as drugs, that may harm the natural environment.\n\nOur findings underscore the need to implement a comprehensive waste management plan at the national level. This strategy should clearly outline the responsibilities of healthcare practitioners, governmental and non-governmental entities, and the pharmaceutical sector. Various stakeholders, such as broadcasting stations, educational institutions, pharmacists, and healthcare practitioners, may contribute to disseminating knowledge via educational initiatives. These efforts aim to enhance public understanding of the environmental implications associated with pharmaceutical residues and promote appropriate practices and disposal standards to mitigate medicine waste.",
"appendix": "Data availability\n\nZenodo: Assessment of general population knowledge, attitude, and practice on safe unused and expired drugs disposal: a cross-sectional study, https://doi.org/10.5281/zenodo.8407783. 50\n\nThis project contains the following underlying data:\n\n- Underlying data new version.xlsx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nZenodo: Assessment of general population knowledge, attitude, and practice on safe unused and expired drugs disposal: a cross-sectional study [questionnaire], https://doi.org/10.5281/zenodo.8408349. 51\n\nThis project contains the following extended data:\n\n- General population questionnaire.pdf\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nWe would like to thank Dr. Dhia Jabbar Kadhim, the head of Clinical Pharmacy Department at the University of Baghdad College of Pharmacy, for his help. 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Publisher Full Text\n\nDepledge M: Reduce drug waste in the environment. Nature. 2011; 478(7367): 36–136. Publisher Full Text\n\nBataduwaarachchi VR, Weeraratne CL: Global medication waste management practices: Challenges and opportunities in developing countries. Int. J. Basic Clin. Pharmacol. 2016; 5(6): 2290–2294.\n\nDias-Ferreira C, Valente S, Vaz J: Practices of pharmaceutical waste generation and discarding in households across Portugal. Waste Manag. Res. 2016; 34(10): 1006–1013. PubMed Abstract | Publisher Full Text\n\nAlthagafi A, Alshibani M, Alshehri S, et al.: Assessment of knowledge and awareness of safe disposal of unused or expired medication in Saudi Arabia: A cross-sectional study. Saudi Pharm. J. 2022; 30(11): 1672–1678. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKahsay H, Ahmedin M, Kebede B, et al.: Assessment of knowledge, attitude, and disposal practice of unused and expired pharmaceuticals in community of Adigrat City, Northern Ethiopia. J. Environ. Public Health. 2020; 2020: 1–11. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHajj A, Hachem R, Khoury R, et al.: Clinical and genetic factors associated with anxiety and depression in breast cancer patients: a cross-sectional study. BMC Cancer. 2021; 21(1): 872. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBurki MR, Shakeel S, Hayat S, et al.: Evaluation of knowledge, attitude and practices of university students towards rational use of medicines. Med. Sci. 2020; 24(106): 4425–4437.\n\nMulugeta R, Merhawi B, Merhawi D, et al.: Knowledge, attitude and practice of antibiotics and their determinants in Eritrea: an urban population-based survey. BMJ Open. 2021; 11(9): e046432. Publisher Full Text\n\nLai PSM, Tan KM, Lee HG, et al.: Effectiveness of an intervention to increase the knowledge, attitude, and practice regarding the return and disposal of unused medications. Malaysian Family Physician: The Official Journal of the Academy of Family Physicians of Malaysia. 2021; 16(1): 56–63. Publisher Full Text\n\nSonowal S, Desai C, Kapadia JD, et al.: A survey of knowledge, attitude, and practice of consumers at a tertiary care hospital regarding the disposal of unused medicines. Journal of Basic and Clinical Pharmacy. 2016; 8(1): 4. Publisher Full Text\n\nKahsay H, Ahmedin M, Kebede B, et al.: Assessment of Knowledge, Attitude, and Disposal Practice of Unused and Expired Pharmaceuticals in Community of Adigrat City, Northern Ethiopia. J. Environ. Public Health. 2020; 2020: 6725423.\n\nHwang B-D: Storage and disposal of unused medications for housewives in the Busan Metropolitan City. The Korean Journal of Health Service Management. 2013; 7(2): 69–79. Publisher Full Text\n\nChasler J, Subramaniam V: Tips for disposal of unused and expired medications. Pharmacy Practice News. 2011; 30–34.\n\nKuspis DA, Krenzelok EP: What happens to expired medications? A survey of community medication disposal. Vet. Hum. Toxicol. 1996; 38(1): 48–49. PubMed Abstract\n\nAzad MAK, Akhtaruzzaman MRHAM, Al-Mamun SMM, et al.: Disposal practice for unused medications amongthe students of the International Islamic UniversityMalaysia. J. Appl. Pharm. Sci. 2012; 2(7): 101–106.\n\nGlassmeyer ST, Hinchey EK, Boehme SE, et al.: Disposal practices for unwanted residential medications in the United States. Environ. Int. 2009; 35(3): 566–572. PubMed Abstract | Publisher Full Text\n\nLamb A: Pharmacists’ Role in Safe and Legal Medication Disposal.2012.\n\nMohammed A-uM: Assessment of general population knowledge, attitude, and practice on safe unused and expired drugs disposal: a cross-sectional study.2023. Publisher Full Text\n\nMohammed A-uM: Assessment of general population knowledge, attitude, and practice on safe unused and expired drugs disposal: a cross-sectional study [questionnaire].2023. Publisher Full Text"
}
|
[
{
"id": "235077",
"date": "05 Feb 2024",
"name": "Sangeetha Raja",
"expertise": [
"Reviewer Expertise Pharmacogenomics",
"Preclinical studies",
"environmental study"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper exhibits overall clarity in language, though some sentences could be refined for enhanced coherence. While the paper's structure is well-organized, smoother transitions between sections would improve the reading experience. The introduction effectively emphasizes global concerns about medication disposal but lacks specificity regarding the issue's prevalence in Iraq, diminishing its regional impact. Strengthening this with specific information on the region would enhance the introduction. The study design and data collection methods are well-described, yet additional details on questionnaire development, validation, and the pilot phase would augment methodological rigor. The mention of ethical approval is present, but further elaboration on ethical considerations, particularly the voluntary nature of participation and anonymity assurance, would be beneficial. The rationale for the sample size of 591 individuals needs more justification, and clarifying the exclusion of healthcare workers is advisable. The comprehensive results section covers participant demographics, knowledge, attitudes, and practices. Presenting data visually, such as through tables and figures, would enhance readability. The discussion adeptly compares findings with existing literature but lacks a deeper analysis of implications for public health and the environment. While limitations are appropriately acknowledged, discussing how these limitations might influence study outcomes would enhance transparency. The conclusion succinctly summarizes key findings, but reinforcing practical implications and offering specific recommendations for policymakers, healthcare providers, and the general public based on study findings would strengthen this section.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "235073",
"date": "06 Mar 2024",
"name": "Souraya Domiati",
"expertise": [
"Reviewer Expertise Pharmacology and epidemiology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article overall is well designed and written yet there are some comments. Abstract: 1. The background in the abstract should be rewritten especially the first sentence stating that it is\" well-recognized issue that has convened growing recognition in several contexts\" (recognized and recognition) 2. 50% is not the majority. 3. what is meant in the conclusion by prescriptions? Please change the word. Method: 1. Please state the name of the ethical guidelines and regulations you followed. 2. Did you check for the normality of your data? Results: 1. omit \"that\" in the second paragraph. 2. No need for figure 1. It is just a repetition of the table 2. 3. Please specify, in the method section, how the attitude was scored using the 5 point Likert scale. Is neutral calculated as 3?? 4. Please double-check if your data was normally distributed otherwise you have to use non-parametric tests. 5. The knowledge score was not shown in the results. Discussion: 1. If the participants answered 4 items out of 8 correctly, we cannot conclude that their knowledge is satisfactory. 2. You assumed that \" those who have higher levels of education and have more financial stability are inclined to exhibit a more intuitive preference towards seeking knowledge\" but you did not do a multivariate analysis. You just analyzed every item alone.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "235068",
"date": "20 Mar 2024",
"name": "Miteshkumar Maurya",
"expertise": [
"Reviewer Expertise Pharmacology and Therapeutics",
"Clinical Pharmacology",
"Pharmacogenetics",
"Pharmacovigilance"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis cross-sectional study is well designed and executed and gives good information for specified population. However, kindly address the following points- 1. Basis of calculation of sample size need justification/reference eg. based on response rate of previous published study and what response rate could you get out of total targeted sample size 2. Elaborate some more points on the inclusion and exclusion criteria eg. some participants would not have access to emails and may have not been able to participate in survey adding to bias in the result outcomes. May be your results are reflective of literate/ educated population KAP having access to google forms only. Please justify if you have overcome these challenges/or specify in limitations. 3. Please add a reference of an article you used for content validity method for your questionnaire. 4. You may site this relevant article -Munshi R, Dhiman A, Maurya M. A cross-sectional survey to assess the drug disposal practices of unused and expired medicines among lay public visiting a tertiary care hospital in an urban metropolis. Indian J Physiol Pharmacol 2023;67:29-35.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1333
|
https://f1000research.com/articles/12-1332/v1
|
16 Oct 23
|
{
"type": "Research Article",
"title": "Developing potential drugs for insomnia through computational analysis",
"authors": [
"Isaac Oronyi",
"Richard Kagia",
"Richard Kagia"
],
"abstract": "Introduction: Insomnia is a condition that affects the quality of life of an individual. It is associated with a lack of sleep or interrupted sleep. If not managed, insomnia may end up causing conditions such as obesity, heart conditions, hypertension, and mental disorders. Lack of sleep is also associated with an increased risk of Alzheimer’s disease. There is, therefore, a need to develop a drug that manages insomnia with desirable clinical outcomes\nMethods: The canonical smiles of Zolpidem, Suvorexant, Ramelteon, and Triazolam were obtained from PubChem. The study used the online tool SwissSimilarity to identify structural analogs for Zolpidem, Suvorexant, Ramelteon, and Triazolam. The canonical smiles were copied to PubChem Sketcher were converted to a 2- dimensional (2D) format. The Avogadro was used to optimize the ligands. The respective receptors were obtained from the Protein Data Bank. Chimera was used to prepare the receptor and the docking, using AutoDock Vina. SwissADME and Protox server was used in the determination of the pharmacokinetics and toxicity profiles, respectively.\nResults: Docking scores, pharmacokinetics, and toxicity profiles of the analogs were recorded. Nine structural analogs from the ZINC database (ZINC000004222622, ZINC000003981996, ZINC000003825731, ZINC000000000903, ZINC000039247014, ZINC000010152022, ZINC000000347721, ZINC000065743121 ZINC000022054496) were found to have a better docking score, blood brain barrier permeability, Lipinski’s violations, synthesizability index, gastrointestinal tract absorption, p-glycoprotein substrate metabolism LD50 compared to the parent drug molecules. All the nine molecules had good synthesizability index, gastrointestinal absorption and zero Lipinski violations indicating good oral availability.\nConclusions: Ramelteon analogs ZINC000004222622, ZINC000003981996, and ZINC000003825731, Triazolam drug-like molecules, ZINC000000000903, ZINC000039247014, ZINC000010152022, and ZINC000000347721 and Zolpidem drug-like molecules ZINC000065743121 and ZINC000022054496 were identified as the best compound bases on the pharmacokinetic binding to the respective receptors and toxicity profiles.",
"keywords": [
"Insomnia",
"Computational analysis",
"MTR – Melatonin Receptor",
"CYP450 - Cytochrome P450",
"GABA - Gamma-Aminobutyric Acid",
"FDA- Food and Drug Administration CNS -Central Nervous System."
],
"content": "Introduction\n\nSleep is considered an essential component of both physical and mental health. Sleep is especially important in the development of the immune system restoration, regulation of emotions, support of cognitive function in human learning, and brain recuperation processes.1 It is recommended that adults sleep for about seven to eight hours a day while in infants, sleeping hours may be increased up to between 14 and 17 hours a day.2 Sleep deprivation, is associated with physical and mental disorders that may eventually lead to conditions such as weight gain, heart disease, and diabetes.3 Lack of sleep has also been associated with suicidal ideation.2,3 Sleep also helps with the clearance of toxic materials from the brain through the glymphatic system.4 This system works 20 folds during sleep than when an individual is awake. Alzheimer’s is believed to be caused by toxic materials such as amyloid and tau proteins.4 Lack of adequate sleep is considered a risk factor for Alzheimer’s disease.4\n\nInsomnia is a condition in which an individual complains of a lack of sleep. These individuals have difficulty in the initiation and maintenance of sleep.5 Insomnia is a condition that affects an individual’s psychological, physical, biological, and social well-being.6 About one-third of the adult population presents with a symptom of insomnia.7 It is more prevalent in women compared to men.8 Individuals who are prone to conditions such as anxiety and those taking certain medication such as antiretrovirals may be disposed of this condition.8 Insomnia can lead to conditions such as depression, coronary heart disease, hypertension, diabetes, and severe migraine.8 Insomnia has also been indicated as a major cause of atrial fibrillation in postmenopausal women.9\n\nInsomnia can be broadly classified into chronic and acute insomnia.7 Acute insomnia is short-term, it can be caused by factors such as a change in environment or even stress related and may only last for days.7 On the other hand, chronic insomnia is described as the lack of sleep for more than three weeks.7 In chronic insomnia, may predispose an individual to psychiatric disorders such as anxiety and depression.10 Symptoms may differ from children to adults with adults more likely to experience more problems related to problem maintaining sleep than problem associated to starting sleep.\n\nEnvironmental factors such as exposure to stressors such as light, poor quality of air, and noise are common causes of insomnia.11 In the world of industrialization, people are migrating from rural areas to cities or towns for employment and personal reasons.12 With every country aiming to become industrialized, sound air and light pollution would be a common manifestation.12 The extremities of weather conditions may cause serious sleep-related disorders. This may be a result of interference with the normal rhythm that controls the sleep cycle.13 The current management of insomnia is based on nonpharmacological and pharmacological interventions. These therapies may be limited based on the tolerance, side effects and the suitability of the given drug for the patient.14\n\nPrescription drugs such as antidepressants, stimulants, bronchodilators such as theophylline, steroids, diuretics15 and some antiretroviral such as efavirenz,16 may present with insomnia as a side effect. The regimen may be designed for twice or three times daily. The patient may need to take the medication every eight hours or 12 hours respectively within a 24-hour interval which may end up interfering with sleep patterns.15 Short acting benzodiazepines and hypnotics are also associated with rebound insomnia as a as a result of chronic use of the drugs.17\n\nPharmacological treatment of insomnia is aimed at improving the quality of sleep. Currently, the European sleep research society has approved guidelines that are used in the treatment of insomnia.18 The classes of drugs in the treatment of insomnia include melatonin receptor agonists, benzodiazepine receptor agonists, anti-depressants and some first-generation antihistamines.18\n\nBenzodiazepine receptor agonists work by binding to the gamma-aminobutyric acid (GABA) receptor. The drugs act as positive allosteric modulators increasing the inward flow of chloride ions. This causes depression of the central nervous system causing sleep.19 The GABBA receptor agonists include both benzodiazepines and the non-benzodiazepines, such as the Z-compounds; Zolpidem and Zaleplon. Quazepam is an The Food and Drug Administration (FDA)-approved benzodiazepine used in the treatment of chronic insomnia. Triazolam, Flurazepam, and Temazepam have been indicated in the treatment of sleep-onset insomnia. Temazepam is the most prescribed drug for insomnia.20,21 Benzodiazepines are common for abuse. For example, Flurazepam has been used in crime for stupefying people.19 These drugs are also associated with tolerance and these drugs are not advised to be given to patients during pregnancy.19\n\nZolpidem has been associated with increased orthostatic hypotension in hospitalized patients, confusion, dizziness, suicidal ideation, rebound insomnia, and daytime sedation.22 It has been categorized in class C. Women in pregnancy are at risk of getting children with a low weight if they take Zolpidem during pregnancy.22,23\n\nZaleplon is available as intravenous and oral preparations. Has the same side effects as zolpidem but has high incidences of hallucination and hypersensitivity22,23 The dose should also be decreased in the elderly because of their slow metabolism.23\n\nAntihistamine drugs are also another group of drugs used in the treatment of insomnia. The commonly used drugs include diphenylamine, doxylamine, and chlorpheniramine. They work by H1 receptor antagonism.20 Their application utilizes the side effect associated with first generations of antihistamines which is sedation. Although they are usually sold over the counter, these drugs are characterized by rapid tolerance and possible anticholinergic side effects such as urinary retention dry mouth, confusion, and constipation which may become worse as the dose is increased to obtain the desired effects.23 Their rapid availability over the counter commonly allows misuse. They are not preferred as first line treatment because they are contraindicated in patients with concurrent medical conditions glaucoma, asthma, and bladder obstruction.24\n\nMelatonin receptor agonists are drugs that work by the activation of the melatonin receptors M1 and M2. Melatonin regulates the sleep-wake cycle and at the same time reproduction activities and growth that commonly happens during sleep.25 The common drugs that have been used include Ramelteon and Melatonin. Others include Tasimelteon and agomelatine. Melatonin is rarely used because of the short duration of action.24\n\nRamelteon binds to MTR1 and MTR2, this causes a reduction sleep-onset latency, slightly improve sleep efficiency and increase total sleep time.24,26 Although ramelteon has been described as not tending to cause tolerance and rebound insomnia, clinical trials did prove that ramelteon dosage at 8 milligrams may cause, retropharyngeal pain, depression galactorrhea, decreased libido, upper respiratory tract infections and exacerbated insomnia. This drug is also expensive and hence not readily available.26\n\nOrexin receptor antagonist suvorexant approved in the year 2014, and was first marketed for insomnia.20 Orexin receptor antagonists influence patient wakefulness and sleep. The antagonism of this receptor is associated with decreased wakefulness.20 Although the medication does not need adjustment in patients with renal and hepatic insufficiencies, the drug is a category c medication. The adverse effects are limited as compared to other drugs used for insomnia but the drug is comparatively costly.27\n\nDoxepin is a tricyclic anti-depressant. It has been approved for the treatment of insomnia based on its activity on the H1 receptor is associated improvement of sleep latency.20 It is a category C drug, with wide metabolism by the CYP2D6 and CYP2C19 enzymes. This property makes the administration of the drug hard with drugs that are inhibitors or inducers of those enzymes. Patients on doxepin may also experience allergic reactions.28\n\nDrug development involves analyzing vast libraries of compounds for their capacity to bind to a target protein. Preclinical testing, clinical trials, and identifying possible drug candidates are all steps in drug discovery and development.29 Virtual screening is a computational technique used in drug development to find prospective therapeutic candidates. Ligand-based virtual screening is a subset of virtual screening that looks for novel ligands with similar binding properties using the 3D structure of an existing ligand.30,31 This technique has been used in the discovery of drugs that are currently or being studied in use in conditions such as COVID-19, cancer, and Alzheimer’s disease.4,32 There is a gap in drug development through virtual screening in the development of insomnia drugs.33\n\nThis study works in line with the currently ongoing research for a drug that is most effective in the treatment of insomnia. Zolpidem, suvorexant, ramelteon, and triazolam are analyzed. The aim is to get a drug that can be given to patients in such a way the patient could continue their current medications and at the same time have a good sleep hence, the drug should have very few interactions with the drugs in concurrent use. The drugs should be effective in the lowest concertation given to patients suffering from insomnia. This means the drugs should then have a better docking score compared to the current drugs used. The drugs should also have minimal side effects. The drug should also be effective in insomnia related to environmental changes. It should also be able to treat the condition completely and treat the patient with the fewest doses possible. The drug should also be safe to use during pregnancy. In general, we aim at getting a drug with better pharmacokinetics pharmacodynamics, and pharmacogenomics compared to the current drugs in use.\n\n\nMethods\n\nThe canonical smiles of Suvorexant, Ramelteon, Zolpidem and Triazolam were individually searched and copied from PubChem online library (RRID:SCR_004284). The Canonical smiles obtained were pasted into the SwissSimilarity search bar. The class of drugs was set as commercial. The combined, Zinc-Drug like was selected with combines 2D and 3D. This was used as a query to generate similar molecular structures from the ZINC database through ligand based virtual screening. The red search button of the page was clicked to allow the query to begin, which took a few minutes to generate the final results. The generated results were downloaded and saved as an excel file.\n\nThe receptors were obtained from the protein data bank GABA-A receptor, Orexin receptor, and melatonin receptor were individually searched on protein data bank (RRID:SCR_012820) search bar and downloaded using the ‘Download file’ option available on the Protein Data Bank. The receptors were saved in the project directory. The receptors were “Cleaned” by removing all non-standard compounds by clicking on the “Select” option on chimera, then selecting all non-standard compounds, and finally deleting using the ‘Actions’ option on chimera software (RRID: SCR_004097).\n\nThe first 20 canonical smiles of each parent drug compound, were pasted in the search bar at PubChem Sketcher and enter button clicked to allow the generation of a to a 2D molecular structure. The generated structure was saved as “All files” format by clicking the export button present in PubChem Sketcher to the Project folder in the desktop. PubChem Sketcher was refreshed before the next canonical smile was inserted for the next query.\n\nThe Avogadro software (RRID: SCR_011958) was opened. The software was used to open the 2D files which were generated from the project folder in the Desktop. The 2D structures of the analogs and the drug compounds were converted to 3D structures automatically, by opening them individually, and clicking “yes” on the prompt by Avogadro to generate a 3D model of the 2D structure that was being opened. The 3D generated structure was optimized by clicking the auto optimization option provided in Avogadro. The settings were set to MMF94s force field, and fixed atoms movable, on the Algorithm settings. The start button was clicked and the structure was allowed to form the most stable conformation. The most stable conformation was determined when the Auto optimization energy became constant. The resulting structure was saved as a.mol file to be used in the next step in chimera.\n\nThe optimized ligands were then opened and minimized (to add charges and hydrogen) using the Chimera software. This was done by clicking tools, then structure editing, using the steric only settings and then Gasteiger as the other residues, in the setting section. The resulting minimized structure was saved in the project folder to for the next process of docking\n\nThe minimized ligands and the cleaned receptor were opened simultaneously in Chimera. The docking process was initiated where the ligands were docked with their respective receptors using the chimera software, embedded with AutoDock Vina (RRID: SCR_011958). The docked compounds with better docking scores than the parent compounds were afterwards analyzed using the Biovia Discovery studio (RRID: SCR_01565) to determine the interaction between the receptor and the ligand using the 2D and 3D models of the complexes.\n\nThe canonical smiles of compound found to have a better docking score than the parent compounds were pasted on SwissADME online tool search box and queried to determine possible pharmacokinetic properties. The results were saved as an excel file. The results contained parameters such as Blood brain barrier permeability, the Lipinski’s violations, Gastrointestinal tract absorption, p-glycoprotein substrate, metabolism and synthesizability index which were used in the study.\n\nThe Protox online tool was used to predict the toxicities of the compounds. The canonical smiles of the parent drug compounds and the analogues were pasted individually on the search bar in the Protox server and queried for the toxicity profiles prediction. The parameters that were analyzed included the individual toxicities based on the LD50 were automatically generated with the Protox which was directly obtained from the search results.\n\nTables of the specific analogues (Table 1, Table 2, Table 3 and Table 4) were recorded showing various data obtained. The data include the docking scores, the pharmacokinetic profile, and the toxicities profile.\n\n\nResults and discussion\n\nSuvorexant interacts with the orexin receptor through van der Waal forces hydrogen bonds, carbon-sulfur, Pi-sulfur, Pi-Pi alkyl, alkyl, and Pi alkyl (Figure 1). The increase in interaction forces between the receptor and the drug molecule increases the duration of activity of the drug in the receptor hence the activity of the drug and decreasing the concentration of the drugs needed to provide therapeutic effects.4\n\nDocking scores, pharmacokinetic and toxicity profiles of 20 compounds similar to suvorexant were analyzed. From the 20 molecules, 12 compounds (Table 1) showed better docking scores compared to the parent drug. All the molecules showed higher Gastrointestinal absorption indicating that the molecules can easily be administered orally.34 The parent molecule had a poor penetration to the central nervous system (CNS) which is their site of action. five molecules showed higher CNS bioavailability as compared to the parent compound. They include ZINC000206774725, ZINC000206774070, ZINC000206774330, ZINC000206774469 and ZINC000253409181.\n\nSuvorexant\n\nZINC000206774070 and ZINC000206774469 have good CNS penetration ability but those molecules are good substrates of P-glycoprotein. P-glycoprotein is a transporter that decreases the absorption of a drug by pumping the molecule back into the lumen. As a substrate of P-glycoprotein, the drug concentration may not be enough to cause the desired therapeutic effects.31\n\nAll the molecules do not have any Lipinski violation. A molecule that violates Lipinski’s rule of five indicates its limited bioavailability and oral absorption, these substances may need to be administered via other methods. In drug development, the rule is often applied.35\n\nZINC000206774725, ZINC000206774330, and ZINC000253409181 are not a substrate of P-glycoprotein (Table 3). These molecules on the other hand have a greater Cytochrome P450 (CYP) enzyme interaction compared to the parent molecule. They all interact with CYP 1A2,2C9, 2C19 2D6,3A4 as an inhibitor. These enzymes are essential in the metabolism of many drugs.36 Inhibition of those molecules may cause a serious interaction with other drugs which are administered to the patient. The molecules can all be synthesized. They all have a synthesizability index of above 3.2.\n\nLD50 was used in the estimation of the molecule’s toxicity profile. This is a dose that is necessary to kill 50% of the population or test subjects. As a result, a higher LD50 value implies that a drug is less dangerous since a larger dose is required to kill half of the population or test subjects.37 ZINC000206774725, ZINC000206774330, and ZINC000253409181 have a higher LD50 compared to the parent compound; suvorexant indicating that the molecules are safer compared to the parent molecule.\n\nDocking scores, pharmacokinetic and toxicity profiles of Ramelteon interacts with the melatonin receptor by the van der Waal forces hydrogen bonds, alkyl, and Pi alkyl (Figure 2). Van der Waal forces are the weakest involved in the interaction while the hydrogen bonds are the strongest forces involved.35\n\nRamelteon\n\n20 molecules similar to Ramelteon were analyzed. Thirteen compounds showed better docking scores compared to the parent molecule Ramelteon (Table 2). Out of the 13 compounds, two compounds had better pharmacokinetic properties compared to the parent compound. The two compounds ZINC000003825731, and ZINC000004222622 (Table 2) were affecting metabolism by affecting only the CYP2D6 enzyme compared to the parent compound affected which inhibits two enzymes CYP 2D6 and CYP 2C19.\n\nInhibition of the CYP enzymes may cause increased cases of drug-drug interactions associated with a particular drug. The parent drug interacts with more cytochrome enzymes compared to the ZINC000003825731, and ZINC000004222622 which only interact with one enzyme.\n\nRamelteon is a substrate for p-glycoprotein and hence may lead to the reduction of the concentration of the drugs in the CNS. P-glycoproteins proteins work to reduce the concentration thus reducing intracellular drug accumulation leading to treatment failure or increased concentration of the drugs used. The two molecules show fewer interactions with this protein which may improve the bioavailability after administration and at the same time decrease dose of administration of the drug and better clinical performance.\n\nThe molecules also have good oral bioavailability. They also pass and also cross the blood-brain barrier where they can execute their function.\n\nThey are both synthesizable. The synthesizability of ZINC000003825731 is 2.91 and ZINC000004222622 is 3.28 compared to that of 2.91 of Ramelteon. The synthesizability index of a molecule indicates how easy a drug is to be synthesized.\n\nTriazolam interacts with the GABA A receptor through van der Waals forces (Figure 3). These are forces that attract neutral molecules to one another in gases solids and liquids. The binding may be weaker than that of other forms of interactions, such as hydrogen bonding or electrostatic interactions. This may reduce the drug’s potency and at the same time increase the drug selectivity.37\n\nTriazolam had a docking score of -8.1 (Table 3). Nine molecules had a better docking score compared to triazolam. Of the nine molecules, only one molecule, ZINC000000702142, has poor penetration to the CNS this indicates that the molecule may not be able to reach the site of action. All the molecules have good oral bioavailability. All the molecules are substrates of the P-glycoprotein. This indicated that the molecules have less bioavailability.34\n\nTriazolam\n\nZINC000000000903, ZINC000010152022, and ZINC000000347721 do not interact with the CYP 3A4. The CYP3A4 enzyme is involved in the metabolism of the majority of drugs36 including Statins, Calcium channel blockers, Benzodiazepines, Macrolide Antibiotics, Antidepressants, Antipsychotics, Immunosuppressants, and Opioids. This makes it a potential for interaction with any drugs hence the need to be careful during co-administration. ZINC000000000903 interacts with only one enzyme CYP 1A2. This molecule has then very few interactions as compared to the other molecules.36 These molecules studies have a higher LD50; ZINC000000000903(1080 mg/kg), ZINC000010152022(1080 mg/kg), ZINC000000347721(1080 mg/kg) compared to triazolam (695 mg/kg) (Table 3).\n\nZolpidem interacts with the GABA A receptor through hydrogen bonds and van der Waal forces (Figure 4). This provides a stronger receptor drug-receptor complex as compared to triazolam. interactions with, arginine, serine, methionine, and leucine at positions 5 1, and 3, and two interactions between proline and arginine at locations 49 and 50 and 6 and 7 respectively.\n\nZolpidem has a docking score of -8.0. 10 molecules had a better docking score compared to the parent molecule (Table 4). Of the 10 molecules ZINC000041288365 and ZINC000426519011 are substrates of P-glycoprotein transporters indicating that the rest of the molecules have a good oral bioavailability. ZINC000065743121 and ZINC000022054496 have very little interaction with CYP 2D6 molecule but interact with CYP 1A2,2C9, 2C19, and 3A4. The rest of the molecules interact with CYP 1A2,2C9, 2C19 2D6, and 3A4 as inhibitors. This increases the range of drugs the molecules can interact with during the administration.\n\nZolpidem\n\nZolpidem has an LD50 of 695 mg/kg. ZINC000022054496 has the highest LD50 value of 1190 mg/kg. ZINC000065743121 has an LD50 of 1000 mg/kg. which is better than the parent molecule. The two molecules can be given at high concentrations compared to zolpidem without the patient experiencing serious adverse effects.38 GI absorption of the drugs of all the molecules is good indicating they can be issued orally. The molecules have no Lipinski violations with a synthesizability index of above 2.5. This is an indication that the drug molecules can be synthesized.\n\n\nConclusions\n\nThe study identifies nine molecules from the Zinc database that have better docking scores pharmacokinetic and toxicity profiles compared to the parent compounds. Ramelteon analogs ZINC000004222622, ZINC000003981996, and ZINC000003825731 are potential drugs for development. They have good pharmacokinetic and toxicity profiles. The drugs interact with either their MT1 and MT2 receptors better compared to the parent molecule. These molecules are also synthesizable. Suvorexant analogs have a better docking score compared to the parent compound but the pharmacokinetic profiles are not better than the parent molecule. Triazolam drug-like molecules, ZINC000000000903, ZINC000039247014, ZINC000010152022, and ZINC000000347721 have better pharmacokinetic profiles compared to the parent compound. They show better binding to the GABA-A receptor compared to the GABA-A receptor suggesting better activity. These compounds are all synthesizable and with good GI bioavailability suggesting that the molecules can be taken orally.31 Zolpidem drug-like molecules ZINC000065743121 and ZINC000022054496 show better pharmacokinetic and toxicity profiles compared to the parent compound. All the molecules are synthesizable.\n\nIn-vitro studies should be conducted for the 9 molecules, ZINC000003981996, ZINC000003825731, ZINC000004222622 ZINC000000000903, ZINC000039247014, ZINC000010152022, ZINC000065743121, and ZINC000022054496 to ensure to determine their activity in the human subject. The molecules should undergo in vivo structure-activity relationship analysis for optimization before testing in their respective receptor.\n\nThe canonical smiles of the Parent compounds (Ramelteon, Zolpidem, Suvorexant and Triazolam) were obtained from PubChem\n\nStructural analogues of the Parent compounds were obtained from SwissSimilarity\n\nThe pharmacokinetic profiles of the structural analogues and the Parent compounds were obtained from SwissADME\n\nProtein Receptors of the parent drugs compounds and their analogues were obtained from the Protein data bank\n\nToxicity profile of the parent compounds and their structural analogues were obtained from the Protox server\n\nFigshare: Developing potential drugs for insomnia through computational analysis: https://doi.org/10.6084/m9.figshare.23674614.39\n\nThis project contains the following underlying data\n\n- Pharmacokinetisc of Ramelteon and its analogues.csv\n\n- Canonical smiles of results for Suvorexant analogues.csv\n\n- Pharmacokinetisc of Suvorexant and its analogues.csv\n\n- Cannonical smiles of triazolam analogues.csv\n\n- Pharmacokinetisc of Triazolam and its analogues.csv\n\n- Pharmacokinetisc of Zolpidem and its analogues.csv\n\n- Canonical Smiles for Zolpidem analogues.csv\n\nFigshare: Developing potential drugs for insomnia through computational analysis: https://doi.org/10.6084/m9.figshare.23674614.39\n\n- Figures.docx\n\n- Results Summary.docx\n\n- Pharmacokinetic Properties.docx\n\n- Docking Scores.docx\n\n- Toxicity Profiles.docx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nWorley SL: The extraordinary importance of sleep: the detrimental effects of inadequate sleep on health and public safety drive an explosion of sleep research. P. T. 2018; 43(12): 758–763. PubMed Abstract | Free Full Text\n\nMcCall WV, Benca RM, Rosenquist PB, et al.: Reducing suicidal ideation through insomnia treatment (REST-IT): a randomized clinical trial. Am. J. Psychiatr. 2019; 176(11): 957–965. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWatson NF, Badr MS, Belenky G, et al.: The recommended amount of sleep for a healthy adult: A joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society. Sleep. 2015; 38(6): 843–844. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHan F, Chen J, Belkin-Rosen A, et al.: Alzheimer’s Disease Neuroimaging Initiative Reduced coupling between cerebrospinal fluid flow and global brain activity is linked to Alzheimer disease-related pathology. PLoS Biol. 2021 Jun 1; 19(6): e3001233. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMarais AM, Osuch EO: Insomnia: what is currently available. S. Afr. Gen. Pract. 2020; 1(1): 39–41. Publisher Full Text\n\nIshak WW, Bagot K, Thomas S, et al.: Quality of life in patients suffering from insomnia. Innov. Clin. Neurosci. 2012; 9(10): 13. Reference Source\n\nOhayon MM: Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med. Rev. 2002; 6(2): 97–111. PubMed Abstract | Publisher Full Text Reference Source\n\nKupfer DJ, Reynolds CF: Management of insomnia. N. Engl. J. Med. 1997; 336(5): 341–346. PubMed Abstract | Publisher Full Text\n\nTandon VR, Sharma S, Mahajan A, et al.: Menopause and sleep disorders. J. Midlife Health. 2022; 13(1): 26–33. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBuscemi N, Vandermeer B, Friesen C, et al.: Manifestations and management of chronic insomnia in adults: Summary. AHRQ evidence report summaries. 2005.\n\nMeltzer LJ, Hiruma LS, Avis KT, et al.: Comparison of a web-based vs in-person cognitive behavioral insomnia therapy for individuals with comorbid conditions: A randomized clinical trial. JAMA Netw. Open. 2019; 2(5): e194258–e194258. Publisher Full Text\n\nLiu Y, Zhou L, Yang J, et al.: The impact of urban migration on rural communities in China. J. Rural. Stud. 2019; 64: 63–72. Publisher Full Text\n\nMattingly SM, Grover T, Martinez GJ, et al.: The effects of seasons and weather on sleep patterns measured through longitudinal multimodal sensing. NPJ Digit. Med. 2021; 4: 76. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAnderson PO: Treating Insomnia During Breastfeeding. Breastfeed. Med. 2022; 17(3): 207–209. PubMed Abstract | Publisher Full Text\n\nHugel H, Ellershaw JE, Cook L, et al.: The prevalence, key causes and management of insomnia in palliative care patients. J. Pain Symptom Manag. 2004; 27(4): 316–321. Publisher Full Text\n\nAbers MS, Shandera WX, Kass JS: Neurological and Psychiatric Adverse Effects of Antiretroviral Drugs. CNS Drugs. 2014; 28: 131–145. PubMed Abstract | Publisher Full Text\n\nMalangu N: Drugs inducing insomnia as an adverse effect. Can’t sleep. 2012; 23–36. Reference Source\n\nRiemann D, Baglioni C, Bassetti C, et al.: European guidelines for the diagnosis and treatment of insomnia. J. Sleep Res. 2017; 26(6): 675–700. PubMed Abstract | Publisher Full Text\n\nSanabria E, Cuenca RE, Esteso MÁ, et al.: Benzodiazepines: They’re used either as essential medicines or as toxic substances. Toxins. 2021; 9(2): 25. Reference Source\n\nLie JD, Tu KN, Shen DD, et al.: Pharmacological treatment of insomnia. Pharmacy and Therapeutics. 2015; 40(11): 759.\n\nBounds CG, Nelson VL: Benzodiazepines. StatPearls. StatPearls Publishing; 2021. Reference Source\n\nEdinoff AN, Wu N, Ghaffar YT, et al.: Zolpidem: efficacy and side effects for insomnia. Health Psychol. Res. 2021; 9(1). Publisher Full Text Reference Source\n\nBhandari P, Sapra A: Zaleplon.2019. Reference Source\n\nBrott NR, Reddivari AKR: Doxylamine.2019. Reference Source\n\nDevi V, Shankar PK: Ramelteon: A melatonin receptor agonist for the treatment of insomnia. J. Postgrad. Med. 2008 [cited 2023 Feb 17]; 54: 45–48. Publisher Full Text Reference Source\n\nSys J, Van Cleynenbreugel S, Deschodt M, et al.: Efficacy and safety of non-benzodiazepine and non-Z-drug hypnotic medication for insomnia in older people: a systematic literature review. Eur. J. Clin. Pharmacol. 2020; 76: 363–381. Publisher Full Text\n\nMuehlan C, Vaillant C, Zenklusen I, et al.: Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders. Expert Opin. Drug Metab. Toxicol. 2020; 16(11): 1063–1078. PubMed Abstract | Publisher Full Text\n\nDoxepin (Oral Route) Description and Brand Names. http\n\nBajorath J: Integration of virtual and high-throughput screening. Nat. Rev. Drug Discov. 2002; 1(11): 882–894. Publisher Full Text\n\nDeveloping a Drug-like Natural Product Library|Journal of Natural Products.n.d. Accessed March 18, 2023. Publisher Full Text\n\nLigand-Based Screening - Creative Biolabs.n.d. Accessed March 6, 2023. Reference Source\n\nTian F, Tong B, Sun L, et al.: N501Y mutation of spike protein in SARS-CoV-2 strengthens its binding to receptor ACE2. elife. 2021; 10: e69091. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDąbrowska K: Phage Therapy: What Factors Shape Phage Pharmacokinetics and Bioavailability? Systematic and Critical Review. Med. Res. Rev. 2019; 39(5): 2000–2025. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDisrupting P-Glycoprotein Function in Clinical Settings: What Can We Learn from the Fundamental Aspects of This Transporter? - PMC.n.d. Accessed March 18, 2023. Reference Source\n\nWaals forces|Intermolecular Interactions & Applications|Britannica. (n.d.). Retrieved October 12, 2023. https://protect-us.mimecast.com/s/LbffCADQm5Ur48Dl4uGttlH?domain=britannica.comhttps://www.britannica.com/science/van-der-Waals-forces\n\nZhang RX, Dong K, Wang Z, et al.: Nanoparticulate drug delivery strategies to address intestinal cytochrome P450 CYP3A4 metabolism towards personalized medicine. Pharmaceutics. 2021; 13(8): 1261. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBast A: Food toxicology. Applied food science. Wageningen Academic Publishers; 2022; pp. 267–288.\n\nEnyoh CE, Maduka TO, Duru CE, et al.: In sillico binding affinity studies of microbial enzymatic degradation of plastics. J. Hazard. Mater. Adv. 2022; 6: 100076. Publisher Full Text\n\nOronyi I: Developing potential drugs for insomnia through computational analysis. [Data]. figshare. 2023. Publisher Full Text"
}
|
[
{
"id": "233324",
"date": "30 Jan 2024",
"name": "Khaled M. Darwish",
"expertise": [
"Reviewer Expertise Drug discovery",
"drug development",
"molecular modelling"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAuthors of the presented manuscript computationally evaluated the potential activity of structural analogs of marketed anti-insomnia compounds against different sleep-associated biotargets. The manuscript is good however, several comments should be addressed:\nA table/figure with all chemical structures of the investigated 20 compounds should be presented. A brief introduction for the target surface topology, secondary protein structures, and pocket/binding site is recommended to allow readers to track the differential binding interaction and affinity of compounds towards the designated target. Authors should elaborate more on the docking analysis. There is a need for explicit discussion regarding the residue-wise interactions between each compound and the target. Authors should mention the Hydrogen bond angles as well as their distances, since the strength of hydrogen bonding is based on both parameters in a way to ensure the adequacy of optimum hydrogen bonding. Moreover, the authors should mention the adopted distance criteria to determine the H-bond and Hydrophobic interactions. Binding energies should be also calculated through mm-GBSA calculations using free on-line platform (HawkDock or similar). This would provide a true affinity index for ligand-target affinity. Additionally, this would allow efficient exploration for the nature of compound-target interactions where energy contribution terms (van def Waal, electrostatic, SASA solvation, polar solvation energies) could be estimated and then authors would identify which being most dominant through the MD simulation runs. Authors should elaborate more on the docking figures. The 2D representation within Figures 2 and 3 are similar!!!! and the compound is not in its full structure. The 3D representations add nothing to the docking discussion, they only represent the target in cartoon structure without zooming in to the pocket/binding site highlighting the main compound-protein residue interactions as well as the compound predicted 3D orientation and conformation within the space. Throughout a discussion section, authors should highlight the takeaway messages that would be adopted in future lead optimization and development based on the molecular docking and ADME analysis. Prospective/recommended structure modifications to improve the ligand’s binding and interactions, as well as pharmacokinetics should be provided within the discussion and conclusion sections. Finally, concerning the conclusion, authors are advised to elaborate more on the future of this work? Will you test more related drugs? Will you broaden the scope to other targets? What are the study limitations and what approaches could be conducted to further address them?\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
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https://f1000research.com/articles/12-1332
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https://f1000research.com/articles/12-763/v1
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29 Jun 23
|
{
"type": "Case Report",
"title": "Case Report: Tuberculosis lymphadenitis with systemic lupus erythematosus in a young woman: a case report",
"authors": [
"Yunita Arliny",
"Dewi Behtri Yanifitri",
"Wilia Aprilisa Utami",
"Samantha Geraldine",
"Dewi Behtri Yanifitri",
"Wilia Aprilisa Utami",
"Samantha Geraldine"
],
"abstract": "Background: Tuberculosis is a chronic infectious disease and can be categorised into pulmonary TB and extra-pulmonary TB based on its spread. TB lymphadenitis is one of the extra-pulmonary TB diseases. Patients with a weakened immune system in systemic lupus erythematosus (SLE) have an increased incidence of TB. Case: Here we present a case report of a 21-year-old female patient with SLE diagnosed with tuberculous lymphadenitis at dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia. The patient complained of a lump in the right neck 4 months ago with a diameter of 4 cm, accompanied by fever, decreased appetite, and weight loss. Other than that, the patient also experiences joint pain, hair loss and sun sensitivity since 12 months ago. Chest radiography showed no abnormalities, and fine-needle aspiration biopsy results confirmed tuberculous lymphadenitis. Antinuclear antibody test was borderline. The patient had been taking steroids and hydroxychloroquine for the past 10 months. Currently, the patient is taking the advanced phase of antituberculosis drugs FDC. After undergoing the intensive phase of antituberculosis drugs, the submandibular lump got smaller to a diameter of 2 cm. Conclusion: TB lymphadenitis is a rare case but can occur in conditions of decreased immunity like SLE. It involves some of the immune disorders caused by the long-term use of immunosuppressive therapy.",
"keywords": [
"Tuberculosis",
"TB lymphadenitis",
"Tuberculous lymphadenitis",
"Systemic Lupus Erythematosus",
"SLE"
],
"content": "Introduction\n\nTuberculosis is a chronic infectious disease caused by the bacterium Mycobacterium tuberculosis.1 Tuberculosis (TB) is still a major global health problem and remains one of the most common infectious diseases globally. It is estimated 8.6 million people suffered from TB in 2012 and it resulted in 1.3 million deaths globally.2 Indonesia placed second in the country with the most TB cases in the world.3 In its distribution, tuberculosis can be categorized into two parts: pulmonary TB and extra-pulmonary TB. Extrapulmonary TB accounts for about 15–20% of all TB cases. One example of extra-pulmonary TB disease is TB Lymphadenitis or are known as lymph node TB. Tuberculous lymphadenitis is seen in almost 35% of cases of extrapulmonary TB.4 It can affect all ages, especially those aged 10–30 years, and more often in women. Enlarged lymph nodes are most commonly seen in the neck area and sometimes in the armpit area.5 The lessened immune system in systemic lupus erythematosus (SLE) can increase the incidence of TB. It is suspected that inherent immunodeficiency states in SLE and the use of immunosuppressant agents as the treatment of SLE increased susceptibility to TB. The risk of TB in patients with autoimmune diseases has increased compared to patients without autoimmune diseases.2 In the following, we report a case of tuberculous lymphadenitis with systemic lupus erythematosus in a young woman.5\n\n\nCase description\n\nA 21-year-old Aceh female student, came to the TB-DOTS clinic at dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia with chief complaints of a lump on the right neck since 4 months ago with a diameter of 4 cm, characterized as a supple, mobile and painless lump. The patient has not complained of cough or has a history of long-standing cough. There is also no shortness of breath, chest pain, or night sweats. However, the patient has a history of fever and experienced weight loss of about 15 kg within 3 months and decreased appetite. The patient also complained of joint pain, especially in cold weather, large amounts of hair loss, feeling tired quickly to tremors when she was tired, and her skin turning red to blackish colour quickly when exposed to the sun. The patient was sent by a rheumatologist and was diagnosed with SLE 12 months ago. The patient has a history of taking hydroxychloroquine and methylprednisolone from 10 months ago. Family history showed the patient’s mother’s sister is also a patient with SLE.\n\nOn examination, vital signs showed compos mentis consciousness and stable hemodynamically. Physical examination (Figure 1A) palpable enlarged lymph node in the right submandibular, 4×2 cm in diameter, less defined, mobile, firm, supple, and painless since 4 months ago. After the patient took 4 tablets of FDC as antituberculosis drugs in the intensive phase, the size of the lymph node in the right submandibular decreased with a diameter of 2×1 cm (Figure 1B). Pulmonary physical examination was normal. The results of laboratory examinations showed hemoglobin 9.9 g/dL, leukocytes 7.59/mm3, platelets 381 103/mm3, urea 11 mg/dL, creatinine 0.55 mg/dL, negative rheumatoid factor (RF) and normal urinalysis results.\n\nRadiological examination (Figure 2) showed normal lung results. The FNAB examination of the submandibular lump showed epithelioid cells between the reticular fibres, and the smear background consisted of minimal red blood cells with the conclusion being suggested to chronic lymphadenitis that is commonly found in tuberculosis infection.\n\nThe working diagnosis in this patient was TB lymphadenitis and planned to give the patient antituberculosis drugs for 9 months, divided into 2 months of the intensive phase and 7 months of the continuation phase. The intensive phase started in July 2022, the patient got antituberculosis drugs, 3 tablets of 4 FDC/day. In October 2022, the patient started the continuation phase and got antituberculosis drugs, 3 tablets of 2 FDC/day. We added vitamin B6 100 mg once a day for the treatment. The patient had previously been diagnosed with SLE from the results of the ANA test that have been checked in November 2021, which indicated a borderline result. When she was first treated at the rheumatology polyclinic, the patient complained of joint pain, frequent weakness, and hair loss, and her skin turned red quickly when exposed to sunlight, which she had complained about 12 months ago. The rheumatologist has given therapy hydroxychloroquine 1×200 mg and methylprednisolone 2×4 mg. After the patient was diagnosed with TB lymphadenitis 3 months ago, the rheumatologist stopped methylprednisolone therapy and the patient is now only taking hydroxychloroquine 1×200 mg from the rheumatology doctor. By this time the patient had completed the entire phase of antituberculosis drugs. During the evaluation after 9 months of antituberculosis drugs, the size of the lymph node decreased and the patient had no complaints.\n\n\nDiscussion\n\nBased on the anamnesis, physical examination and supporting examination, the patient was diagnosed with TB lymphadenitis. The general symptoms between tuberculosis lymphadenitis and pulmonary tuberculosis are the same. The symptoms that can always be found include sub febrile, decreased appetite, weight loss, weakness, and night sweats. The physical appearance of superficial TB lymphadenitis is classified into 5 stages by Jones and Campbell, namely: (a) Stage I: Enlarged lymph nodes with a spongy consistency, mobile/easy to move, separated from other nodules, this indicates a nonspecific hyperplastic reaction; (b) Stage 2: larger than stage 1 with a spongy consistency, adherent to the surrounding tissue/confluent; (c) Stage 3: central tenderness due to abscess formation; (d) Stage 4: collar stud abscess formation/redness over the abscessed skin; (e) Stage 5: formation of sinuses that drain purulent secretions.6 As noted in this case the patient was stage 1. One of the difficulties in establishing a clinical diagnosis of TB lymphadenitis is the absence of gene expert results from tissue samples, so we can only diagnose based solely on the patient’s clinical condition.\n\nFine needle aspiration biopsy (FNAB) is a simple, safe, and inexpensive procedure for diagnosing TB lymphadenitis. In addition, it has high sensitivity (78.95%) and specificity (90.32%) values.7 Epithelioid morphology (Figure 3) with necrosis was found in all TB cases in the study by Suryadi, 2020, which occurred due to inflammation and tissue damage caused by stimulation macrophages to eradicate mycobacteria so that the Th1 response leads to the formation of granulomas and necrosis. Activated macrophages can form cytoplasm that resembles many epithelial cells called epithelioid cells.8\n\nSystemic lupus erythematosus (SLE) is an autoimmune disease whose cause is unknown with very diverse clinical features, so it is often referred to as a disease with a thousand faces.9 The most common symptoms of SLE are in the musculoskeletal system, in the form of arthritis or arthralgia (93%) often precedes other symptoms. Disorders of the skin, hair or mucous membranes are found in 85% of cases of SLE, and kidney disorders are found in 68% of cases of SLE.10 This disease is more common in women than men with a ratio of 12:1 and can affect all ages. Based on research by Kasjmir et al., genetic, gender, and environmental factors are thought to be factors that influence SLE. Early diagnosis of SLE is not easy because the course of the disease is very varied and often manifests as other diseases.11\n\nAutoimmune diseases including SLE, especially where immunosuppressive drugs are required based on disease activity, can increase the risk of TB. In SLE patients there is an abnormality of the immune system and the patient is receiving an immunosuppressant agent as therapy. This condition causes the patient to have a high risk of infection, one of which is TB infection. This has also become the major risk factor that accounts for the high prevalence of TB infection in SLE.12 A cohort study on the incidence of TB in SLE patients in Indonesia showed a higher incidence in patients diagnosed with SLE under the age of 25, just like the patient in this report. The study also showed that the median time of being diagnosed with TB was 2 years after being diagnosed with SLE.13 Corticosteroids and immunosuppressive agents are the mainstays of treatment in SLE. A retrospective case–control study in Colombia showed that 12 months of cumulative steroid doses of 1830 mg nearly tripled the risk of TB.14 A 13-year cohort study of SLE patients in Taiwan has shown that corticosteroid treatment is associated with a more than 10-fold increased risk of TB.15 It is in line with our study where the patient was diagnosed with SLE and took an immunosuppressant agent before the development of the lump that was suspected as TB lymphadenitis. This case is also in accordance with research by Hamijoyo et al. and Damara et al. Those with the most extrapulmonary TB manifestations were tuberculous lymphadenitis followed by miliary TB and TB meningitis.13,16\n\nIn general, the management of extra-pulmonary TB is divided into medical therapy and surgical therapy. Medical therapy uses first-line anti-TB drugs as the main therapy. Antituberculosis drugs are given using the same regimen as in pulmonary TB therapy, but with a longer treatment period of 9 months.17 SLE therapy with hydroxychloroquine and chloroquine is recommended as initial therapy for mild or moderate SLE, for example in skin rashes and arthritis. It is currently recommended that all patients with active SLE be given antimalarials, hydroxychloroquine has a lower chance of kidney damage compared to patients who do not receive it.18 For a suitable surgical approach for cervical tuberculous lymphadenitis, we need to consider the characteristics and location of the lesion, along with CT imaging and manifestations during presurgical evaluation. In closing, this case report is a case from a tertiary hospital that does not yet have complete registered follow-up data and incomplete bacteriological examination, including TB gene experts from sputum and biopsy tissue, however, it still provides comprehensive information that leads to increased awareness of TB in SLE patients. It is necessary to improve screening and preventive therapy for latent TB so that the risk of developing active TB can be minimized.\n\n\nConclusion\n\nIn SLE patients with high-dose steroid treatment and clinical infection that does not improve, it is necessary to consider the presence of TB infection, especially extrapulmonary TB, like lymphadenitis. The risk patients with immunocompromised conditions like SLE and getting immunosuppressant agents as therapy can increase the risk of developing TB infection 7 times more compared to the general population.\n\n\nConsent to participate\n\nInformed written consent was obtained from the patient for the publication of this report and any accompanying images.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReferences\n\nMinistry of Health: National Guidelines for Tuberculosis Management Medical Services. Jakarta: 2020 Jan.\n\nBhattacharya PK: SLE and Tuberculosis: A Case Series and Review of Literature. J. Clin. Diagn. Res. 2017; 11: OR01–OR03. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organization: Global Tuberculosis Report.2016; 201 p.\n\nPatel K: A clinical study of tuberculous cervical lymphadenopathy: surgeon’s perspectives. Int. Surg. J. 2019 Jan 28; 6(2): 581. Publisher Full Text\n\nBurhan E, Isbaniah F, Sinaga BY, et al.: Tuberculosis – Guidelines for Diagnosis and Management in Indonesia. Jakarta: Indonesian Pulmonary Doctors Association (PDPI); 2021.\n\nSari IY, Kusmiati T: Primary Multidrug-Resistant Tuberculosis Mixed with Lymphadenitis Tuberculosis in a Woman with SLE. J. Respirasi. 2019 Apr 1; 1(3): 81. Publisher Full Text\n\nQasmi SA, Kiani F, Malik AI, et al.: Cervical Lymphadenopathy: A Common Diagnostic Dilemma.2012.\n\nSuryadi D, Delyuzar S: Analysis Morphological of Tuberculosis Lymphadenitis Features between Cytology Biopsy of Fine Needle Aspiration Polymerase Chain Reaction Methods. Maj. Patol. Indones. 2020 May 1; 29(2): 95–100. Publisher Full Text\n\nFava A, Petri M: Systemic lupus erythematosus: Diagnosis and clinical management. J. Autoimmun. 2019 Jan; 96: 1–13. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIsselbacher KJ, Braunwald E, Wilson JD, et al.: Systemic Lupus Erythematosus. Harrison: Principles of Internal Medicine. Jakarta: EGC; 2000; pp. 1835–1839.\n\nKasjmir YI, Handono K, Wijaya LK, et al.: Diagnosis and Management of Systemic Lupus Erythematosus. Indonesia; 2011.\n\nAgrawal S, Prabu VNN: Systemic lupus erythematosus and tuberculosis: A review of complex interactions of complicated diseases. J. Postgrad. Med. 2010; 56(3): 244. Publisher Full Text\n\nHamijoyo L, Sahiratmadja E, Ghassani NG, et al.: Tuberculosis Among Patients With Systemic Lupus Erythematosus in Indonesia: A Cohort Study. Open Forum. Infect. Dis. 2022 Jul 4; 9(7). Publisher Full Text\n\nGonzález-Naranjo LA, Coral-Enríquez JA, Restrepo-Escobar M, et al.: Factors associated with active tuberculosis in Colombian patients with systemic lupus erythematosus: a case-control study. Clin. Rheumatol. 2021 Jan 11; 40(1): 181–191. Publisher Full Text\n\nYang SC, Lai YY, Huang MC, et al.: Corticosteroid dose and the risk of opportunistic infection in a national systemic lupus erythematosus cohort. Lupus. 2018 Oct 13; 27(11): 1819–1827. PubMed Abstract | Publisher Full Text\n\nDamara I, Ariane A, Winston K: Predisposing Factors of Tuberculosis Infection in Systemic Lupus Erythematosus Patients: A Single-Center Case-Control Study. Cureus. 2022 Jun 28. Publisher Full Text\n\nLee JY: Diagnosis and Treatment of Extrapulmonary Tuberculosis. Tuberc. Respir. Dis (Seoul). 2015; 78(2): 47–55. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGatto M, Zen M, Iaccarino L, et al.: New therapeutic strategies in systemic lupus erythematosus management. Nat. Rev. Rheumatol. 2019 Jan 11; 15(1): 30–48. Publisher Full Text"
}
|
[
{
"id": "193131",
"date": "10 Aug 2023",
"name": "PB Sryma",
"expertise": [
"Reviewer Expertise ARDS",
"Tuberculosis",
"sarcoidosis",
"mediastinal lymphadenopathy"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article is well written, constructed well and organised. Discussion is well written with detailed review of literature.\nMinor comments:\nIt will be better if the authors can provide any data regarding microbiological confirmation of tuberculosis and describe the histopathology with presence of necrotising granulomas if they were present.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": [
{
"c_id": "10051",
"date": "29 Aug 2023",
"name": "Yunita Arliny",
"role": "Author Response",
"response": "Dear Reviewer, Thank you for the input, but we have some questions and confirmation regarding this. 1. We already wrote the FNAB result in the text. Can you elaborate more on what you mean by the histopathology result? 2. The patient was confirmed to have TB lymphadenitis based on the FNAB result. We didn't do the microbiology test from sputum because the patient didn't show the TB sign and symptoms and the x-ray result was clear. We're looking forward to your reply. Thank you. Regards, Yunita Arliny"
}
]
},
{
"id": "205688",
"date": "12 Oct 2023",
"name": "Gyanshankar Mishra",
"expertise": [
"Reviewer Expertise Respiratory Diseases",
"Tubercuolosis"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis case report underscores the critical clinical consideration of tuberculosis suspicion in autoimmune patients undergoing immunosuppressive therapy. The prudent application of timely tuberculosis preventive therapy before the commencement of immunosuppressive treatment is a rational approach for such patient populations.\nA grammatical review and corrections are warranted for the manuscript. The following are suggested:\nAbstract:\nThe case report should employ past tense: e.g. \"In addition, the patient had been experiencing joint pain, hair loss, and sun sensitivity for the past 12 months.\" Change: \"Currently, the patient is taking the advanced phase of antituberculosis drugs FDC\" to \"Currently, the patient is undergoing the continuation phase of antituberculosis drugs FDC.\"\n\nConclusion: \"TB lymphadenitis is a rare case but can occur in conditions of decreased immunity like SLE. It involves some of the immune disorders caused by the long-term use of immunosuppressive therapy.\" Change to: \"TB lymphadenitis can occur in conditions of decreased immunity, particularly in cases of SLE, especially when patients are on long-term immunosuppressive or corticosteroid therapy.\"\n\nTB lymphadenitis is not a rare disease; as mentioned in the introduction section of the case report, it comprises 35% of extrapulmonary TB cases.\n\nCase report:\nIntroduction: \"In 2012, an estimated 8.6 million people suffered from TB, resulting in 1.3 million deaths globally. Indonesia ranked second among countries with the highest TB cases in the world.\" The World Health Organization's Global Tuberculosis Report for 2016 has been referenced. Please update the statistics to refer to the World Health Organization's Global Tuberculosis Report for 2023.\n\nThe case report part can be rewritten as follows: Case report: \"The patient did not complain of cough symptoms and had no history of chronic cough. Furthermore, there were no manifestations of dyspnea, chest pain, or nocturnal sweats. However, the patient had a documented history of fever and experienced a weight loss of approximately 15 kg over the course of three months, accompanied by a notable decrease in appetite. The patient also complained of joint pain, particularly exacerbated in cold environmental conditions, substantial hair loss, rapid onset of fatigue leading to tremors when fatigued, and a tendency for her skin to undergo rapid erythematous and sometimes hyperpigmented changes upon sun exposure. Notably, the patient was referred by a rheumatologist and was diagnosed with Systemic Lupus Erythematosus (SLE) 12 months ago. The patient had been on a therapeutic regimen incorporating hydroxychloroquine and methylprednisolone for the past 10 months. Additionally, the patient's family history revealed that her maternal aunt also had a confirmed diagnosis of SLE.\"\n\nChange: \"Figure 2. Results of thoracic photos\" to \"Chest radiograph PA view.\"\n\nChange: \"Radiological examination (Figure 2) showed normal lung results\" to \"The chest radiograph was normal.\"\n\nChange: \"The FNAB examination of the submandibular lump showed epithelioid cells between the reticular fibres, and the smear background consisted of minimal red blood cells with the conclusion being suggested to chronic lymphadenitis that is commonly found in tuberculosis infection\" to \"The Fine Needle Aspiration Biopsy (FNAB)...\".\n\nDiscussion and conclusion align with the case report.\n\nOverall the article is a useful addition to medical literature\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "10383",
"date": "28 Nov 2023",
"name": "Yunita Arliny",
"role": "Author Response",
"response": "Thank you for your input. We will revise it as soon as possible. Thank you. Regards, Yunita Arliny"
}
]
},
{
"id": "205699",
"date": "31 Oct 2023",
"name": "Henna Iqbal",
"expertise": [
"Reviewer Expertise microbiology"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis case only diagnosed TB on the basis of histological findings of a lymph node, while no other confirmatory tests were performed. It was fortunate to have a response to treatment, but ethically, anti-TB drugs should not be prescribed on suspicion only. There should be a confirmatory culture or molecular assay to certainly say this was tuberculosis. Technically, anti-inflammatory effect on antibiotics can also work in favor. SLE was also similarly diagnosed just on basis of ANA, no SLE specific antigen was found. This could have been discoid lupus if skin hypersensitivity was the only striking feature.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": [
{
"c_id": "10491",
"date": "09 Nov 2023",
"name": "Yunita Arliny",
"role": "Author Response",
"response": "Dear Reviewer, Thank you for your review. Here we present you the clarification based on guidelines from the Indonesian Ministry of Health about the diagnostic of TB Lymphadenopathy. “Tuberculosis lymphadenopathy can affect all ages, especially at the age of 10-30 years, more often in women. Constitutional symptoms occur in 33-85% of patients. Diagnosis is made through needle aspiration smooth or gland biopsy. Preparations from fine needle aspiration or Biopsy can reveal caseous granulomatous inflammation with cells Datia Langhans. The diagnosis can ALSO be confirmed through the TB rapid molecular test.” So, needle aspiration can be a diagnostic method as in our article with or without molecular tests to confirm the diagnostic. If you have any other suggestions, please don’t hesitate. Thank you. Regards, Yunita Arliny"
}
]
}
] | 1
|
https://f1000research.com/articles/12-763
|
https://f1000research.com/articles/12-322/v1
|
23 Mar 23
|
{
"type": "Research Article",
"title": "Are we aware of stroke risk factors and warning signs amid COVID-19? Knowledge and attitude towards risk-factors, signs and symptoms of stroke among the UAE population during COVID-19 pandemic: A cross-sectional study",
"authors": [
"Azza Ramadan",
"Zelal Kharaba",
"Rose Ghemrawi",
"Asim Ahmed Elnour",
"Nadia Hussain",
"Parisa Kouhgard",
"Nosayba Al-Damook",
"Shymaa Abou Hait",
"Lena Al Ghanem",
"Rawan Atassi",
"Ranem Chkh Sobeh",
"Ahmad Z. Al Meslamani",
"Zelal Kharaba",
"Rose Ghemrawi",
"Asim Ahmed Elnour",
"Nadia Hussain",
"Parisa Kouhgard",
"Nosayba Al-Damook",
"Shymaa Abou Hait",
"Lena Al Ghanem",
"Rawan Atassi",
"Ranem Chkh Sobeh",
"Ahmad Z. Al Meslamani"
],
"abstract": "Background: Despite significant advancements in healthcare, the burden of stroke continues to rise in the developed world, especially during the COVID-19 pandemic. Association between COVID-19 infection and stroke is well established. Factors identified for the delay in presentation and management include a lack of awareness regarding stroke. We aimed to assess the general public knowledge and attitudes on stroke and stroke risk factors in the United Arab Emirates during the COVID-19 pandemic. Methods: A cross-sectional study was conducted between September 2021 and January 2022 among adults ≥18 years old. Participants completed a self-administered questionnaire on sociodemographic characteristics and stroke knowledge and attitudes. Knowledge and attitude scores were calculated based on the number of correct responses. Linear regression analysis was performed to determine the factors related to knowledge and attitude towards stroke. Results: Of the 500 respondents, 69.4% were females, 53.4% were aged between 18 and 25, and nearly half were students (48.4%). The mean knowledge score was 13.66 (range 2-24). Hypertension (69%), smoking (63.2%), stress (56.4%) obesity/overweight (54.4%), and heart disease (53.6%) were identified as risk factors. Overall, the knowledge of signs/symptoms was suboptimal. The mean attitude score was 4.41 (range, 1-6); 70.2% would call an ambulance if someone were having a stroke. A monthly income of 11,000-50,000 AED and being a student were associated with positive knowledge. Being a non-health worker and lacking access to electronic media sources were associated with worse attitudes. Conclusion: Overall, we identified poor knowledge and suboptimal attitudes toward stroke. These findings reflect the need for effective public health approaches to improve stroke awareness, knowledge, and attitudes for effective prevention in the community. Presently, this is of utmost necessity, given the increased occurrence of stroke and its severity among COVID-19 patients.",
"keywords": [
"Knowledge",
"Attitude",
"Awareness",
"Cross-sectional",
"Stroke",
"Survey"
],
"content": "Introduction\n\nAccording to the World Health Organization, stroke is the ‘incoming epidemic of the 21st century’, which is unsurprising considering that it accounted for 12.2 million incident cases, 101 million prevalent cases, 143 million disability-adjusted life-years lost, and 6.6 million deaths in 2019.1 The United Arab Emirates (UAE) was reported to be among the three countries within the Middle East and North Africa region with the highest prevalence of stroke in 2019.2 Alarmingly in 2022, it was reported by the Ministry of Health and prevention that 50% of stroke patients were under the age of 45 as opposed to the global incidence of 80% over the age of 65.3 Despite significant medical advancements, morbidity and mortality from stroke remain high.4–6 It is associated with a high burden of healthcare costs, upwards of US$ 721 billion estimated in 2017.7 Furthermore, the absolute number of strokes is expected to rise due to the worldwide aging phenomenon.\n\nKnowledge and awareness play an essential part in the early detection of chronic conditions such as stroke. The World Health Organization has recognized the importance of driving efforts toward increasing knowledge about disease conditions and risk factors. Epidemiological studies have shown that higher health literacy positively relates to preventive measures, especially against chronic non-communicable diseases.8,9 The level of knowledge can affect people’s attitudes and practices; on the other hand, negative attitudes and practices could increase the risk of disease and subsequent morbidity and mortality. Regarding stroke, early identification of symptoms and appropriate and timely management can positively influence individuals’ outcomes.10\n\nStroke is a multifactorial condition; the most significant risk drivers include hypertension, high body mass index, dyslipidemia, diabetes, smoking, and a family history of stroke.11,12 Analysis of reports pertaining to the COVID pandemic shed light on the fact that COVID infection raised the risk of stroke by more than two times.13 Also, another study has demonstrated that COVID-19 associated ischaemic strokes tend to be more severe and can lead to death compared to non-infected stroke patients14 and COVID vaccination was associated with both ischemic stroke and vaccine-induced immune thrombotic thrombocytopenia15; and cerebral venous thrombosis.16\n\nDespite effective therapies for stroke, only a small proportion of patients receive medications due to delayed presentation.17 However, many strokes are preventable, suggesting that prevention strategies should be at the forefront of stroke management with primary and secondary prevention measures that target the risk factors.18 Factors influencing the management of stroke include awareness of stroke signs and symptoms, awareness of the importance of early management, educational level, distance from the hospital, and past history of stroke.19,20\n\nIdentifying baseline stroke knowledge in the general population is crucial to developing effective, targeted, and appropriate health promotion programs for stroke prevention. There is limited data on people’s knowledge and attitudes towards stroke in the UAE. In 2019, a knowledge survey study pertaining to stroke was conducted in Sharjah city, UAE.21 It was reported that most participants had low to average knowledge levels.21 Given the increased risk of stroke in COVID patients and the scarcity of data regarding stroke, we aimed to assess the general public knowledge and attitudes on stroke and stroke risk factors across the entire UAE during the COVID pandemic.\n\n\nMethods\n\nThe study received the required ethical approval from the research ethics commission (REC) at Al Ain University (AAU-REC-B3, September 2021).\n\nThis was a cross-sectional study among 500 subjects ≥ 18 years and from the general public in Abu Dhabi, Dubai, Sharjah, Ajman, and other UAE cities. The study was conducted from September 2021 to January 2022 i.e. during the COVID-19 period. Random/stratified sampling included subjects who fulfilled the inclusion criteria and were willing to participate in this study. The sample size was chosen with an assumed prevalence of hypertension, the most significant risk factor for stroke, 52%22 also via using a Raosoft sample size calculator,23 a confidence limit of 5%, and a 95% confidence interval estimate of the proportion. A minimum sample size of 384 was needed. The study included both locals (Emiratis) and expats (residents).\n\nUAE residents (> 2 years living in the UAE) regardless of their nationality, over the age of 18 years and consented (on the questionnaire by ticking the agreement option) to participate were included in this study. Participants who lived < 2-years in the UAE or did not consent to participate were excluded.\n\nThe questionnaire was developed after a careful literature review of previous studies utilizing standardized and validated instruments24–28 and expert feedback. The questionnaire was constructed in Arabic and English. The translation process was via an Authentic Medical Translator who was officially approved to translate English to Arabic (the official language of residents in the UAE). Pretesting of the questionnaire was performed to gather information on its feasibility, and assess time to completion, understandability, and consistency. After pretesting, the survey was conducted online, and the responses were collected in an Excel sheet.\n\nQuestions evaluating the knowledge of stroke comprised the organ affected, stroke attributes (preventable or recurrent), effect on daily activities, treatment, prevention, risk factors, and signs and symptoms. Questions evaluating attitude (the approach) comprised actions to take if someone showed signs and symptoms of a stroke. Lastly, there was a question about the sources of information. For the 25-item knowledge questions, the score range was 0-25. For attitudes, the score range was 0-6. Each correct statement for knowledge and optimal attitude got a 1 otherwise 0.\n\nThe validation test was conducted for the edited questionnaire version. A questionnaire draft was written and sent to a panel of experts in the pharmacy profession at Al-Ain University to test the content validity of the survey. They examined many factors of the questionnaire, including the length, conciseness, language, clarity, time, appropriateness, and bias of questions. Content validation of a questionnaire was aligned with recommendations.24\n\nThe reliability test was conducted as a pilot study on 50 students to achieve the most acceptable Cronbach’s values. Additionally, preliminary pilot testing was carried out to ensure the understandability and practicality of the questionnaire.\n\nThe final version of the study survey was administered online. Participants were briefed about the study’s purpose and informed about the study’s confidentiality and anonymity policy.\n\nData were verified at the end of the survey and before the analysis. The data analysis was performed using the SAS software (version 9.4 SAS Institute, Cary, NC) (alternative; PSPP software; free open source). Respondent’s socio-demographic characteristics were stated using descriptive statistics. Means, standard deviations (SD), and proportions were generated to describe the overall sample characteristics (age, gender, occupation, marital status, education, income, country of birth, and comorbidities). Multivariable linear regression modeling was applied to determine the variables associated with stroke-related knowledge and attitude. All associations were considered significant at the alpha level of 0.05.\n\n\nResults\n\nTable 1 presents the sociodemographic characteristics of the study population. Of the 500 participants who completed the questionnaire, 69.4) were females, 53.4% were aged between 18 and 25, and 59.4% were single. Among the participants, 79.8% were expats. Additionally, roughly half earned AED ≤10,000 (Dirham) per month. Among the study participants, 50.8% had no known comorbid, 9.4% had hypertension, 6.6% had diabetes, 3.4% had cardiovascular disease, and 1.8% had a history of a stroke. Regarding the sources of information about stroke, approximately 50.4% and 40.4% of the study participants reported electronic media and friends, respectively. Fewer than one-third stated a healthcare provider as an information resource. Around 15.63% were healthcare students, and 10.03% were healthcare workers. It’s noteworthy to mention that 339 of the 500 participants answered the question that determines if the respondents are either healthcare workers or healthcare students.\n\na The denominator is 339.\n\nThe mean (SD) knowledge score was 13.66 (5.31) and ranged from 2 to 24. Table 2 presents the responses regarding knowledge of stroke. Around (82%) of the study participants knew the brain was the organ affected by stroke, 41.8% knew that a stroke could be recurrent, and 63.2% knew that a stroke could be prevented. On the other hand, many participants (83.2%) knew that stroke affects the patients’ daily lives and activities.\n\nFigure 1 presents positive (yes) responses to questions on the signs and symptoms of a stroke. More than half of the participants correctly identified confusion (64.6%), numbness (64.4%), and trouble walking (58.8%). Less than half could identify trouble seeing (49.2%), vomiting (21.2%), headache (46.8%), and fever (10.6%) as signs of a stroke. Approximately (23%) of the participants incorrectly identified a nose bleed as a sign of stroke.\n\nThe Y axis represents percentages of positive (yes) responses. (*) on x-axis label indicate incorrect sign/symptom of stroke.\n\nFigure 2 presents positive (yes) responses to questions on stroke risk factors. More than half of the participants correctly identified smoking (63.2%), lack of exercise (51.8%), high blood pressure (69%), heart disease (53.6%), high cholesterol (50.4%), being overweight/obese (54.2%), and stress (56.4%). Fewer than half knew about a family history of stroke (46%), diabetes (34.6%), an unhealthy diet (43 %), atrial fibrillation (24.2%), and 8% incorrectly identified cough as a risk factor for stroke.\n\nThe Y axis represents percentages of positive (yes) responses. (*) on x-axis label indicates incorrect risk factor of stroke.\n\nThe mean (SD) score of participants’ attitudes towards stroke was 4.41 (1.40) and ranged from 1 to 6. Table 3 presents the participants’ attitudes toward stroke development in a person. Over two-thirds (70.2%) of the study participants would call an ambulance if someone showed signs and symptoms of stroke, (12.4%) would take the person to a hospital, and (4.6%) would call a healthcare provider.\n\nRegarding stroke prevention, more than two-thirds (67.0%) knew a controlled diet could prevent stroke, many (72.0%) knew control of hypertension was important, and over half (54.6%) knew the importance of the control of blood glucose. Merely 10.2% thought that stroke could not be prevented.\n\nWe determined the variables associated with the knowledge and attitudes toward stroke using linear regression analysis. Note that the nine respondents with history of stroke were excluded from analysis and hence the sample size is 491. As shown in Table 4, a monthly income 11,000 to 50,000 AED (estimate = 0.52; P = 0.05) and being a student (estimate = 2.45; P = 0.04) were associated with positive knowledge. On the other hand, not having heard of stroke (estimate = -3.45; P < 0.01), not knowing someone with stroke (estimate = -2.03; P < 0.01), not receiving information from a healthcare provider (estimate = -1.35; P < 0.01), and lack of information on electronic media (estimate = -1.11; P = 0.02) were associated with worse knowledge (Table 4).\n\n* P-value ≤ 0.05.\n\n** P-value ≤ 0.01.\n\nRegarding attitudes, being a non-healthcare worker (estimate = -0.73; P < 0.01) and lack of information on electronic media (estimate = -0.30; P = 0.02) were associated with poorer attitudes (Table 5).\n\n* P-value ≤ 0.05.\n\n** P-value ≤ 0.01.\n\n\nDiscussion\n\nThe present study was conducted to assess the knowledge and attitudes towards stroke in a general population sample in the UAE during the COVID-19 pandemic. Generally, we identified suboptimal knowledge and attitudes toward stroke. Attitudes toward stroke prevention seemed suboptimal for preventive measures; many knew about hypertension, and less than two-thirds knew about blood glucose control. The sources of information were also varied and underutilized, especially healthcare providers.\n\nGenerally, and to the best of our knowledge, studies from the Middle East have reported suboptimal levels of knowledge of stroke. Most of the studies from the Middle East have reported inadequate knowledge regarding stroke risk factors and warning symptoms25–30; on the other hand, only a few studies have reported an adequate level of awareness.31,32 Similarly, studies from different parts of the world have reported an inadequate understanding of stroke in the general population.33,34\n\nMore than half of our study participants were aged 18 to 25. There have been few previous studies on stroke awareness among adolescents and young adults. Studies from Nepal have reported knowledge of stroke in the younger demographics.35,36 Participants reported knowing someone with a stroke which could have contributed to better understanding.36 However, many participants did not recognize stroke as a brain disease.36 Similarly, some studies in western countries have shown inconsistent awareness of this aspect.37,38 In the Nepalese studies, many identified hypertension, alcohol, and smoking as risk factors. However, few could identify all risk factors together. Many believed that stroke could present with sudden weakness or numbness of limbs, and less than half were able to identify three or more symptoms of a stroke. More than two-thirds of participants believed stroke could be treated, and more than four-fifth believed stroke could be prevented.36 Many said they would take patients to the hospital and that they would need immediate medical treatment.\n\nPradhan et al. reported better knowledge among male participants35; however, Thapa et al. reported that gender was not associated with knowledge of risk factors or warning signs.36 This was in contrast to our study, as gender was not a determinant of either knowledge or attitudes. Nevertheless, several studies have reported differences in knowledge scores by gender; females possessed better knowledge39–41 which perhaps could be related to the fact that women experience more strokes42 or knew someone with a stroke in the capacity of a caregiver.43 Furthermore, a review has reported better knowledge of stroke warning signs in women compared with men44; women tended to know more evidence-based stroke risk factors than men, which could be attributed to a more proactive health-seeking approach in women; stroke knowledge also appeared to be related to the country of study origin, age, education, and medical history.\n\nIn comparison, a recent study from the USA among adolescents reported that stroke knowledge was relatively inadequate.45 Approximately half knew that stroke occurs in the brain, two-thirds said they would call emergency services, and about half were aware of the acronym FAST (face, arms, speech, time). The knowledge of stroke symptoms and risk factors was generally low, with no difference in scores according to gender in similarity to our findings. Furthermore, a surrogate marker of socioeconomic status, the parental education level, was used to assess the contribution to stroke knowledge; no relationship between survey scores and the father’s level of education was seen, but there was a significant association between survey scores and the mother’s level of education.\n\nA community-based study from India, where stroke is a leading cause of morbidity and mortality, reported that participants knew the basic connotations of stroke and paralysis. However, knowledge about red flags and stroke risk factors was inadequate.34 Signs and symptoms identified were paralysis and loss of consciousness, but there was a lack of awareness of headache, vomiting, and fits. Participants were well aware of hypertension as a risk factor but less for diabetes and smoking. Hypertension was one of the most frequently recognized risk factors, as in another study from Iran.45 In comparison, a survey in South Korea reported better awareness about stroke; hypertension was the most common risk factor identified, and paresis was the most commonly reported symptom. Around two-thirds were able to identify one or more symptoms46; in contrast, in our study, half of the participants identified five symptoms (results not tabulated).\n\nIn our study, knowledge and attitudes toward stroke did not differ by age category. Nevertheless, previous studies have consistently shown that different age groups were differently associated with knowledge and attitudes towards stroke.28,45,47,48 In our study, being a student was associated with positive knowledge scores and a non-healthcare worker with poorer attitudes. Similar to our findings, a study from Saudi did not report that attitudes differed by gender.49 Moreover, some studies have reported that knowledge differed with academic level, and higher education was a predictor of better knowledge.45,50–52 Similarly, a recent European review reported that a higher socioeconomic position was associated with better knowledge of stroke risk factors and warning signs.53 A review from the UK reported a good awareness of red flags of unilateral weakness and speech disturbance; however, the first point of contact mentioned was a general practitioner rather than emergency services.54 In our study, a little over two-thirds said they would call an ambulance, and this finding is not very different from the Middle East.30\n\nIt is reassuring to see that despite studies reporting inadequate understanding of stroke, there was a positive attitude toward calling an emergency in case a person displayed signs or symptoms of stroke,55,56 while others are reporting taking the patient to the hospital.57 In our study, being a non-health care worker was associated with poorer attitudes. Hence efforts should be made to reach out to different sectors and address gaps in knowledge and attitudes towards stroke. Moreover, electronic media campaigns could play an important role in raising public awareness and improving attitudes by employing a variety of social media platforms and types of messages.\n\nSome of the strengths of this study are as follows: First, the study is one of the few studies that comprehensively quantify knowledge and practices and would help identify common knowledge gaps in the UAE population. Second, the study was conducted on a representative sample of the general population comprising of diverse backgrounds and provided a projection of the knowledge and attitudes in the community. Third, we used a validated and reliable questionnaire to collect responses. Lastly, we had a large sample size and a reasonable response rate, allowing us to conduct analyses with good statistical power to detect associations.\n\nThere are some limitations, however: The self-reported nature of specific measures such as income may lead to misclassification bias of the independent variables in the study. Moreover, self-reporting of information may be biased by overestimating or underestimating actual attitudes related to stroke. Next, as with studies of observational nature, it can be challenging to draw definite conclusions about causality and temporal relationships; hence we need further research with more robust study designs and pre-post interventional studies to assess the impact on knowledge and attitudes towards stroke in the community. Also, some of the respondents did not answer the questions if they were either working or studying in the healthcare field or not. Finally, the age distribution of participants in our study does not reflect the age distributed in the general population in the UAE. Bias in data collection may produce this problem. Nonetheless, we believe that the impact of this bias on the validity of the findings may not be significant.\n\n\nConclusions\n\nThe present study showed a general inadequacy of knowledge regarding stroke and suboptimal attitudes towards someone presenting with stroke signs and symptoms. The community should be familiarized with the “FAST” acronym to recognize a stroke and access appropriate services as soon as possible. There is an urgent need for widespread educational interventions regarding stroke risk factors, especially among non-medical professions, and involving healthcare providers to address the growing burden of stroke worldwide, especially in the era of Covid-19, which increases the risk of stroke via infection and post-vaccination.\n\nThe burden of stroke and its associated DALYs necessitates the evaluation of stroke KAP in the community. Especially in the Middle East, where despite the advances in stroke management, we continue to see a substantial stroke burden. As suggested by previous literature, knowledge and attitudes towards stroke may influence stroke prevention and outcome, and is a cornerstone of the WHO’s efforts toward increasing chronic disease literacy. In the UAE, literature is scarce about the level of knowledge of stroke in the community. Currently, this assessment is of outmost importance given the association of COIVD infection with stroke. Therefore, we aimed to conduct this study in a representative sample of the general population. Our study revealed suboptimal knowledge and suboptimal attitudes towards stroke, consistent with some studies in other parts of the region. We recommend that such findings be the base for educational awareness efforts among the general population and high-risk individuals in the community. This could improve stroke outcomes and encourage the adoption of healthy behaviors in all risk profile groups.",
"appendix": "Data availability\n\nOpen Science Framework: Stroke Study, https://doi.org/10.17605/OSF.IO/5WNAF. 58\n\n- Stroke study Responses and Scores.xlsx\n\nOpen Science Framework: Stroke Study, https://doi.org/10.17605/OSF.IO/5WNAF. 58\n\n- Stroke questionaire.docx\n\n- STROBE_checklist_cross-sectional- Stroke Study.docx\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nCollaborators GBDS: Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021; 20(10): 795–820. Publisher Full Text\n\nJaberinezhad M, Farhoudi M, Nejadghaderi SA, et al.: The burden of stroke and its attributable risk factors in the Middle East and North Africa region, 1990-2019. Sci. Rep. 2022; 12(1): 2700. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nSoto-Camara R, Gonzalez-Bernal JJ, Gonzalez-Santos J, et al.: Knowledge on Signs and Risk Factors in Stroke Patients. J. Clin. Med. 2020; 9(8). PubMed Abstract | Publisher Full Text | Free Full Text\n\nNagendra CV, Kumar TSS, Bohra V, et al.: Factors Affecting the Effective Management of Acute Stroke: A Prospective Observational Study. Indian J. Crit. Care Med. 2018; 22(3): 138–143. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKarkout RA, Shamaa O, Al Ammour ST, et al.: Knowledge about stroke among adults in Sharjah, United Arab Emirates. Int. J. Res. Med. Sci. 2019; 7(10): 3632–3635. Publisher Full Text\n\nChow CK, Teo KK, Rangarajan S, et al.: Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. JAMA. 2013; 310(9): 959–968. PubMed Abstract | Publisher Full Text\n\nRaosoft Sample Size Calculator:(accessed on Sept 2021).Reference Source\n\nMackison D, Wrieden WL, Anderson AS: Validity and reliability testing of a short questionnaire developed to assess consumers’ use, understanding and perception of food labels. Eur. J. Clin. Nutr. 2010; 64(2): 210–217. PubMed Abstract | Publisher Full Text\n\nBakraa R, Aldhaheri R, Barashid M, et al.: Stroke Risk Factor Awareness Among Populations in Saudi Arabia. Int. J. Gen. Med. 2021; 14: 4177–4182. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMubaraki AA, Alqahtani AS, Almalki AA, et al.: Public knowledge and awareness of stroke among adult population in Taif city, Saudi Arabia. Neurosciences (Riyadh). 2021; 26(4): 339–345. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAbdalla SM, Mohamed EY, Almehmadi BA, et al.: Stroke prevention: knowledge of the general population in Riyadh Region, Saudi Arabia. Eur. Rev. Med. Pharmacol. Sci. 2021; 25(17): 5424–5428. PubMed Abstract | Publisher Full Text\n\nAlluqmani MM, Almshhen NR, Alotaibi RA, et al.: Public Awareness of Ischemic Stroke in Medina city, Kingdom of Saudi Arabia. Neurosciences (Riyadh). 2021; 26(2): 134–140. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEl-Hajj M, Salameh P, Rachidi S, et al.: The epidemiology of stroke in the Middle East. Eur. Stroke J. 2016; 1(3): 180–198. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlreshidi FM, Alrashidi AS, Alshammari FNM, et al.: Knowledge, Attitude and Practicetowards Stroke Risk Factors and Warning Symptoms in Saudi Arabia. Egypt. J. Hosp. Med. 2017; 69(3): 2082–2087.\n\nAbutaima MKT, Almaghrabi A, Alhazzaa R, et al.: Level of awareness regarding stroke among Riyadh population. J. Family Med. Prim. Care. 2021; 10(1): 538–541. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBarakat M, AlSalamat HA, Jirjees F, et al.: Factors Associated with Knowledge and Awareness of Stroke Among the Jordanian Population: A Cross-Sectional Study. F1000Res. 2021; 10: 1242. Publisher Full Text\n\nDas S, Hazra A, Ray BK, et al.: Knowledge, attitude, and practice in relation to stroke: A community-based study from Kolkata, West Bengal, India. Ann. Indian Acad. Neurol. 2016; 19(2): 221–227. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNakibuuka J, Sajatovic M, Katabira E, et al.: Knowledge and Perception of Stroke: A Population-Based Survey in Uganda. ISRN Stroke. 2014; 2014: 1–7. Publisher Full Text\n\nPradhan RR, Jha A, Bhandari S, et al.: Knowledge, attitude, and practice of stroke and thrombolysis among students preparing for undergraduate medical entrance examination in Kathmandu, Nepal. Health Sci. Rep. 2021; 4(2): e268. PubMed Abstract | Publisher Full Text\n\nThapa L, Sharma N, Poudel RS, et al.: Knowledge, attitude, and practice of stroke among high school students in Nepal. J. Neurosci. Rural Pract. 2016; 7(4): 504–509. PubMed Abstract | Publisher Full Text\n\nSug Yoon S, Heller RF, Levi C, et al.: Knowledge of stroke risk factors, warning symptoms, and treatment among an Australian urban population. Stroke. 2001; 32(8): 1926–1930. PubMed Abstract | Publisher Full Text\n\nFalavigna A, Teles AR, Vedana VM, et al.: Awareness of stroke risk factors and warning signs in southern Brazil. Arq. Neuropsiquiatr. 2009; 67(4): 1076–1081. PubMed Abstract | Publisher Full Text\n\nMadsen TE, Baird KA, Silver B, et al.: Analysis of Gender Differences in Knowledge of Stroke Warning Signs. J. Stroke Cerebrovasc. Dis. 2015; 24(7): 1540–1547. PubMed Abstract | Publisher Full Text\n\nMarx JJ, Klawitter B, Faldum A, et al.: Gender-specific differences in stroke knowledge, stroke risk perception and the effects of an educational multimedia campaign. J. Neurol. 2010; 257(3): 367–374. PubMed Abstract | Publisher Full Text\n\nRamirez-Moreno JM, Alonso-Gonzalez R, Peral-Pacheco D, et al.: Knowledge of stroke a study from a sex perspective. BMC. Res. Notes. 2015; 8: 604. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBushnell CD: Stroke and the female brain. Nat. Clin. Pract. Neurol. 2008; 4(1): 22–33. Publisher Full Text\n\nMenon B, Salini P, Habeeba K, et al.: Female Caregivers and Stroke Severity Determines Caregiver Stress in Stroke Patients. Ann. Indian Acad. Neurol. 2017; 20(4): 418–424. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStroebele N, Muller-Riemenschneider F, Nolte CH, et al.: Knowledge of risk factors, and warning signs of stroke: a systematic review from a gender perspective. Int. J. Stroke. 2011; 6(1): 60–66. PubMed Abstract | Publisher Full Text\n\nUmar AB, Koehler TJ, Zhang R, et al.: Stroke knowledge among middle and high school students. J. Int. Med. Res. 2019; 47(9): 4230–4241. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKim YS, Park SS, Bae HJ, et al.: Public awareness of stroke in Korea: a population-based national survey. Stroke. 2012; 43(4): 1146–1149. Publisher Full Text\n\nLiu X, Gui H, Yao S, et al.: Age-Related Disparities in Stroke Knowledge Among Community Older Adults. Front. Neurol. 2021; 12: 717472. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMelnikov S, Itzhaki M, Koton S: Age-Group and Gender Differences in Stroke Knowledge in an Israeli Jewish Adult Population. J. Cardiovasc. Nurs. 2018; 33(1): 55–61. Publisher Full Text\n\nAlOtaibi MK, AlOtaibi FF, AlKhodair YO, et al.: Knowledge and Attitude of Stroke Among Saudi Population in Riyadh, Kingdom of Saudi Arabia. Int. J. Acad. Sci. 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BMC Health Serv. Res. 2010; 10: 157. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNeau JP, Ingrand P, Godeneche G: Awareness within the French population concerning stroke signs, symptoms, and risk factors. Clin. Neurol. Neurosurg. 2009; 111(8): 659–664. PubMed Abstract | Publisher Full Text\n\nSchneider AT, Pancioli AM, Khoury JC, et al.: Trends in community knowledge of the warning signs and risk factors for stroke. JAMA. 2003; 289(3): 343–346. PubMed Abstract | Publisher Full Text\n\nDar NZ, Khan SA, Ahmad A, et al.: Awareness of Stroke and Health-seeking Practices among Hypertensive Patients in a Tertiary Care Hospital: A Cross-sectional Survey. Cureus. 2019; 11(5): e4774. PubMed Abstract | Publisher Full Text\n\nRamadan A, Kharaba Z, Ghemrawi R, et al.:Stroke Study. [Dataset].2023, January 29. Publisher Full Text"
}
|
[
{
"id": "167530",
"date": "12 Apr 2023",
"name": "Walid Al-Qerem",
"expertise": [
"Reviewer Expertise Therapy"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe current cross-sectional study highlights the level of knowledge and attitude of stroke and among a sample of the UAE population. Also, the association of variables including sociodemographics with knowledge and attitude scores was carried out using linear regression analysis. The rationale of the study is sound given the link between COVID 19 infection and vaccination with stroke. Results are clear and organized with acceptable statistical analysis. The conclusions drawn from the findings are appropriate and not overinterpreted. The study is of significance given the findings and the recommendations for educational awareness among the general population and high-risk individuals in the community. However, there is an issue with the population representation.\nThe following recommendations to improve the paper are listed below:\nAbstract:\nConclusion section “Presently, this is of utmost necessity, given the increased occurrence of stroke and its severity among COVID-19 patients.” Reword this sentence as it is unclear\n\nIntroduction:\n1st paragraph: Indicate what co-morbidities that can increase the risk of occurrence, given that the survey has questions regarding medical history of subjects.\n2nd paragraph, last sentence: “Regarding stroke, early identification of symptoms and appropriate and timely management.\" Remove “and” from symptoms and appropriate\n3rd paragraph, last sentence:\n“Analysis of reports pertaining to the COVID pandemic shed light etc…,\" insert had after the word pandemic\n\nNeed to expand on why Covid increase stroke occurrence. Provide recent references\n\nElaborate on why Covid vaccine can cause stroke?\nMethods:\nState the domains clearly\n\nWhat constitutes poor, moderate and good for knowledge/attitude scores?\n\nWhat part of the population was the study performed on?\n\nWhat was/were the main attitude question(s)? Provide examples to focus the reader’s attention.\nResults:\n(Table 5). There was no mention between the association of lack of information from health care provide with attitude in the results description\nDiscussion:\nPage 10, last paragraph: “This was in contrast to our study, as gender etc..” doesn’t fit the context. Revise the statement\n\nKnowledge was suboptimal, state plausible reasons for that. Is there a disconnect between resources and the population? Is there scarcity of provided information?\n\n~ 30% of the UAE are bachelors graduates. However, post analysis, nearly half of the subjects were young and undergraduate students. Provide the implication regarding this discrepancy?\n\nWhat about rural based participants? Were they included in the study. This needs to be included in the limitation section\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10370",
"date": "13 Oct 2023",
"name": "Azza Ramadan",
"role": "Author Response",
"response": "Dear Reviewer, Thank you for taking the time to review our work titled “Are we aware of stroke risk factors and warning signs amid COVID-19? Knowledge and attitude towards risk-factors, signs and symptoms of stroke among the UAE population during COVID-19 pandemic: A cross-sectional study” and providing us with your insightful feedback to improve the manuscript. We have included answers in the manuscript to the questions put forth. Please see below the point-by-point responses to the questions. Abstract: Conclusion section “Presently, this is of utmost necessity, given the increased occurrence of stroke and its severity among COVID-19 patients.” Reword this sentence as it is unclear Response: Thank you for your comment. The sentence has been reworded to “Presently, this is of utmost necessity, given the increased occurrence of stroke and its severity during the COVID-19 pandemic ” Introduction: 1) 1st paragraph: Indicate what co-morbidities that can increase the risk of occurrence, given that the survey has questions regarding medical history of subjects. Response: Thank you for your comment. The following has been added to the end of the 1st paragraph in the introduction section. \"Also, the high prevalence of comorbidities such as hypertension, congenital heart disease, previous stroke, and diabetes is associated with increased risk for all types of stroke (Zhang et al. 2021, Elamy et al. 2020)\" References - Zhang, Y., Wang, C., Liu, D. et al. Association of total pre-existing comorbidities with stroke risk: a large-scale community-based cohort study from China. BMC Public Health 21, 1910 (2021). - Elamy, A., Shuaib, A., Carriere, K., & Jeerakathil, T. (2020). Common Comorbidities of Stroke in the Canadian Population. Canadian Journal of Neurological Sciences, 47(3), 314-319. doi:10.1017/cjn.2020.17 2) 2nd paragraph, last sentence: “Regarding stroke, early identification of symptoms and appropriate and timely management.\" Remove “and” from symptoms and appropriate Response: The word “and” has been removed. The sentence now in the manuscript is: “Regarding stroke, early identification of symptoms, appropriate and timely management. 3) 3rd paragraph, last sentence: “Analysis of reports pertaining to the COVID pandemic shed light etc…,\" insert had after the word pandemic Response: “Analysis of reports pertaining to the COVID pandemic had shed light, etc…. 4) Need to expand on why COVID increase stroke occurrence. Provide recent references Response. Thank you for the comment. The following was added to the intro section: Multisystem thrombosis, including ischemic stroke, has been associated with severe COVID-19 infection. The pathogenesis is further compounded, given that the fibrinolytic pathway ceases operation. Also, ACE receptors, where the COVID-19 virus binds to gain intracellular entry, are expressed in many cells, including endothelial cells of the blood vessels. This could disrupt the renin–angiotensin system, which modulates blood flow, further contributing to the pathogenesis process (Wijeratne et al. 2021). Response: Wijeratne, T., Gillard Crewther, S., Sales, C., & Karimi, L. (2021). COVID-19 Pathophysiology Predicts That Ischemic Stroke Occurrence Is an Expectation, Not an Exception-A Systematic Review. Frontiers in neurology, 11, 607221. https://doi.org/10.3389/fneur.2020.607221 5) Elaborate on why the COVID vaccine can cause stroke. Response: The vaccine's most adverse side effect is vaccine-induced immune thrombocytopenia and thrombosis (VITT), also known as thrombosis with thrombocytopenia syndrome. This immune-mediated condition is caused by the development of pathological anti-platelet factor 4 (PF4) antibodies following vaccination against COVID-19, which leads to intense activation of platelets and the coagulation system. The subsequent clinical syndrome includes life-threatening thrombosis and secondary haemorrhage (Kolahchi et al. 2022). Reference: Kolahchi, Z., Khanmirzaei, M., & Mowla, A. (2022). Acute ischemic stroke and vaccine-induced immune thrombotic thrombocytopenia post COVID-19 vaccination; a systematic review. Journal of the neurological sciences, 439, 120327. https://doi.org/10.1016/j.jns.2022.120327 6) Methods: State the domains clearly Response: Thank you for this comment. Below is the additional information added to the manuscript to clarify the domains. The survey started with a brief introduction that described the study objectives, emphasized the confidentiality of the participants, and informed them that completing the survey represents consent to participate in the study. The survey included the following domains: socio-demographic questions, twenty-five questions evaluating the knowledge of stroke comprising the organ affected, stroke attributes (preventable or recurrent), effect on daily activities, treatment, prevention, risk factors, and signs and symptoms. Six questions evaluating attitude (the approach) towards preventative measures and actions to take if someone showed signs and symptoms of a stroke. All knowledge and attitude questions had a yes/no answer. Lastly, there was a question about the sources of information. For the 25-item knowledge questions, the score range was 0-25. For attitudes, the score range was 0-6. Each correct statement for knowledge and optimal attitude got a 1; otherwise, 0. What constitutes poor, moderate and good for knowledge/attitude scores? Response: The following was placed in the methodology section of the questionnaire: Based on the modified Bloom’s cut-off point, a participant who scored ≥80% of the correct knowledge questions (≥20 points out of 25) was considered as having “good/adequate knowledge”; moderate if the score was between 60 and 79%, (≥15-19 out of 25), and poor/inadequate if the score was less than 60% (<15 points out of 25). For attitude, a respondent who scored ≥80% of the correct attitude questions (≥4.8 points out of 6) was considered as having a “good attitude”, moderate/suboptimal attitude if the score was between 60 and 79%, (≥3.6-4.7 out of 6), and poor attitude if the score was less than 60% (<3.6 points out of 6) (Feleke et al. 2021). What part of the population was the study performed on? Response: The study included both locals (Emiratis) and expats (residents) What was/were the main attitude question(s)? Provide examples to focus the reader’s attention. Response: Six questions evaluating attitude (the approach) towards preventative measures and actions to take if someone shows signs and symptoms of a stroke. 7) Results: (Table 5). There was no mention between the association of lack of information from health care provide with attitude in the results description Response: Thank you for the comment. The following (in yellow highlight) has been added: “Regarding attitudes, being a non-healthcare worker (estimate = -0.73; P < 0.01) and lack of information from health care provider (estimate = -0.31; P=0.03) and on electronic media (estimate = -0.30; P = 0.02) were associated with poorer attitudes 8) Discussion: Page 10, last paragraph: “This was in contrast to our study, as gender etc..” doesn’t fit the context. Revise the statement Response: Thank you. Replaced the above with “Similar to Thapa et al. study (36), in our study, gender............... Knowledge was suboptimal; state plausible reasons for that. Is there a disconnect between resources and the population? Is there a scarcity of provided information? Response: Thank you for the feedback. The following have been added to the discussion section: We observed that poor knowledge was significantly associated with not having heard of stroke, not knowing someone with a stroke, and not receiving stroke-related information from either a healthcare provider or electronic media. Note that the study was conducted during COVID-19 when there was a nationwide extended lockdown. Hence, the lack of stroke knowledge and awareness could be due to the public limited access to healthcare providers or limited healthcare provider-led educational campaigns during quarantine. Also, the lack of use of electronic media by the participants could have contributed to the public’s gap in knowledge. Hence, the lack of accessibility to healthcare providers and perhaps also to electronic media could have resulted in poor stroke awareness and knowledge. ~ 30% of the UAE are bachelor's graduates. However, post-analysis, nearly half of the subjects were young and undergraduate students. Provide the implication regarding this discrepancy? Response: The authors agree with the comment. The following is mentioned in the limitation section of the manuscript: “ the age distribution of participants in our study was mostly young people/students and hence does not reflect the age distributed in the general population in the UAE. Bias in data collection may produce this problem. Nonetheless, we believe that the impact of this bias on the validity of the findings may not be significant” What about rural-based participants? Were they included in the study? This needs to be included in the limitation section Response: The following has been added to the limitation section: “While the study was conducted in several UAE major urban cities, rural cities participants were not represented.”"
}
]
},
{
"id": "203646",
"date": "08 Sep 2023",
"name": "Adrià Arboix",
"expertise": [
"Reviewer Expertise Cerebrovascular diseases",
"stroke",
"lacunar infarcts",
"vascular cognitiva impairment."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors present the results of a cross-sectional study aimed to assess the general public knowledge and attitudes on stroke and stroke risk factors in the United Arab Emirates during the COVID-19 pandemic. 500 participants ≥ 18 years and from the general public in The United Arab Emirates completed a self-administered questionnaire constructed in Arabic and English on sociodemographic characteristics and stroke knowledge and attitudes. The authors identified poor knowledge and suboptimal attitudes toward stroke. For a better presentation of the data, it is necessary to clarify the following issues:\nIt would be interesting to know if there were differences between the young (18-25 years old) and non-young healthy recruits with respect to knowledge and attitudes toward stroke.\n\nIn the Discussion, it should be noted that in a study on the knowledge of stroke in Catalonia (Spain) it was observed a scant knowledge of cerebrovascular disease in a sample of teenagers. Therefore, this knowledge should be integrated into the school curriculum (see and add this reference Rev Neurol 2003; 37: 500).\n\nA brief concluding comment on other possible lines of future research on the presented topic would be appreciated\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10371",
"date": "13 Oct 2023",
"name": "Azza Ramadan",
"role": "Author Response",
"response": "Dear Reviewer, Thank you for taking the time to review our work titled “Are we aware of stroke risk factors and warning signs amid COVID-19? Knowledge and attitude towards risk-factors, signs and symptoms of stroke among the UAE population during COVID-19 pandemic: A cross-sectional study” and providing us with your insightful feedback to improve the manuscript. We have included answers in the manuscript to the questions put forth. Please see below the point-by-point responses to the questions. 1. It would be interesting to know if there were differences between the young (18-25 years old) and non-young healthy recruits with respect to knowledge and attitudes toward stroke. Author Response: Thank you for your comment. Indeed, our findings suggest that knowledge among young participants (18-25 years old) was not statistically different in comparison to the ³ 65 years old group (estimate coefficient= 0.87; P=0.84, Table 4). Similarly, there was not a statistical difference in attitude scores when comparing the two groups (estimate coefficient= -0.42; P=0.84, Table 5). 2. In the Discussion, it should be noted that in a study on the knowledge of stroke in Catalonia (Spain) it was observed a scant knowledge of cerebrovascular disease in a sample of teenagers. Therefore, this knowledge should be integrated into the school curriculum (see and add this reference Rev Neurol 2003; 37: 500). Author Response: Thank you for your comment. The following was added to the discussion section. Additionally, limited knowledge of cerebrovascular disease was observed among teenagers in Spain, hence the need for integrating topics related to neurovascular disease within the school curriculum (Arboix and Arboix-Alió, 2003). Reference: Arboix A, Arboix-Alió A, Hernández-Arrieta M. Escaso conocimiento de la enfermedad vascular cerebral en una muestra de jovenes adolescentes [Scant knowledge about cerebrovascular disease in a sample of teenagers]. Rev Neurol. 2003;37(5):500. 3. A brief concluding comment on other possible lines of future research on the presented topic would be appreciated Author Response: Thank you for the suggestion: The following was inserted at the end of the discussion section: The future direction of the study can focus on conducting a cross-sectional study to assess the stroke knowledge and attitude among COVID-19-infected individuals and COVID-19 vaccine recipients, a significant risk group highly susceptible to stroke occurrence. Also, it is interesting to asses if stroke incidence dropped post-COVID-19 period."
}
]
},
{
"id": "178418",
"date": "25 Sep 2023",
"name": "Subish Palaian",
"expertise": [
"Reviewer Expertise Pharmacovigilance"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI appreciate the authors for undertaking this important piece of research. It is a well-conducted study with scientific merits. This study can be a baseline research for many potential future researchers and hence must be published.\nTitle: The title should be made simple and clearer. Currently, it is too long and confusing.\nKeywords: Need to be alphabetically arranged\nStroke is generally considered to occur in elderly people. However, in this research, the participants are mainly young people/students. Authors need to mention this as a major limitation. This limits the study to generalize the findings to the general public. It would have been nice to focus only on the students rather than the general public in this case.\nThe Introduction section has to mention more about the probable mechanism of stroke in COVID-19 patients. Authors need to focus more on the topic with more literature added.\nIt is not clear why authors have chosen ‘hypertension’ to assume the prevalence of stroke. This needs more explanation.\nThe questionnaire design is not clearly mentioned in the methodology section. The construct, content, and face validity need to be mentioned in detail. The final questionnaire must be added as an appendix. The authors also need to mention why they developed a new questionnaire rather than adopting an existing one. What is the uniqueness of the newly developed tool? The actual Cronbach alpha value has to be mentioned. The data collection process has to be elaborated. What was the mode of circulation of the questionnaire? How were the subjects chosen?\nThe discussion rarely mentions about the relationship between COVID-19 and stroke knowledge. Hence some rewriting is needed.\nThe Conclusion is misleading. How can the authors say the knowledge on stroke is ‘inadequate’ and ‘suboptimal’ attitudes? Authors need to first establish the criteria for how they arrived at such conclusions. This has to be clearly mentioned in the methodology.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "10372",
"date": "13 Oct 2023",
"name": "Azza Ramadan",
"role": "Author Response",
"response": "Dear Reviewer, Thank you for taking the time to review our work titled “Are we aware of stroke risk factors and warning signs amid COVID-19? Knowledge and attitude towards risk-factors, signs and symptoms of stroke among the UAE population during COVID-19 pandemic: A cross-sectional study” and providing us with your insightful feedback to improve the manuscript. We have included answers in the manuscript to the questions put forth. Please see below the point-by-point responses to the questions. Q1. Title: The title should be made simple and clearer. Currently, it is too long and confusing. Are we aware of stroke risk factors and warning signs amid COVID-19? Knowledge and attitude towards risk-factors, signs and symptoms of stroke among the UAE population during COVID-19 pandemic: A cross-sectional study Answer: Thank you for your comment. The above title was shortened to “Assessment of Knowledge and attitude towards Stroke among the UAE population during COVID-19 pandemic: A cross-sectional study” Q 2. Keywords: Need to be alphabetically arranged Answer: Please see the re-arranged keywords that were inserted in the manuscript Attitude, Awareness, Cross-sectional, Knowledge, Stroke, Survey Q 3. Stroke is generally considered to occur in elderly people. However, in this research, the participants are mainly young people/students. Authors need to mention this as a major limitation. This limits the study to generalize the findings to the general public. It would have been nice to focus only on the students rather than the general public in this case. Answer: The authors agree with the comment. The following is mentioned in the limitation section of the manuscript: “ the age distribution of participants in our study was mostly young people/students and hence does not reflect the age distributed in the general population in the UAE. Bias in data collection may produce this problem. Nonetheless, we believe that the impact of this bias on the validity of the findings may not be significant” Q 4. The Introduction section has to mention more about the probable mechanism of stroke in COVID-19 patients. Authors need to focus more on the topic with more literature added. Answer: Thank you for the suggestion. The following was added to the introduction section. ACE receptors, where the COVID virus binds to gain intracellular entry, is expressed in many cells, including epithelial and endothelial cells, which trigger an immediate immunological activation that can lead to hypercoagulability and thrombosis. Multisystem thrombosis, including ischemic stroke, has been associated with severe COVID-19 infection. The pathogenesis is further compounded, given that the fibrinolytic pathway ceases operation. While the pathogenesis of COVID-19-related neurovascular events is not yet clear, some major pathogenic mechanisms have been put forth. These include innate system hyperinflammation, endothelial dysfunction, and disruption of the renin-angiotensin-aldosterone system, hence impacting blood flow, oxidative stress and excessive platelet aggregation (Wijeratne et al. 2021). Reference: Wijeratne T, Gillard Crewther S, Sales C, Karimi L. COVID-19 Pathophysiology Predicts That Ischemic Stroke Occurrence Is an Expectation, Not an Exception-A Systematic Review. Front Neurol. 2021;11:607221. Published 2021 Jan 28. doi:10.3389/fneur.2020.607221 Q 5. It is not clear why authors have chosen ‘hypertension’ to assume the prevalence of stroke. This needs more explanation. Answer: Thank you for this valuable comment. Hypertension is the single most important modifiable stroke risk factor therefore, its value from the literature was used in the calculation of the sample size. This approach has also been used in previous literature: https://www.tandfonline.com/doi/full/10.1080/2331205X.2017.1327129 (Namaganda P, Nakibuuka J, Kaddumukasa M, Katabira E. Stroke in young adults, stroke types and risk factors: a case control study. BMC Neurol. 2022;22(1):335. Published 2022 Sep 6. doi:10.1186/s12883-022-02853-5) Q 6. The questionnaire design is not clearly mentioned in the methodology section. The construct, content, and face validity need to be mentioned in detail. The final questionnaire must be added as an appendix. The authors also need to mention why they developed a new questionnaire rather than adopting an existing one. What is the uniqueness of the newly developed tool? The actual Cronbach alpha value has to be mentioned. The data collection process has to be elaborated. What was the mode of circulation of the questionnaire? How were the subjects chosen? A) The construct, content, and face validity need to be mentioned in detail Answer: Thank you for this comment. The bolded text is the additional info added to the manuscript to clarify this point as requested. The survey started with a brief introduction that described the study objectives, emphasized the confidentiality of the participants, and informed them that completing the survey represents consent to participate in the study. The survey included socio-demographic questions, twenty-five questions evaluating the knowledge of stroke comprising the organ affected, stroke attributes (preventable or recurrent), effect on daily activities, treatment, prevention, risk factors, and signs and symptoms. Six questions evaluating attitude (the approach) towards preventative measures and actions to take if someone showed signs and symptoms of a stroke. All knowledge and attitude questions had a yes/no answer. Lastly, there was a question about the sources of information. For the 25-item knowledge questions, the score range was 0-25. For attitudes, the score range was 0-6. Each correct statement for knowledge and optimal attitude got a 1; otherwise, 0. A questionnaire draft was written and sent to a panel of experts in the pharmacy profession at Al-Ain University for face and content validity. They examined many factors of the questionnaire, including the length, conciseness, language, clarity, time, appropriateness, and bias of questions. Content validation of a questionnaire was aligned with recommendations. The content validity was as follows: B) The final questionnaire must be added as an appendix. Answer: Thank you for this comment. Please find the questionnaire at the extended data section: Open Science Framework: Stroke Study, https://doi.org/10.17605/OSF.IO/5WNAF. 58 - Stroke questionaire.docx C) The authors also need to mention why they developed a new questionnaire rather than adopting an existing one. What is the uniqueness of the newly developed tool? Answer: Thank you for this valuable comment. The yellow highlights is the additional info. that was added to the methods section (Design of questionnaire): The questionnaire was developed after a careful literature review of previous studies utilizing standardized and validated instruments (25–28). Some questions were included to suit the public within the UAE e.g. city of residence, place of birth. The uniqueness of this questionnaire is that it is designed to suit the UAE public. To the best of our knowledge and up to the time this study was conducted, there was not any single study that was conducted across the UAE. D) The actual Cronbach alpha value has to be mentioned. Answer: Thank you. The following was added The Cronbach alpha value determined was 0.72. According to Nunnally's criteria, an α ≥ 0.70 should be regarded as an acceptable reliability E) The data collection process has to be elaborated. Answer: Thank you for this comment. The following was included: Data was collected from study participants using Google Forms between September 2021 to January 2022. Participants were briefed about the study’s purpose and informed about the study’s confidentiality and anonymity policy. Each participant was invited to answer the survey after consent. The questionnaire was self-administered. F) What was the mode of circulation of the questionnaire? Answer: The following was added to the method sections The online, self-administered survey was randomly distributed via a convenience sampling technique G) How were the subjects chosen? Answer: Thank you for your comment. Please refer to the Inclusion and exclusion criteria: They were the following: UAE residents (> 2 years living in the UAE) regardless of their nationality, over the age of 18 years and consented (on the questionnaire by ticking the agreement option) to participate were included in this study. Participants who lived < 2-years in the UAE or did not consent to participate were excluded. Q 7. The discussion rarely mentions about the relationship between COVID-19 and stroke knowledge. Hence some rewriting is needed. Answer: Thank you for the feedback. The following will be inserted after 7th paragraph of the discussion (highlighted yellow in the manuscript). We observed that inadequate knowledge was significantly associated with not having heard of stroke, not knowing someone with a stroke, and not receiving stroke-related information from either a healthcare provider or electronic media. Note that the study was conducted during the COVID-19 when there was a nationwide extended lockdown. Hence, the lack of stroke knowledge and awareness could be due to the public limited access to healthcare providers or due to the limited healthcare provider-led educational campaigns during the quarantine period. Also, the lack of use of electronic media by the participants could have contributed to the public’s gap in knowledge. Hence, overall, the lack of accessibility to healthcare providers and perhaps also to electronic media could have resulted in poor stroke awareness and knowledge. Stroke inadequate knowledge is of great concern given that ischemic stroke is a well-documented side effect of COVID-19. In a US study, it was observed that 46.35% of imaging confirmed ischemic stroke patients had COVID-19 (Belani et al. 2020). Also, the incidence of stroke in COVID-19 patients ranged between 0.9% to 3.3% in several large retrospective studies. Also, higher mortality was reported in patients with COVID-19 who have ischemic stroke compared to control ischemic stroke patients. Furthermore, ischemic stroke was shown to develop in COVID-19 patients with or without co-morbidities (Elfasi et al. 2021). Hence, stroke knowledge-based educational campaigns provided and led by health care personnel are of utmost importance during the pandemic. References - Belani P, Schefflein J, Kihira S, et al. COVID-19 Is an Independent Risk Factor for Acute Ischemic Stroke. AJNR Am J Neuroradiol. 2020;41(8):1361-1364. doi:10.3174/ajnr.A6650 - Elfasi, A., Echevarria, F. D., Rodriguez, R., Roman Casul, Y. A., Khanna, A. Y., Mankowski, R. T., & Simpkins, A. N. (2021). Erratum to \"Impact of COVID-19 on Future Ischemic Stroke Incidence\" [eNeurologicalSci, 22C (2021) 100325]. eNeurologicalSci, 23, 100342. https://doi.org/10.1016/j.ensci.2021.100342 Q 8. The Conclusion is misleading. How can the authors say the knowledge on stroke is ‘inadequate’ and ‘suboptimal’ attitudes? Authors need to first establish the criteria for how they arrived at such conclusions. This has to be clearly mentioned in the methodology. Answer: The following was placed in the methodology section-Design of the of questionnaire: Based on the modified Bloom’s cut-off point, a participant who scored ≥80% of the correct knowledge questions (≥20 points out of 25) was considered as having “good/adequate knowledge”; moderate if the score was between 60 and 79%, (≥15-19 out of 25), and poor/inadequate if the score was less than 60% (<15 points out of 25). For attitude, a respondent who scored ≥80% of the correct attitude questions (≥4.8 points out of 6) was considered as having a “good attitude” or moderate/suboptimal attitude if the score was between 60 and 79%, (≥3.6-4.7 out of 6), and poor attitude if the score was less than 60% (<3.6 points out of 6) (Feleke et al. 2021)."
}
]
}
] | 1
|
https://f1000research.com/articles/12-322
|
https://f1000research.com/articles/12-515/v1
|
18 May 23
|
{
"type": "Research Article",
"title": "Development of a Japanese version of the Awe Experience Scale (AWE-S): A structural topic modeling approach",
"authors": [
"Ryota Takano",
"Akiko Matsuo",
"Kazuaki Kawano",
"Akiko Matsuo",
"Kazuaki Kawano"
],
"abstract": "Background: Awe, a complex emotion, arises in response to perceptually and conceptually vast stimuli that transcend one’s current frames of reference, which is associated with subjective psychological phenomena, such as a sense of self and consciousness. This study aimed to develop a Japanese version of the Awe Experience Scale (AWE-S), a widely used questionnaire that robustly measured the state of awe, and simultaneously investigated how the multiple facets of awe related to the narrative representations of awe experiences. Methods: The Japanese AWE-S was created via back-translation and its factor structure and validity was investigated through an online survey in Japan. Results: The results revealed that the Japanese AWE-S consisted of the same six factors as the original (i.e., time, self-loss, connectedness, vastness, physiological, and accommodation) and had sufficient internal consistency, test-retest reliability, construct validity, and also Japan-specific characteristics. The structured topic modeling generated seven potential topics of the descriptions of awe experiences, which were differently associated with each factor of the Japanese AWE-S. Conclusions: Our findings contribute to a deeper understanding of awe and reveal the constructs of awe in Japan through cross-cultural comparisons. Furthermore, this study provides conceptual and methodological implications regarding studies on awe.",
"keywords": [
"awe",
"emotion",
"scale",
"text-mining",
"narrative",
"topic modeling",
"culture",
"questionnaire"
],
"content": "Introduction\n\nAwe is an emotional response to perceptually and conceptually vast stimuli that transcend one’s current frames of reference (Keltner & Haidt, 2003). It has been studied in various fields, such as psychology, economics, neuroscience, immunology, and public health (Guan et al., 2018; Ibanez et al., 2017; Monroy & Keltner, 2022; Piff et al., 2015; Sawada & Nomura, 2020; Stellar et al., 2015; Sun et al., 2021; Takano & Nomura, 2022b; van Elk et al., 2019). Previous studies have shown that awe is associated with subjective psychological phenomena, such as a sense of self and consciousness, which highlights the need for a standardized questionnaire to assess the various dimensions of awe experiences (Bai et al., 2017; Rudd et al., 2012; Takano & Nomura, 2021). The Awe Experience Scale (AWE-S), a widely used questionnaire that robustly measures the state of awe (Yaden et al., 2019), has been translated into several languages (Landrum et al., 2022; Ling-xiao et al., 2022; Rodrigues et al., 2022; van Houwelingen-Snippe et al., 2020). However, how the multiple facets of awe measured by the AWE-S relate to the representations of awe experiences in different cultural contexts remains unclear. Simultaneously, there is no reliable and valid standardized Japanese version of the AWE-S. Therefore, it is important to develop a standardized Japanese AWE-S and investigate its narrative dimensions not only for a deeper understanding of the complex emotion of awe and revealing the construct of awe in Japan through cross-cultural comparisons, but also for investigating the psychological mechanisms underlying the various effects of awe on mental health and social behavior (Bai et al., 2021; Liu et al., 2023; Piff et al., 2015; Stellar et al., 2018; Sturm et al., 2022; Takano & Nomura, 2021).\n\nThe AWE-S questionnaire comprises six factors: time, self-loss, connectedness, vastness, physiological, and accommodation (Yaden et al., 2019). Time captures the perception of time expansion in awe experiences, which may indicate a shift in mental state towards a more mindful, moment-to-moment awareness, such as here and now (Gregory et al., 2023; Kramer et al., 2013; Rudd et al., 2012; Yaden et al., 2019). Self-loss reflects the phenomenon where awe can diminish one’s sense of self, leading to feelings of insignificance (Bai et al., 2017; Piff et al., 2015; Takano & Nomura, 2021). Connectedness indicates that awe experiences can create a greater sense of connection between individuals and their surroundings, which includes the supernatural, such as God(s) (Liu et al., 2023; Van Cappellen & Saroglou, 2012). Vastness pertains to the perception of vastness vis-à-vis the self, where individuals encounter physically or conceptually enormous stimuli (Keltner & Haidt, 2003; Landrum et al., 2022). Physiological captures awe-related physiological phenomena, such as goosebumps (Quesnel & Riecke, 2018; Williams et al., 2022). Accommodation reflects the process of needing to adjust one's understanding or cognitive framework to comprehend new information or experiences, often experienced during awe-inspiring situations (Keltner & Haidt, 2003; Taylor & Uchida, 2019; Valdesolo et al., 2016). Yaden et al. (2019) showed that the AWE-S, measured after one recalled and described their experience of awe, was positively associated with trait measures of tendency to experience awe, which was salient for the factors of time, connectedness, vastness, and the physiological. This suggested that the state measure of awe had enough convergent and divergent validity.\n\nDue to its robustness and usefulness, the AWE-S has been validated in several countries and cultures via translation into other languages, such as Chinese, Portuguese, and Dutch (Landrum et al., 2022; Li & Qian, 2022; Ling-xiao et al., 2022; Rodrigues et al., 2022; van Houwelingen-Snippe et al., 2020). Universal components and cultural variations of awe-related phenomena have been identified via this scale. However, despite the creation and development of other scales to measure awe in Japan, the AWE-S has not yet been translated into the Japanese language (Nakayama et al., 2020; Sawada & Nomura, 2022). To facilitate more comprehensive cross-cultural comparisons, the development of a Japanese version of the AWE-S, which can provide a deeper understanding of awe, is necessary.\n\nPrevious studies suggested that cultural similarities and differences in awe experiences were important perspectives to understand the generality and heterogeneity of awe (Bai et al., 2017; Nakayama et al., 2020; Nakayama & Uchida, 2020; Razavi et al., 2016; Sawada & Nomura, 2022). Specifically, it was necessary to consider how awe altered the sense of self and differed across cultures, although the small self-effect was a general and robust phenomenon (Bai et al., 2017; Nomura et al., 2021; Takano & Nomura, 2021). Awe may manifest differently among individuals from East Asian cultures, such as Japan, compared to those from Western cultures according to their culturally, historically, and religiously cultivated views of the self. Particularly, the self is represented as being non-substantial, denial, and embedded as default in Japan, a country with Buddhist and Shinto backgrounds. Meanwhile, it is represented as separated and continuous concepts by others in Western cultures (Nomura et al., 2021; Sugimoto, 2020; Takano & Nomura, 2019, 2022a). Thus, a Japanese AWE-S might reveal culture-specific patterns, especially regarding the sense of self.\n\nFrom the perspective of state awe, it is important to address how people narrate their awe experiences in their cultural context for a deeper understanding (Nakayama & Uchida, 2020). Since the AWE-S is measured after participants recall and describe (i.e., write) their awe experiences (Yaden et al., 2019), their contents may have a role manifesting the responses to the AWE-S. Studies revealed that ratings on the AWE-S varied based on the elicitors of awe experiences (Graziosi & Yaden, 2021; Yaden et al., 2019). However, the aspects of narrated experience (i.e., the “potential topics”) associated with each factor of the AWE-S have not been investigated beyond the typology of awe experience. For example, looking up at the night sky or touching a grand theory are different types of experiences. However, both might be accompanied with common potential topic of “universe.” Similarly, different awe experiences narrated through the same elicitor could involve distinct potential topics, which could lead to the AWE-S being rated differently.\n\nThis study aimed to develop a standardized Japanese AWE-S as well as investigate its relationships with linguistic generative processes underlying the expression of awe experiences. First, we created a Japanese version of the AWE-S via back-translation and confirmed its factor structure and test-retest reliability compared to the original AWE-S. Furthermore, its convergent and divergent validities were examined regarding its relation to the trait-awe (dispositional awe) questionnaire. Second, we used a structural topic model (STM) and exploratorily examined whether and how each factor of AWE-S was associated with topics that underlie the narrative of awe experiences (Roberts et al., 2014). Using this model, we can focus not only on the type of experience, but also on the generative process of potential topics underlying how people feel in that experience and express it in natural language.\n\n\nMethods\n\nThis study recruited 358 Japanese participants through Qualtrics (http://www.qualtrics.com) via a Japanese crowdsourcing service, Crowd Works (https://crowdworks.jp/). Responses were collected during November 2022. Participants were required to meet the a priori criterion that they were native Japanese speakers. After 43 participants with incorrect answers for attention checks or duplicated IP addresses were excluded, 315 respondents were included (156 males, 156 females, and three others, Mage = 42.64 years, SD = 10.08, Range: 20–79 years). Our target sample size was determined using a priori power analysis (G*Power) (Faul et al., 2007). To achieve 0.90 power at an α level of 0.05 for an effect size of r = .20, a medium effect of some explanatory and practical use even in the short run, a sample of 255 participants was required (Funder & Ozer, 2019). To evaluate the test-retest reliability of the Japanese AWE-S, we requested participants to complete the same questionnaire again approximately one week later (N = 91, 42 males, 48 females, and one other, Mage = 43.37 years, SD = 9.86, Range: 24–71 years). Additionally, before data were collected for the main study, we conducted a separate pilot survey to assess the mean and variance of each item in the Japanese version of the AWE-S (N = 137, 66 males, 70 females, and one other, Mage = 42.26 years, SD = 8.78, Range: 22–64 years). Since the items used in the pilot survey were identical to those in the main study, we conducted factor analyses of the Japanese version of the AWE-S and text analyses via a combined sample of participants from both the pilot and main study (N = 452). The questionnaires took approximately 15–20 minutes to answer and participants were paid 200 yen for their time (regarding the additional survey for the test-retest reliability, we paid 50 yen for 5 minutes).\n\nThe study conformed to the principles expressed in the Declaration of Helsinki and its future amendments. This study was approved by the Ethics Committee of Tokaigakuen University (Ref-No. 2022-11). Written informed consent was obtained from all the study participants at the start of the survey. Participants had the right to withdraw from the experiment at any time without providing a reason. It was also explained to them that their responses would not be tied to them personally. This study was partly preregistered at https://aspredicted.org/n6ga7.pdf. Data and analysis codes are available under Underlying data (Takano & Matsuo, 2023).\n\nThe following measures were used (we assessed other questionnaires for other related investigations), and participants’ demographic information (gender, age, and nationality) were enquired.\n\nJapanese versions of the Awe Experience Scale\n\nWe translated the instructions and items of the AWE-S into Japanese with permission from the original authors. Subsequently, we used a translation service (NAI Inc.; https://www.nai.co.jp/) to back-translate the provisional Japanese version. Specific instructions in Japanese are available under Extended data (Takano & Matsuo, 2023).\n\nAs per Yaden et al.’s study (2019), participants were instructed to recall a recent and intense awe experience and write it. Specifically, the instructions asked participants to reflect on a specific moment in time when they felt intense awe, and describe that experience in approximately two paragraphs in a designated text box. The instructions emphasized that participants should focus on the experience itself rather than what led up to it, what happened afterwards, or their interpretation. In addition, they were required to be as descriptive and specific as possible. Subsequently, participants responded to 30 items on the aspects of their awe experience. Each item was rated on a 7-point scale (1 = Strongly Disagree, 7 = Strongly Agree). To prevent the effects of recalling an awe experience on responses to other questionnaires, participants completed the AWE-S after all the other questionnaires.\n\nDispositional Positive Emotion Scale (DPES)\n\nThe Dispositional Positive Emotion Scale (DPES), a trait-based assessment tool that measured an individual’s tendency to experience various positive emotions in daily life, was used to examine the construct validity of the Japanese version of the AWE-S. The scale consisted of 38 items that included several subscales, which included joy (six items, α = .86), amusement (five items, α = .78), awe (six items, α = .80), contentment (five items, α = .95), love (six items, α = .86), pride (five items, α = .81), and compassion (five items, α = .83). The original version of this scale was developed by Shiota et al. (2006). We used the Japanese version developed by Nomura et al. (2021).\n\nData analyses were conducted using R software (version 4.2.2 [2022-10-31]). First, we conducted confirmatory factor analyses for the DPES and Japanese AWE-S using lavaan SEM package (Rosseel, 2012). Second, to examine the test-retest reliability of the Japanese AWE-S, we calculated the intraclass correlation coefficients between the first and second responses for each factor using the irr package (Gamer et al., 2012). Third, we used an independent t-test to compare the means of the Japanese AWE-S factors with those of the original AWE-S factors (Yaden et al., 2019). Fourth, zero-order correlation analyses were conducted to assess the relationships among the subfactors of these scales. Fifth, linear regression analyses were performed with a robust estimation method to investigate whether the Japanese AWE-S factors were associated with the DPES awe factor, controlled for other DPES factors, using the ‘lm_robust’ function in the estimatr package (Blair et al., 2021). For the regression analyses, all (in) dependent variables were standardized.\n\nFor the text analyses, participants’ descriptions of their awe experiences were analyzed using the stm package to estimate a Structural Topic Model (Roberts et al., 2019, 2014). We investigated how the AWE-S was associated with their narratives of awe (note that these analyses were exploratory and not pre-registered). This method considered additional information regarding the data structure (i.e., the AWE-S in this study), which was incorporated into the model to help identify and extract more meaningful and interpretable topics. Furthermore, we added six factors of the AWE-S as covariates to examine how the prevalence of each topic changed when each factor rating increased or decreased and whether the change was significant.\n\nDescriptions of the awe experiences underwent tokenization and pre-processing based on Roberts et al.’s study (2014) (N = 452). We regarded each participant’s description as one document. Tokens were limited to adjectives, verbs, and nouns that occurred at least three times across all the participants. Additionally, we used the 'prepDocuments' function in the stm package and eliminated numbers, common punctuation, and stop-words considered semantically meaningless. The number of topics (K) was determined using the 'searchK' function by generating models based on potential Ks that ranged from 2 to 50. The model with K=7 had the highest held-out log-likelihood and sufficient average semantic coherence across topics, whereas these indices dropped drastically when Ks were over 20. Therefore, we selected K = 7. After the STM was estimated, each author independently assigned labels based on the most frequent words listed in each topic. We discussed these until a consensus was reached on a label for the topic (Idler et al., 2022; Sterling et al., 2019).\n\n\nResults\n\nA total of 452 participants (222 males, 226 females, and four others, Mage = 42.52 years, SD = 9.69, Range: 20–79 years) were included in the factor analysis, t-tests, and the STM for the Japanese AWE-S. Of these, a total of 91 participants (42 males, 48 females, and one other, Mage = 43.37 years, SD = 9.86, Range: 24–71 years) were included in the intra-class correlation analyses to examine the test-retest reliability, while a total of 315 participants (156 males, 156 females, and three others, Mage = 42.64 years, SD = 10.08, Range: 20–79 years) were included in the factor analysis for the DPES, the correlation analyses, and the multiple regression analyses. The full dataset can be found under Underlying data (Takano & Matsuo, 2023).\n\nConfirmatory factor analyses were conducted to examine the factor structure of the Japanese AWE-S (Table 1) and DPES. The results showed that the six-factor model provided an adequate fit to the data for the Japanese AWE-S, chi-squared (χ2) (390) = 1070.31, Comparative Fit Index (CFI) = .905, Goodness Fit Index (GFI) = .854, Root Mean Square Error of Approximation (RMSEA) = .062 [90% lower = .058], and Standardized Root Mean Square Residual (SRMR) = 0.068. In addition, the seven-factor model of the DPES as fitted well as in previous studies, χ2 (644) = 1728.55, CFI = .860, GFI = .763, RMSEA = .073 [90% lower = .069], and SRMR = .064 (Nomura et al., 2021; Shiota et al., 2006; Sugawara et al., 2020). To examine the internal consistent of the Japanese AWE-S, Cronbach’s alpha coefficients were calculated for each subscale (Table 1). Sufficient internal consistency was confirmed, which was consistent with the results of previous studies (Ling-xiao et al., 2022; Yaden et al., 2019). In addition, the intraclass correlations analyses for each subscale of AWE-S showed sufficient and good test-retest reliability (ρs > .60, p < .001, Table 1).\n\nThere were differences in the means of some factors of the AWE-S between the Japanese and original versions, as shown in Table 1. Independent t-tests indicated that the mean scores for the self-loss and vastness factors were higher in the Japanese version than in the original. In contrast, those for the connectedness and physiological factors were lower in the Japanese version than in the original (self-loss: t (1086) = 4.90, p < .001, vastness: t (1086) = 4.97, p < .001, connectedness: t (1086) = -11.66, p < .001, and physiological: t (1086) = -2.20, p = .028).\n\nCorrelation analyses between the subscales of the Japanese AWE-S and DPES were conducted to examine construct validity. Time, connectedness, vastness, and physiological factors were significantly positively correlated with awe (r = .12–.36, p < .038) and other factors of the DPES, while self-loss and accommodation were not (Table 2). In addition, while the inter-factor correlations coefficients of the Japanese AWE-S ranged from moderate to large, those of the DPES were large (AWE-S: r = .26–.47, p < .001, DPES: r = .44–.83, p < .001).\n\n* = p < .05.\n\nLinear regression analyses with a robust estimation method showed that the time and connectedness factors were significantly positively associated with awe factor of the DPES, controlled for other positive emotions (β = .21–.23, p < .013). This indicated that these factors of the AWE-S were specifically associated with dispositional awe. These results did not change when controlled for participants’ age and gender.\n\nFurthermore, seven topics were generated by the STM and labeled: “Spirituality,” “Threat,” “Spatiality,” “Universe,” “Scenery,” “Humanity,” and “Aesthetics” (see Figure 1). The top 20 highest probability words are listed in Table 3. The results revealed that participants with higher scores on the time factor of the Japanese AWE-S were more likely to use words related to “Spatiality” and “Scenery.” In contrast, they were less likely to use words of “Humanity.” (Figure 1A). Similarly, positive associations were found between the connectedness factor and “Spirituality” and “Aesthetics” (Figure 1C), vastness factor and “Universe” and “Scenery” (Figure 1D), physiological factor and “Threat” and “Scenery” (Figure 1E), and accommodation factor and “Spirituality” and “Threat” (Figure 1F). In addition, negative associations were found between the connectedness factor and “Threat” and “Scenery” (Figure 1C), vastness factor and “Spirituality,” “Threat,” and “Humanity” (Figure 1D), physiological factor and “Universe” (Figure 1E), and accommodation factor and “Scenery” and “Aesthetics” (Figure 1F). The self-loss factor was not significantly associated with any topic (Figure 1B).\n\nNote. Effects computed using a structural topic model. Parameter estimates depicted as dots. Expected topic proportions are depicted by dot size. Error bars represent 95% confidence interval.\n\n\nDiscussion\n\nThis study aimed to develop a Japanese version of the AWE-S, a robust questionnaire that measured the subjective state in awe experiences, and investigate its relations to the representations of awe experiences in natural language. We examined the validity of the Japanese AWE-S and explored how each factor of the AWE-S was related to topics that underlie the narrative of awe experiences via a structural topic model. The results showed that the six-factor model of the original AWE-S sufficiently fit the data for the Japanese AWE-S. Furthermore, the mean scores for the self-loss and vastness factors were higher in the Japanese version than in the original. In contrast, the connectedness and physiological factors were lower in the Japanese version. In addition, the time, connectedness, vastness, and physiological factors were positively associated with trait-awe (dispositional awe). Even when controlled for other positive emotions, age, and sex, the relationships with the time and connectedness factors remained constant. The STM generated seven potential topics, which were differently associated with each factor of the Japanese AWE-S.\n\nThe confirmatory factor analysis revealed that the factor structure and items of the Japanese AWE-S were comparable to the original (Yaden et al., 2019). In addition, Cronbach’s alpha coefficients and intraclass correlations showed that this scale had sufficient internal consistency and test-retest reliability, respectively. Therefore, our results suggested that the structure and reliability of the Japanese AWE-S, developed in this study, was comparable to that of the original version. Hence, it was adequate for international comparisons.\n\nThe time, connectedness, vastness, and physiological factors of the Japanese AWE-S were positively associated with trait measures of tendency to experience awe (i.e., dispositional awe). These results were consistent with Yaden et al.’s results (2019), which suggested that the Japanese version had similar construct validity to the original. Furthermore, we used linear regression analyses and revealed that the time and connectedness factors were specifically related to trait-awe, controlled for other positive emotions. Previous studies suggested that the dispositional awe questionnaire mainly focused on the positivity, beauty, and mindful aspects of awe (example: “I see beauty all around me” (Shiota et al., 2006). Therefore, our results suggested that the AWE-S was a state scale that could capture other aspects of awe.\n\nRegarding the culturally specific perspectives, the mean scores for the self-loss and vastness factors were higher, while those for the connectedness and physiological factors were lower in the Japanese version than in the original. Previous research suggested that the sense of the self was mainly characterized by being non-substantial, denied, and embedded as default in Japan with its Buddhist and Shinto backgrounds, while it is represented as separated and continuous concepts by others in Western cultures (Nomura et al., 2021; Sugimoto, 2020; Takano & Nomura, 2021, 2022a). Consistent with this perspective, Takano and Nomura (2021) revealed that experimentally induced awe reduced one’s sense of self-size and also blurred the sense of boundary of the self. Hence, Japanese people might be more and less likely to respond to self-reductive (i.e., self-loss and vastness) and self-expansive aspects during awe experiences (i.e., connectedness and physiological), respectively.\n\nRegarding the narrative aspect of awe, the STM revealed that each factor of the AWE-S was related to seven topics of descriptions of awe experiences. There were positive (negative) associations between the time factor and “Scenery” and “Spatiality” (“Humanity”), connectedness factor and “Spirituality” and “Aesthetics” (“Threat” and “Scenery”), vastness factor and “Universe” and “Scenery” (“Spirituality,” “Threat,” and “Humanity”), physiological factor and “Threat” and “Scenery” (“Universe”), and accommodation factor and “Spirituality” and “Threat” (“Scenery” and “Aesthetics”). These results were consistent with the characteristics of each factor of AWE-S as proposed by the original version (Yaden et al., 2019). Previous studies also demonstrated that the elicitors of awe experiences had different roles in manifesting responses to the AWE-S (Graziosi & Yaden, 2021; Yaden et al., 2019). Therefore, beyond the typology, this was the first study to reveal that the various psychological elements of awe emerged differently based on the potential topics of narratives.\n\nThis study has some limitations and directions for future research. First, along with the original version, the effect sizes of the correlations between some of the factors of the AWE-S and trait-awe were relatively low (Yaden et al., 2019). This may have been caused by ceiling effects, which should be investigated in future studies. Second, when writing regarding previous experiences, it was possible that the participants’ ratings were influenced by their memory of the event and not the actual experience of awe. The recollection method allowed us to investigate the narrative dimensions of the AWE-S. As in a previous study (Bai et al., 2017; Valdesolo & Graham, 2014; Van Cappellen & Saroglou, 2012), other manipulation methods (e.g., video stimuli) should be used to confirm the generalizability of our results. Third, this study investigated the relationship between the Japanese AWE-S and self-reported measures to reveal its construct validity. Given that the advantage of the AWE-S was that it revealed psychological processes that could only be captured subjectively, further studies should investigate whether and how this scale was associated with other behavioral, physiological, and neural measures.\n\nIn summary, this study is the first to develop a Japanese version of the AWE-S, confirm its convergent and divergent validities, and investigate its narrative dimensions during awe experiences. Our findings contribute to a deeper understanding of awe and revealing its construct in Japan through cross-cultural comparisons. Furthermore, this study provides conceptual and methodological implications regarding studies on awe.",
"appendix": "Data availability\n\nOSF: Japanese ver. of AWE-S and Purity. https://doi.org/10.17605/OSF.IO/8CSR4. (Takano & Matsuo, 2023)\n\nThis project contains the following underlying data:\n\n- data_cleaned.csv (dataset for the main study)\n\n- data_pilot_cleaned.csv (dataset for the pilot study)\n\n- data_testretest.csv (dataset for the test-retest validity)\n\n- instructionsforJverAWE-S.docx (specific instructions for the Japanese AWE-S)\n\n- main_script.R (analysis code)\n\nOSF: Japanese ver. of AWE-S and Purity. https://doi.org/10.17605/OSF.IO/8CSR4\n\nThis project contains the following extended data:\n\n- questionnaire_in_Japanese.pdf\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nBai Y, Maruskin LA, Chen S, et al.: Awe, the diminished self, and collective engagement: Universals and cultural variations in the small self. J. Pers. Soc. Psychol. 2017; 113(2): 185–209. PubMed Abstract | Publisher Full Text\n\nBai Y, Ocampo J, Jin G, et al.: Awe, daily stress, and elevated life satisfaction. J. Pers. Soc. Psychol. 2021; 120(4): 837–860. PubMed Abstract | Publisher Full Text\n\nBlair G, Cooper J, Coppock A, et al.: estimatr: Fast estimators for design-based inference. 2021. Reference Source\n\nFaul F, Erdfelder E, Lang A-G, et al.: G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav. Res. Methods. 2007; 39(2): 175–191. PubMed Abstract | Publisher Full Text\n\nFunder DC, Ozer DJ: Evaluating Effect Size in Psychological Research: Sense and Nonsense. Adv. Methods Pract. Psychol. Sci. 2019; 2(2): 156–168. Publisher Full Text\n\nGamer M, Lemon J, Gamer MM, et al.: Package ‘irr’: Various coefficients of interrater reliability and agreement. 2012. Reference Source\n\nGraziosi M, Yaden D: Interpersonal awe: Exploring the social domain of awe elicitors. J. Posit. Psychol. 2021; 16(2): 263–271. Publisher Full Text\n\nGregory AL, Quoidbach J, Haase CM, et al.: Be here now: Perceptions of uncertainty enhance savoring. Emotion. 2023; 23(1): 30–40. PubMed Abstract | Publisher Full Text\n\nGuan F, Xiang Y, Chen O, et al.: Neural basis of dispositional awe. Front. Behav. Neurosci. 2018; 12: 209. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIbanez L, Moureau N, Roussel S: How do incidental emotions impact pro-environmental behavior? Evidence from the dictator game. J. Behav. Exp. Econ. 2017; 66: 150–155. Publisher Full Text\n\nIdler E, Bernau JA, Zaras D: Narratives and counter-narratives in religious responses to COVID-19: A computational text analysis. PLoS One. 2022; 17(2): e0262905. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKeltner D, Haidt J: Approaching awe, a moral, spiritual, and aesthetic emotion. Cognit. Emot. 2003; 17(2): 297–314. Publisher Full Text\n\nKramer RSS, Weger UW, Sharma D: The effect of mindfulness meditation on time perception. Conscious. Cogn. 2013; 22(3): 846–852. Publisher Full Text\n\nLandrum AR, Janét K, Opat K, et al.: When science journalism is awesome: Measuring audiences’ experiences of awe from reading science stories. Journal. Pract. 2022; 1–17: 1–17. Publisher Full Text\n\nLi O, Qian D: An analysis of the relationship between risk perceptions and willingness-to-pay for commodities during the COVID-19 pandemic. J. Consum. Aff. 2022; 56(1): 257–275. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLing-xiao Z, Shan-yin LI, Kai-ping P, et al.: Revision the Chinese version of the Awe Experience Scale. Chin. J. Clin. Psych. 2022; 30(5): 1138–1148. Publisher Full Text\n\nLiu J, Huo Y, Wang J, et al.: Awe of nature and well-being: Roles of nature connectedness and powerlessness. Personal. Individ. Differ. 2023; 201: 111946. Publisher Full Text\n\nMonroy M, Keltner D: Awe as a pathway to mental and physical health. Perspect. Psychol. Sci. 2022; 18(2): 309–320. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNakayama M, Nozaki Y, Taylor PM, et al.: Individual and cultural differences in predispositions to feel positive and negative aspects of awe. J. Cross-Cult. Psychol. 2020; 51(10): 771–793. Publisher Full Text\n\nNakayama M, Uchida Y: Meaning of awe in Japanese (con) text: Beyond fear and respect. Psychologia. 2020; 62(1): 46–62. Publisher Full Text\n\nNomura M, Tsuda A, Rappleye J: How awe works in humanitarian setting in East Asia: Cultural differences in describing the experience of awe.Chiao J, Li S-C, Seligman R, et al., editors. Oxford Handbook of Cultural Neuroscience and Global Mental Health. Oxford University Press; 2021; (pp. 221–232).\n\nPiff PK, Dietze P, Feinberg M, et al.: Awe, the small self, and prosocial behavior. J. Pers. Soc. Psychol. 2015; 108(6): 883–899. PubMed Abstract | Publisher Full Text\n\nQuesnel D, Riecke BE: Are you awed yet? How virtual reality gives us awe and goose bumps. Front. 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Publisher Full Text\n\nRudd M, Vohs KD, Aaker J: Awe expands people’s perception of time, alters decision making, and enhances well-being. Psychol. Sci. 2012; 23(10): 1130–1136. PubMed Abstract | Publisher Full Text\n\nSawada K, Nomura M: Influence of positive and threatened awe on the attitude toward norm violations. Front. Psychol. 2020; 11: 148. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSawada K, Nomura M: Developing and validating the Japanese version of the situational Awe scale (SAS-J). Curr. Psychol. 2022. Publisher Full Text\n\nShiota MN, Keltner D, John OP: Positive emotion dispositions differentially associated with Big Five personality and attachment style. J. Posit. Psychol. 2006; 1(2): 61–71. Publisher Full Text\n\nStellar JE, Gordon A, Anderson CL, et al.: Awe and humility. J. Pers. Soc. Psychol. 2018; 114(2): 258–269. PubMed Abstract | Publisher Full Text\n\nStellar JE, John-Henderson N, Anderson CL, et al.: Positive affect and markers of inflammation: discrete positive emotions predict lower levels of inflammatory cytokines. Emotion. 2015; 15(2): 129–133. PubMed Abstract | Publisher Full Text\n\nSterling J, Jost JT, Hardin CD: Liberal and conservative representations of the good society: A (social) structural topic modeling approach. SAGE Open. 2019; 9(2): 215824401984621. Publisher Full Text\n\nSturm VE, Datta S, Roy ARK, et al.: Big smile, small self: Awe walks promote prosocial positive emotions in older adults. Emotion. 2022; 22(5): 1044–1058. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSugawara D, Arimitsu K, Sugie M: Development of the Japanese version of Dispositional Positive Emotion Scales. J. Health Psychol. Res. 2020; 33(1): 57–65. Publisher Full Text\n\nSugimoto Y: An introduction to Japanese society. Cambridge University Press; 2020.\n\nSun X, Su W, Guo X, et al.: The Impact of Awe Induced by COVID-19 Pandemic on Green Consumption Behavior in China. Int. J. Environ. Res. Public Health. 2021; 18(2). Publisher Full Text\n\nTakano R, Nomura M: Anodal transcranial direct current stimulation of the right temporoparietal junction enhances the self-effacing bias in Japanese individuals. Culture and Brain. 2019; 7(1): 80–91. Publisher Full Text\n\nTakano R, Nomura M: Awe liberates the feeling that “my body is mine.”. Cognit. Emot. 2021; 35(4): 738–744. PubMed Abstract | Publisher Full Text\n\nTakano R, Nomura M: Relationships between right-wing authoritarianism and spirituality in Japan. Psychol. Relig. Spiritual. 2022a. Publisher Full Text\n\nTakano R, Nomura M: Neural representations of awe: Distinguishing common and distinct neural mechanisms. Emotion. 2022b; 22(4): 669–677. PubMed Abstract | Publisher Full Text\n\nTaylor PM, Uchida Y: Awe or horror: differentiating two emotional responses to schema incongruence. Cognit. Emot. 2019; 33(8): 1548–1561. Publisher Full Text\n\nValdesolo P, Graham J: Awe, uncertainty, and agency detection. Psychol. Sci. 2014; 25(1): 170–178. PubMed Abstract | Publisher Full Text\n\nValdesolo P, Park J, Gottlieb S: Awe and scientific explanation. Emotion. 2016; 16(7): 937–940. PubMed Abstract | Publisher Full Text\n\nVan Cappellen P, Saroglou V: Awe activates religious and spiritual feelings and behavioral intentions. Psychol. Relig. Spiritual. 2012; 4(3): 223–236. Publisher Full Text\n\nvan Elk M , Arciniegas Gomez MA, van der Zwaag W , et al.: The neural correlates of the awe experience: Reduced default mode network activity during feelings of awe. Hum. Brain Mapp. 2019; 40(12): 3561–3574. PubMed Abstract | Publisher Full Text | Free Full Text\n\nvan Houwelingen-Snippe J , van Rompay TJL , de Jong MDT , et al.: Does digital nature enhance social aspirations? An experimental study. Int. J. Environ. Res. Public Health. 2020; 17(4). PubMed Abstract | Publisher Full Text | Free Full Text\n\nWilliams PG, Johnson KT, Bride DL, et al.: Individual differences in aesthetic engagement and proneness to aesthetic chill: Associations with awe. Psychol. Aesthet. Creat. Arts. 2022. Publisher Full Text\n\nYaden DB, Kaufman SB, Hyde E, et al.: The development of the Awe Experience Scale (AWE-S): A multifactorial measure for a complex emotion. J. Posit. Psychol. 2019; 14(4): 474–488. Publisher Full Text\n\nTakano R, Matsuo A: Japanese ver. of AWE-S and Purity.2023, May 6. Publisher Full Text"
}
|
[
{
"id": "174203",
"date": "19 Jun 2023",
"name": "Hidefumi Hitokoto",
"expertise": [
"Reviewer Expertise Cross-cultural psychology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI enjoyed reading the manuscript a lot. As it is deals with the cultural generalization of the AWE experience measure, especially in a culture where previous studies showed some interesting cultural differences between the West (Nakayama et al., 2020), the scale standardization should contribute to the test of universality of the emotion.\nMy comments are listed below. They are mostly on the logic building up to the interpretation of the main results.\nI understand the authors are trying to make the case that the newly translated J-AWE-S has reliability and validity, including factorial and criterion-related. However, the current unfolding seems to make an impression that the correlations with DPES are given post-hoc interpretations. In other words, how can the validity correlations with DPES (or the lack thereof with self-loss and accommodation) be understood as supporting the validity of the J-AWE-S? Similarly, what was the logic behind controlling other positive emotions of DPES to arrive at the regression result of selected positive emotions explaining seemingly different aspects of J-AWE-S as in Table 2?\nRegarding J-AWE-S, Item 30 seems to show low factor loading. Would removing it contribute to the improvement of the fit?\nDPES seems to show a marginal fit. Does it reliably measure the 7 positive emotions? Or, removing some items/emotions increases the overall reliability, and that makes a better test?\nAs the text analysis of the experience topic and its correspondence with J-AWE-S response is so interesting, if the main aim of the study is to validate the scale in conjunction with the former, authors may present some expected findings given the nature of the J-AWE-S. This seemed possible a-pri-ori, when authors argued that awe involves vastness in scenes or has cultural roots of selfhood.\nHow do we make of the \"Expected Topic Proportion\" presented in Fig1? The value \"0.20\" seems the largest level presented, but would that mean, for example, a response \"Vastness\" occupied approximately 20% of the case when the \"Scenery\" was described as the eliciting situation?\nJust a check: on Table 3, there seem to be multiple \"can(de-ki-ru)\"s observed across topics, and in some cases, its Chinese character version is present with the same English counterpart (at Humanity). Is this normal for this technique?\nI was wondering to what extent \"the self (as) represented as being non-substantial, denial, and embedded as default in Japan, a country with Buddhist and Shinto backgrounds (p3)\" is related to the interdependent views of the self (Markus & Kitayama, 1991). When the self is understood as socially conferred, it may render non-substantial in order to preserve harmony in one's in-group, denied so as to catch up with the group-held norm, and embedded in the group in which one should be a part.\nTypo: P5: internal consistent\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "10366",
"date": "13 Oct 2023",
"name": "Ryota Takano",
"role": "Author Response",
"response": "Response to Reviewer #1: I enjoyed reading the manuscript a lot. As it is deals with the cultural generalization of the AWE experience measure, especially in a culture where previous studies showed some interesting cultural differences between the West (Nakayama et al., 2020), the scale standardization should contribute to the test of universality of the emotion. My comments are listed below. They are mostly on the logic building up to the interpretation of the main results. Reply: Thank you so much for your valuable comments and queries. We have incorporated all your comments and revised the manuscript. Please find the point-by-point responses and the corresponding revised text below. Comment 1. I understand the authors are trying to make the case that the newly translated J-AWE-S has reliability and validity, including factorial and criterion-related. However, the current unfolding seems to make an impression that the correlations with DPES are given post-hoc interpretations. In other words, how can the validity correlations with DPES (or the lack thereof with self-loss and accommodation) be understood as supporting the validity of the J-AWE-S? Similarly, what was the logic behind controlling other positive emotions of DPES to arrive at the regression result of selected positive emotions explaining seemingly different aspects of J-AWE-S as in Table 2? Reply: Thank you for your comment. Since no previous studies have longitudinally examined the relationship between the trait and state aspects of awe, it is unclear how the tendency to feel awe on a daily basis (awe factor of the DPES) is associated with state responses to experiencing actual awe (AWE-S). However, several studies have shown that awe-related phenomena observed via the awe factor of the DPES (dispositional awe) could also be seen through the measurement of state-awe (Bai et al., 2017; Piff et al., 2015; Stellar et al., 2018). Hence, we investigated the relationships between the DPES and Japanese AWE-S to verify its construct validity. In addition, we controlled other positive emotions of the DPES to examine specific relationships between dispositional awe and each factor of the Japanese AWE-S. We have incorporated your comment by adding the following sentences in the last paragraph of the Introduction section. (Added sentences) We used the Dispositional Positive Emotion Scale (DPES) since previous studies demonstrated that awe-related phenomena observed via the DPES could also be seen through the measurement of state-awe ( Bai et al., 2017; Piff et al., 2015; Stellar et al., 2018). We controlled other positive emotions to examine specific relationships between dispositional awe and each factor of the Japanese AWE-S Comment 2. Regarding J-AWE-S, Item 30 seems to show low factor loading. Would removing it contribute to the improvement of the fit? Reply: When item 30 was removed from the factor analysis, goodness-of-fit was slightly improved. With item 30: χ2 (390) = 1070.31, CFI = .905, GFI = .854, RMSEA = .062, SRMR = 0.068 Without item 30: χ2 (362) = 931.34, CFI = .919, GFI = .867, RMSEA = .059, SRMR = 0.053 Thus, we did not remove it to make international comparisons using the AWE-S easier. Comment 3. DPES seems to show a marginal fit. Does it reliably measure the 7 positive emotions? Or, removing some items/emotions increases the overall reliability, and that makes a better test? Reply: The goodness-of-fit of the DPES in this study fitted well as those in previous studies, such as Sugawara et al.’s study (2020). This study: χ2 (644) = 1728.55, CFI = .860, RMSEA = .073 Sugawara et al.'s study (2020): χ2 （644）＝ 4171.89, CFI＝.851, RMSEA＝.081 With the exception of one item, 38, whose item loading was below .40, the results were significantly unchanged (χ2 (608) = 1650.09, CFI = .864, GFI = .769, RMSEA = .074, SRMR = .063). In addition, correlation analysis with each of the awe factors yielded similar results. DPES item 4: I feel wonder almost every day (私はほとんど毎日驚嘆の念を感じる) Time: r = .18*, Self-loss: r = .01, Connectedness: r = .30*, Vastness: r = -.04, Physiological: r = .15*, Accommodation: r = .10 DPES item 16: I often feel awe (私はよく畏敬の念を感じる) Time: r = .28*, Self-loss: r = .06, Connectedness: r = .27*, Vastness: r = .09, Physiological: r = .14*, Accommodation: r = .04 DPES item 17: I seek out experiences that challenge my understanding of the world (私は世界を自分なりに理解するための経験を探し求めている) Time: r = .27*, Self-loss: r = .09, Connectedness: r = .26*, Vastness: r = .14*, Physiological: r = .16*, Accommodation: r = .11 DPES item 22: I see beauty all around me (私は自然の美しさを見る機会が多い) Time: r = .27*, Self-loss: r = .02, Connectedness: r = .21*, Vastness: r = .09, Physiological: r = .05, Accommodation: r = -.10 DPES item 31: I often look for patterns in the objects around me (私はしばしば自分の周りのものの中にパターンを探す) Time: r = .19*, Self-loss: r = .17*, Connectedness: r = .16*, Vastness: r = .13*, Physiological: r = .13*, Accommodation: r = .14* DPES item 36: I have many opportunities to see the beauty of nature (私は自分の周りのすべてに美しさを見出す) Time: r = .25*, Self-loss: r = .02, Connectedness: r = .35*, Vastness: r = .09, Physiological: r = .15*, Accommodation: r = .02 Thus, even if there were problems with the factor structure of the DPES, our conclusions would not change. Comment 4. As the text analysis of the experience topic and its correspondence with J-AWE-S response is so interesting, if the main aim of the study is to validate the scale in conjunction with the former, authors may present some expected findings given the nature of the J-AWE-S. This seemed possible a-pri-ori, when authors argued that awe involves vastness in scenes or has cultural roots of selfhood. Reply: At first, we did not plan to perform a Structural Topic Modeling (STM). As mentioned in the Method section, the STM were exploratory and not pre-registered. After data were collected, improvement in the first authors’ statistical knowledge and skills enabled us to conduct the STM. Therefore, it was difficult to discuss any predictions of the textual analysis a-priori in the Introduction section. However, as pointed out in Comment 5, the findings that “Scenery” and “Threat” were the two most common topics were interesting regarding the cultural characteristics of the awe experience in Japan. It would be important to discuss these results. The narrative of the awe experiences included many elements of “Scenery” (landscapes, mountain, sea), which was associated with the vastness factor of the Japanese AWE-S. These results were consistent with the Japanese view of the self (non-substantial, denial, embedded), which was thought to be related to nature worship prevalent among Japanese people (recognition of the self as a part of deified nature). In addition, the high proportion of “Threat” (ifu, earthquake, typhoon) was thought to be associated with negative aspects of awe, threat-awe, which was in line with the fact that natural disasters occurred frequently in Japan due to its climate and topography. Since even a positive awe manipulation (recall and describe their experiences of positive awe) evoked the feelings of ifu, negative awe in Japanese, sufficiently (Takano & Nomura, 2023), Japanese people could be more likely to feel threatened during awe experiences due to geographic and historical background in Japan. Thus, we have incorporated your comment by adding the following sentences in the Discussion section. (Added paragraphs) It should be also noted that “Scenery” was the most common topic, which was positively related to the vastness factor of the Japanese AWE-S. This topic mainly consisted of nature-related words, such as “landscape,” “mountain,” and “sea.” Previous studies have demonstrated that many Japanese people are familiar with nature worship, a belief that the self is a part of deified nature that is cultivated under the syncretism of Shinto and Buddhism ( Sugimoto, 2020; Takano & Nomura, 2022a). Therefore, these results might reflect the Japanese view of the self in relation to nature worship (i.e., non-substantial, denial, embedded). Interestingly, “Threat,” the second common topic, might be associated with negative aspects of awe (i.e., threat-awe), which is in line with the fact that natural disasters occur frequently in Japan due to its climate and topography. Previous studies suggested that feelings of awe that are triggered by threatening stimuli such as natural disasters could be tinged with the perception of threat ( Takano & Nomura, 2022b). Given that even the recollection of awe experiences based on examples that do not include negative elements (e.g., seeing aurora) evokes the feelings of ifu, negative awe in Japanese ( Takano & Nomura, 2023), Japanese people might be more likely to feel threatened during awe experiences due to Japan’s geographic and historical background. Comment 5. How do we make of the \"Expected Topic Proportion\" presented in Fig1? The value \"0.20\" seems the largest level presented, but would that mean, for example, a response \"Vastness\" occupied approximately 20% of the case when the \"Scenery\" was described as the eliciting situation? Reply: Thank you for your comment. The expected topic proportion represents what proportion of the total documents (responses) fall into each topic. For example, the value “0.20” indicates that approximately 20% of the responses fell into the topic of “Scenery,” regardless of their association with each of the AWE-S factors. We have incorporated this comment by adding statements in Note of Figure 1 as below in italic. (Added sentences) Expected topic proportions, proportion of the total documents (responses) falling into each topic, are depicted by dot size. In addition, these results themselves would provide meaningful insight regarding the cultural characteristics of awe experiences in Japan. Therefore, we modified the Results section by adding some results as shown below in italic, which were also discussed in the Discussion section (for details, please see the Reply to Comment 4). (Added sentences) Furthermore, seven topics were generated by the STM and labeled: “Spirituality,” “Threat,” “Spatiality,” “Universe,” “Scenery,” “Humanity,” and “Aesthetics” (see Figure 1). The top 20 highest probability words are listed in Table 3. In particular, “Scenery” and “Threat” were the two most common topics that emerged in all the responses. Regarding the Japanese AWE-S, participants with higher scores on the time factor were more likely to use words related to “Spatiality” and “Scenery.” Comment 6. Just a check: on Table 3, there seem to be multiple \"can(de-ki-ru)\"s observed across topics, and in some cases, its Chinese character version is present with the same English counterpart (at Humanity). Is this normal for this technique? Reply: The word “de-ki-ru” written in the Chinese character was owing to conversion errors when Table 4 was created. We have corrected all the mistakes to “de-ki-ru” in Hiragana (please see Table 4). Comment 7. I was wondering to what extent \"the self (as) represented as being non-substantial, denial, and embedded as default in Japan, a country with Buddhist and Shinto backgrounds (p3)\" is related to the interdependent views of the self (Markus & Kitayama, 1991). When the self is understood as socially conferred, it may render non-substantial in order to preserve harmony in one's in-group, denied so as to catch up with the group-held norm, and embedded in the group in which one should be a part. Reply: Nomura et al. (2020) stated that these characteristics of the sense of self based on Japanese religious and historical backgrounds were consistent with Markus and Kitayama's (1991) theory in cultural psychology. To attract a wider range of readers, we have added the following sentences in the Introduction section. (Added sentences) Similarly, Markus and Kitayama (1991) advocated independent and interdependent self-construals. Independent self-construals, more widespread in North American and Western European cultures, prioritize an individual’s needs, whereas interdependent self-construals, more common in Asian, Latin American, and African cultures, prioritize one’s social interactions. Comment 8. Typo P5: internal consistent Reply: Thank you for your feedback. We have modified the words accordingly."
}
]
},
{
"id": "207846",
"date": "28 Sep 2023",
"name": "William L. D. Krenzer",
"expertise": [
"Reviewer Expertise Research integrity",
"open science practices",
"awe",
"facial recognition"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors for this paper set out to create a Japanese version of the AWE-S scale previously published (Yaden et al., 2019). Following the steps of previous researcher translating AWE-S, the researchers in this article went forward with translating the AWE-S into Japanese and getting the appropriate population to complete the survey in order to validate the translation.\nThe researchers conducted a fairly conservative power analysis for determining the proper sample size needed, as well as setting an a prori criteria for including participants.\nOverall, i think that the researchers did a great job with this manuscript and conducting this study. I think that they have all the relevant citations, the study design is sound, and the researchers did a great job with addressing the findings that were specific to their Japanese participants.\nThere is one main recommendation to the researchers to enhance the clarity of the paper:\nIn the study design and participant section they do a great job of describing the main sample (N = 315) but rush through the other two samples that they use, and it makes it hard to really understand who these people are and why exactly they are being used and how they are different.\nI think that this manuscript will be a great addition to the awe literature and psychology as a whole.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10367",
"date": "13 Oct 2023",
"name": "Ryota Takano",
"role": "Author Response",
"response": "Response to Reviewer #2: The authors for this paper set out to create a Japanese version of the AWE-S scale previously published (Yaden et al., 2019). Following the steps of previous researcher translating AWE-S, the researchers in this article went forward with translating the AWE-S into Japanese and getting the appropriate population to complete the survey in order to validate the translation. The researchers conducted a fairly conservative power analysis for determining the proper sample size needed, as well as setting an a prori criteria for including participants. Overall, i think that the researchers did a great job with this manuscript and conducting this study. I think that they have all the relevant citations, the study design is sound, and the researchers did a great job with addressing the findings that were specific to their Japanese participants. Reply: Thank you for taking the time and effort to check our manuscript. We appreciate your helpful comment. We incorporated all your comments in the manuscript. Point-by-point responses and the corresponding revised text are provided below. Comment 1. There is one main recommendation to the researchers to enhance the clarity of the paper: In the study design and participant section they do a great job of describing the main sample (N = 315) but rush through the other two samples that they use, and it makes it hard to really understand who these people are and why exactly they are being used and how they are different. Reply: Thank you for your suggestion. According to your comment, we have summarized the demographic information of samples in the main and pilot study, along with the respective statistical analyses applied, in Table 1."
}
]
}
] | 1
|
https://f1000research.com/articles/12-515
|
https://f1000research.com/articles/12-1328/v1
|
13 Oct 23
|
{
"type": "Research Article",
"title": "Occupational risk factors associated with Covid-19 among Health Workers in a tertiary referral Hospital, Nairobi Kenya: A case control study",
"authors": [
"John Macharia Kiragu",
"Richard Ayah",
"Richard Ayah"
],
"abstract": "Background: Covid-19 disease disproportionately affected health workers (HWs) by worsening the preexisting shortage of HWs in developing countries , thus overwhelming health systems and disrupting health delivery. However, evidence on the predominant sources of Covid-19 exposure among HWs in sub-Saharan Africa remains scarce. This study sought to identify the occupational risk factors associated with Covid-19 disease among HWs in a tertiary hospital in Kenya. Methods: An unmatched case-control study design was used to assess exposure differences between 39 randomly sampled PCR Covid-19 positive HWs (cases) and 108 conveniently sampled PCR Covid-19 negative and asymptomatic HWs(controls). An adapted WHO risk assessment questionnaire was administered via phone interviews to measure occupational exposure in the last two weeks before each participant’s PCR Covid-19 test between November 2021 and December 2021. Multivariable logistic regression was applied to identify the statistically significant risk factors and the results on adjusted Odds Ratio (aOR) were reported at 95% Confidence Intervals (P<0.05). Results: Controlling for the sex and the clinical status, sub-optimal adherence to face shields ((aOR 4,p<0.05), suboptimal infection prevention control (IPC) adherence in common staff dining rooms (aOR 8,p<0.05), working in medium risk departments (aOR 7,p<0.05) in the last 2 weeks before PCR Covid-19 testing were the significant occupational risk factors to Covid-19 disease among HWs. Conclusions: Reinforcing adherence to facial protective gears together with other personal protective equipment and promoting adherence to infection prevention protocols among HWs in occupational areas with perceived lower risk of infectious disease such as common hospital rooms can reduce the spread of Covid-19 among HWs. Future validation of occupational exposure risk assessment tool across different hospital and health delivery settings can improve comparability and generalizability of findings to inform policies for optimal protection of HWs during SARSCoV2 and similar infectious disease pandemics.",
"keywords": [
"Covid-19",
"Pandemic",
"SARSCoV2",
"Health Workers",
"Risk factors",
"Occupational health",
"Sub-Saharan Africa"
],
"content": "Introduction\n\nGlobally, health workers (HWs) were over-represented in Covid-19 cases compared to the general population at 14% of all reported Covid-19 cases.1 HWs, people working within health settings with direct input to improving health, are at a relatively higher risk of contracting Covid-19 disease than the general population.2,3 In Kenya, 2.3% of Covid-19 cases were of HWs with an initial number of 39 Covid-19 related HW deaths recorded.4 But with limited PCR diagnostic testing capacity for Covid-19 disease in low-middle income countries, these figures underestimated the true Covid-19 burden among HWs in Kenya. A serological testing survey reported 20.8% sero-prevalence of Covid-19 disease among HWs (range of 11.5-43.8%); while the sero-prevalence among the general population was shown at 4.3%.5–7 Consequently, the disease itself and measures taken to control it, have been associated with worsening the shortage of health workers (HWs) and reducing the capacity of health systems to handle other pressing health conditions.8 In the face of a pandemic, HW protection is a priority in sustaining the capacity of the health systems to contain Covid-19 disease and other prevalent non-covid-19 disease conditions.\n\nOccupational exposure is work related predisposition to disease and is a significant determiner of disease outcomes such as Covid-19 disease for the workers at the frontline of health service delivery.9–12 During the MERSCoV disease outbreak, occupational and hospital spread accounted for the major source of spread, where HWs accounted for 50% of all nosocomial cases.13 In Spain, 24% of Covid-19 infections were of HWs with 70% of these infections being attributed to occupational exposure sources.14 Breaches in Infection Prevention and Control (IPC) measures such as improper use of face masks, gloves, gowns and goggles (face protective gears and shields) and improper disposal of PPE are among the major sources of occupational exposure to Covid-19 disease among HWs.15,16 Disinfection of hospital surfaces has also been cited as a key infection control measure against surface droplets and disease spread through fomites.17 A study utilizing data from hospitals in Qatar observed that hospital unit specialization status such as a Covid-19 designated facility (workers directly care for Covid-19 patients) does not necessarily translate into a higher risk of contracting the disease among the HWs.18 The PCR test for Covid-19 is the recommended gold-standard viral genetic markers as a guide for containment measures among infected asymptomatic and symptomatic patients.19,20 However, there is an occupational risk of Covid-19 exposure related to insufficient and imperfect PCR tests for Covid-19 disease among patients and among HWs especially in low resource settings.21 Imperfection of PCR tests due to imperfect sensitivity (range from 63% to 78%20) for Covid-19 disease has been implicated in the spread of Covid-19 disease to HWs due to misclassification of the actual Covid-19 cases within the healthcare settings.20,22 Furthermore, the occupational sources of Covid-19 exposure to HWs have been characterized as higher viral load exposures due to multiple and frequent infectious clinical procedures compared to non-occupational exposure sources. Therefore, HWs are postulated to develop a severer form of the Covid-19 disease compared to the general population.9,23 Protection of HWs from spread of Covid-19 disease and related complications is hinged on safe health systems and working environments.24 Sufficient supply of personal protective equipment (PPE) is protective against occupational Covid-19 and infectious disease exposure.25 Wearing of face masks, hand hygiene measures, and social distancing measures have been recommended as protective measures against Covid-19 disease among HWs.13,19\n\nDespite the growing evidence on the occupational risk factors to Covid-19 disease among HWs, contextual evidence on predominant sources of Covid-19 exposure among HWs remains scant.23 For example, the Kenyan policy measures to contain and prevent the transmission of Covid-19 are based primarily on WHO guidelines which include sustained supply of PPE for frontline workers, reinforcing adherence to optimal PPE use, reorganization of health workforce and hospitals in response to Covid-19, and HWs’ prioritization in the PCR Covid-19 testing and Covid-19 vaccination.26–28 In Kenya, the HWs, the elderly, the essential service providers such as teachers and people with preexisting medical conditions such as heart diseases were prioritized in the Covid-19 vaccination program of the Ministry of Health, with 68.2% of the Kenyan HWs having been fully vaccinated against Covid-19 disease as of 18th August 2021. In addition the Ministry of Health (MOH) Kenya adopted the WHO’s definition of health workers as listed in the WHO's Interim guidelines for Human Resources for Health during the Covid-19 response.27 While the risk of Covid-19 mortality in the Kenyan population has been traced, specific Covid-19 exposure risk profile for HWs in the Kenyan hospital settings has not been traced and thus unknown.29 Therefore, the main known occupational risk factors for the Covid-19 disease among HWs such as non-adherence to optimal PPE use and other IPC measures have not been confirmed within Kenyan hospital settings.18 This study sought to identify occupational risk factors associated with Covid-19 disease among HWs at a Kenyan tertiary referral hospital.\n\nThe occupation of a health worker, defined by their clinical roles, is a known risk factor for contracting diseases related to respiratory pathogens such as SARS viruses.11 Schulte et al.’s framework on personal and occupational risk factors to disease outcomes was adapted to hypothesize the relationship between potential Covid-19 exposure risk factors based on the review of literature and the Covid-19 disease status among HWs as shown in Figure 1 below. Other factors that potentially confound the occupational exposure factors and the Covid-19 disease outcome among HWs were considered to guide the variables of measurement for the study (Table 7).\n\nAs per the conceptual framework in Figure 1, suboptimal PPE and IPC adherence use was hypothesized as the primary exposure of interest which together with other risk factors such as improper PPE reuse, perceived sufficiency of PPE supply and the fit of face masks have been implicated in literature as sources of occupational and nosocomial Covid-19 exposure to HWs.30–32 Proper use of PPE is an important for the safety of HWs during an outbreak of highly infectious respiratory pathogens such as SARSCoV, MERSCoV, and Covid-19 disease-causing SARSCoV2 virus.33 Optimal PPE use and compliance rank at the base of the Hierarchy of controls for infectious diseases in the health care setting34,35 which means that optimal PPE use protects HWs when all other levels of controls fail to guard workers against occupational viral pathogens such as SARSCoV2 virus.36 A systemic review grouped risk factors to Covid-19 disease among HWs into lack of PPE, exposure to infected patients, work overload, poor adherence to infection control measures and pre-existing medical conditions.37 The global shortage of PPE as well as atypical clinical SARSCoV infection presentation were previously cited to pronounce occupational exposure sources of Covid-19 disease among HWs38 as documented in previous SARSCoV outbreak.39 Adherence to face masks, by both the infected and infectious person as the source and the HW as a susceptible host has been underscored in literature as additively protective against Covid-19 disease.40 Unit designation or the department of work or Covid-19 designation, has also been cited as a significant contributor to Covid-19 positivity among the HWs in addition to the long duration of duty hours and sub-optimal hand hygiene.41,42\n\nDeveloping countries such as Kenya reportedly experienced severe shortage of PPE supplies such as face masks43 during the acute phase of the pandemic. However, knowledge on the effect of PPE shortage on Kenyan HWs remains scant and PPE shortage coping mechanisms such as reuse of PPE has not been scientifically studied or documented based on the Kenyan hospital settings hence its inclusion in the conceptual framework.44 PPE reuse has been cited to offer inferior protection for SARSCoV viruses although it has also been cited that reused masks are better than none at all.32 Another literature cites that PPE reuse is a feasible and safe strategy that can be used in helping to slow the spread of Covid-19 disease but this has to be done under specific sterilization autoclaving conditions.45 Evidence supporting the decontamination of face masks for reuse cite that use of ultraviolet germicidal irradiation and vaporized hydrogen peroxide is most advantageous.46\n\nIn line with the WHO recommendations on the need to provide HWs with PPE according to their risk profiles, clinical and non-clinical hospital staff categories have been utilized in health planning on pandemic response and research.47,48 The current study adopted a broader definition of HWs that includes clinical and non-clinical staff. HWs were thus defined as people employed and working in the Kenyatta National Hospital within the two-month study period whose primary role was the provision of health care services either directly to the patients or indirectly through assistive roles to HWs in line with Kenya Human Resource for Health (HRH) norms and standards 2014 report which enlists staff, clinical and non-clinical workers, required for delivery of health.49 Consequently, direct care providers and clinical staff (nurses, midwives, pharmacists, medical doctors and specialists) and indirect care providers, non-clinical and supportive staff (cleaners, porters, security, and departmental administrative staffs such as unit and hospital managers, health information officers and hospital clerks) were studied. This contrasts the narrower definition of health workers as professionals trained in approved institutions and licensed to practice by cadre-specific and respective regulatory bodies to deliver health care following the Kenya Health Workforce Report 201550 which would exclude workers in supportive, unregulated and unlicensed hospital roles.\n\nPreviously, HWs engaged in night shift work (NSW) schedules were found to have a higher prevalence of common cold, flu-like illnesses, and gastroenteritis compared to day shift workers.51,52 Literature exists on various mechanisms by which shift work weakens worker immunity states through a reduction in immune cells such as natural killer cells, CD16, and Inter-luekin 2 factors which are responsible for fighting viral pathogens. In addition, NSW is associated with abnormal cytokine levels.53 NSW is also a direct modulator of the physiology of the immune systems and through circadian rhythm deregulation, it has an indirect effect on individual health status. For example, a systematic and meta-analytic review by Liu et al. 2018 established that night shift work increases the workers’ risk of being overweight and obese.54 Both being overweight and obese have been strongly associated with Covid-19 positivity and severe forms of Covid-19 pneumonia.55,56 Further evidence links sleep habits and the risk of Covid-19 disease among HWs.57,58 Knowledge on the role of shift work, NSW status and HWs’ sleep habits as occupational and personal risk factors to Covid-19 disease remains incomplete.\n\nThe role of staff to staff Covid-19 exposure source among HWs is emerging as observed and reported in a cross-sectional study examining characteristics of HWs with Covid-19 disease in a tertiary public health hospital.59 Authors observe that non-significant HW’s occupational type, the peaking of Covid-19 cases among HWs before the peak among Covid-19 disease patients and admissions, and few clustering of Covid-19 among the HWs within certain departments, were suggestive of the predominance of HW to HW spread of the disease rather than the patient to HW spread.59 Recent studies on Covid-19 among HWs have also observed that most HWs contracted Covid-19 disease from a non-index case that further supports the predominance of the Covid-19 transmission through staff-to-staff, and surface contamination methods.57 The HW to HW spread of Covid-19 may be propagated by common tea and dining rooms breaks where HWs socialize and take meals together while lowering their guard against Covid-19 disease. Hence, more knowledge is needed on common rooms as sources of Covid-19 exposure in occupational settings.\n\nInsufficient HWs’ training on IPC and PPE use has also been implicated in the spread of Covid-19 disease among HWs.60,61 Less than two hours of training or no training on IPC was associated with a SARS infection among HWs as reported in previous SARSCoV outbreaks.36\n\nThis review of literature informed the variables of interest and their relationships as illustrated in the conceptual framework (Figure 1) which further informed the methods of the study in assessing occupational exposure for Covid-19 within the Kenyan hospital setting as detailed in the next section.\n\n\nMethods\n\nA case-control study design was used. The study was conducted at Kenyatta National Hospital (KNH), the largest public tertiary referral and teaching hospital in Kenya with over 6,000 workers and a bed capacity of 1,800.62 The hospital offers specialized health services through its various specialties including accident and emergency unit, specialized outpatient clinics, medical and surgical inpatient units, infectious disease units.\n\nThe study population were the health workers (HWs) in full time employment at KNH who were involved in the direct or indirect care of patients with Covid-19 disease or patients with unknown status of Covid-19 disease during the study period between November 2021 and December 2021. This study was conducted just after the peak of the fourth wave of Covid-19 outbreak experienced in Kenya based on the updates from the MOH Kenya.63 Covid-19 testing records at the Covid-19 Testing Unit of KNH were reviewed to identify the confirmed cases of Covid-19 disease among HWs employed and working at Kenyatta National Hospital within the 2 months study period.\n\nSample size determination was done by application of Kelsey's (1996) sample size formula for case control study design as follows:\n\nOf the 160 (40 cases and 120 controls) HWs desired from the sample size formula, a total sample of 147 health workers (39 cases and 108 controls) were recruited. 39 cases with Covid-19 diagnoses were selected through simple random sampling from the RT-PCR laboratory testing records between November and December 2021 and invited to participate in the study. To select controls, matching information on Covid-19 testing dates and cadre for cases was used to identify and conveniently invite 3 potential controls from the Covid-19 database and as referrals from each case in the study as shown in the sampling procedure diagram (Figure 2). Further screening of the HWs in the control group for eligibility was done by use of a screening tool (appendix 6.2) that examined whether a HW had 3 or more symptoms related to Covid-19 and if they had any imaging findings or medical reports suggestive of Covid-19 disease before their negative PCR Covid-19 test results within the study period.\n\nHealth workers with a laboratory-confirmed Covid-19 disease, based on RT-PCR SARSCoV2 testing results as per the MOH Kenya case definition for Covid-19 disease, were selected as the cases for the study. Controls were defined as a health workers exposed to the same department of work as a case, PCR tested for Covid-19 but not classified as a suspected or probable, or confirmed Covid-19 case within the last 2 weeks before the Covid-19 test results in the study period between November 2021 and December 2021. The inclusion criteria for controls entailed a HW who reported not having experienced 3 or more symptoms suggestive of Covid-19 pneumonia in the last 2 weeks before Covid-19 test results (either fever and cough of acute onset or any three of these symptoms: Fever, difficulty in breathing, general weakness/fatigue, headache, myalgia, sore throat, coryza, dyspnea, anorexia/nausea/vomiting, diarrhea, altered mental status), and the HW was not classified as either a suspected, probable, or confirmed Covid-19 case in the last two weeks before receiving Covid-19 test results (tested for Covid-19 in the study period with negative test results for SARSCoV2 virus, and did not have any chest X-ray or High-resolution CT scan imaging reports suggestive of Covid-19 pneumonia or disease).64 The exclusion criteria for controls included any HW not employed and not working at KNH within the study period, reporting having had either any positive PCR Covid-19 test results within the study period, or had experienced three or more symptoms related to Covid-19 symptoms as per MOH case definition (fever, breathing difficulty, cough, headache, and chills) or had imaging findings suggestive of Covid-19 pneumonia in the last 2 weeks before Covid-19 testing. The screening tool for the study (Table 4) controls was applied to restrict the inclusion of Covid-19 asymptomatic HWs during PCR testing as study controls and exclude symptomatic HWs to minimize misclassification bias for selection of controls (who may have had sysmtomatic and with false negative SARSCoV2 test results).\n\nStudy participants were interviewed via phone, using a structured questionnaire adapted from the WHO Interim guidance (2020) on Risk assessment and management of exposure of health care workers in the context of Covid-19,65 Fatima et al. (2021) study tool to assess night shift status and its association with Covid-19 Infection among HWs58 and a case-control study tool by Celebi et al. (2020) utilized to assess the spread of Covid-19 among HWs in common dining rooms.66 The questionnaire can be found under the section on Extended data.85\n\nKey variables in the study questionnaire on occupational factors included self-reported frequency of PPE adherence, and usage of each PPE including gloves, N95 masks, surgical masks, gown, surface decontamination practice, face shield, moments of hand hygiene measures, and history of the accidental splash of body fluids 2 weeks before PCR testing and attributable type of exposure to Covid-19 case or suspect case 2 weeks before Covid-19 PCR testing, the performance of aerosol-generating procedures 2 weeks before Covid-19 PCR testing, specific department of work within 1 month before Covid-19 PCR testing and self-reported adherence to PPE and IPC protocol in staff dining room in the last weeks before Covid-19 PCR testing (Table 7).\n\nEthical study approval was obtained from Kenyatta National Hospital-University of Nairobi (KNH-UON) Ethics and Research Committee (P462/06/2021). Administrative permission was obtained from the KNH hospital to access laboratory Covid-19 testing records. Physical contacts were avoided to minimize chances of Covid-19 transmission, therefore, interviewer-administered written informed consent was sought virtually and consent recorded on a printed informed consent form and later de-identified once the interview process was over. Identifying contact information of the participants were password protected and used only for the purposes of the current study.\n\nData was entered into an excel spreadsheet. After double checking for errors, completeness, and accuracy of the data, the excel sheet was exported into R studio version 4.1.2 (2021-11-01) for statistical analysis. Descriptive analysis of the data was reported in form of counts, percentages, and proportions for categorical variables. Categorical variables were derived from the primary data to form aggregate variables including overall PPE/IPC adherence, HW to HW IPC adherence in common rooms, HWs’ clinical status, and departmental risk type categories.\n\nClinical and non-clinical staff categories were derived to cover HWs who were directly and indirectly involved in provision of care to the patients in the hospital (Table 6). These categories capture all the hospital workers as per the norms and standards for HRH in Kenya.49 Departmental risk categories namely, high risk, medium risk, and low-risk- were adapted from the U.S. Occupational Safety and Health Act (OSHA) Guidance on Preparing Workplaces for Covid-19 and the recent studies assessing Covid-19 exposure risk factors among HWs59,30,67 (Table 5). For this study, the definition for high-risk departments were defined as hospital units that routinely perform high-risk procedures that generate aerosols such as dental units, intensive care units and high dependency unit, accident and emergency units, and any Covid-19 designated units such as infectious disease units (IDU), Covid-19 isolation wards and Covid-19 designated medical wards.30 Medium risk departments were defined as hospital units where staff have frequent contact with patients without confirmed or suspected Covid-19 disease and those with unknown and unspecified Covid-19 status including outpatient medical and surgical clinics, general medical and surgical wards, radiology departments, and maternity. Low-risk departments were defined as units without any contact with patients regardless of Covid-19 status and have minimal contact with patients’ immediate environment such as the administrative and catering departments.\n\nOverall adherence to optimal PPE and IPC measures was assessed using the 13 item criteria for PPE and IPC measures (Table 8). This is supported by hospital guidelines which do not mandate PPE adherence and usage the same way for a clinical staff and for a non-clinical staff especially when PPE supply is constrained.5 Therefore, criteria for adherence was applied to clinical and non-clinical staff differently whereby failure to check all the category-specific PPE requirements was classified as either overall sub-optimal adherence or overall optimal adherence.65 Frequency of specific PPE use was assessed in four levels, namely, always as recommended (>90% of the time), mostly (>50% of the time), occasionally (20% to under 50% of the time), and rarely (<20% of the time).68 HWs who reported having regularly practiced social distancing in the shared dining rooms and having completely doffed before using shared dining rooms in the last 2 weeks before the Covid-19 test conducted within the study period, were categorized to have adhered to IPC in staff dining or common rooms.\n\nThe odds ratio OR were reported at 95% confidence intervals and at an alpha of 0.05 (p-value) for statistical significance. Wald’s Odds ratio test for the bivariate analysis in the cross-tabulation of the independent and dependent variables was applied to compute the p-value for variables whose observations had no more than 20% of the counts with less than 5 counts. Otherwise, Fisher’s exact test was applied. Shapiro Wilk test was used to test for normality of the continuous variable (age) in the data set. Under the bivariable analysis, each explanatory study variable was cross-tabulated with the Covid-19 disease status of the HW and the corresponding Odds Ratio (OR) at 95% Confidence Intervals were reported and tabulated.\n\nIn the multivariable analysis, a liberal p-value of less than 0.25 was chosen as the cut-off for selecting multiple variables to enter into the multivariable logistic regression model to control for confounding.69 Additional independent variables hypothesized to be important confounders in the association between the overall sub-optimal PPE/IPC adherence and the Covid-19 status were added a priori in the multivariable analysis even if they did not attain the 0.25 cut-off for liberal variable selection due to their clinical importance in occupational disease transmission as per the review of literature. These included the sex, overall adherence to optimal PPE/IPC use, department risk type, and the clinical status category of the health worker. The Akaike Information Criteria (AIC) was used to run the modeling simulations of the logistic regression analysis to arrive at the most statistically significant combination of the independent variables that majorly accounted for the variation in the dependent variable among the participant HWs.\n\nAdditional hierarchical models to re-introduce variables de-selected by AIC simulation were applied to assess for their impact in the overall model. Likelihood ratio tests were applied for each model to determine the model with the best fit and the model with the least residual deviance which was taken as the most accurate and best fit for the data. A p-value of less than 0.05 was taken to indicate that the fitted model was significantly different from the null model. The effect size was computed by the use of the pseudo R2 estimates by the Hosmer and Lemeshow, NegelKerke, and McFadden pseudo R2 estimation methods. Interaction terms were also fitted under hierarchical models to assess for significant interaction (p<0.05). An interaction term was applied to assess the effect of gender on the association between department risk type and Covid-19 disease status based on previous evidence of interaction between gender and the effect of department type and Covid-19 disease status.30 Variance Inflation Factor (VIF) was applied to detect any multi-collinearity between the explanatory variables in the fitted model with a VIF of less than 4 indicating a lack of collinearity among the explanatory variables in the model.70\n\n\nResults\n\nA total of 147 health workers (39 cases and 108 controls) consented to participate in the study. Overall, 55% of the participants were female with a median age of 35 years (cases) and 37 years (controls) respectively. A slight majority (51%) had professional work experience greater than 10 years, with most (71%) being clinical health providers with direct patient interaction. A significant majority were fully or partially vaccinated against Covid-19 disease (34/39 cases) and (102/108 controls). By co-morbidity status, 74% of the study participants did not have any preexisting medical condition, while 26% reported having a pre-existing condition including hypertension asthma, diabetes mellitus, heart disease, obesity, chronic kidney disease, and cancer (Table 1). The full dataset can be found under Underlying data.85\n\nSelf-reported adherence to PPE including gloves, face masks and N95 mask or equivalents, gowns, face shields and hand hygiene measures was assessed. The crude odds ratio of contracting Covid-19 were 2.57 times higher for HWs who self-reported not adhering to gloves as recommended (cOR, 1.45; 95%CI, 1.11-5.67; p<0.05), 3.5 times higher for not adhering to gown as recommended (cOR, 3.50; 95%CI, 1.35-9.06; p<0.05) and 3.5 times higher for not adhering to face shields as recommended (cOR, 3.50; 95%CI, 1.37-8.36; p<0.05). Self-reported reuse of the PPE within-shift (cOR, 1.86; 95%CI, 0.89-3.90; p>0.05) and between shifts (cOR, 3.00; 95%CI, 0.70-12.50; p>0.05) were not significantly associated with increased risk of Covid-19 disease.\n\nThe WHO five moments of hand hygiene including hand hygiene before and after touching a patient (cOR,1.103,95%CI 0.48-3.65, p>0.05), hand hygiene before and after a procedure (cOR,0.88;95%CI 0.41-1.92; p>0.05), hand hygiene after exposure to body fluids (cOR,1.14;95%CI 0.45-2.84, p>0.05) and hand hygiene after touching patients’ surroundings (cOR,0.70;95% CI 0.30-1.54; p>0.05) did not differ between the cases and the controls. There was no difference in the use of surgical or medical masks (cOR, 1.72; 95%CI 0.39-7.50; p>0.05) and N95 masks (cOR, 1.23; 95%CI 0.50-3.00; p>0.05) between cases and controls. Self-reported practice of surface decontamination as recommended did not differ between cases and controls (cOR, 1.87; 95%CI 0.90-4.22; p>0.05) (Table 2).\n\nIn the multivariable analysis, overall suboptimal PPE/IPC adherence variable (primary exposure of interest) was excluded by the AIC model simulations. To eliminate collinearity effects, the independent variable on suboptimal PPE/IPC use was not reintroduced in the model owing to its relatedness with specific PPE items such as face shields and gloves. None of the socio-demographic characteristics had any statistically significant association with the Covid-19 disease status of the HW. However, the effect of sex of the HW was impactful in the overall model as a confounder whose statistical control improved the accuracy of the overall model (Table 3). Occupational factors identified to be associated with Covid-19 disease after controlling for covariates in model 1 of the AIC simulation included lack of optimal use of gloves (aOR,4.80; 95%CI, 1.28-20.10; p<0.05), face shield (aOR,3.88; 95%CI, 1.28-13.37; p<0.05) and non-adherence to IPC protocol while using tea-breakout rooms (aOR,7.65; 95%CI 1.54-66.51; p<0.05), working in a medium risk department (aOR,4.38; 95%CI,1.22-18.40; p<0.05) in the last 2 weeks before PCR Covid-19 testing (Table 5). After re-introducing the clinical status in the model to control for the differences in clinical and non-clinical staff categories, statistical significance of suboptimal use of gloves was lost (p>0.05) as shown in model 2 (Table 3).\n\n\n\n1. I did not have any three of these symptoms in the last 2 weeks before testing for Covid-19 (Fever, difficulty in breathing, cough, general weakness/fatigue, headache, myalgia, sore throat, coryza, dyspnea, anorexia/nausea/vomiting, diarrhea, altered mental status; Covid-19 symptoms as per MOH Kenya Interim Guidance on case management68) and the WHO case definitions83\n\n\n\n2. I did not have severe acute respiratory illness (characterized by fever > 38.0° and cough) that required hospitalization in the last 1 month before testing\n\n\n\n3. I did not have severe acute respiratory illness (characterized by fever > 38.0° and cough) that required hospitalization in the 1 month after testing for Covid-19 disease\n\n\n\n4. I did not have radiologic and imaging findings suggestive of Covid-19 pneumonia in the last 2 weeks of Testing for Covid-19 and 2 weeks after testing for Covid-19 disease.\n\n\n\n5. I did not have a medical report suggestive of Covid-19 pneumonia in the last 2 weeks of Testing for Covid-19 and 2 weeks after testing for Covid-19 disease.\n\n\n\n• Categorized as High risk, Medium risk, Low risk based on Attendance to Covid-19 patients and presence of AGPs\n\n\n\n• Assessed with an adapted Questionnaire from the WHO Questionnaire on assessing HW PPE use and Exposure status. Where PPE use and IPC measures specific to clinical status of the health worker were not adhered to, the HW was considered to be Covid-19 exposed or having a status of suboptimal PPE and IPC adherence. Thus, the study participant HW was classified as having had Suboptimal PPE/IPC use (not adhered) or having Optimal PPE/IPC use status (adhered).\n\n• Frequency of use of each type of PPE was assessed including face mask, face shield, Gloves, Respirator or N95 masks, Gown and Surface Decontamination and Hand Hygiene Moments.\n\n\n\n• Reported double masking status within the last two weeks before Covid-19 testing as either Yes or No.\n\n\n\n• Symptomatic or asymptomatic exposure or uncertain exposure\n\n\n\n• A subjective HW response on sufficiency of PPE supply in your workstation in the last two months of the survey during which the HW was attending suspected, confirmed or patients with unknown Covid-19 status. Perceived PPE adequate during last encounter with suspected or confirmed case of Covid-19, Rated as adequate or Not Adequate.\n\n\n\n• Less than 8 hours per day, 8 to 12 hours per day, more than 12 hours per day\n\n\n\n• Defined by either working during all day shifts, mixed day and night shifts and only night shifts in the last two months before Covid-19 testing.\n\n\n\n• Single shift: - Yes or No\n\n• More than one shift - Yes or No\n\nThere was negligible collinearity (VIF <2) between the predictors in the final multivariable logistic model (model 2 in Table 3). In addition, the final model had significant goodness of fit (p<0.05) and had an explicative value estimate of 36.5% (Hosmer-Lemeshow, pseudo R2), 34.5% (Cox and Snell pseudo-R2) 37% (McFadden pseudo R2), and 50.3% (NagelKerke pseudo R2) on the variation in the outcome (Table 3).\n\n\nDiscussion\n\nOccupational factors observed to increase the risk for a positive PCR Covid-19 test results included failure to adhere to face shields as recommended when handling patients, working in medium risk department compared to a low-risk department, self-reported non-adherence to infection prevention protocols while in the common staff dinning rooms in the last two weeks before PCR Covid-19 test.\n\nFailure to use specific PPE including face shields always as recommended was observed to significantly increase the odds of a health worker having Covid-19 disease by 4 folds. The key finding on use of face shields puts emphasis on the importance of protecting mucous membranes including the mouth and the eyes while caring for patients during an infectious disease outbreak similar to Covid-19 (from SARSCoV2 viral transmission) regardless of patient’s disease status as corroborated by a recent retrospective cohort study on occupational Covid-19 exposure among health care professionals.71 The authors cite that omission of face protection while attending to patients not suspected of Covid-19 disease was associated with Covid-19 disease positivity.71 Further simulation experiments have established the efficacy and protectiveness of using face shields for face and eye protection from droplet and aerosol contamination.72 Our findings support earlier recommendations by the WHO recommendations on the use of face shields as an adjunct protective PPE.73\n\nControlling for clinical status, failure to wear gloves as recommended did not significantly increase the risk of Covid-19. Use of gloves in addition to hand hygiene measures to prevent excess contamination with infectious viral droplets in case of SARS and novel acute respiratory infections (ARI) is highly recommended by the WHO.73 The WHO recommends that gloves should be discarded after use and followed by hand hygiene at all times. Therefore, the usage of gloves alone is not a substitute for hand hygiene but the use of gloves together with hand hygiene is recommended since gloving prevents excessive contamination and protects the non-intact skin from infectious pathogens.33 Contrary to our findings on lack of significance of gloves usage on the risk of Covid-19 disease , a recent case-control study observed a greater risk of Covid-19 disease among health workers who always used face shields, surgical caps, and gloves.74 These findings were attributed to the possibility of self-contamination from the continuous use of the face shields and gloves without proper donning and doffing measures.74 Despite the similarity in the broad definition of health workers in our study and the study by Rodriguez-Lopez et al.,74 we posit that our findings differ because our study controlled for the effect of clinical status on the association between adherence to gloves as recommended and risk of Covid19 disease. Clinical and non-clinical workers have different requirements and recommendations on the usage of gloves and other PPE as observed in the study setting (Table 8). Future research should confirm our findings and explore risk of infectious disease from self-contamination from improper use of gloves and face shields.\n\n\n\n1. Self-reported PPE use\n\n\n\n2. Use of Gloves\n\n\n\n3. Use of surgical masks\n\n\n\n4. Use of N95 mask or equivalent respirator mask\n\n\n\n5. Use of face shield\n\n\n\n6. Use of Gown\n\n\n\n7. Adherence to protocol of PPE\n\n\n\n8. Hand Hygiene before and after touching a patient\n\n\n\n9. Hand Hygiene after a procedure\n\n\n\n10. Hand hygiene after exposure to body fluids\n\n\n\n11. Hand hygiene after touching patients surroundings\n\n\n\n12. Surface decontamination\n\n\n\n13. Accidental exposure to body fluids (nasal, mouth,open skin or eye splashes)\n\nOverall, the 8% self-reported overall level of compliance with optimal PPE use and IPC adherence (PPE included gloves, masks, gown, and face shield while IPC measures included adhering to PPE protocol use and hand hygiene measures) in our study grossly differs from recent studies with higher self-reported compliance levels of 88% for hand hygiene and 90% for PPE use reported in one study75 and a 76% self-reported compliance level on PPE use among the controls for the study in another study.76 Similar to our study findings, inadequate IPC compliance at 6% during the pre-pandemic period31 and an 18.1% self-reported compliance level by the health workers have been previously reported.77 Lower PPE and IPC compliance levels have been attributed to stricter and more objective compliance and adherence observation assessment methods as compared to levels based on subjective and more biased self-reported PPE/IPC compliance assessment methods. We posit that lower overall levels of self-reported adherence to PPE/IPC measures in our study was attrubutable to the study period,75 whereby, data collection was done when Covid-19 infections rates had waned in the study setting and coincided with progressive easing and relaxation of public health policy mandates on PPE/IPC compliance and other restrictive Covid-19 prevention protocols.4 In addition, we posit that a higher coverage of Covid-19 vaccination among the participant health workers during the study period could have impacted their compliance to Covid-19 IPC measures and PPE use whereby HWs become less cautious and less afraid to contract the disease owing to assured forms of vaccination immunity compared to the acute phases of the pandemic when there weren’t any vaccines available and compliance level to PPE were shown to be higher.75,76\n\nThe 4 times higher odds ratio of Covid-19 disease among HWs with suboptimal PPE/ IPC adherence in our study was due to chance (OR,4; p>0.05) unlike a statistically significant similar magnitude of risk (P<0.05) reported previously74 and a 29% (CI, 16% to 41%) reduced risk ratio for Covid-19 disease among HWs adequately using the PPE from a meta-analysis of three recent studies.78 Lack of statistical significance for the suboptimal PPE/IPC adherence variable in our study could be related to the use of contextualized and adapted tool for assessing overall PPE/IPC adherence compared to the previous studies. In the absence of a standard definition or criteria of what constitutes a proper PPE for a given task, cadre and per given hospital, adapting and context-tailoring the WHO Risk Assessment and Exposure protocol as well as tools used for the same objective from other studies is supported in literature.65,79,78 While adapting the tool to fit the context improved the validity of our findings in the current study population and hospital setting, caution is warranted when comparing the study findings across different hospital settings. Future research in standardizing and validating the study tools for assessing overall PPE/IPC adherence across common and diverse settings would support generalizability of findings on exposure factors and has been recommended in previous literature.78,79\n\nBesides the PPE and IPC adherence, other occupational risk factors observed in the current study to significantly impact on the risk of Covid-19 disease among HWs included the department type and HW’s adherence to IPC measures while using common and shared dining rooms. HWs working in medium and high-risk departments had their odds of Covid-19 disease multiplied by 4.4 times (95%CI, 1.22-18.40; p<0.05) and 2.4 times (95%CI, 0.46-12.87; p>0.05, not significant) compared to HWs from low-risk departments respectively. These findings are consistent with previous literature from a retrospective cohort study that observed a significantly higher risk of Covid-19 disease for HWs working in high-risk departments compared to low-risk departments albeit the presence of statistical interaction of effects of being male, the clinical status of the HW and hand hygiene adherence.30 However, statistical interaction on levels of departmental risk with other covariates and the study outcome was not significant, a phenomenon partly attributed to lower power in the present study. In line with OSHA's definition of occupational risks, low-risk departments were defined as distinct physical units of the hospital without direct patient involvement and with very minimal patient interaction including the administrative offices, kitchen, and catering and communication departments. Medium-risk departments were defined as hospital units handling a patient with less severe illnesses and unspecified respiratory illnesses including outpatient medical and surgical clinics, general medical and surgical wards, radiology departments, and maternity while high-risk departments were defined as unit handling severely sick patients, those with a confirmed diagnosis of Covid-19 and departments with a higher frequency of aerosol-generating procedures including ICU, HDU, Covid-19 designated wards and accident, and emergency. Consistent with current study, a recent case-control study showed that HWs in nonCovid-19 designated unit had higher infections rates than those in Covid-19 designated units (57% vs. 43%)80 while on the contrary, a multicenter study found no association between cadres and departmental type categories and risk of Covid-19 disease.40 In addition, Dev et al. cites the cadre of the health worker as an independent risk factor for Covid-19 disease,80 however, the differences in the odds of Covid-19 disease between the cadres were not examined in the current study since the cadre category was utilized in matching the controls to the cases for referrals thus any risk differential effect according to cadre was eliminated at design or is to be regarded as an outlier observation.\n\nWhile controlling for covariates, HWs who had a self-reported failure to socio-distance and failure to completely doff their PPE before using common rooms for dining had 7.7 times (95%CI 1.54-66.51; p<0.05) higher odds of Covid-19 disease than those who social distanced and completely doffed before using common rooms within the last 2 weeks before having their Covid-19 test. However, a further category of HWs who never used hospital common rooms before their PCR Covid-19 did not have significantly different odds across cases and controls (95%CI 0.64-49.56; p>0.05). Consistent with a prospective study examining PPE use among HWs during social interactions in common rooms, 19% of the HWs with positive Covid-19 diagnosis had a self-reported removal of face masks during tea breaks and lunch breaks with their colleagues despite the universal masking protocol in the hospital.81 Another recent retrospective cohort study further authenticates the findings of our study given the observation that health worker to health worker Covid-19 transmission was reportedly dominant and was reflected in the pattern of Covid-19 infections clustering within one profession and within a few hospital departments while the peak of Covid-19 cases among HWs peaked before the peak in the cases presenting from outside the hospital.59 Ibiebele et al.’s study also cites the predominance of exposure of HWs from their coworkers during dining rather than from the patients.71 These findings underscore the need for IPC sensitive and friendly common dining and shared rooms for HWs as well as the need for behavior change among HWs and the need for hospital employees to maintain physical distancing when dining and to adhere to other infection prevention protocols such as proper PPE disposal and appropriate doning and doffing especially when moving from patient surroundings to common staff rooms in the event of a resurgence of Covid-19 or any other similar infectious outbreaks.\n\nThis study has several strengths. First, an adaptation and context-tailoring of WHO risk assessment for Covid-19 exposure to estimate overall adherence to PPE/IPC as recommended enhanced context validity of the tool and of the study findings. Second, the case-control design allowed for the study of a rare outcome variable within the study period and allowed for assessment of multiple independent exposure variables within a short period of time. In addition, the design allowed for increasing power of the study through the sampling of 3 controls for every case in the study. Third, recall period for independent variables was restricted to a 2-week period before PCR Covid-19 testing by the participants while the differential recall between the cases and the control was minimized through matching of the cases and control in terms of cadre of work and testing date monthly matching. Fourth, misclassification of the cases and the controls was minimized by the strict control group assessment through a pre-exclusion of Covid-19-symptomatic study participants in controls while cases were sampled from laboratory records on PCR confirmed Covid-19 positive HWs.\n\nHowever, the study was not without limitations. First, study findings were based on a single center, tertiary level hospital as the study setting from which we selected a study population. Therefore, if this study was done in different non-tertiary hospital settings such as a health center, the risk factors to Covid-19 disease among HWs could differ. Therefore, the findings of this study are not generalizable to HWs in lower level and different health care settings. Second, in the choice of the study design a relatively small sample size was obtained that could not have been robust and powered enough in detecting statistical association of key variables such as the effect of sex of the HW on risk of Covid-19 as well as the impact of overall PPE/IPC adherence. Third, the study was prone to sampling bias on male HWs who are reportedly likely to go for testing due to pronounced symptoms and get diagnosed with Covid-19 than female HWs.82 However, over-representation of female HWs in our sample at 55% of all participants reflects the predominance of female HWs in the study as in the general population of the HWs. The effects of the preponderance of male HWs in PCR Covid-19 testing and higher proportion of the female HWs could negatively impact on the true association between the sex of the HW and their risk of Covid-19 from this study. Therefore, more controlled and randomized design would be recommended for a robust assessment of the effect of sex on the risk of Covid-19 in the current study setting. Fourth, the recall bias was not fully minimized since HWs were required to report their exposure back in time a few days and weeks before PCR Covid-19 test considered within the two-month study period. In addition, differential recall between cases and controls could not be fully eliminated despite monthly matching on Covid-19 testing dates and examining exposure in reference to recent 2 weeks before Covid-19 PCR test conducted within the two-month study period. Lastly, the self-reporting of the exposure variables could have resulted to interviewee bias whereby the participants could have preferred to report positive answers such as false self-report on compliance with PPE and IPC measures. As a result, this could have resulted in invalid responses on the true association between the exposure and the outcome.\n\nMeasures made to minimize the limitations included monthly matching the Covid-19 testing dates while sampling cases and controls and restricting the assessment of the occupational exposure factors to the last two weeks before the participants’ recent Covid-19 PCR test in the study period (a two-week recall period for occupational and community exposure variables was considered relatively short during which the health worker could remember their clinical practices and health behaviors). A simple random sampling of the cases was employed to minimize selection bias associated with non-random case samples. However, the selection bias was not fully eliminated because only the Covid-19 cases that survived the disease and consented to voluntary participation were included in the study. Multivariable regression modelling was done to control and minimize confounding bias.\n\n\nConclusion\n\nHWs who sub-optimally adhered to PPE and IPC measures such as using face shields and disregarded IPC protocols while using shared hospital common rooms had an increased risk of Covid-19 disease. Level of risk across departments of work had an effect on the risk of Covid-19 disease among HWs. From our study, working in medium-risk departments (such as outpatient clinics which are traditionally regarded as having a lower risk of disease compared to high-risk specialized units such as ICU) was shown to increase the risk of Covid-19 disease compared to low-risk non-clinical and administrative units.\n\nHospitals should reinforce and facilitate optimal adherence to the recommended PPE and IPC measures to prevent occupational infectious disease transmission among HWs especially during infectious disease outbreaks. This should include supporting and reinforcing adherence to facial mucosal protective gears such as face shields among HWs as recommended for SARSCoV and similar highly infectious outbreaks together with other PPE. Institutional measures focusing on IPC around HWs are needed to minimize exposure of infectious disease from staff to staff transmission when sharing common areas such as dining and rest rooms. Future research on occupational infectious disease risk factors should support the validation of exposure risk assessment tool across different health settings for improved external validity of policy recommendations and guidelines around the protection of HWs at all levels.",
"appendix": "Data availability\n\nMendeley data: Dataset on potential risk factors to COVID19 disease among Health Workers in Kenya. Doi. 10.17632/x47k6prsv8.5 85\n\nThis project contains the following underlying data:\n\n- Dataset on risk factors to COVID19 disease among Health Workers in Kenya.xlsx\n\nThis project contains the following extended data:\n\n- Informed consent form_Kiragu J et al.pdf\n\n- Study Questionnaire on risk factors for Covid_19 among Health workers at Kenyatta National Hospital_Kiragu et al.pdf\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgements\n\nWe are sincerely grateful to Dr. John Kinuthia and his team at the department of medical research as well as the entire administration of Kenyatta National Hospital for the permission to collect data and the grant funding towards this study. We would also like to thank Dr. J. Atina of the Respiratory Infectious Disease Unit (RIDU) of Kenyatta National Hospital for recommending this study on its clinical and hospital policy impact.\n\nWe acknowledge Mr. Joshua Atunga from the Department of Medical statistics of University of Nairobi for his support on data analysis statistical for this research.\n\nFurther guidance and mentorship by Dr. Marshall Mweu of the Department of Public and Global health of the University of Nairobi is highly appreciated.\n\nLastly, the data collectors and the participant health workers are greatly acknowledged for their participation in this study.\n\n\nReferences\n\nWorld Health Organization (WHO): Coronavirus Disease (COVID-19). nCov weekly Situation report. Geneva: 2020. Reference Source\n\nWHO: Health, Workers’. Health Workers: a global profile.2006. Reference Source\n\nWHO: Protocol for assessment of potential risk factors for 2019-novel coronavirus (2019-nCoV) infection among health care workers in a health care setting.2020; Vol. 2019. Reference Source\n\nMOH: COVID-19 OUTBREAK IN KENYA DAILY SITUATION REPORT - 404. Nairobi.2021; Vol. 148.\n\nWHO: Rational use of personal protective equipment for COVID-19 and considerations during severe shortages: interim guidance23 December 2020; 2020. Reference Source\n\nCheng MP, Papenburg J, Desjardins M, et al.: Diagnostic Testing for Severe Acute Respiratory Syndrome-Related Coronavirus 2: A Narrative Review. Ann. Intern. Med. 2020; 172(11): 726–734. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEtyang AO, Lucinde R, Karanja H, et al.: Seroprevalence of Antibodies to Severe Acute Respiratory Syndrome Coronavirus 2 Among Healthcare Workers in Kenya. Clin. Infect. Dis. 2021; 74: 288–293. (Xx Xxxx). Publisher Full Text\n\nWHO: WHO-2019-nCoV-HCW_risk_factors_protocol-2020.3-eng.2020; Vol. 2019. Reference Source\n\nNienhaus A, Hod R: COVID-19 among health workers in germany and Malaysia. Int. J. Environ. Res. Public Health. 2020; 17(13): 1–10.\n\nBaker MG, Peckham TK, Seixas NS: Estimating the burden of United States workers exposed to infection or disease: A key factor in containing risk of COVID-19 infection. PLoS One. 2020; 15(4): e0232452–e0232411. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYassi A, Moore D, Fitzgerald JM, et al.: Research gaps in protecting healthcare workers from SARS and other respiratory pathogens: An interdisciplinary, multi-stakeholder, evidence-based approach. J. Occup. Environ. Med. 2005; 47(1): 41–50. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchulte PA, Pandalai S, Wulsin V, et al.: Interaction of occupational and personal risk factors in workforce health and safety. Am. J. Public Health. 2012; 102(3): 434–448. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWHO: MERS Situation Update March 2018.2018; (August): 22765492. Reference Source\n\nEquipo profesional de Red Nacional de Vigilancia Epidemiologica (RENAVE): Análisis de los casos de COVID-19 en personal sanitario notificados a la RENAVE hasta el 10 de mayo en España. Inst Salud Carlos III.2020; 11. Reference Source\n\nMuñoz-Leyva F, Niazi AU: Common breaches in biosafety during donning and doffing of protective personal equipment used in the care of COVID-19 patients. Can. J. Anesth. 2020; 67(7): 900–901. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNg K, Poon BH, Kiat Puar TH, et al.: COVID-19 and the Risk to Health Care Workers: A Case Report. Ann. Intern. Med. 2020; 172(11): 766–767. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKampf G, Todt D, Pfaender S, et al.: Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents. J. Hosp. Infect. 2020; 104(3): 246–251. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlajmi J, Jeremijenko AM, Abraham JC, et al.: International Journal of Infectious Diseases COVID-19 infection among healthcare workers in a national healthcare system: The Qatar experience. Int. J. Infect. Dis. 2020; 100: 386–389. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWHO: Public Health Surveillance for COVID-19. Public health surveillance for COVID-19: Interim guidance.2022. Reference Source\n\nZitek T: The appropriate use of testing for Covid-19. West. J. Emerg. Med. 2020; 21(3): 470–472. Publisher Full Text\n\nGandhi M, Yokoe DS, Havlir DV: Asymptomatic transmission, the achilles’ heel of current strategies to control Covid-19. N. Engl. J. Med. 2020; 382(22): 2158–2160. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBaker MA, Rhee C, Fiumara K, et al.: COVID-19 infections among healthcare workers exposed to a patient with a delayed diagnosis of COVID-19. Infect. Control Hosp. Epidemiol. 2020; 41: 1075–1076. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWander PL, Orlov M, Merel SE, et al.: Risk factors for severe COVID-19 illness in healthcare workers: Too many unknowns. Infect. Control Hosp. Epidemiol. 2020; 41(11): 1369–1370. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFolke C, Carpenter S, Walker B, et al.: Regime shifts, resilience, and biodiversity in ecosystem management. Annu. Rev. Ecol. Evol. Syst. 2004; 35(1): 557–581. Publisher Full Text\n\nJin Y, Huang Q, Wang Y, et al.: Perceived infection transmission routes, infection control practices, psychosocial changes, and management of COVID-19 infected healthcare workers in a tertiary acute care hospital in Wuhan: a cross- sectional survey.2020; 1–13.\n\nMOH: Final-guidelines-on-the-Management-of-Covid-19-in-Kenya-2021-Edition.2021. Reference Source\n\nMOH: INTERIM GUIDELINES ON HUMAN RESOURCE FOR HEALTH DURING COVID 19 RESPONSE 8th.2020. Reference Source\n\nMOH: COVID-19 Antigen Rapid Diagnostic Testing Interim Guide.2020.\n\nOmbajo LA, Mutono N, Sudi P, et al.: EPIDEMIOLOGICAL AND CLINICAL CHARACTERISTICS OF COVID-19 PATIENTS IN KENYA.2020.\n\nRan L, Chen X, Wang Y, et al.: Risk Factors of Healthcare Workers With Coronavirus Disease 2019: A Retrospective Cohort Study in a Designated Hospital of Wuhan in China. Clin. Infect. Dis. 2020; 71(16): 2218–2221. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPowell-Jackson T, King JJC, Makungu C, et al.: Infection prevention and control compliance in Tanzanian outpatient facilities: a cross-sectional study with implications for the control of COVID-19. Lancet Glob. Health. 2020; 8(6): e780–e789. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGarcia Godoy LR, Jones AE, Anderson TN, et al.: Facial protection for healthcare workers during pandemics: A scoping review. BMJ Glob. Health. 2020; 5(5): 1–9.\n\nWHO: Rational Use of Personal Protective Equipment for Coronavirus Disease 2019 (COVID-19) and Considerations During Severe Shortages. Interim guidance.2020. Reference Source\n\nCDC: Interim U.S. Guidance for Risk Assessment and Work Restrictions for Healthcare Personnel with Potential Exposure to COVID-19. Interim U.S. Guidance for Risk Assessment and Work Restrictions for Healthcare Personnel with Potential Exposure to COVID-19.2021 [cited 2020 Nov 25]. Reference Source\n\nKapust PJ: Temporary Enforcement Guidance - Healthcare Respiratory Protection Annual Fit-Testing for N95 Filtering Facepieces During the COVID-19 Outbreak.2020. Reference Source\n\nLau JTF, Fung KS, Wong TW, et al.: SARS Transmission among Hospital Workers in Hong Kong. Emerg. Infect. Dis. 2004; 10(2): 280–286. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMhango M, Dzobo M, Chitungo I, et al.: COVID-19 Risk Factors Among Health Workers: A Rapid Review. Saf. Health Work. 2020; 11(3): 262–265. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang X, Zhang X, He J: Challenges to the system of reserve medical supplies for public health emergencies: Reflections on the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic in China. Biosci. Trends. 2020; 14(1): 3–8. Publisher Full Text\n\nChan-Yeung M: Severe acute respiratory syndrome (SARS) and healthcare workers. Int. J. Occup. Environ. Health. 2004; 10(4): 421–427. Publisher Full Text\n\nBoffetta P, Violante F, Durando P, et al.: Determinants of SARS-CoV-2 infection in Italian healthcare workers: a multicenter study. medRxiv. 2020; 2020.07.29.20158717. Publisher Full Text\n\nRan L, Chen X, Wang Y, et al.: Risk Factors of Healthcare Workers with Corona Virus Disease 2019: A Retrospective Cohort Study in a Designated Hospital of Wuhan in China. Clin. Infect. Dis. 2020; 71: 2218–2221. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZheng L, Wang X, Zhou C, et al.: Analysis of the infection status of the health care workers in Wuhan during the COVID-19 outbreak: A cross-sectional study. Infect. Dis. Soc. Am. 2020; 71: 2109–2113. Publisher Full Text\n\nMwema FM, Nyika JM: Challenges in facemasks use and potential solutions: The case study of Kenya. Sci. African. 2020; 10: e00563. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAdeleye OO, Adeyemi AS, Oyem JCAS, et al.: Rational Use of Personal Protective Equipment (PPE) among Health Workers in COVID-19 Frontline. Acta Sci. Med. Sci. 2020; 4(10): 68–75. Reference Source\n\nCzubryt MP, Stecy T, Popke E, et al.: N95 mask reuse in a major urban hospital: COVID-19 response process and procedure. J. Hosp. Infect. 2020; 106(2): 277–282. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRodriguez-Martinez CE, Sossa-Briceño MP, Cortés JA: Decontamination and reuse of N95 filtering facemask respirators: A systematic review of the literature. Am. J. Infect. Control. 2020; 48(12): 1520–1532. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSeto WH, Cowling BJ, Lam HS, et al.: Clinical and nonclinical health care workers faced a similar risk of acquiring 2009 pandemic H1N1 infection. Clin. Infect. Dis. 2011; 53(3): 280–283. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShah ASV, Wood R, Gribben C, et al.: Risk of hospital admission with coronavirus disease 2019 in healthcare workers and their households: Nationwide linkage cohort study. BMJ. 2020; 371.\n\nMOH: Human Resources For Health Norms and Standards Guidelines For The Health Sector Required investments for equitable, and adequate capacity to deliver the Kenya Essential Package for Health The Kenya Health Strategic and Investment. Minist Heal Kenya; 2014; 2014–2018. Reference Source\n\nMinistry of Health (MOH): Kenya Health Workforce Report: The Status of Healthcare Professionals in Kenya, 2015.2015. Reference Source\n\nMohren DCL, Jansen NWH, Ij K, et al.: Prevalence of common infections among employees in different work schedules. J. Occup. Environ. Med. 2002; 44(11): 1003–1011. PubMed Abstract | Publisher Full Text\n\nFondell E, Axelsson J, Franck K, et al.: Short natural sleep is associated with higher T cell and lower NK cell activities. Brain Behav. Immun. 2011; 25(7): 1367–1375. Publisher Full Text\n\nLim RK, Wambier CG, Goren A: Are night shift workers at an increased risk for COVID-19? Med. Hypotheses. 2020; 144(July): 110147. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLiu Q, Shi J, Duan P, et al.: Is shift work associated with a higher risk of overweight or obesity? A systematic review of observational studies with meta-analysis.2018; (May): 1956–71.\n\nSimonnet A, Chetboun M, Poissy J, et al.: High Prevalence of Obesity in Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Requiring Invasive Mechanical Ventilation. Obesity. 2020; 28(7): 1195–1199. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGao F, Zheng KI, Wang XB, et al.: Obesity Is a Risk Factor for Greater COVID-19 Severity. Diabetes Care. 2020; 43(7): E72–E74. Publisher Full Text\n\nBai Y, Wang X, Huang Q, et al.: SARS-CoV-2 infection in health care workers: a retrospective analysis and a model study. medRxiv. 2020; 2020.03.29.20047159. Publisher Full Text\n\nFatima Y, Bucks RS, Mamun AA, et al.: Shift work is associated with increased risk of COVID-19: Findings from the UK Biobank cohort. J. Sleep Res. 2021; (February): 1–11. Publisher Full Text\n\nSuárez-García I, de Aramayona M , López MJ, et al.: SARS-CoV-2 infection among healthcare workers in a hospital in Madrid, Spain. J. Hosp. Infect. 2020; 106(2): 357–363. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAli S, Noreen S, Farooq I, et al.: Risk assessment of healthcare workers at the frontline against COVID-19. Pakistan J. Med. Sci. 2020; 36(COVID-19-S4): S99–S103. Publisher Full Text\n\nXiang YT, Jin Y, Wang Y, et al.: Tribute to health workers in China: A group of respectable population during the outbreak of the COVID-19. Int. J. Biol. Sci. 2020; 16(10): 1739–1740. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKNH: KENYATTA NATIONAL HOSPITAL Strategic Plan 2018-2022. Nairobi: 2018. Reference Source\n\nMOH: Disease Outbreak Situation Report As At 20th Aug 2021-EPI WEEK 32.2021.\n\nMOH: Case Definition for COVID-19-25th March 2020.2020.\n\nWHO: Risk assessment and management of exposure of health care workers in the context of COVID-19: Interim Guidance.19 March 2020; 2020.\n\nÇelebi G, Pişkin N, Çelik Bekleviç A, et al.: Specific risk factors for SARS-CoV-2 transmission among health care workers in a university hospital. Am. J. Infect. Control. 2020; 48(10): 1225–1230. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOSHA: Guidance on Preparing Workplaces for COVID-19.2020. Reference Source\n\nMinistry of Health Kenya: INTERIM GUIDELINES ON MANAGEMENT OF COVID-19 IN KENYA.2020.\n\nHosmer D, Lemeshow S: Applied Logistic Regression. 2nd Editio.Wiley Series in Probability and Statistics; 2008; pp. 91–97.\n\nKim JH: Multicollinearity and misleading statistical results. Korean J. Anesthesiol. 2019; 72(6): 558–569. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIbiebele J, Silkaitis C, Dolgin G, et al.: Occupational COVID-19 exposures and secondary cases among healthcare personnel. Elsevier; 2021; 49(January): 1334–6. Reference Source\n\nLindsley WG, Noti JD, Blachere FM, et al.: Efficacy of face shields against cough aerosol droplets from a cough simulator. J. Occup. Environ. Hyg. 2014; 11(8): 509–518. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWHO: Infection prevention and control of epidemic- and pandemic-prone acute respiratory infections in health care. Vol. 2, PANDEMIC AND EPIDEMIC DISEASES.2014.\n\nRodriguez-Lopez M, Parra B, Vergara E, et al.: A case–control study of factors associated with SARS-CoV-2 infection among healthcare workers in Colombia. BMC Infect. Dis. 2021; 21(1): 878–879. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAshinyo ME, Dubik SD, Duti V, et al.: Infection prevention and control compliance among exposed healthcare workers in COVID-19 treatment centers in Ghana: A descriptive cross-sectional study. PLoS One. 2021; 16(3 March): e0248282–e0248213. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEl-Sokkary RH, El-Kholy A, Eldin SM, et al.: Characteristics and predicting factors of Corona Virus Disease-2019 (COVID-19) among healthcare providers in a developing country. PLoS One. 2021; 16(1 January): e0245672–e0245614. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLakshmi A, Jeniffer G, Meriton S, et al.: A study on personal protective equipment use among health care providers, Tamil Nadu. Int. J. Community Med. Public Heal. 2018; 5(5): 1771–1774. Publisher Full Text\n\nDzinamarira T, Nkambule SJ, Hlongwa M, et al.: Risk factors for COVID-19 infection among healthcare workers. A first report from a living systematic review and meta-analysis. Saf. Health Work. 2022; 13(xxxx): 263–268. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBandini MC, de Lucca SR , Francisco PB, et al.: Assessment instrument of risk factors for exposure to SARS-CoV-2 among health care workers with suspected COVID-19. Rev. Bras. Med. Trab. 2022; 20(1): 27–35. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDev N, Meena RC, Gupta DK, et al.: Risk factors and frequency of COVID-19 among healthcare workers at a tertiary care centre in India: A case-control study. Trans. R. Soc. Trop. Med. Hyg. 2021; 115(5): 551–556. PubMed Abstract | Publisher Full Text | Free Full Text\n\nContejean A, Leporrier J, Etienne C, et al.: Comparing dynamics and determinants of SARS-CoV-2 transmissions among health care workers of adult and pediatric settings in central Paris. Infect. Dis. Soc. Am. 2020.\n\nBallering AV, Oertelt-Prigione S, Olde Hartman TC, et al.: Sex and Gender-Related Differences in COVID-19 Diagnoses and SARS-CoV-2 Testing Practices during the First Wave of the Pandemic: The Dutch Lifelines COVID-19 Cohort Study. J Women’s Heal. 2021; 30(12): 1686–1692. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWHO: WHO COVID-19 Case definition. Updat Public Heal Surveill COVID-19.2020; (December 16): 1. Reference Source\n\nArevalo-Rodriguez I, Buitrago-Garcia D, Simancas-Racines D, et al.: False-negative results of initial RT-PCR assays for COVID-19: A systematic review. PLoS One. 2020; 15(12 December): e0242958–e0242919. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKiragu J, Ayah R: Dataset on potential risk factors to COVID19 disease among Health Workers in Kenya. Mendeley Data. 2023; V5. Publisher Full Text"
}
|
[
{
"id": "228533",
"date": "23 Dec 2023",
"name": "Arvind Kumar",
"expertise": [
"Reviewer Expertise Cytopathology",
"oncopathology and molecular pathology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis research could be more fruitful if these points were included 1-Correlation of comorbidities with the status of COVID-19 2-Any repeat PCR examination of two groups 3- Age groups should be uniform 4-Any specification of time duration of aggravation of symptoms or mortality in COVID-19 patients 5-Grade of signs and symptoms of Covid-19 positive patients 6-Statistical tools should be incorporated into the respective tables to achieve the P value\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "233008",
"date": "30 Jan 2024",
"name": "Jamiu S Olumoh",
"expertise": [
"Reviewer Expertise Biostatistics and Categorical Data Analysis"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI appreciate the opportunity to offer feedback on the manuscript titled \"Occupational Risk Factors Associated with COVID-19 among Health Workers in a Tertiary Referral Hospital, Nairobi, Kenya: A Case-Control Study.\"\n\nThe study models COVID-19 status as a function of Personal and occupational risk factors while controlling for gender status, clinical status, sub-optimal adherence to face shields, and suboptimal infection prevention control (IPC) adherence in common staff dining rooms. The research contributes valuable contextual evidence regarding the primary sources of COVID-19 exposure among healthcare workers (HWs). However, it is noteworthy that the models do not account for the potential impact of comorbidity on COVID-19, and age-related factors were omitted.\nAdditionally, I would like to highlight the following areas that require attention:\nAcronyms: The manuscript introduces the term \"PCR\" on the abstract page without providing an initial definition. Clarifying abbreviations at the point of introduction is crucial to enhance reader comprehension. Results: The reporting of statistical significance lacks specificity, as p-values are not provided; instead, expressions such as \"p <5%\" or \"p >5%\" are used. It is recommended to include actual p-values for a more precise interpretation of statistical significance. Table 1: The age intervals in Table 1 are observed to be unequal, which may impact the accuracy and clarity of the presented data. Ensuring equal age intervals in the frequency table is advisable for improved consistency and comparability.\nI believe addressing these concerns will enhance the manuscript's overall clarity, rigor, and interpretability. Thank you for considering these suggestions as you revise the document.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1328
|
https://f1000research.com/articles/11-1579/v1
|
23 Dec 22
|
{
"type": "Method Article",
"title": "Manual annotation of Drosophila genes: a Genomics Education Partnership protocol",
"authors": [
"Chinmay P. Rele",
"Katie M. Sandlin",
"Wilson Leung",
"Laura K. Reed",
"Katie M. Sandlin",
"Wilson Leung",
"Laura K. Reed"
],
"abstract": "Annotating the genomes of multiple species allows us to analyze the evolution of their genes. While many eukaryotic genome assemblies already include computational gene predictions, these predictions can benefit from review and refinement through manual gene annotation. The Genomics Education Partnership (GEP; https://thegep.org/) developed a structural annotation protocol for protein-coding genes that enables undergraduate student and faculty researchers to create high-quality gene annotations that can be utilized in subsequent scientific investigations. For example, this protocol has been utilized by the GEP faculty to engage undergraduate students in the comparative annotation of genes involved in the insulin signaling pathway in 27 Drosophila species, using D. melanogaster as the reference genome. Students construct gene models using multiple lines of computational and empirical evidence including expression data (e.g., RNA-Seq), sequence similarity (e.g., BLAST and multiple sequence alignment), and computational gene predictions. Quality control measures require each gene be annotated by at least two students working independently, followed by reconciliation of the submitted gene models by a more experienced student. This article provides an overview of the annotation protocol and describes how discrepancies in student submitted gene models are resolved to produce a final, high-quality gene set suitable for subsequent analyses. The protocol can be adapted to other scientific questions (e.g., expansion of the Drosophila Muller F element) and species (e.g., parasitoid wasps) to provide additional opportunities for undergraduate students to participate in genomics research. These student annotation efforts can substantially improve the quality of gene annotations in publicly available genomic databases.",
"keywords": [
"comparative genomics",
"Course-based Undergraduate Research Experience",
"CURE",
"structural gene annotation"
],
"content": "Introduction\n\nGenome annotation requires assessing and integrating multiple lines of computational and empirical evidence. Several computational pipelines have been developed (e.g., BRAKER and MAKER) for constructing an initial set of structural gene annotations for eukaryotic genomes.1,2 Accuracy of the gene models produced by gene prediction algorithms depends on multiple biological (e.g., genome size, ploidy, repeat density, and complexity of the transcriptome) and technical factors (e.g., quality of the genome assembly, evolutionary distance from the reference species, and availability of transcriptome data).3 These factors can contribute to differing numbers of gene predictions in closely related species (Figure 1).\n\nThe number of predicted genes can show large variations across algorithms (algorithm information in extended data4) and species, particularly for gene predictors using sequence similarity to genes in a reference species as their primary source of evidence. Some algorithms consistently either predict more (e.g., genBlastG) or less (e.g., GeMoMa) genes than the number of D. melanogaster genes as curated by FlyBase (purple line). Prediction differences can partly be attributed to some algorithms predicting a single isoform in a genomic region (e.g., GeneID), while others predict multiple isoforms per genomic region (e.g., genBlastG, Spaln). The genome assemblies indicated in the cladogram5,6 correspond to those listed in the “UCSC Assembly” column of Table 1.\n\nEvidence-based gene prediction algorithms (e.g., Gnomon7) use extrinsic evidence, such as RNA sequencing (RNA-Seq) data derived from the target species, and sequence similarity to proteins from a reference species, to predict genes within the target assembly. The advent of high-throughput RNA sequencing technologies have led to substantial improvement in the quality of gene annotations,8,9 particularly for species that lack high-quality gene annotations from a closely related reference species; however, the efficacy of assembling transcripts from RNA-Seq data depends on transcript expression levels in the specific developmental stages and tissue types that are sampled.10 Long-read RNA sequencing technologies (e.g., Iso-Seq by Pacific Biosciences and Direct RNA sequencing by Oxford Nanopore) can produce reads that span the entire transcript, which facilitates identification of alternative splicing patterns and characterization of different gene isoforms. There are, however, several challenges for producing high quality long-read data including the robustness of RNA extraction methods, bias towards short transcripts, low sequencing throughput, and low read accuracy (reviewed in Ref. 11). Additionally, past studies have shown that transcriptomes constructed from long-read RNA-Seq data have high sensitivity but low precision.12\n\nConsequently, despite recent advances in gene prediction algorithms and the increasing availability of RNA-Seq data, gene predictions produced by computational algorithms can still benefit from manual review and refinement.13,14 This article describes a protocol, developed by the Genomics Education Partnership (GEP; https://thegep.org), to engage undergraduate students in the comparative annotation of protein-coding genes involved in the insulin signaling pathway (ISP) across 27 species of Drosophila, using D. melanogaster as the reference species (Table 1).\n\nFor each UCSC Assembly, the table shows the corresponding NCBI RefSeq Accession Numbers, species names, and BioProject Accession Numbers for the RNA-Seq data.\n\nAs of August 2022, GEP students from 79 institutions have used this annotation protocol to construct 2,101 gene models across 27 Drosophila species. Despite differing in instructional settings and teaching modalities, this protocol ensures that GEP students use a uniform standard to construct gene models that are best supported by the available evidence. As an additional level of quality control, each gene is annotated by at least two students working independently, and the submitted gene models are then reconciled by an experienced student using the Apollo genome annotation editor.15 Reconciled gene models will typically be described in microPublication articles16 and submitted to the NCBI Third Party Annotation (TPA) database.17 Researchers can utilize the high-quality, manually curated gene models constructed by GEP students to investigate the evolution of genes and genomes (Figure 2).\n\nSummarized workflow for annotation and reconciliation to produce a set of high-quality gene models suitable for comparative and pathway analyses.\n\n\nMethods\n\nDrosophila researchers and curators at FlyBase have produced high-quality, comprehensive gene annotations for D. melanogaster based on a large amount of genetic and sequencing data.18 Our protocol utilizes the gene annotations from D. melanogaster (reference species) to facilitate annotation of the protein-coding sequence (CDS) of orthologous genes in other Drosophila species (target species). In the absence of compelling evidence (e.g., RNA-Seq data) indicating significant differences in the gene model, the proposed gene model in the target species minimizes the number of changes compared to the ortholog in the reference species (i.e., construct the most parsimonious gene model assuming evolutionary conservation).\n\nIn order to generate manual annotations for the CDS of a gene in the target species, we need to (1) identify the ortholog of that gene from D. melanogaster in the target species using sequence similarity and local synteny, (2) determine the structure and approximate coordinates of each isoform and their coding exons, and then (3) refine those coordinates for each isoform. The key analysis steps are also summarized in the Results section and in the Annotation Workflow for the Pathways Project.19 A walkthrough illustrating each step of the annotation protocol from the perspective of a naive student annotator on an example gene is both available on the Pathways Project page of the GEP website (https://thegep.org/pathways/) and in Ref. 20. Here we highlight the essential conceptual steps the student annotator will follow.\n\nThe annotation and reconciliation protocols described below utilize multiple bioinformatics tools that are briefly summarized in the “Data (and Software) Availability” section.\n\nCDS annotation procedure\n\nProject claiming\n\nGEP faculty members select at least one D. melanogaster gene involved in the ISP (i.e., target gene in the reference genome) and one or more of the 27 Drosophila species (i.e., target species) for their students to annotate. Each gene project includes an estimated difficulty level based on the number of isoforms, number of coding exons, and evolutionary distance from the reference genome. Faculty members can take the estimated difficulty of the gene projects into consideration when selecting projects that best suit the pedagogical goals of their courses, the amount of class time devoted to the annotation project, the academic levels of their students, and specific interests in the biological function of a gene. For example, faculty members might select the same gene in multiple Drosophila species for their students to annotate (working individually or in groups) in order to teach students about conservation relative to divergence time.\n\nIdentify the ortholog\n\nOrtholog assignment in the target species is based on the analysis of protein sequence similarity and local synteny (i.e., relative gene order and orientation within a syntenic chromosomal region) compared to the reference species.21,22 The key analysis steps for identifying the ortholog are also summarized in the extended data.23\n\nTo identify the ortholog of the target gene, the student annotator examines the genomic neighborhood surrounding the gene in both the reference species and the target species using the GEP UCSC Genome Browser (further described in the Software section below; https://gander.wustl.edu). This analysis includes identifying the nearest two upstream and downstream genes and their orientations relative to the target gene. The local synteny analysis also includes any nested genes in the locus surrounding the putative ortholog in the target species.\n\nLocating the putative ortholog requires the student to obtain the protein sequence for the target gene in the reference species from the Gene Record Finder, and use it as the query to perform a tblastn search against the genome assembly of the target species via NCBI Web BLAST (https://blast.ncbi.nlm.nih.gov/Blast.cgi). This protocol uses the tblastn program to compare the protein sequence query against a nucleotide database because amino acid sequences show higher sequence conservation than nucleotide sequences across evolutionary time. In addition, due to the degeneracy of the genetic code, sequence similarity searches at the amino acid level are more sensitive than searches at the nucleotide level.24,25 There are three possible outcomes of their tblastn search: (1) zero matches, (2) one match, or (3) more than one match. If there is a single high-quality match, that match is a good candidate for being the ortholog.\n\nThe tblastn search may report zero significant matches even if the ortholog exists in the target species due to gaps or misassemblies in the genome assembly or the lack of sequence conservation between orthologs. In the latter case, the two genes upstream and downstream of the target gene in the reference species will be used to infer the location of the target gene in the target species (i.e., local synteny). The student first identifies the orthologs to the genes flanking the target gene in the target species. If there is a locally syntenic region in the target species, then there will likely be an additional feature located between the flanking orthologs in the target species. This additional feature can then be considered as the likely ortholog to the target gene in the target species based on local synteny. Orthology should be confirmed using a blastp search of the predicted protein sequence of the feature in the target species against a database of annotated proteins for the reference species. If the location and candidate for the ortholog cannot be established using this strategy, then the ortholog may be absent from the genome assembly for the target species.\n\nIf the tblastn search reports two or more significant matches, then the ortholog assignment will be based on parsimony with the reference species. The match with the lowest E-value, highest percent identity, and highest alignment coverage to the target gene will be assigned as the putative ortholog in the target species. The student then confirms the putative ortholog assignment derived from the best tblastn match via local synteny by comparing the genes surrounding the target gene in the target and reference species. If there is no match for neighboring genes in an evolutionarily diverged species but a single match exists for the target gene, then the ortholog assignment will be determined by BLAST searches using the Reciprocal Best Hits (RBH) strategy.26\n\nFigure 3 shows an example of how the student can use local synteny to establish the ortholog of the target gene Ilp2. The coding region of the same two genes are located upstream (i.e., Zasp67 and Ilp1) and downstream (i.e., Ilp3 and Ilp4) of Ilp2 in D. melanogaster and D. yakuba. In addition, Ilp2, Ilp3, and Ilp4 are all nested within the coding span of CG32052 in both species, which further supports the hypothesis that the genomic neighborhood is conserved, and thus, the ortholog of Ilp2 has likely been identified.\n\nSchematic of genomic neighborhood surrounding the Ilp2 gene in D. melanogaster and D. yakuba, showing that Ilp2, Ilp3, and Ilp4 are nested within CG32052 in both species.\n\nIdentify the approximate coordinates of each coding exon\n\nOnce the student identifies the putative ortholog, they begin constructing the gene model by separately mapping each coding exon to determine their approximate locations and their reading frames in the target genome using the “Align two or more sequences” (bl2seq) feature provided by NCBI Web BLAST.\n\nFor each isoform of the target gene in D. melanogaster (reference genome), they perform tblastn searches of each coding exon of the isoform (query) in D. melanogaster against the scaffold which contains the putative ortholog of the target gene in the target species (subject). The amino acid sequence for each coding exon in the D. melanogaster isoform is obtained from the Gene Record Finder (further described in the Software section below). The scaffold in the target species, which contains the putative ortholog of the target gene, is identified by the “Identify the ortholog” step above. For scaffolds larger than 10 Megabases (Mb), the “From” and “To” fields under “Subject subrange” in the NCBI tblastn search interface are used to limit the size of the search region to the approximate location of the target gene (inferred from results of the “Identify the ortholog” step).\n\nThe default tblastn search parameters for NCBI Web BLAST are used in this search except for the following parameters:\n\n1. Select the “Align two or more sequences” checkbox\n\n2. Specify a subject subrange that corresponds to the approximate location of the target gene estimated at the “Identify the ortholog” step\n\n3. Select “No adjustment” under “Compositional adjustments”\n\n4. Uncheck the “Low complexity regions” filter (under “Filters and Masking”)\n\nAt the end of this process, the student usually identifies a collinear set of coordinates for most of the coding exons of the isoform. Results of the tblastn searches provide further supporting evidence for the ortholog assignment and provide anchors from which to define the search regions for small or weakly conserved coding exons.\n\nRefine coding exon coordinates\n\nSince tblastn only aligns to complete codons, the BLAST alignments will not include partial codons adjacent to the splice junctions. In addition, tblastn does not take the locations of potential splice sites into account when it generates the alignment. Consequently, other lines of evidence (e.g., computational gene predictions, RNA-Seq data) must be used to refine the start and end coordinates of each coding exon. The student manually refines the collinear coding exon coordinates identified above through visual inspection of the region in the Genome Browser utilizing the RNA-Seq track, other homology-based alignment algorithms, and gene predictions, as well as comparing the sequence to other Drosophila species based on whole genome multiple sequence alignments (more details about the tracks used can be found in the extended data).4\n\nIf available, the RNA-Seq data can provide empirical support for the proposed gene model in the target species. RNA-Seq data for the target species were obtained from the NCBI Sequence Read Archive (Table 127). The RNA-Seq reads were mapped against the target genome using HISAT2,28 and putative introns were inferred from the alignments of spliced RNA-Seq reads using the junctions extract command provided by RegTools.29\n\nWhen defining the intron coordinates, canonical splice sites (i.e., GT donor and AG acceptor) are adhered to unless there is good evidence to the contrary, such as spliced RNA-Seq reads from the target species and conservation of non-canonical splice sites across the clade. The student also needs to ensure the donor and acceptor sites have compatible phases (i.e., the sum of the phases of the donor and acceptor sites of an intron is either zero or three) in order to maintain the open reading frame after splicing. A more detailed version of the workflow for refining the coding exon coordinates, from the perspective of a naive student, can be found within extended data.30 Figure 4 gives an example coordinate refinement to account for the complete exon boundaries considering RNA-Seq data and splice site compatibility, and Table 2 shows the comparison of the approximate coding exon coordinates determined by the tblastn searches with their refined counterparts for the Rheb gene in D. yakuba.\n\n(A) The tblastn alignment for the D. melanogaster CDS 2_9850_2 (query) against the D. yakuba scaffold CM000160.2 (chr3R) placed the start of the CDS at 17,358,844 in frame +1. (B) Examination of the other lines of evidence (e.g., RNA-Seq read coverage, splice junction predictions, gene predictions, protein alignments) using the Genome Browser placed the start of the coding exon at 17,358,842. Since there are two nucleotides (GC; blue lines) prior to the first complete codon (AAA) that codes for first amino acid in the tblastn alignment (K), CDS 2_9850_2 in D. yakuba has a phase 2 splice acceptor site relative to reading frame +1.\n\nComparison between the tblastn and refined coordinates for the model of Rheb in D. yakuba. Note that in most cases, the coordinates identified by the tblastn search are adjusted by a few nucleotides (difference columns) via visual curation to account for incomplete codons and over-extensions of the tblastn alignment.\n\nVerify gene model\n\nThe student uses the Gene Model Checker to verify that the refined coordinates for the gene model in the target species satisfy the biological constraints for protein-coding genes in most eukaryotes and reflect the gene structure of the D. melanogaster ortholog. The dot plot and protein alignment identify differences between the proposed gene model and the D. melanogaster ortholog, and they help to verify that their proposed gene model is the most parsimonious compared to the D. melanogaster ortholog. For more information on the Gene Model Checker, refer to the “Data (and Software) Availability” section.\n\nThe student repeats the “Identify the approximate coordinates of each coding exon” and “Refine coding exon coordinates” steps to construct gene models for each unique protein-coding isoform of their target gene and then verifies them with the Gene Model Checker.\n\nFinal submission\n\nThe student submits a file containing the coordinates of the coding exons for all isoforms in the Generic Feature Format (GFF), a file containing the transcript sequence for the coding region of all isoforms in FASTA format (FNA), and a file containing the peptide sequence for all isoforms in FASTA format (FAA). These files are generated for each isoform by the Gene Model Checker and then concatenated by the Annotation Files Merger tool described below. They also submit an Annotation Report31 to document the evidence supporting their proposed gene models.\n\nExceptions to the standard annotation workflow\n\nWhile the standard annotation workflow provides a good starting point for the annotation of target genes in the Pathways Project, additional tools and strategies are needed to address challenges with the annotations of a subset of genes. Resolving these challenges typically require the integration of multiple lines of empirical and computational evidence. Below we describe the process for resolving two common challenges—non-canonical splice sites and assembly errors—and provide a list of other potential challenges annotators may encounter.\n\nNon-canonical splice sites\n\nThe most common (canonical) sequence for the splice donor site is GT (GU in the pre-mRNA), and the most common sequence for the splice acceptor site is AG. Variant splice sites are termed non-canonical. For example, the GC splice donor site appears in ~0.8% (603/71,922) of the unique introns in D. melanogaster (FlyBase release 6.43). The use of a non-canonical splice site in a gene model will typically be supported by splice junction predictions derived from spliced RNA-Seq reads. The presence of a non-canonical splice site in the orthologous intron in the reference species (D. melanogaster), or in multiple Drosophila species closely related to the target species, can also be used as supporting evidence for the annotation of a non-canonical splice site.\n\nAssembly errors\n\nEach sequencing platform (e.g., Sanger, Illumina, PacBio, and Nanopore) has a distinct error profile32,33 that could introduce errors (e.g., base substitutions, insertions, and deletions) into the consensus sequence of an assembly. Transposons and other repetitive sequences (e.g., tandem repeats) in eukaryotic genomes can also lead to gaps and misassemblies.34 Gene annotation challenges caused by assembly errors include partial or missing genes due to gaps in the assembly, apparent frameshifts within CDSs due to extra or missing nucleotides in the consensus sequence, and errors in ortholog/paralog assignments (e.g., due to “duplications” caused by misassemblies).\n\nThe publicly available genome assemblies utilized by the Pathways Project were constructed using different sequencing technologies and assembly protocols. Since these genome assemblies have not been manually improved, they might contain assembly errors that could interfere with coding region annotations. Consequently, in cases where proposed gene models for the target species includes changes in gene structure compared to the D. melanogaster ortholog (e.g., novel/missing isoforms, exons, and/or introns), further investigations are needed to ascertain if the difference is caused by an assembly error or reflects true divergence. As part of this assessment, the student evaluates multiple lines of evidence including: (1) sequence conservation with other Drosophila species besides D. melanogaster, (2) consistency with Illumina genomic reads and RNA-Seq reads in the NCBI Sequence Read Archive (SRA), and (3) consistency with other genome assemblies for the same species.35\n\nOther exceptions\n\nPast studies have shown that the number of genes involved in the ISP varied in the different Drosophila species due to gene duplications and pseudogenization,36 which leads to challenges in ortholog assignments. Other annotation challenges are caused by changes in gene structure (e.g., gain or loss of coding exons and isoforms) compared to the target gene in the reference species.\n\nAnother set of challenges pertain to gene models that do not conform to the typical characteristics of protein-coding genes, including genes with a non-canonical start codon (e.g., Akt), stop codon readthrough (e.g., jim), or trans-splicing (e.g., mod (mdg4)).\n\nCommon issues in gene models prior to submission\n\nThe Gene Model Checker sometimes reports multiple “fails” for a proposed gene model because it deviates from the expected biological characteristics of most protein-coding genes (e.g., gene model with multiple in-frame stop codons). Typically, the multiple failures can be attributed to an error in the upstream regions of the proposed gene model that propagates downstream.\n\nFor example, one common cause of multiple failures is frameshifts caused by selecting incompatible donor and acceptor splice sites. When a coding exon ends in an incomplete codon, the 3’ end of that coding exon and the 5’ beginning of the next coding exon must include nucleotides that form a complete codon once the intron has been spliced out. The number of nucleotides between the end of the last complete codon and the splice donor site is defined as the phase of the splice donor site. Similarly, the number of nucleotides between the splice acceptor site and the start of the first complete codon is defined as the phase of the splice acceptor site. In order to maintain the open reading frame (ORF) after the intron has been spliced out, the sum of the donor and acceptor phases for adjacent coding exons must either be zero (i.e., no extra codon) or three (i.e., one extra codon). Selecting incompatible donor and acceptor splice sites causes a frameshift that changes the reading frames of the coding exons downstream of that splice junction. Using the incorrect reading frame to translate the downstream coding exons will likely introduce stop codons in the translation, thereby triggering multiple failures in the Gene Model Checker.\n\nTo resolve gene models with multiple fails, the student starts troubleshooting at the beginning of the gene. In many cases, correcting errors in the upstream portion of the gene model resolves the fails reported downstream.\n\nWhile most of the gene models produced by GEP students using the annotation protocol described above are congruent with each other, incongruent models require further examination by a student reconciler. Reconciliation is carried out by experienced students who have received additional training under the guidance of a GEP faculty, and/or senior-scientist, mentor.\n\nEach target gene in a target species is annotated by at least two students working independently. This quality control step is predicated on the assumption that it is relatively common for one student to make a single error but relatively rare for multiple students working independently to make the same error.\n\nStudent reconcilers look for differences in the submitted gene models, paying special attention to the three most common errors that might invalidate a model (described below), and investigate any large-scale anomalies (e.g., proposed novel isoform and missing specific exons or isoforms).\n\nReconciliation process\n\nReconciliation is performed using Apollo,15 a web-based collaborative genome annotation editor that allows reconcilers to view student-generated models alongside the evidence tracks (Figure 5) used for annotating those models.\n\nFinal gene models for Akt in D. arizonae (User-created Annotations track, yellow background), along with the NCBI RefSeq gene model (RefSeq Genes track), submitted student models (Student Annotations track), and RNA-Seq data aligning to the region (RNA-Seq Coverage – HPLS Diet track, histograms). Despite RefSeq predicting only one isoform (XM_018018591) for this gene, the final model contains two unique protein-coding isoforms (Akt-PC and Akt-PE), which were annotated using multiple lines of evidence. The Akt-PE isoform has a larger coding region in the reconciled gene model that is missed by the RefSeq gene predictions. In the Student Annotations track, the top two models included annotations of the 5’ and 3’ untranslated regions (UTRs, thinner dark green rectangles), and the bottom student model (DariGB1_Akt-PC.b6d9d2a) incorporated a coding exon that was likely not part of Akt.\n\nReconcilers evaluate the available student annotations for each isoform in conjunction with the other evidence tracks (e.g., sequence similarity, RNA-Seq data, and gene predictions) to construct the final gene model for the protein-coding isoform(s) that is best supported by the available evidence. Reconcilers then draft a microPublication describing the supporting evidence for the final gene model.16 The student annotators and their faculty mentors review and approve the article draft. Reconciled models are also used in downstream meta-analyses and deposited into the NCBI Third Party Annotation (TPA) database.\n\n\nResults\n\nIdentify the ortholog\n\nIdentification of the ortholog is done using BLAST and local synteny analysis of the genomic neighborhood of the target gene. For example, to locate the Ilp2 gene (target gene) in D. yakuba (target species), a tblastn search was used to compare the protein sequence for D. melanogaster Ilp2-PA (query) against the D. yakuba DyakCAF1 genome assembly (subject). The two collinear alignment blocks that correspond to the best match to the D. melanogaster Ilp2-PA protein (137aa) are located in the 9,766,395-9,766,887 region of the D. yakuba scaffold CM000159.2 (chr3L) (Figure 6). The alignment block for the first 54aa of Ilp2-PA is located at 9,766,395-9,766,556 in frame +3, with a normalized score of 171 bits and 94% identity. The alignment block for residues 56-137 of Ilp2-PA is located at 9,766,642-9,766,887 in frame +1, with a normalized score of 261 bits and 94% identity. The joint E-value for the two collinear alignment blocks is 3e-114. The two alignment blocks account for 136aa out of 137aa of D. melanogaster Ilp2-PA (residue 55 of the protein is not covered by the two alignment blocks). Local synteny analysis shows that the genomic neighborhood surrounding Ilp2 is conserved between D. melanogaster and D. yakuba (Figure 3).\n\nCollectively, the available evidence supports the hypothesis that the 9,766,395-9,766,887 region of the D. yakuba scaffold CM000159.2 contains the putative ortholog of Ilp2.\n\nIdentify the coordinates of each coding exon\n\nThe approximate coding exon coordinates for the target gene in the target species are defined by tblastn searches of the coding exons of the target gene in D. melanogaster against the genomic scaffold in the target species determined by the “Identify the ortholog” step. The approximate coding exon coordinates are then refined by examining the evidence tracks in the GEP UCSC Genome Browser. For example, Figure 4A shows the approximate placement of the second coding exon of the Rheb gene in the D. yakuba DyakCAF1 assembly based on the results of the tblastn search (i.e., scaffold CM000160.2 (chr3R) at 17,358,844-17,358,912 in frame +1). In Figure 4B, the refined start coordinate for the second coding exon of Rheb (i.e., at 17,358,842) was determined by RNA-Seq read coverage, splice junction predictions, gene predictions, and protein alignments evidence tracks on the GEP UCSC Genome Browser. Table 2 shows the refinement of all CDS exons of Rheb in D. yakuba. The “Difference” column indicates the necessity of manually refining BLAST derived coordinates.\n\nVerify gene model\n\nThe final step prior to submission to the GEP is for the student to confirm the proposed gene model using GEP’s Gene Model Checker. This tool can help the annotator verify that the proposed gene model satisfies the biological constraints of most protein-coding genes and identify differences between the proposed gene model and the D. melanogaster ortholog. In Figure 7, we can see the checklist for the model of Rheb-PA in D. yakuba passed the Gene Model Checker (i.e., the proposed gene model begins with a start codon, ends with a stop codon, and the five coding exons use the canonical splice donor and acceptor sites). It is, however, possible to “pass”’ all the checks in the tool and still have an entirely incorrect model since the tool does not specifically test for protein sequence conservation or orthology.\n\nMost common annotation errors\n\nReconciliation consists of reviewing two or more gene models created by student annotators working independently. The main advantage of manually curated gene models relative to computational predictions is the ability for the curator (in this case the student annotator) to evaluate and integrate across non-conforming pieces of evidence. Reconcilers provide further quality control measures as they closely scrutinize each idiosyncrasy in the gene models proposed by student annotators. The most common idiosyncrasies/errors are listed below.\n\nSelection of incorrect splice sites\n\nOne of the most common annotation errors is the selection of splice donor and acceptor sites that are not the most parsimonious candidates compared to the target gene in the reference genome. Another type of splice site error is caused by the annotators placing too high of a priority on the use of canonical sequences for splice donor sites (GT) and splice acceptor sites (AG). While non-canonical splice sites are rare in Drosophila (i.e., found in < 1% of introns), they should be used if the non-canonical splice sites are supported by RNA-Seq data and conservation in other Drosophila species.37–39\n\nMultiple failures in the Gene Model Checker checklist (as shown in Figure 8) are typically caused by the selection of incompatible splice sites during the “Refine coding exon coordinates” stage of the analysis. Most of these errors can be resolved by scrutiny of the coordinates for the checklist item where the first error is reported by the Gene Model Checker. Figure 9 shows the incorrect assignment of a splice site in D. eugracilis indicated by the first “fail” in the Gene Model Checker in Figure 8. The proposed splice donor site is one nucleotide away from the correct splice donor site with the canonical sequence of GT. Reconcilers are well equipped to identify the proper splice site when the student model has an error.\n\nThe checklist also reports the use of a non-canonical GG splice donor site for CDS 1, and that the total length of the coding region (2,807 nt) is not divisible by three. To address these errors, the annotator should verify the annotation for the item associated with the first error in the checklist (i.e., the end coordinate for the first coding exon and its corresponding splice donor site). In this example, the end of the first coding exon should be changed from 4,678,301 to 4,678,302 based on the available evidence on the GEP UCSC Genome Browser. This change will resolve the remaining failures in the checklist.\n\nExtending the end of the proposed coding exon by one nucleotide (to 4,678,302) will utilize the canonical splice donor site (GT) and is more consistent with the available gene predictions and RNA-Seq data. The revised coding exon coordinate is supported by the splice junction prediction JUNC00062858 (score = 216).\n\nMissing/extra exons\n\nAnother common error is gene models with missing or extra coding exons compared to the D. melanogaster ortholog. Sometimes these proposed changes in gene structure are well supported by the data (e.g., a novel intron supported by splice junction predictions), but often the mismatch in the number of coding exons is due to the student annotator failing to fully account for all lines of evidence.\n\nIncorrect ortholog assignment\n\nCorrect assignment of an ortholog depends on the proper configuration of the BLAST search parameters, proper interpretation of the BLAST search result, and proper consideration of local synteny compared to the reference species. If a student annotates a gene that is not the ortholog, then their gene model cannot be used to establish the final ortholog model in the target species.\n\nNon-canonical splice sites\n\nWhile non-canonical splice sites are rare in Drosophila (i.e., found in < 1% of introns), they should be included if they are supported by RNA-Seq read coverage, splice junction predictions, and conservation in other species.37–39 An example of a gene with a non-canonical spice site is sgg-RN in D. melanogaster, which has a GC splice donor site rather than the GT donor site between exons sgg:15 and sgg:18 (Figure 10). The presence of a non-canonical splice site in a proposed model will be indicated by a “Warning” label in the Gene Model Checker. If a non-canonical splice site is substantiated by multiple lines of evidence (e.g., RNA-Seq data, conservation across multiple species), the student may conclude that the non-canonical splice site is also present in the target species.\n\nAssembly errors\n\nAssembly errors (e.g., gaps) can affect the coding region gene annotations. The Chained Alignments between the D. melanogaster dm6 assembly and the D. pseudoobscura DpseGB3 assembly (GCA_000001765.2) show that the chico gene is split across two different scaffolds in the D. pseudoobscura DpseGB3 assembly—the first coding exon of chico is located in the D. pseudoobscura scaffold CH673091 and the rest of the gene is located in scaffold CH475478 (Figure 11).\n\nThe primary goal of reconciliation is to elucidate any inconsistencies or idiosyncrasies that might occur with two independent students generating the models. The majority of student models received for the Pathways Project (n=310) agree with the final reconciled model (83%; Figure 12A). Those with errors include mislabeled or missing isoforms (38%), incorrect splice sites (41%), extra or missing exon(s) (19%), and failing to identify the proper ortholog (2%) as seen in Figure 12B.\n\n(A) The raw error rate of models, and the (B) breakdown of the error rates into the classes of errors.\n\nAfter student models are reconciled and manuscripts are drafted, they are sent for review and publication via the microPublication journal (https://www.micropublication.org). The goal of this journal is to publish brief and novel findings whose results may lack a broader scientific narrative. The gene models generated and reconciled by students fit neatly within this description (e.g., Ref. 40).\n\n\nDiscussion\n\nThis annotation protocol has been used by GEP faculty to engage undergraduate students in the comparative annotation of ISP genes in 27 Drosophila species. Similar protocols have previously been used by the GEP on other scientific projects.41–44 Those protocols were used as the basis to develop the protocol described here.\n\nTo ensure gene models produced by GEP students are of high quality, each gene is annotated by at least two students working independently and then reconciled by a more experienced student. This manual curation process ensures the availability of an accurate set of gene models from multiple Drosophila species for the comparative study of network architecture and the evolution of genes involved in signaling pathways (e.g., the ISP).\n\nThe annotation effort of the student annotators is of value because the students can outperform computational gene predictors. For example, GEP students were able to annotate a conserved isoform not predicted by the NCBI RefSeq pipeline for Akt in D. arizonae (Figure 5). This isoform was not predicted computationally due to a non-canonical ACG start codon that is conserved in Akt in D. melanogaster.\n\nAnnotation and reconciliation protocols similar to the one described in this article are also currently used to investigate the expansion of the Muller F element in four Drosophila species and the evolution of venom proteins in four parasitoid wasp species. Faculty can also use this protocol to create new Course-based Undergraduate Research Experiences (CUREs) that engage students in the comparative analysis of genes involved in other metabolic and signaling pathways.\n\nThe protocol described here is focused only on the annotation of coding regions. Once additional experimental data (e.g., CAGE, RAMPAGE, and long-read RNA-Seq data) becomes available in more species, future analyses will focus on the annotation of untranslated regions and transcription start sites.\n\n\nData and software availability\n\nRepository: NCBI\n\nThe GenBank accession numbers for the assemblies and BioProject accession numbers for the RNA-Seq datasets are available on NCBI under the accession numbers listed in Table 1. Data is available in the public domain through NCBI (https://www.ncbi.nlm.nih.gov).\n\nRepository: FlyBase\n\nFlyBase data used for tool creation mentioned below is publicly available through the FlyBase FTP site (https://ftp.flybase.net/releases/).\n\nData under license by a third party\n\nThe UCSC Genome Browser is developed by the Genomics Institute at the University of California Santa Cruz. The source code for the UCSC Genome Browser is covered by five different licenses. Most of the source code is available under the MIT License, and all the source code is freely available to non-commercial entities. The source code is available on GitHub (https://github.com/ucscGenomeBrowser/kent), and it can also be obtained through the UCSC Genome Browser Store (https://genome-store.ucsc.edu/).\n\nLarge data\n\nThe datasets displayed in the GEP UCSC Genome Browser are too large to be feasibly hosted by an F1000Research-approved repository, such as RNA-Seq read alignments and Whole-Genome Multiple Sequence Alignments. The data is available through the GEP UCSC Genome Browser and the UCSC Table Browser (https://gander.wustl.edu). Details on the datasets and tools used to construct each evidence track are available through the settings page for each track in the GEP UCSC Genome Browser. As stated under the “Repository-hosted Data” section, the genome assemblies and the RNA-Seq datasets used to construct the evidence tracks on the GEP UCSC Genome Browser are in the public domain, and they can be obtained through NCBI (https://www.ncbi.nlm.nih.gov).\n\nRepository: GitHub\n\n• Annotation Files Merger (https://github.com/wilsonleung-gep/annotation-files-merger)\n\n• Dot Plot Viewer (https://github.com/wilsonleung-gep/dot-plot-viewer)\n\n• Gene Record Finder (https://github.com/wilsonleung-gep/gene-record-finder)\n\n• Sequence Updater (https://github.com/wilsonleung-gep/sequence-updater)\n\n• Small Exons Finder (https://github.com/wilsonleung-gep/small-exons-finder)\n\nAll the source code in the above repositories is available under the MIT License.\n\n• Gene Model Checker (https://github.com/wilsonleung-gep/gene-model-checker)\n\nThe Gene Model Checker is available under the GNU General Public License v3.0.\n\nAll custom software and tools generated by the GEP can be accessed from the GEP website (https://thegep.org). The annotation tools are publicly available web-based applications, thus requiring no installation on the part of the user. Versions of the tools can be found in Table 3. All the GEP annotation tools are synchronized to the same FlyBase release. The FlyBase D. melanogaster gene annotations used by the GEP annotation tools are updated twice a year (i.e., just before the start of the Fall and the Spring semesters) in order to mitigate the impact of FlyBase updates to the D. melanogaster reference gene annotations during the semester.\n\nGEP UCSC Genome Browser\n\nSince GEP materials are catered towards undergraduates that may have limited or no experience with programming and command-line interfaces, we endeavor to make all data easily accessible, thereby reducing the barrier to engagement in genomics research. The GEP maintains a mirror of the UCSC Genome Browser with Drosophila genomes (https://gander.wustl.edu). We created these Genome Browsers45 with multiple evidence tracks using data generated by various algorithms4 and experimental data obtained from the NCBI SRA.\n\nGene Record Finder\n\nThe Gene Record Finder (https://gander.wustl.edu/%7ewilson/dmelgenerecord/index.html) summarizes the FlyBase annotations for protein-coding genes in D. melanogaster. It provides information about the structure of each D. melanogaster gene, such as the number of isoforms (and number of isoforms with unique coding regions), as well as the amino acid sequence for each coding exon and the nucleotide sequence for each exon. The Gene Record Finder also provides exon usage maps that demarcate the exons used by each isoform. This information is used in the “Identify the approximate coordinates of each coding exon” step of the annotation protocol. While this information can be directly obtained from FlyBase, annotators can more easily retrieve the gene structure information from a single page instead of through multiple FlyBase Transcript and Polypeptide Reports.\n\nGene Model Checker\n\nThe Gene Model Checker (https://gander.wustl.edu/%7ewilson/genechecker/index.html) provides a way for annotators to check their own work when constructing gene models. It verifies that the proposed gene model satisfies basic biological constraints (e.g., maintains an ORF, uses canonical start and stop codons, and canonical splice donor and acceptor sites). It also indicates whether the number of coding exons for the proposed gene model in the target species matches that in the orthologous isoform in D. melanogaster. If there is empirical evidence indicating the gene has unusual characteristics (e.g., the use of a non-canonical start codon, stop codon read-through, or polycistronic transcripts18), students provide the supporting evidence for their claims in the Annotation Report form.\n\nThe “Dot Plot” section of the Gene Model Checker output compares the proposed gene model against the putative ortholog in D. melanogaster using protein alignment algorithms. Large gaps in the dot plot or protein alignment might indicate the selection of an incorrect splice site, missing exons, or extra exons in the proposed gene model. Note that this tool does not compare the proposed gene model against other lines of evidence, such as RNA-Seq data or computational gene predictions. The Gene Model Checker also produces the three annotation files for the proposed gene model that are required for project submission (a GTF file to define genomic feature coordinates, a transcript sequence file in FASTA format (FNA), and a peptide sequence file in FASTA format (FAA)).\n\nThe Gene Model Checker requires input of the species, assembly, and the scaffold of the putative ortholog. In addition, the Gene Model Checker requires the name of the ortholog in D. melanogaster, the set of coding exon coordinates for the gene in the target species, orientation of the gene, noting whether or not the untranslated regions are included, whether the gene model is complete (i.e., encompasses all CDSs/UTRs), and whether the genomic region containing the gene in the target species has consensus errors (e.g., Figure 7). Presently, this tool only supports the 28 Drosophila species that are currently in the GEP UCSC Genome Browser.\n\nSmall Exons Finder\n\nThe typical use case for the Small Exons Finder (https://gander.wustl.edu/%7ewilson/smallexonfinder/index.html) tool is identifying CDSs that are too small or too weakly conserved to be detected by BLAST. The tool is designed to look for ORFs that satisfy a set of biological constraints including the type of CDS (i.e., initial, internal, or terminal CDS), the phase of the donor or acceptor splice site, and the expected CDS size according to the D. melanogaster model. The Small Exons Finder then looks for ORFs in the provided sequence that conform to the aforementioned constraints. Compared to the ORF-FINDER tool developed by NCBI,46 the Small Exons Finder allows users to search for ORFs that are less than 30bp in size and can search for initial, internal, and terminal coding exons with constraints on the phases of the donor and acceptor sites.\n\nSequence Updater\n\nThe Sequence Updater (https://gander.wustl.edu/%7ewilson/sequence_updater/index.html) tool is primarily used to create a Variant Call Format (VCF) file47 to correct errors (i.e., base substitutions, insertions, and deletions) in the consensus sequence of a genome assembly. The VCF file produced by the Sequence Updater can be used with the Gene Model Checker to validate a gene model with consensus errors.\n\nAnnotation Files Merger\n\nThe Gene Model Checker produces GFF, FNA, and FAA files for each isoform. The submission pipeline requires a single GFF, FNA, and FAA file that includes all the unique isoforms in a project. For each type of annotation file, the Annotation Files Merger (https://gander.wustl.edu/%7ewilson/submissionhelper/index.php) is used to combine the annotations for all the unique isoforms in a project into a single file. The Annotation Files Merger also enables the user to view the combined GFF file as a custom track on the GEP UCSC Genome Browser.\n\nBEDTools\n\nBEDTools48 was used to perform genomic arithmetic and compare locations of genomic features in multiple tracks of the GEP UCSC Genome Browser.\n\nNCBI BLAST+\n\nThe local sequence alignments produced by the tools in NCBI BLAST+ suite were used for multiple aspects of the protocol including, but not limited to, sequence annotation and local synteny assignment.\n\nFigshare. Supplement 1.pdf, DOI: https://doi.org/10.6084/m9.figshare.21235341\n\nFigshare. Supplement 2.pdf, DOI: https://doi.org/10.6084/m9.figshare.21235345\n\nFigshare. Supplement 3.docx, DOI: https://doi.org/10.6084/m9.figshare.21235376\n\nFigshare. Supplement 4.docx, DOI: https://doi.org/10.6084/m9.figshare.21235367\n\nFigshare. Supplement 5.pdf, DOI: https://doi.org/10.6084/m9.figshare.21235343\n\nFigshare. Supplement 6.docx, DOI: https://doi.org/10.6084/m9.figshare.21235380\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "Acknowledgements\n\nWork done by GEP faculty and their students generated gene models that allowed us to refine our protocol. We would specifically like to acknowledge Dr. Alexa Sawa and her students at College of the Desert for providing input on initial drafts of the protocol and the reconcilers who generated models that can be used for downstream analyses.\n\n\nReferences\n\nCarson H, Mark Y: MAKER2: an annotation pipeline and genome-database management tool for second-generation genome projects. BMC Bioinformatics. 2011; 12: 491–491. PubMed Abstract | Publisher Full Text\n\nHoff KJ, Lomsadze A, Borodovsky M, et al.: Whole-Genome Annotation with BRAKER. Methods Mol. Biol. 2019; 1962: 65–95. PubMed Abstract | Publisher Full Text\n\nBrůna T, Hoff KJ, Lomsadze A, et al.: BRAKER2: automatic eukaryotic genome annotation with GeneMark-EP+ and AUGUSTUS supported by a protein database. Nar. Genom. Bioinform. 2021; 3: lqaa108. Publisher Full Text\n\nLeung W, Rele CP: Supplement 4.docx. figshare. 2022. Publisher Full Text\n\nConsortium D 12 G et al.: Evolution of genes and genomes on the Drosophila phylogeny. Nature. 2007; 450: 203–218. Publisher Full Text\n\nChen ZX, et al.: Comparative validation of the D. melanogaster modENCODE transcriptome annotation. Genome Res. 2014; 24: 1209–1223. PubMed Abstract | Publisher Full Text\n\nSouvorov A, Kapustin Y, Kiryutin B, et al.: Gnomon – NCBI eukaryotic gene prediction tool. NCBI. 2010.\n\nHoff KJ, Lange S, Lomsadze A, et al.: BRAKER1: Unsupervised RNA-Seq-Based Genome Annotation with GeneMark-ET and AUGUSTUS. Bioinformatics. 2016; 32: 767–769. PubMed Abstract | Publisher Full Text\n\nKeilwagen J, Hartung F, Paulini M, et al.: Combining RNA-seq data and homology-based gene prediction for plants, animals and fungi. BMC Bioinformatics. 2018; 19: 189–189. PubMed Abstract | Publisher Full Text\n\nShao M, Kingsford C: Accurate assembly of transcripts through phase-preserving graph decomposition. Nat. Biotechnol. 2017; 35: 1167–1169. PubMed Abstract | Publisher Full Text\n\nByrne A, Cole C, Volden R, et al.: Realizing the potential of full-length transcriptome sequencing. Philos. Trans. R. Soc. B. 2019; 374: 20190097–20190097. PubMed Abstract | Publisher Full Text\n\nKovaka S, Zimin AV, Pertea GM, et al.: Transcriptome assembly from long-read RNA-seq alignments with StringTie2. Genome Biol. 2019; 20: 278–278. PubMed Abstract | Publisher Full Text\n\nMudge JM, Harrow J: The state of play in higher eukaryote gene annotation. Nat. Rev. Genet. 2016; 17: 758–772. PubMed Abstract | Publisher Full Text\n\nTello-Ruiz MK, et al.: Double triage to identify poorly annotated genes in maize: The missing link in community curation. PLoS One. 2019; 14: e0224086–e0224013. PubMed Abstract | Publisher Full Text\n\nDunn NA, et al.: Apollo: Democratizing genome annotation. PLoS Comput. Biol. 2019; 15: e1006790–e1006790. PubMed Abstract | Publisher Full Text\n\nRaciti D, Yook K, Harris TW, et al.: Micropublication: incentivizing community curation and placing unpublished data into the public domain. Database. 2018; 2018: bay013. Publisher Full Text\n\nClark K, Karsch-Mizrachi I, Lipman DJ, et al.: GenBank. Nucleic Acids Res. 2016; 44: D67–D72. PubMed Abstract | Publisher Full Text\n\nMatthews BB, et al.: Gene Model Annotations for Drosophila melanogaster: Impact of High-Throughput Data. G3 Genes Genomes Genetics. 2015; 5: 1721–1736. PubMed Abstract | Publisher Full Text\n\nRele CP, Sandlin KM: Supplement 1.pdf. figshare. 2022. Publisher Full Text\n\nSandlin KM, Leung W, Reed LK: Supplement 2.pdf. figshare. 2022. Publisher Full Text\n\nJun J, Mandoiu II, Nelson CE: Identification of mammalian orthologs using local synteny. BMC Genomics. 2009; 10: 630–630. Publisher Full Text\n\nJahangiri-Tazehkand S, Wong L, Eslahchi C: OrthoGNC: A Software for Accurate Identification of Orthologs Based on Gene Neighborhood Conservation. Genom Proteom Bioinform. 2017; 15: 361–370. PubMed Abstract | Publisher Full Text\n\nRele CP, Leung W, Sandlin KM, et al.: Supplement 3.docx. figshare. 2022. Publisher Full Text\n\nGonzalez DL, Giannerini S, Rosa R: On the origin of degeneracy in the genetic code. Interface Focus. 2019; 9: 20190038–20190038. PubMed Abstract | Publisher Full Text\n\nStates DJ, Gish W, Altschul SF: Improved sensitivity of nucleic acid database searches using application-specific scoring matrices. Methods. 1991; 3: 66–70. Publisher Full Text\n\nTatusov R, Koonin E, Lipman D: A genomic perspective on protein families. Science. 1997; 278: 631–637. Publisher Full Text\n\nLeinonen R, Sugawara H, Shumway M: The sequence read archive. Nucleic Acids Res. 2011; 39: D19–D21. PubMed Abstract | Publisher Full Text\n\nDaehwan K, Ben L, Steven LS: HISAT: a fast spliced aligner with low memory requirements. Nat. Methods. 2015; 12: 357–360. PubMed Abstract | Publisher Full Text\n\nFeng Y-Y, et al.: RegTools: Integrated analysis of genomic and transcriptomic data for discovery of splicing variants in cancer. Biorxiv. 2018; 436634. Publisher Full Text\n\nWong J, Rele CP, Sandlin KM: Supplement 5.pdf. figshare. 2022. Publisher Full Text\n\nRele CP, Reed LK: Supplement 6.docx. figshare. 2022. Publisher Full Text\n\nHuang W, Li L, Myers JR, et al.: ART: A next-generation sequencing read simulator. Bioinformatics. 2012; 28: 593–594. PubMed Abstract | Publisher Full Text\n\nYang C, Chu J, Warren RL, et al.: NanoSim: Nanopore sequence read simulator based on statistical characterization. Gigascience. 2017; 6: 1–6. Publisher Full Text\n\nMikheenko A, Prjibelski A, Saveliev V, et al.: Versatile genome assembly evaluation with QUAST-LG. Bioinformatics. 2018; 34: i142–i150. PubMed Abstract | Publisher Full Text\n\nMiller DE, Staber C, Zeitlinger J, et al.: Highly Contiguous Genome Assemblies of 15 Drosophila Species Generated Using Nanopore Sequencing. G3 Genes Genomes Genetics. 2018; 8: 3131–3141. PubMed Abstract | Publisher Full Text\n\nAlvarez-Ponce D, Aguade M, Rozas J: Network-level molecular evolutionary analysis of the insulin/TOR signal transduction pathway across 12 Drosophila genomes. Genome Res. 2009; 19: 234–242. PubMed Abstract | Publisher Full Text\n\nSheth N, Roca X, Hastings ML, et al.: Comprehensive splice-site analysis using comparative genomics. Nucleic Acids Res. 2006; 34: 3955–3967. PubMed Abstract | Publisher Full Text\n\nParada GE, Munita R, Cerda CA, et al.: A comprehensive survey of non-canonical splice sites in the human transcriptome. Nucleic Acids Res. 2014; 42: 10564–10578. PubMed Abstract | Publisher Full Text\n\nSibley CR, Blazquez L, Ule J: Lessons from non-canonical splicing. Nat. Rev. Genet. 2016; 17: 407–421. PubMed Abstract | Publisher Full Text\n\nLose B, Myers A, Fondse S, et al.: Drosophila yakuba – Tsc1. MicroPubl. Biol. 2021; 2021. PubMed Abstract | Publisher Full Text\n\nSlawson EE, et al.: Comparison of dot chromosome sequences from D. melanogaster and D. virilis reveals an enrichment of DNA transposon sequences in heterochromatic domains. Genome Biol. 2006; 7: R15–R15. PubMed Abstract | Publisher Full Text\n\nLeung W, et al.: Drosophila muller f elements maintain a distinct set of genomic properties over 40 million years of evolution. G3 Genes Genomes Genetics. 2015; 5: 719–740. PubMed Abstract | Publisher Full Text\n\nLeung W, et al.: Evolution of a distinct genomic domain in Drosophila: comparative analysis of the dot chromosome in Drosophila melanogaster and Drosophila virilis. Genetics. 2010; 185: 1519–1534. PubMed Abstract | Publisher Full Text\n\nLeung W, et al.: Retrotransposons Are the Major Contributors to the Expansion of the Drosophila ananassae Muller F Element. G3 Genes Genomes Genetics. 2017; 7: 2439–2460. PubMed Abstract | Publisher Full Text\n\nShaffer CD, et al.: A course-based research experience: how benefits change with increased investment in instructional time. Cbe-life Sci. Educ. 2014; 13: 111–130. PubMed Abstract | Publisher Full Text\n\nRombel IT, Sykes KF, Rayner S, et al.: ORF-FINDER: a vector for high-throughput gene identification. Gene. 2002; 282: 33–41. PubMed Abstract | Publisher Full Text\n\nDanecek P, et al.: The variant call format and VCFtools. Bioinformatics. 2011; 27: 2156–2158. PubMed Abstract | Publisher Full Text\n\nQuinlan AR, Hall IM: BEDTools: A flexible suite of utilities for comparing genomic features. Bioinformatics. 2010; 26: 841–842. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "158890",
"date": "25 Jan 2023",
"name": "Terence D. Murphy",
"expertise": [
"Reviewer Expertise Expertise in manual and automated gene annotation techniques and supporting datasets"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper describes a protocol for manual annotation of genes involved in insulin signaling pathway (ISP) in Drosophila species using a platform developed by Genome Education Partnership (GEP) as a tool to educate undergraduate students and get them interested in scientific research. The platform also helps generate valuable manually curated annotation in these species where there isn’t much evidence data available, by leveraging data from D. melanogaster. The protocol is well conceived to meet the needs of an educational program. The paper is generally sound, but would benefit from a few clarifications and corrections as described below.\n\nWhile this is a ‘Methods” paper, the authors should perhaps provide some context in the Introduction about what GEP is and what its broader goals are (citing the latest publication on GEP) for the benefit of the naïve reader before diving into the details of the manual annotation protocol.\n\nIn figure 1, the Y-axis is labeled as “number of predicted protein-coding genes”, but the legend includes the following statement that implies it’s actually number of isoforms: “Prediction differences can partly be attributed to some algorithms predicting a single isoform in a genomic region (e.g., GeneID), while others predict multiple isoforms per genomic region (e.g., genBlastG, Spaln).” Furthermore, the values for NCBI RefSeq Genes are all in the 20-45k range, when NCBI reports most Drosophila species as having 13-15k protein-coding genes. The authors need to check the data for all annotation programs provided in figure 1 and correct the figure.\n\nIn table 1, the authors list “UCSC Assembly” with names that largely aren’t shown in UCSC and don’t correspond to the published assembly names. For example, the D. miranda assembly GCA_000269505.2 is named DroMir_2.2. Where did the name DmirGB2 come from? The authors should clarify the meaning of the first column, and add an additional column with the official name for each assembly since it’s difficult to recognize assembly accessions.\n\nMany of the assemblies being used by the GEP project have been superseded by newer and higher quality assemblies. Do the authors periodically upgrade to new assemblies, or is this viewed as unnecessary effort for the educational goals of the project?\n\nTo support the statement “As of August 2022, GEP students from 79 institutions have used this annotation protocol to construct 2,101 gene models across 27 Drosophila species.”, it would be useful to provide a supplemental table with the list of gene models curated for this project so far. Additional data on conformance of student models to the final consolidated annotations would also be of interest if readily available.\n\nIn order to aid access to the final gene models, in addition to the TPA submissions the authors could construct a genome browser track available through the remote Track Hub system. This could be updated periodically (e.g. at the end of each semester or year) with additional gene models, and made available through the Track Hub Registry system. While it would be useful to include the availability of this track in the paper if the authors have the resources to generate it, it’s not a requirement for publication.\n\nFigure 5: It seems that the isoform names are reversed in the legend. Looking at the ‘User-created Annotations’ track, Akt-PC is the isoform with the longer coding region and not Akt-PE as stated in the legend.\n\nAssembly errors: For cases where the student identifiers an error in a target assembly, how is that information conveyed in the TPA records? Is the TPA sequence corrected via a VCF file? What is done with a case like D. pseudoobscura chico from Figure 11?\n\nFor the reconciliation process, how would you determine that an isoform is ‘mislabeled’? Is it in comparison to D. melanogaster isoform name? In general, what are the rules to name isoforms in target species?\n\n“The annotation effort of the student annotators is of value because the students can outperform computational gene predictors.” - This statement seems a bit misleading unless there is a mention of scale. Computational annotation methods can predict gene and transcript models on a genomic scale, which is not possible by manual annotators (in a reasonable timeframe). It would be reasonable to say that manual annotators can correct errors found in computational predictions and can fill in gaps, as in the example cited in the paper where computational methods could not detect an additional protein isoform due to the use of an upstream non-AUG start codon. If the authors wish to keep the statement, a suggestion is to add something that conveys “at the level of an individual gene or a small set of genes” at the end. It would also be helpful to add some statistics on how often students identify errors or additions to automated gene sets.\n\nThe report is primarily focused on describing aspects of the annotation protocol. However, the key aspect of this work is its use as an educational tool to engage students. It would be helpful to add some data or at least anecdotal statements to the discussion about the success of the educational goals. For example, do instructors joining the project tend to stay with it in successive years? Is there survey or other data from the students or TAs about whether it’s a valuable aid? Adding some text to the discussion, or results if available, would help other instructors decide if this would be a valuable addition to their curricula.\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Yes\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "9819",
"date": "31 Jul 2023",
"name": "Chinmay Rele",
"role": "Author Response",
"response": "Thank you for your time and detailed descriptions of the ways you think our methods article could be better improved. We have made most of the changes that you have suggested, and have detailed them below. *While this is a ‘Methods” paper, the authors should perhaps provide some context in the Introduction about what GEP is and what its broader goals are (citing the latest publication on GEP) for the benefit of the naïve reader before diving into the details of the manual annotation protocol.*You suggested to add some context about what the GEP is, and what its broader goals of the GEP are. This suggestion is very helpful, and more information about the GEP, its mission statement, and larger scientific publications has been added after the third paragraph of the Introduction. In figure 1, the Y-axis is labeled as “number of predicted protein-coding genes”, but the legend includes the following statement that implies it’s actually number of isoforms: “Prediction differences can partly be attributed to some algorithms predicting a single isoform in a genomic region (e.g., GeneID), while others predict multiple isoforms per genomic region (e.g., genBlastG, Spaln).” Furthermore, the values for NCBI RefSeq Genes are all in the 20-45k range, when NCBI reports most Drosophila species as having 13-15k protein-coding genes. The authors need to check the data for all annotation programs provided in figure 1 and correct the figure. We have made clear that some predictors predict single transcripts or multiple transcripts per genomic region while providing examples of such predictors in the caption of Figure 1. In table 1, the authors list “UCSC Assembly” with names that largely aren’t shown in UCSC and don’t correspond to the published assembly names. For example, the D. miranda assembly GCA_000269505.2 is named DroMir_2.2. Where did the name DmirGB2 come from? The authors should clarify the meaning of the first column, and add an additional column with the official name for each assembly since it’s difficult to recognize assembly accessions. Thank you for this suggestion and we apologize for the confusion. We have added the canonical assembly names from NCBI under the “Assembly Name” column, and the new assembly name within the GEP framework has been clarified in the caption of this table. Many of the assemblies being used by the GEP project have been superseded by newer and higher quality assemblies. Do the authors periodically upgrade to new assemblies, or is this viewed as unnecessary effort for the educational goals of the project? We do intend to use newer assemblies as they become available. Our rate of adoption is delayed by the need to synchronize all curricular materials with updated genome assemblies, but we do this as we are able. We have added this at the end of the third paragraph of Introduction. To support the statement “As of August 2022, GEP students from 79 institutions have used this annotation protocol to construct 2,101 gene models across 27 Drosophila species.”, it would be useful to provide a supplemental table with the list of gene models curated for this project so far. Additional data on conformance of student models to the final consolidated annotations would also be of interest if readily available. We have updated the date, the number of models, and the number of Drosophila species. We have also included a heatmap showing the number of models submitted for each species/gene combination as a supplemental file. The outcome of student gene model conformance to the final model is provided in Figure 12, note that many of the models listed in supplement 7 have not yet been reconciled. In order to aid access to the final gene models, in addition to the TPA submissions the authors could construct a genome browser track available through the remote Track Hub system. This could be updated periodically (e.g. at the end of each semester or year) with additional gene models, and made available through the Track Hub Registry system. While it would be useful to include the availability of this track in the paper if the authors have the resources to generate it, it’s not a requirement for publication. Thank you for this suggestion. We have created a supplemental file (Supplement 8) with all the TrackHub links that have been generated as of March 24, 2023. We will be creating a TrackHub registry. We have added the reference to the supplemental file at the end of ”Reconciliation Process” at the end of the Methods section. Figure 5: It seems that the isoform names are reversed in the legend. Looking at the ‘User-created Annotations’ track, Akt-PC is the isoform with the longer coding region and not Akt-PE as stated in the legend. Thank you for pointing this error out – it has been corrected to mention that the PC isoform is the isoform with the longer coding region. Assembly errors: For cases where the student identifiers an error in a target assembly, how is that information conveyed in the TPA records? Is the TPA sequence corrected via a VCF file? What is done with a case like D. pseudoobscura chico from Figure 11? Assembly errors are documented using a VCF file, which is then submitted to NCBI along with the TPA record for the specific model. This has been added to the end of ”Assembly Errors” in the ”Exceptions to the standard annotation workflow” section. If the model is in two scaffolds in our assemblies, we opt to complete the reconciliation in a newer (for this instance, we would choose to reconcile the model in the DpseRefSeq1 (GCF_009870125.1)) assembly because our internal tools cannot adequately validate models that are present in two scaffolds. For the reconciliation process, how would you determine that an isoform is ‘mislabeled’? Is it in comparison to D. melanogaster isoform name? In general, what are the rules to name isoforms in target species? Good question. An explanation of how an isoform is defined/named has been added as a new section called Missing/Mislabeled Isoforms at the end of the Most Common Annotation Errors section. (a)“The annotation effort of the student annotators is of value because the students can outperform computational gene predictors.” - This statement seems a bit misleading unless there is a mention of scale. Computational annotation methods can predict gene and transcript models on a genomic scale, which is not possible by manual annotators (in a reasonable timeframe). It would be reasonable to say that manual annotators can correct errors found in computational predictions and can fill in gaps, as in the example cited in the paper where computational methods could not detect an additional protein isoform due to the use of an upstream non-AUG start codon. If the authors wish to keep the statement, a suggestion is to add something that conveys “at the level of an individual gene or a small set of genes” at the end. Thank you for pointing out this important distinction and lack of elaboration. We have now added the “individual gene level” qualifier to this at the end of the requested sentence. We have also pointed out the computational gene prediction algorithms are very valuable at the genome scale. (b) It would also be helpful to add some statistics on how often students identify errors or additions to automated gene sets. This is an interesting question, and we hope to report on it in a future study, once we have enough data to be statistically robust. The report is primarily focused on describing aspects of the annotation protocol. However, the key aspect of this work is its use as an educational tool to engage students. It would be helpful to add some data or at least anecdotal statements to the discussion about the success of the educational goals. For example, do instructors joining the project tend to stay with it in successive years? Is there survey or other data from the students or TAs about whether it’s a valuable aid? Adding some text to the discussion, or results if available, would help other instructors decide if this would be a valuable addition to their curricula.**** Studies on student learning outcomes showing the benefits to students have been performed by the GEP in separate publications, and a brief description of these findings have been added as the last paragraph of Discussion. Thank you again for all your input to help us make this manuscript more complete and robust."
}
]
},
{
"id": "162520",
"date": "16 Feb 2023",
"name": "Madeline Crosby",
"expertise": [
"Reviewer Expertise Relevant area of expertise: gene model annotation in Drosophila melanogaster."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper is a detailed description of a protocol used for undergraduate-based annotation of gene models in various Drosophila species. Undergraduate students benefit from a hands-on experience using computational tools and real genomic data. As primarily a methods paper, it appears to be admirably thorough.\n\nTwo minor errors that need to be corrected:\nFigure 5 legend confuses Akt-PC and Akt-PE. Link for reference 40 goes to a retracted paper.\nAdditional comments, questions, and suggestions:\nThe initial project-claiming step includes an estimated difficulty level; this is potentially very useful, but the current assessment appears to be based on the overly simplistic criteria of the number of isoforms, number of coding exons, and evolutionary distance from the reference genome. If this difficulty assessment could be expanded to include atypical phenomena such as non-canonical splicing and non-canonical start codons, it would be much more useful.\nTime permitting, it would be beneficial for a student to receive two genes to annotate: one simple case and a second more complicated case.\nWere students asked to complete the gene model for the described case of an incomplete genome assembly (split scaffold, Figure 11)? I should think these would fall in the very difficult category and should be screened out.\nNo ortholog identified by tBLASTn: Can you give an example of successful annotation of a model that was located based on synteny and pieced together from ‘additional features’ in the syntenic region?\n\n“Correct” naming of protein isoforms is mentioned. The policy appears to be that an isoform should be named with the same suffix as the analogous isoform for the orthologous D. melanogaster gene. This is perhaps helpful, but it is not strictly necessary.\nResults using a group of 310 students who submitted gene models are very briefly described (Figure 12); it would be informative if this assessment were expanded. For example:\nHow effective was the strategy to have two independent students annotate a given gene? (Was an incorrect submission usually accompanied by a correct submission?) What percentage of incorrect submissions were in the more difficult category? What percentage of incorrect submissions involved atypical phenomena?\nWhat percentage of students were unable to create a gene model on their own (initially)? What type of assistance was provided to these students?\nHas feedback from students precipitated any changes?\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Yes\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Partly",
"responses": [
{
"c_id": "9820",
"date": "31 Jul 2023",
"name": "Chinmay Rele",
"role": "Author Response",
"response": "Thank you for your time and detailed descriptions of the ways you think our methods article could be better improved. We have made most of the changes that you have suggested, and have detailed them below. Two minor errors that need to be corrected: Figure 5 legend confuses Akt-PC and Akt-PE. Link for reference 40 goes to a retracted paper. The two minor corrections that have been suggested have been corrected. We have made these corrections pertaining to the Figure 5 legend confusing Akt-PC and Akt-PE , and also updated reference 40 to the correct final publication (note the initial retraction and republication was for a technical issue in the publication process, not a scientific issue) . The initial project-claiming step includes an estimated difficulty level; this is potentially very useful, but the current assessment appears to be based on the overly simplistic criteria of the number of isoforms, number of coding exons, and evolutionary distance from the reference genome. If this difficulty assessment could be expanded to include atypical phenomena such as non-canonical splicing and non-canonical start codons, it would be much more useful. This is a very good suggestion, and we will definitely consider incorporating this kind of information in our claim pipeline in the future. The primary intent for including the difficult score is for faculty to gauge the approximate challenge of the gene to determine if it might be appropriate to their class, and is not a piece of information intended to be shared with the student. For this purpose, we have found that the current definition of the difficulty (including the number of polypeptides, isoforms, and species divergence) seems to be adequate. From the student perspective, the labor required to complete their project generally scales with the number of unique polypeptides and exons. . Time permitting, it would be beneficial for a student to receive two genes to annotate: one simple case and a second more complicated case. It would definitely be beneficial to have students annotate (at least) two genes, one simple, and the second more complicated. We recommend to our faculty that they do this if possible, but, this decision ultimately lies with the faculty member who is implementing GEP curriculum within their course, and their pedagogical goals. Further, faculty are welcome to perform their own screening on the various potential projects before claiming them, to determine whether they feel a model is at the right scale for their students. Were students asked to complete the gene model for the described case of an incomplete genome assembly (split scaffold, Figure 11)? I should think these would fall in the very difficult category and should be screened out. Instances where the assembly is idiosyncratic are prime examples where manual annotation of models by students is beneficial. Cases this extreme are rare. However, these kinds of cases are what make students most excited and proud of their work when they solve them. We do not recommend that a student’s first project be this difficult but once they understand the basics, many students are able to tackle these more complex scenarios. We also provide support to the faculty and students through virtual office hours and a Slack team with the project leaders for the faculty, virtual TAs for the students. We describe and analyze the effectiveness of our pedagogical approaches in other manuscripts either published and or in preparation. We have added some of those citations to the manuscript discussion. No ortholog identified by tBLASTn: Can you give an example of successful annotation of a model that was located based on synteny and pieced together from ‘additional features’ in the syntenic region? Thank you for pointing out that we did not include an example. We apologize for this oversight. We have added an explanation of how to resolve an error like this by citing Ilp3 in D. grimshawi. We have also added a figure to show this “Correct” naming of protein isoforms is mentioned. The policy appears to be that an isoform should be named with the same suffix as the analogous isoform for the orthologous D. melanogaster gene. This is perhaps helpful, but it is not strictly necessary. Correct naming of protein isoforms is mentioned in order to maintain consistency across the entire project. Though this is not explicitly necessary, it is beneficial to assess and predict putative function of each transcript in the target species. Results using a group of 310 students who submitted gene models are very briefly described (Figure 12); it would be informative if this assessment were expanded. For example: How effective was the strategy to have two independent students annotate a given gene? (Was an incorrect submission usually accompanied by a correct submission?) What percentage of incorrect submissions were in the more difficult category? What percentage of incorrect submissions involved atypical phenomena? In general, we do see more errors in models classified as being more difficult, but understanding a more discrete error profile is out of the scope of this paper. The primary goal of this manuscript is to provide the description of the standard protocol used by the student annotators part of the GEP to annotate a gene within the target species. Once more data is available, we can make a more detailed assessment of the quality of student models relative to the nature of the gene characteristics. What percentage of students were unable to create a gene model on their own (initially)? What type of assistance was provided to these students? We really cannot quantify what percentage of students were unable to create their own model initially for a variety of technical and semantic reasons, primarily since the reconciliation process only sees the summative product of the student work, not the formative steps the students experienced. We do know however that the formative frustration of the challenges of generating a model, followed by ultimate success is essential for driving the positive impact of the research experience (Lopatto et al., 2020; PMID: 32148609). The GEP provides a variety of support for students and their faculty mentors including extensive curriculum resources, video tutorials, virtual teaching assistants, and virtual office hours with project leaders. Has feedback from students precipitated any changes? Student feedback is constantly considered as the curriculum and project protocols evolves to keep pace with changes in genomic data resources, with semi-annual updates. Student comments, especially in the pilot stages for new curriculum, are actively solicited by the project leaders. Further, the faculty and virtual TAs observations of how students may struggle with new concepts, inspire new or improved educational resources. Thank you again for all your input to help us make this manuscript more complete and robust."
}
]
}
] | 1
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https://f1000research.com/articles/11-1579
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https://f1000research.com/articles/11-598/v1
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01 Jun 22
|
{
"type": "Systematic Review",
"title": "Effectiveness of balance training on pain and functional outcomes in knee osteoarthritis: A systematic review and meta-analysis",
"authors": [
"Ashish John Prabhakar",
"Shruthi R",
"Dias Tina Thomas",
"Pradeepa Nayak",
"Abraham M. Joshua",
"Srikanth Prabhu",
"Yogeesh Dattakumar Kamat",
"Ashish John Prabhakar",
"Shruthi R",
"Pradeepa Nayak",
"Abraham M. Joshua",
"Srikanth Prabhu",
"Yogeesh Dattakumar Kamat"
],
"abstract": "Background: Knee osteoarthritis (OA) is a musculoskeletal disorder that causes pain and increasing loss of function, resulting in reduced proprioceptive accuracy and balance. Therefore, the goal of this systematic review and meta-analysis is to evaluate the effectiveness of balance training on pain and functional outcomes in knee OA. Methods: “PubMed”, “Scopus”, “Web of Science”, “Cochrane”, and “Physiotherapy Evidence Database” were searched for studies conducted between January 2000 and December 2021. Randomized controlled trials (RCTs) that investigated the effectiveness of balance training in knee OA, as well as its effects on pain and functional outcome measures, were included. Conference abstracts, case reports, observational studies, and clinical commentaries were not included. Meta-analysis was conducted for the common outcomes, i.e., Visual Analog Scale (VAS), The Timed Up and Go (TUG), Western Ontario and McMaster Universities Arthritis Index (WOMAC). The PEDro scale was used to determine the quality of the included studies. Results: This review includes 22 RCTs of which 17 articles were included for meta-analysis. The included articles had 1456 participants. The meta-analysis showed improvement in the VAS scores in the experimental group compared to the control group [I2 = 92%; mean difference= -0.79; 95% CI= -1.59 to 0.01; p<0.05] and for the WOMAC scores the heterogeneity (I2) was 81% with a mean difference of -0.02 [95% CI= -0.44 to 0.40; p<0.0001]. The TUG score was analyzed, the I2 was 95% with a mean difference of -1.71 [95% CI= -3.09 to -0.33; p<0.0001] for the intervention against the control group. Conclusions: Balance training significantly reduced knee pain and improved functional outcomes measured with TUG. However, there was no difference observed in WOMAC. Although due to the heterogeneity of the included articles the treatment impact may be overestimated. Registration: The current systematic review was registered in PROSPERO on 7th October 2021 (registration number CRD42021276674).",
"keywords": [
"knee osteoarthritis",
"balance assessment",
"proprioception",
"exercise therapy",
"visual reality"
],
"content": "Introduction\n\nKnee osteoarthritis (OA) is a common disease in older adults that causes chronic disability.1 With age the occurrence of knee OA increases, with rates of approximately 13% among women and 10% among men aged 60 years and above. Pathology is associated with changes in cartilage, bones, surrounding soft tissues, and muscles. Patients with knee OA gradually lose function, indicating an increased reliance while climbing stairs and walking, and demonstrate an increased dependency in functional tasks.2 Balance forms a fundamental component of many of these activities.3 Balance is a complex function of multiple neuromuscular systems, which includes sensory, motor and integrative components. In older adults, impaired balance is linked to the risks of falls and diminished mobility.\n\nFalls have been shown to be more frequent during activities that require relocation of the body’s center of mass (COM), such as ascending and descending stairs and walking.4,5 According to existing data, older adults with bilateral or unilateral knee OA exhibit lower postural stability. Understanding the influence of knee OA on balance may aid in the identification of potential impairment pathways in these individuals, permitting for a more comprehensive disease management.3\n\nThe functional knee joint is subjected to continual strain. Though the active muscle contraction and bone geometry offer stability to the knee joint during normal daily activities and the mechanoreceptors help to maintain stability by providing sensory feedback that facilitates antagonist-agonist muscle activity,6 alterations in joint kinematics as a result of disease processes can have a direct impact on balance control and gait parameters. Proprioceptive insufficiency can be caused by pain, inflammation or mechanical stress. This impairment has been linked to aberrant pressure buildup in the surrounding tissues, which prevents the influx of sensorimotor information regarding joint position sense (JPS) and movements.7 Such inadequacies affect the dynamic stability provided by the muscles surrounding the joint, likely to result in functional instability.8\n\nConservative treatment is recommended to relieve symptoms and enhance functional activity performance, and may prevent muscle weakness and thereby halt disease progression.8 As per the existing literature, many types of exercises have been undertaken to improve proprioception and balance in knee osteoarthritis. Walking, retro walking, kinesthetic balancing, closed kinetic chain and aerobic dance, have all been shown to improve proprioception and balance function. The majority of past research involved individuals with mild to intermediate stages of knee OA, while some patients with advanced stages were also involved. Despite the presence of literature on the effectiveness of the various forms of exercises in individuals with knee OA, no systematic review, to the best of our knowledge, describes the effectiveness of various balance exercise strategies. Therefore, the purpose of this systematic review is to examine and identify the available information on the impact of various balance training strategies on pain and functional outcomes in people with knee OA.\n\n\nMethods\n\nThe current systematic review was registered in PROSPERO with the registration number CRD42021276674. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria were followed throughout the review procedure. The key search words and completed PRISMA checklist can be found as Extended data.43\n\nInclusion criteria\n\n1) Randomized controlled trials (RCTs) comparing balance exercises to conventional exercises or no therapy and examining functional results in participants with knee OA were examined.\n\n2) Participants in the chosen studies could be either male or female, of any age or severity level.\n\n3) Articles with a PEDro score9 of five or above were considered.\n\nExclusion criteria\n\n1) Conference abstracts, case reports, observational studies, and clinical commentaries were not included.\n\n2) Systemic arthritic illnesses, tibial osteotomy, hip or knee joint replacement, and any other muscle or neurological ailment that may affect the lower extremity and impair balance were excluded.\n\n“PubMed” (PubMed, RRID:SCR_004846), “Scopus”, “Web of Science”, “Cochrane” (Cochrane Library, RRID:SCR_013000) and “PEDro” were searched in January 2022 for relevant articles that established the efficacy of various methods of balance training for participants with knee OA. The studies featured were written in English. Two independent investigators conducted the search, which included a combination of two primary keywords: “Knee OA” (population) AND “Balance.” The Boolean operators “AND” and “OR” were used to combine the two terms. The search techniques were adjusted based on the databases. The publication dates were not confined, and the review included works published between January 2000 and December 2021.\n\nConference abstracts, case reports, observational studies, and clinical commentaries were not included. Systemic arthritic illnesses, tibial osteotomy, hip or knee joint replacement, and any other muscle or neurological ailment that may affect the lower extremity and impair balance were excluded. RCTs comparing balance exercises to conventional exercises or no therapy and examining functional results in participants with knee OA were examined. Participants in the chosen studies could be either male or female, of any age or severity level. Articles with a PEDro score9 of five or above were considered. Two independent reviewers screened the articles to check if they met the inclusion criteria, conflicts between the reviewers was resolved by an intervening third reviewer.\n\nThe included articles were RCTs, therefore the risk of bias was done using the PEDro score. The PEDro scoring system consists of a checklist of 10 scored yes-or-no questions pertaining to the internal validity and the statistical information provided. PEDro scores of 0-3 were considered ‘poor’, 4-5 ‘fair’, 6-8 ‘good’, and 9-10 ‘excellent’.\n\nStandard mean difference was used as an effect measure for comparison between balance treatment and routine rehabilitation.\n\nThe search was conducted by two independent reviewers (DT, SR) on various databases, following which all the identified studies were imported into online software Rayyan QCRI (Rayyan QCRI, RRID:SCR_017584). The titles and abstracts were also screened by two reviewers. For any ambiguities in the studies, consensus was obtained by discussing with the third reviewer (AP). The eligibility assessment under the inclusion-exclusion criteria was carried out by reviewing full-text articles.\n\nThe first reviewer obtained data from the included articles, which was then substantiated by a second reviewer and were entered into a standard form developed for the review. Information about the authors, journal, year of publication, characteristics of the subjects (age, inclusion criteria, gender, sample size), method (i.e., design, subjects, intervention, measures), outcome assessed, details of the interventions (parameters, frequency, intensity, type, time) and comparison groups were extracted from the included articles. Quantitative analysis, for the homogenous outcomes, i.e., VAS, TUG and WOMAC, was done. The pooled estimates of effect size were calculated using the effects model. These pooled estimations will subsequently be depicted in forest plots.\n\nThe first two reviewers independently completed a procedural quality assessment of the studies based on the PEDro scale, and papers with a PEDro score of less than five were eliminated. The fourth reviewer resolved any doubts about the study’s quality (SP). Each question on the PEDro scale evaluates the statistical significance and internal validity of the trials. Studies having a score of greater than five out of 10 (Table 1) were determined to have high procedural quality, and the study included 22 articles.\n\n\nResults\n\nSearch results: We identified 22 studies for the systematic review and 17 studies for the meta-analysis out of 835 identified through the database screening. The results of the search and selection process are presented in the PRISMA flow diagram (Figure 1). The included articles were published between January 2000 and December 2021.\n\nPRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCT, Randomized controlled trial.\n\nStudy designs: All the included articles were RCTs.\n\nParticipants: A total of 1456 people were involved in the included studies. The participants ranged in age from 30 to 65 years. The study encompassed all Kellgren Lawrence severity levels of knee OA.10\n\nIntervention: The intervention group in eight of the 22 trials received isolated balance training programs with no other form of exercise. Whereas 14 out of the 22 studies provided balance training along with some other form of exercises. Two trials provided agility training to the experimental group,11,12 whereas the experimental group in the other two studies received Wu Qin xi Qigong and Wuqinxi exercise programs.13,14 Two trials used virtual reality and virtual feedback to give balance training,15–17 while the third employed Kinesio tapping to improve stability in subjects with knee OA.18 In one study, body weight (BW) training was paired with needle knife therapy as a treatment modality.19\n\nControl intervention: The participants in the control groups received routine rehabilitation and strengthening exercises.\n\nOutcomes: The included studies analyzed the following outcomes: VAS,11,15,17,20–24 WOMAC, TUG, self-reported knee joint instability, Berg Balance Scale (BBS), Lequesne index, knee joint proprioception, Tinetti’s Performance Oriented Mobility Assessment (POMA) scale and static postural stability. Eight of the included studies analyzed pain using the VAS,11,15,17,20–24 and 12 studies analyzed the function using WOMAC score.11–13,15,17,19,20,25–30 TUG score was analyzed by six studies.11,14,17,20,31–33\n\nStudy characteristics: The size of the samples ranged from 30 to 190 subjects. All the subjects included in the trial were analyzed based on the American College of Rheumatology criteria.34 All the studies used the Kellgren Lawrence score for radiological grading.\n\nThe effects of interventions are explained in Table 2.\n\nEffect of intervention for multiple groups: Rogers et al.,29 conducted a study to compare the efficacy of home-based kinesthesia, balance and agility exercises to resistance exercise, a combination of kinesthesia and resistance exercises, and no exercise. WOMAC pain and physical function significantly improved for all four groups after eight weeks of intervention, with no group differences, although the exercise groups improved more between the midpoint and the eight weeks follow-up, the control group did not. A study conducted by Lin et al.,16 conducted a study with 89 individuals in which they examined proprioceptive function between computerized proprioception facilitation exercise (CPFE) and closed kinetic chain exercise (CKCE) in subjects with knee OA. After an eight-week exercise intervention, both the CPFE and CKCE groups demonstrated a reduction in knee position error and WOMAC functional scores, as well as increased walking speeds (p = 0.016) on four distinct terrains.\n\nRahlf et al.,30 studied the effects of Kinesio taping (KT) on pain and function in patients with knee OA. The WOMAC subscales of pain showed significant differences. However, the effects of KT were more noticeable. Post hoc analysis revealed significant WOMAC differences between the tape and control groups (pain: p = 0.047, function: p = 0.004), the tape and sham groups (pain: p = 0.05, function: p = 0.03), and no difference between the sham and control groups. Trans et al.,26 studied the effects of whole-body vibration training on proprioception in patients with knee OA. The balance board with built-in vibration (VibF) group improved significantly in the threshold for detection of passive movement (TDPM) when compared to the control group, with a mean difference of -0.59 seconds (95% CI, 1.13 to 0.05; p = 0.0326). When compared to the control group, the balance board with stable vibration platform (VibM) group improved by 0.52 seconds (95% CI, 1.04 to 0.00; p = 0.0511). There was no discernible difference between the VibM and VibF groups in the above study.\n\nAnother study, conducted by Braghin et al.,25 analyzed the effect of exercise on balance and function in people with knee OA. Two of the three groups did physical exercises for 50-60 minutes every day for around eight weeks. The intragroup analysis of the WOMAC questionnaire revealed no differences between the asymptomatic and control groups, whereas the symptomatic group had significantly lower pain and functional outcome scores.\n\nJan et al.,33 conducted a study to assess the effects of weight-bearing (WB) and non-weight bearing (NWB) exercise on walking speed, position sensing, and function in people with knee OA. The WOMAC function and walking times on four different terrains improved significantly in the WB group (p = 0.08), but not in the control group. When compared to the control group, both intervention groups improved in WOMAC function (p = 0.08). However, there was no difference between the NWB and WB groups. When compared to the NWB and control groups, the WB group improved more in walking speed on the spongy surface, figure of eight, and positioning error (p = 0.08). The subjects in the NWB exercise group improved their walking speed up and down the stairs. There was no difference in walking speed on level ground between groups, nor was there a difference in walking speed on a figure of eight or a spongy surface, nor was there a difference in reposition error between NWB and the control group.\n\nMeta-analysis was considered for 17 of the included studies, due to heterogeneity in the outcomes. The meta-analysis was done for the common outcomes of VAS, TUG and WOMAC.\n\nMeta-analysis was conducted for 15 of the 22 included studies. The common outcomes analyzed were VAS scores, WOMAC score and the TUG score.\n\nFor pain, (Figure 2) eight studies were analyzed for the VAS scores, pre-and post-intervention. Heterogeneity [I2] was 92% (p < 0.05). The mean difference was -0.79 with (95% CI, -1.59 to 0.01) for the intervention versus the control group (Table 3).\n\nVAS, Visual Analog Scale.\n\nVAS, Visual Analog Scale.\n\nFor functional outcome, seven studies were analyzed using the WOMAC (Figure 3) scores the heterogeneity [I2] was 81% (p < 0.0001). The mean difference was -0.02 (95% CI, -0.44 to 0.40) for the intervention against the control group (Table 4).\n\nWOMAC, Western Ontario and McMaster Universities Arthritis Index.\n\nWOMAC, Western Ontario and McMaster Universities Arthritis Index.\n\nAnother functional parameter was analyzed using the TUG (Figure 4) score. Five studies were analyzed and the heterogeneity [I2] was 95% (p < 0.0001). The mean difference was -1.71 (95% CI, -3.09 to -0.33) for the intervention against the control group (Table 5).\n\nTUG, The Timed Up and Go.\n\nTUG, The Timed Up and Go.\n\nAccording to the findings of the included studies and their meta-analysis, balance-based exercises help to reduce pain and improve functional outcomes in people with balance alteration following knee OA. The above values are displayed in a small confidence interval range, indicating the analyses’ validity and sensitivity, as well as the significant influence. Furthermore, the random-effects model used provided accurate results by using sample size and standard error. The meta-analysis likewise comes up with a positive conclusion balance-based exercise. Even though the key outcome measures of VAS, WOMAC and TUG scores were homogeneous, the analyzed studies differed in the mode and duration of intervention and hence a meta-analysis was conducted using the random-effects model.\n\nThe studies in included our review were of moderate to good methodological quality, however, risk of bias was noted in terms, of blinding of subjects, therapist and assessors. A detailed description of the same is given in Table 1.\n\nCertainty of evidence is low to moderate due to the quality of the included studies and higher heterogeneity.\n\n\nDiscussion\n\nOur systematic analysis included 22 trials that assessed the effectiveness of balance exercises on functional outcomes and pain in people with knee OA. We were only able to include 13 publications in the meta-analysis due to the variety of the therapies and outcomes investigated. Several therapies, including strength training, Wu Qin xi Qigong (WQXQ), Wuqinix, visual reality feedback exercises, and agility training, dramatically improved balance, reduced discomfort, and improved functional outcomes in people with knee OA. Functional outcomes examined using sit to stand and balance measured using the BBS did not show statistically significant improvement in the experimental group among the trials included in the review. Functional results based on gait speed, on the other hand, TUG,11,14,17,20,31,32 WOMAC,11–14,17,20,27,31 VAS,11,12,15,17–21,23,24,35 and six minute walk test (6MWT).14,23 The experimental group outperformed the control group significantly.\n\nThe meta-analysis comprised 13 articles that employed VAS, WOMAC, and TUG as outcome measures. When compared to regular routine rehabilitation exercises, VAS and TUG outcomes for subjects assigned to the investigational group showed superior results, indicating that rehabilitation strategies improved knee joint proprioception and balance, indicating efficacy for the intervention, whereas WOMAC showed no significant difference between the experimental and control group.\n\nPrevious studies have demonstrated that pain can produce inflammatory chemicals that can sensitize a significant number of nerve terminals. Afferent nerve impulses from small-diameter groups three and four (pain) and large-diameter group two (proprioceptive) may fire abnormally, resulting in aberrant JPS and muscle spindle activity.36,37 It was theorized that implementing pain-relieving exercise therapies in such situations may improve JPS and thereby enhance balance by reducing stiffness, increasing joint lubrication and enhancing muscle strength.38 The aforementioned mechanism may explain the meta-analysis difference in VAS between experimental and control groups.\n\nAgility and perturbation training exercises were utilized as the mode of intervention in studies by Fitzgerald et al.,12 and Rogers et al.29 The reasoning for integrating agility and perturbation programs was to expose the participants to demanding movements such as quick changes in direction, and short stop and starts to improve actions during routine activity. The aforementioned strategies may be beneficial for younger and athletic people.12 In older adults with knee OA, the requirements of agility and daily challenges to balance may be less frequent when compared to younger athletes and therefore, inclusion of agility and perturbation techniques into exercise regimens may have no beneficial effect in enhancing knee stability and general function among older individuals. Among all the studies, the study conducted by Fitzgerald et al.,12 had the largest sample size compared to the rest, and excluded participants based on the risk for fall and need for assistive devices for ambulation.12\n\nCho et al.,18 conducted a study that included taping as an intervention and determined that taping improved balance and anticipated that the elastic property of the tape and its application under tension leads to mobilization of the skin during movements and increases blood and lymph circulation. The aforementioned process is believed to have a direct impact on pain perception.39,40\n\nAs the current systematic review includes data from studies with varied sample sizes, the treatment impact could be overestimated. Additionally, comparing outcome measures was difficult due to the diversity of the assessment procedures utilized between studies. A thorough literature search conducted to expand empirical understanding yielded various areas of recommendation. To begin, a larger, suitably powered RCT should be done to offer critical data on the type and dosage of exercises needed. Second, we advocate conducting another systematic review to look into other factors that influence balance, such as OA symptoms (functional limitation, pain, stiffness), quality-of-life domains, and other functional measures.\n\n\nConclusions\n\nOur review’s findings are persuasive that a basic balance training program may improve physical function, reduce pain, and increase physical activity levels in individuals with knee OA. Although proprioceptive and balance exercises reduced pain and TUG considerably, there was no noticeable difference in WOMAC ratings among individuals. Further research into various therapy techniques in a bigger population is required.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nOpen Science Framework: Effectiveness of balance training on pain and functional outcomes in knee osteoarthritis - a systematic review and meta-analysis. https://doi.org/10.17605/OSF.IO/4H7TQ.43\n\nThis project contains the following extended data:\n\n- DATA EX TABLE.docx (Effects of intervention of the included studies)\n\n- Key Word F1000.docx (Key search terms)\n\n- Protocol OSF F1000 (1).docx\n\n- TITLE PAGE.docx\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nOpen Science Framework: PRISMA checklist for ‘Effectiveness of balance training on pain and functional outcomes in knee osteoarthritis: A systematic review and meta-analysis’. https://doi.org/10.17605/OSF.IO/4H7TQ.43\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "References\n\nHeidari B: Knee osteoarthritis prevalence, risk factors, pathogenesis and features: Part I. Casp. J. Intern. Med. 2011; 2(2): 205. Accessed December 31, 2021. Free Full Text\n\nMcDonough CM, Jette AM: The contribution of osteoarthritis to functional limitations and disability. Clin. Geriatr. Med. 2010; 26(3): 387–399. PubMed Abstract | Publisher Full Text\n\nGuccione AA, Felson DT, Anderson JJ, et al.: The effects of specific medical conditions on the functional limitations of elders in the Framingham study. Am. J. Public Health 1994; 84(3): 351–358. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLee PA, Wu KH, Lu HY, et al.: Compromised balance control in older people with bilateral medial knee osteoarthritis during level walking. Sci. Reports 2021; 11(1): 3742–3748. PubMed Abstract | Publisher Full Text\n\nChuang SH, Huang MH, Chen TW, et al.: Effect of Knee Sleeve on Static and Dynamic Balance in Patients with Knee Osteoarthritis. Elsevier (Singapore) Pte Ltd; 2007; vol. 23. . Publisher Full Text\n\nJohansson H: Role of knee ligaments in proprioception and regulation of muscle stiffness. J. Electromyogr. Kinesiol. 1991; 1(3): 158–179. PubMed Abstract | Publisher Full Text\n\nJohn Prabhakar A, Joshua AM, Prabhu S, et al.: Effectiveness of proprioceptive training versus conventional exercises on postural sway in patients with early knee osteoarthritis – A randomized controlled trial protocol. Int. J. Surg. Protoc. 2020; 24: 6–11. PubMed Abstract | Publisher Full Text\n\nAndressa Silva PRMSS: The effects of therapeutic exercise on the balance of women with knee osteoarthritis: a systematic review. Accessed January 1, 2022. Publisher Full Text\n\nCashin AG, McAuley JH: Clinimetrics: Physiotherapy Evidence Database (PEDro) Scale. J. Physiother. 2020; 66(1): 59. Publisher Full Text\n\nKohn MD, Sassoon AA, Fernando ND: Classifications in Brief: Kellgren-Lawrence Classification of Osteoarthritis. Clin. Orthop. Relat. Res. 2016; 474(8): 1886–1893. PubMed Abstract | Publisher Full Text\n\nGomiero AB, Kayo A, Abraão M, et al.: Sensory-motor training versus resistance training among patients with knee osteoarthritis: randomized single-blind controlled trial. Sao Paulo Med. J. 2017; 136(1): 44–50. PubMed Abstract | Publisher Full Text\n\nFitzgerald GK, Childs JD, Ridge TM, et al.: Agility and perturbation training for a physically active individual with knee osteoarthritis. Phys. Ther. 2002; 82(4): 372–382. PubMed Abstract | Publisher Full Text\n\nXiao Z, Li G: The effect of Wuqinxi exercises on the balance function and subjective quality of life in elderly, female knee osteoarthritis patients. Am. J. Transl. Res. 2021; 13(6): 6710–6716. PubMed Abstract\n\nXiao C, Zhuang Y, Kang Y: Effects of Wu Qin xi Qigong exercise on physical functioning in elderly people with knee osteoarthritis: A randomized controlled trial. Geriatr. Gerontol. Int. 2020; 20(10): 899–903. PubMed Abstract | Publisher Full Text\n\nOh H, Lee S, Lee K, et al.: The effects of visual feedback balance training on the pain and physical function of patients with chronic degenerative knee arthritis. J. Phys. Ther. Sci. 2020; 32(9): 563–565. PubMed Abstract | Publisher Full Text\n\nLin D-H, Lin C-HJ, Lin Y-F, et al.: Efficacy of 2 non-weight-bearing interventions, proprioception training versus strength training, for patients with knee osteoarthritis: a randomized clinical trial. J. Orthop. Sports Phys. Ther. 2009; 39(6): 450–457. PubMed Abstract | Publisher Full Text\n\nJahanjoo F, Eftekharsadat B, Bihamta A, et al.: Efficacy of balance training in combination with physical therapy in rehabilitation of knee osteoarthritis: A randomized clinical trial. Crescent. J. Med. Biol. Sci. 2019; 6(3): 325–334. Reference Source\n\nCho H-y, Kim E-H, Kim J, et al.: Kinesio taping improves pain, range of motion, and proprioception in older patients with knee osteoarthritis: a randomized controlled trial. Am. J. Phys. Med. Rehabil. 2015; 94(3): 192–200. PubMed Abstract | Publisher Full Text\n\nChen Z, Ye X, Wang Y, et al.: The Efficacy of Backward Walking on Static Stability, Proprioception, Pain, and Physical Function of Patients with Knee Osteoarthritis: A Randomized Controlled Trial. Evid. Based Complement. Alternat. Med. 2021; 2021: 5574966–5574969. PubMed Abstract | Publisher Full Text\n\nTunay VBVB, Baltacı G, Atay AÖAO, et al.: Hospital-based versus home-based proprioceptive and strengthening exercise programs in knee osteoarthritis. Acta Orthop. Traumatol. Turc. 2010; 44(4): 270–277. PubMed Abstract | Publisher Full Text\n\nReza A, Ashtiani A, Akbari NJ, et al.: The Effect of Balance Exercises on Knee Instability and Pain Intensity in Patients with Knee Osteoarthritis: A Randomized Clinical Trial. J. Res. Med. Dent. Sci. 2018; 6(2). Publisher Full Text\n\nJongbloed L, Van Twist D, Swart N: Kinesio Taping Improves Pain, Range of Motion, and Proprioception in Older Patients with Knee Osteoarthritis. Am. J. Phys. Med. Rehabil. 2016; 95(1): e7–e8. PubMed Abstract | Publisher Full Text\n\nKuru Çolak T, Kavlak B, Aydoğdu O, et al.: The effects of therapeutic exercises on pain, muscle strength, functional capacity, balance and hemodynamic parameters in knee osteoarthritis patients: a randomized controlled study of supervised versus home exercises. Rheumatol. Int. 2017; 37(3): 399–407. PubMed Abstract | Publisher Full Text\n\nHussein NAMM, Saad MMA-H, El Sawey NA-H : Effect of Combined Balance and Isotonic Resistive Exercises VersusIsotonic Resistive Exercise alone on Proprioception and StabilizingReactions of Quadriceps and Hamstrings and Functional Capacity of KneeOsteoarthritis Patients. J. Nov. Physiother. 2015; 05(5): 1–8. Publisher Full Text\n\nBraghin RDMB, Libardi EC, Junqueira C, et al.: Exercise on balance and function for knee osteoarthritis: A randomized controlled trial. J. Bodyw. Mov. Ther. 2018; 22(1): 76–82. Publisher Full Text\n\nTrans T, Aaboe J, Henriksen M, et al.: Effect of whole body vibration exercise on muscle strength and proprioception in females with knee osteoarthritis. Knee 2009; 16(4): 256–261. PubMed Abstract | Publisher Full Text\n\nOjoawo AOAO, Olaogun MOBMOB, Hassan MAMA: Comparative effects of proprioceptive and isometric exercises on pain intensity and difficulty in patients with knee osteoarthritis: A randomised control study. Technol Heal care Off J Eur Soc. Eng. Med. 2016; 24(6): 853–863. Publisher Full Text\n\nLi Z, Zhuang J, Zhang S, et al.: Therapeutic Effects of Traditional Chinese Exercises on Musculoskeletal Pain: A Systematic Review and Meta-Analysis. Pain Res. Manag. 2021; 2021: 1–14. PubMed Abstract | Publisher Full Text\n\nRogers MW, Tamulevicius N, Semple SJ, Krkeljas Z: Efficacy of Home-Based Kinesthesia, Balance & Agility Exercise Training Among Persons with Symptomatic Knee Osteoarthritis. J. Sports Sci. Med. 2012; 11(4): 751–758. Accessed August 4, 2021. PubMed Abstract | Free Full Text\n\nRahlf AL, Braumann K-M, Zech A: Kinesio Taping Improves Perceptions of Pain and Function of Patients With Knee Osteoarthritis: A Randomized, Controlled Trial. J. Sport Rehabil. 2019; 28(5): 481–487. PubMed Abstract | Publisher Full Text\n\nUzunkulaoĞlu A, Kerİm D, Ay S, et al.: Effects of Single-Task Versus Dual-Task Training on Balance Performance in Elderly Patients With Knee Osteoarthritis. Arch. Rheumatol. 2020; 35(1): 35–40. PubMed Abstract | Publisher Full Text\n\nHiyama Y, Yamada M, Kitagawa A, et al.: A four-week walking exercise programme in patients with knee osteoarthritis improves the ability of dual-task performance: a randomized controlled trial. Clin. Rehabil. 2012 May; 26(5): 403–412. Epub 2011 Oct 5.Publisher Full Text PubMed Abstract |\n\nJan M-H, Lin C-H, Lin Y-F, et al.: Effects of Weight-Bearing Versus Nonweight-Bearing Exercise on Function, Walking Speed, and Position Sense in Participants With Knee Osteoarthritis: A Randomized Controlled Trial. Arch. Phys. Med. Rehabil. 2009; 90(6): 897–904. PubMed Abstract | Publisher Full Text\n\nEdwards MH, Litwic AE, Jameson KA, et al.: Self-reported and clinical osteoarthritis are associated with low physical performance across six countries: The european project on osteoarthritis. Rheumatol (United Kingdom). 2013; 52: i135–i172. Publisher Full Text\n\nSun HB: Mechanical loading, cartilage degradation, and arthritis. Ann. N. Y. Acad. Sci. 2010; 1211: 37–50. Publisher Full Text\n\nBouët V, Gahéry Y: Muscular exercise improves knee position sense in humans. Neurosci. Lett. 2000; 289(2): 143–146. PubMed Abstract | Publisher Full Text\n\nHewett TE, Paterno MV, Myer GD: Strategies for enhancing proprioception and neuromuscular control of the knee. Clin. Orthop. Relat. Res. 2002; 402(402): 76–94. PubMed Abstract | Publisher Full Text\n\nBennell KL, Wrigley TV, Hunt MA, et al.: Update on the Role of Muscle in the Genesis and Management of Knee Osteoarthritis. Rheum. Dis. Clin. N. Am. 2013; 39(1): 145–176. PubMed Abstract | Publisher Full Text\n\nAlbuquerque KK: 2003 U. Clinical therapeutic applications of the Kinesio (! R) taping method. Clin Ther Appl Kinesio Taping Method Tokyo 2003. Accessed June 10, 2021. Reference Source\n\nHalseth T, McChesney JW, DeBeliso M, et al.; The Effects of KinesioTM Taping on Proprioception at the Ankle. J. Sports Sci. Med. 2004; 3(1): 1–7. Accessed January 25, 2022. PubMed Abstract | Free Full Text\n\nJan M-H, Tang P-F, Lin J-J, et al.: Efficacy of a target-matching foot-stepping exercise on proprioception and function in patients with knee osteoarthritis. J. Orthop. Sports Phys. Ther. 2008; 38(1): 19–25. PubMed Abstract | Publisher Full Text\n\nKelley Fitzgerald G, Piva SR, Gil AB, et al.: Agility and perturbation training techniques in exercise therapy for reducing pain and improving function in people with knee osteoarthritis: A randomized clinical trial. Phys. Ther. 2011; 91(4): 452–469. PubMed Abstract | Publisher Full Text\n\nPrabhakar AJ, Shruthi R, Thomas DT, et al.: Effectiveness of balance training on pain and functional outcomes in knee osteoarthritis - a systematic review and meta-analysis.2022, April 27. Publisher Full Text"
}
|
[
{
"id": "154625",
"date": "11 Nov 2022",
"name": "Pratik Phansopkar",
"expertise": [
"Reviewer Expertise My area of expertise includes Musculoskeletal Physiotherapy",
"Physiotherapy Research",
"Advances in Physiotherapeutics."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis systematic review and meta-analysis included 22 randomized controlled trials for systematic review and 17 studies for meta-analysis assessing the impact of balance exercises on pain and functional activities in patients with knee osteoarthritis.\n\nIn the method section, the author is requested to add the lower age limit of the patients included in the randomized controlled trial which was then included in this systematic review and meta-analysis.\nThe content included in the study selection and inclusion and exclusion criteria is repeating itself. Kindly check for a better content presentation.\nThe authors have mentioned 15 studies included in the meta-analysis result section however in the discussion section they have mentioned the inclusion of 13 publications. Therefore, the authors are requested to clarify the inclusion of articles in the meta-analysis.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": [
{
"c_id": "9015",
"date": "14 Nov 2022",
"name": "Tina Dias",
"role": "Author Response",
"response": "Dear Reviewer, We thank the reviewer and the editorial team for taking the time to conduct an in-depth review of our article. We thank you for the appreciation you have given us regarding this systematic review. We acknowledge the corrections and will upload them in the corrected version of the document REVIEWER 1 1) In the method section, the author is requested to add the lower age limit of the patients included in the randomized controlled trial which was then included in this systematic review and meta-analysis. RESPONSE - Under the description of the included studies sub-topic (Participant description) The age limit of the included subjects in the RCT has been mentioned. 2)The content included in the study selection and inclusion and exclusion criteria is repeating itself. Kindly check for a better content presentation. RESPONSE - The correction will be made in the new uploaded version of the article. 3) The authors have mentioned 15 studies included in the meta-analysis result section however in the discussion section they have mentioned the inclusion of 13 publications. Therefore, the authors are requested to clarify the inclusion of articles in the meta-analysis. RESPONSE - The correction will be made in the new uploaded version of the article."
}
]
},
{
"id": "179304",
"date": "23 Aug 2023",
"name": "Sohrab Ahmad Khan",
"expertise": [
"Reviewer Expertise Musculoskeletal Physiotherapy",
"Biomarkers in Osteoarthritis",
"Orthopedic physiotherapy"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nExplain the rationale of the research in detail, with need of doing this systematic review as there is ample number of studies and reviews already done. What does your article adds to the existing pool of literature.\nIn the methodology section, Inclusion and exclusion criteria needs to be explained well, Did you include all paid full text articles in all languages? Also mention about paid articles included or not/ open access only\n\nIn 22 years, with such a variety of databases, only 840 articles were available? In search strategy, only online databases are mentioned. In Prisma flowchart, registers show 5 records screened. Edit the search strategy accordingly.\nThe search strategy should be mentioned. Write the exact search strategy that you used using Boolean phrases.\n\nDiscussion section needs to be rephrased in a better understandable way.\nConclusion needs to be as per the aim of the study.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Partly\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Partly\n\nIs the statistical analysis and its interpretation appropriate? Partly\n\nAre the conclusions drawn adequately supported by the results presented in the review? No",
"responses": [
{
"c_id": "10297",
"date": "26 Sep 2023",
"name": "Tina Dias",
"role": "Author Response",
"response": "Dear Reviewer, We thank the reviewer and the editorial team for taking the time to conduct an in-depth review of our article. We thank you for the appreciation you have given us regarding this systematic review. We acknowledge the corrections and will upload them in the corrected version of the document"
}
]
}
] | 1
|
https://f1000research.com/articles/11-598
|
https://f1000research.com/articles/12-191/v1
|
20 Feb 23
|
{
"type": "Research Article",
"title": "Subject playing with flat images: Transmedia spreadability of anime and manga character images",
"authors": [
"Kohki Watabe"
],
"abstract": "Anime and manga characters are so ubiquitous in Japan that people see them anywhere, regardless of public or private. The two-dimensional flatness of line drawing allows the character images to straddle the boundaries of the worlds of works and media. The analysis of individual artworks needs to be revised to understand the transmedia spreadability of characters and our living conditions. This paper, thus, overviews the preceding discussions of anime and manga scholars on human-character relations and compares them with the theory of subject formation in film studies, whose realist tendency once emphasized the three-dimensional space and time. While psychoanalysis-influenced theories such as suture and male gaze model after one-point perspective and subordinate two-dimensionality, Thomas Lamarre formulates a de-unified perspective in relation to the multilayered image field of Japanese anime. In conjunction with the orientation of cultural and fan studies to emphasize audience agency, this article discusses the de-unified perspective on flat images which has the potential for understanding the complexity of subject formation through the interplay with two-dimensional images.\n日本においてはアニメや漫画のキャラクターは公私の別なく様々な場所で目にするものである。平面的に描かれた二次元の線画であることがキャラクターが作品世界やメディアの境界線を超えて流通することを可能にしている。キャラクターのトランスメディア的拡散とその中での我々の生がどのようなものであるかを理解するためには、個別の作品を単位とした分析では不十分である。したがって、本稿はアニメや漫画の研究者の人間主体とキャラクターとの関係についての議論を概括し、それらを三次元の時空間を強調するリアリズム的傾向を有していた映画研究における主体形成の議論と比較する。精神分析の影響を受け一点透視図法をモデルにした縫合や男性のまなざしの議論が二次元性を下位に置くのに対して、トーマス・ラマールは日本のアニメの多平面的イメージの場に対する脱一点透視図法的な関係性を定式化した。これをカルチュラル・スタディーズやファン研究のオーディエンスの能動性を強調する傾向と接続することで、本稿は平面的イメージに対する脱一点透視図法的関係は二次元のイメージとの遊戯的戯れを通した主体形成の複雑性を理解する一助となることを議論する。",
"keywords": [
"character",
"manga",
"anime",
"fan",
"film",
"kyara",
"audience participation",
"cosplay"
],
"content": "導入 : なぜキャラクターが重要なのか\n\n日本で生活していると多くの場面で漫画やアニメのキャラクターに遭遇する。コンビニやスーパーマーケットに行けば食品、日用品、文房具、玩具などの商品がキャラクターの図像を付帯して販売されている(Steinberg, 2009, 130)。近年では安価な消耗品ばかりでなく、高級ブランドが漫画やアニメのキャラクターを利用することも珍しくない。営利企業に限らず、駅や行政施設などの公共空間でも注意喚起のためにキャラクターは多用される (Nozawa, 2013)。日本の地方の観光地に行くとゆるキャラと呼ばれる観光促進のキャラクターが見られ、また商業作品のキャラクターが起用されている例も見られる。観光資源に乏しい地方自治体が漫画やアニメのキャラクターのブロンズ像を建設し観光客を呼び寄せようという取り組みも珍しいものではなくなった。このようにキャラクターは、認知の向上とそれに伴う経済的利益を期待して公共的あるいは営利的な目的に利用されている。\n\nキャラクターにかけられる期待は経済的なものに限らず、キャラクターが喚起する情動を用いた政治的動員効果も期待されている。例えば、安倍晋三首相は2016年にリオデジャネイロで行われた五輪の閉会式にスーパーマリオの姿で登場し、2020年に行われるはずであったオリンピックの宣伝を行った (Rich, 2016)。国際的な観客に対するアピールとして彼自身より有名なマリオのキャラクターを利用し、同時に日本国内的にはポピュラー文化を利用した人気取りという側面もあっただろう。このようなキャラクターを利用する政治現象は日本に限らない。2016年の米国大統領選挙に際しドナルド・トランプの支持者たちは、「カエルのペペ」というキャラクターのイメージをトランプに重ね合わせたミームを作成し、このミームはトランプの勝利にも多少なりとも貢献したと言われている (Bramesco, 2020)。\n\n経済や政治において既に利用されていることをみれば、漫画やアニメの研究の一部としてではなく、キャラクターという現象それ自体の重要性は明らかであろう。「カエルのペペ」のミームがトランプ支持者らに利用され法的措置を通じて名誉を回復する過程を描いたドキュメンタリー映画『フィールズ・グッド・マン』（アーサー・ジョーンズ監督、2020年）は、結末で香港の雨傘革命で「カエルのペペ」が利用されていることをある種の希望として描き出していた。しかし、これはある特定の政治的立場からの価値判断であり、本質的にはキャラクター・イメージが力を持って人を動員するメカニズム自体の検討が必要である。\n\n\n方法\n\nこの点を検討するために、本稿は、日本のアニメや漫画のキャラクター論をより広く主体とイメージの関係についての議論として捉え、関連するメディア研究、映画研究、ファン研究などの議論と比較検討する。まず、キャラクター論の画期となった伊藤剛『テヅカ・イズ・デッド』において、日本のキャラクター文化を可能にしているキャラクターが比較的簡単な線画であり容易に複製可能な平面的記号であることを確認し、伊東の議論の影響を受けた岩下朋世やマーク・スタインバーグらの議論を確認する。これらキャラクターの図像的特性への議論と並行して、大塚英志と東浩紀がキャラクターを通した主体と世界の関係を議論していたことを取り上げ、そうすることでキャラクター論をより一般的な主体とイメージの関係についての議論として再定式化する。その際に、三次元の時空間に優位を置いた英語圏の映画理論と比較することで、平面と空間という次元性が主体とイメージとの関係の中でどのように概念化されているかを整理する。これらの比較の中で、トーマス・ラマールがアニメの平面的な物質性に一点透視図法とは異なる主体と客体の関係を見出したことの重要性が浮かび上がってくる。脱一点透視図法的な主体とイメージとの関わりの具体的な実践の事例としてコスプレを捉えることができることを論じ、平面的なイメージとしてのキャラクターと鑑賞する主体との間に発生する複雑な関係性を明らかにする。\n\n\nキャラクター論における平面性\n\nキャラクターが平面的な記号の組み合わせとして成立していることは漫画やアニメの研究者に限らず一般に広く理解されている。漫画家の手塚治虫は自作の中で、キャラクターは目や口、輪郭といったパーツの組み合わせで記号的に構成されていることを明示し後続の多くの漫画家に影響を与えてきた（大塚, 2003, 64-71; 大塚, 2009, 60-70）。本節では、漫画やアニメのキャラクターが記号的な図像であることを論じた漫画やアニメの研究者の議論を概観し、日本のキャラクター文化を可能にしている平面性についてまとめる。\n\nまず多くの漫画・アニメの研究者が依拠する伊藤剛の「キャラ」と「キャラクター」を区別する議論を確認しよう。伊藤剛は、後述する大塚英志のキャラクター記号論や東浩紀の萌え要素のデータベース的組み合わせとしてのキャラクター論を受けて、登場人物のあくまで線画としての側面である「キャラ」とストーリーの展開の中で現れる人格面である「キャラクター」を区別した。伊藤はそれぞれを次のように定義している。\n\nキャラ : 多くの場合、比較的に簡単な線画を基本とした図像で描かれ、固有名で名指されることによって（あるいは、それを期待させることによって）、「人格・のようなもの」としての存在感を感じさせるもの\n\nキャラクター :「キャラ」の存在感を基盤として、「人格」を持った「身体」の表象として読むことができ、テクストの背後にその「人生」や「生活」を想像させるもの（伊藤, 2005, 126）\n\n伊藤によるこのキャラとキャラクターの区別には曖昧な要素がある。この点を指摘して岩下朋世は伊藤の「キャラ」概念を「比較的に簡単な線画を基本とした図像」と「人格・のようなもの」とに分割し、前者を「キャラ図像」、後者を「キャラ人格」と呼称し議論を精緻化した（岩下, 2013, 87-154）。ここで重要なことは、伊藤のキャラにしても岩下のキャラ図像にしても、これらの概念によって漫画の中の個々のコマにおける個々の線画を、作品世界内に立ち現れる一貫した人格的存在から切り離して議論の俎上に載せたことにある。\n\nキャラクターの個々の図像的側面と人格的一貫性を分離して議論することで、作品世界の外側でのキャラクター・イメージの流通という現象を議論の俎上に載せることができるようになる。前述の通り、キャラクターのイメージは我々の家庭・学校・職場・公的施設といった生活のさまざまな側面に浸透し営利的・政治的・公共的目的を実現するために利用されているという事実が、現代日本におけるキャラクター文化現象を重要なものにしている。だとすると、漫画やアニメといったメディウム内在的な固有の記号作用の分析とともに、キャラクターがマーケティングや宣伝・広告に利用されるときにこれらを鑑賞する主体との間でいかなる感情・情動的関係性が発生するのかを分析する必要がある。\n\nこの点は、日本のアニメのメディア・ミックスの歴史を辿る中でマーク・スタインバーグが議論している。スタインバーグは日本初の商業テレビアニメ『鉄腕アトム』のキャラクターたちが、マーブル・チョコレートをはじめとする商品におまけのシールとして添付され、それによって作品世界を飛び出し人々の生活に浸透していたことを論じた（スタインバーグ, 2015; Steinberg, 2009, 121-126）。日本のテレビアニメはリミテッド・アニメであり、線画で描かれる単純なキャラの静的なイメージが同時に運動性を持つことができた。このため、アトムのシールに見られるような、キャラクターのトランスメディア環境への拡散が可能になった（スタインバーグ, 2015, 113-138）。スタインバーグが考察の対象とするのはアニメであり、伊藤と岩下が対象とした漫画とは異なるメディアである。しかし両者の議論は線画による図像としてのキャラに注目する点が共通し、実際スタインバーグが論じているように、消費者の受容環境においてはこのようなメディウムの固有性による区切りを跨いで線画によるキャラが拡散する。キャラクターという論点に絞る限りにおいては、漫画とアニメを共通の土台において議論することは可能であろう。\n\nもちろん漫画研究とアニメ研究を完全に同じ枠組みで論じてよいわけではない。例えば、アニメ研究における原形質性の議論は漫画研究に適用できる可能性は低い。原形質性とはエイゼンシュテインによって提起されたアニメーションにおける自由で不定形な可塑性に注目する概念である（小山, 2022, 22-45）。例えば、細馬宏通は『アルプスの少女ハイジ』における火で炙って溶けるチーズが熱を受けて時間的に変化する様に原形質的な特徴を見出している（細馬, 2022, 117-133）。このとき、チーズが溶けるのを待つハイジは輪郭線が安定的に固定されたキャラクターとして描かれており、同じメディウムの中に異なる原形質性とキャラクターという異なる原理が共存している。時間性をもったアニメーションというメディアにおいては物質の流動的な可塑性に注目することは自然である。一方で、読者の鑑賞経験の中に時間性は出現するが、描かれた個々のコマに内在的に時間性が存在する訳ではない漫画において、アニメと同じように原形質性を見出すことはできない。もちろん、漫画家のペンの運動の跡をなぞることで時間性が喚起されると言うことはあるだろうが、通常そのようには鑑賞されていない。\n\n原形質性はアニメに固有なものとして考えられているが、キャラクターは漫画・アニメにまたがった現象であり、だからこそこれらメディアの枠を超えた拡散性を有している。伊藤は「キャラが間テクスト的に環境中に遊離し、偏在すること」を「キャラの自律化」（伊藤, 2005, 76）と呼び、このようにキャラが自律することが二次創作を可能にしていることを指摘している。スタインバーグはアトムのシールが家庭内の家具や冷蔵庫に貼り付けられるという状況をトランス・メディア的なキャラクターの拡散として描き出しているが、これも「キャラの自律的」運動によって可能になった二次創作の一種であると言えるだろう。\n\nキャラの「間テクスト的に環境中に遊離し、偏在する」特性が表れている文化現象の典型例が 2.5次元舞台である。2.5次元舞台では、「キャラの自律化」によってメディアを跨いで拡散したキャラクターの図像的側面が具体的な俳優の身体を通して発動する。須川亜紀子は、漫画やアニメの中でのキャラクターをめぐる複層的な記号作用の構造が、演劇という具体的な身体性を有したメディアに重なることでさらに多層化した現象として 2.5次元舞台を精緻に描き出している（須川, 2021, 22-38, 68-82）。3次元空間に肉体をもつ俳優自身も生身の人間としての顔と俳優としての姿を持つ複層的な存在であるが、彼ら/彼女らがキャラクターを模したメイクと衣装を纏い「キャラ図像」を獲得し、さらには「キャラクター」としての人格を演じることで、2.5次元舞台には複雑な意味の層が現れる。須川はこのような身体性を「ヴァーチャル・コーポラリティー(virtual corporality)」と呼び、1) 素の俳優の身体、2) キャラクターをまとったキャスト、3) 現象的肉体、4) 記号的身体、5) キャラクターといった 5つの層が舞台上にあらわれることを指摘している（須川, 2021, 73-82）。これら記号作用の層が「前景化・後景化を繰り返し、常に緊張関係にある」（須川, 2021, 81）ことが 2.5次元舞台の楽しみとなる。漫画やアニメの鑑賞と異なり、2.5次元舞台上に平面的な線画が存在するわけではない。しかし、観客たちは彼ら/彼女らが知っているキャラ図像を投影することで舞台上にキャラクターを認知的に現出させているのであり、原理的にはアトムのシールを家具や冷蔵庫に貼り付ける子供の行為と同じ二次創作的側面を持っている。\n\nここまで見てきた通り、キャラクターが比較的簡単な線画として平面的に図像化されていることが、そのトランスメディア的拡散を可能にしている。結果的に、漫画やアニメといったメディア的境界線を超えて、キャラクターは現代の日本社会の中に幅広く浸透している。\n\n\n平面の向こう側\n\nこのように自律化した平面的なキャラのイメージが社会の中への拡散するとき、そのキャラクターがもともと置かれる作品世界は完全に捨象されているのだろうか? 伊藤が参照した大塚や東の議論においてはキャラクターの図像的側面だけでなく鑑賞者が図像を介してどのように作品世界あるいは作品として表現される現実世界と関わっているかが論じられている。大塚と東の議論を追い、人間主体――文脈に応じて鑑賞者・観客・読者・視聴者・ユーザーとなりうる――のキャラクターを通した世界との関わりがどのように理論化されてきたかを確認しよう。\n\n1989年に出版された『物語消費論』において、大塚英志は商品それ自体の使用価値ではなくその背後にある物語との関係で消費される事態を「物語消費」と名づけ、その事例としてビックリマンチョコレートに封入されるシールを取り上げた。ビックリマンチョコにはキャラクターが描かれた小さなシールが封入されており、シールの裏側にはそのキャラクターにまつわる断片的なエピソードが描かれている。シールは合計で 772種類あり、ある程度の枚数を集めてエピソードを収集すると、全体として叙事詩的な「大きな物語」が浮かび上がってくるという仕掛けになっている。大塚によれば、当時の子供たちは菓子を捨てて、キャラクターと物語が描かれたシールを収集するという「物語消費」をし、単にキャラクターのイメージを貼り付けただけの仮面ライダーのスナック菓子とは異なる消費形態であった（大塚, 2001, 7-22）。\n\n子供たちはシールの表面に描かれたキャラクターの図像自体にも魅力を感じていた可能性は否定できないが、大塚の議論はキャラクターを作品世界との接点として捉え、キャラクターの向こう側に「大きな物語」たる作品世界があることに力点をおいている。2003年の『キャラクター小説の作り方』の中では、キャラクターを読者と作品世界との接点として捉え、そのキャラクターを通してみる特定の観点から作品世界が立ち上がることを強調する（大塚, 2003, 9-29）。\n\nお話の中に「世界観」を見出さない、というのは近代という時代の、しかも「文学」という特殊なジャンルでの決まり事であって、同時にこの「世界観」に創作の比重をおくことが「文学」に対する「キャラクター小説」のもう一つの特徴とも言えます。\n\nあれ、キャラクター小説の本質はキャラクターにある、とこの講座では前からしつこく主張してきた、と思うかもしれません。しかし「世界観」とは繰り返しますが「世界」の「観」方です。作中のキャラクターが「世界」をどのように「観」て、受け止めるかということがキャラクター作りにおいて不可欠であり、同時に「世界観」作りにおいて最も見落とされている点でもあるのです。[…]「世界観」とは読者がキャラクターの目を通じて「観」る「世界」でなくてはなりません。（大塚, 2003, 221）\n\nここには大塚のキャラクター理解が凝縮している。大塚にとっては個々のキャラクターよりもキャラクターを通して浮かび上がる大きな物語あるいは作品世界全体が重要となる。手塚が記号的に描かれるキャラクターの身体を傷つき得る、死に得るものへと変えたことを強調しすることで、大塚は漫画をリアリズム的問題系へと引きつけ、戦後民主主義的価値観を倫理的審級として漫画批評に導入した（大塚, 2003, 259-282; 大塚, 2009, 117-144）。この大塚の議論からは、キャラクター自体は記号的であるとしてもその向こう側に出現する世界が我々の現実と乖離したものでないことを要請する立場が必然的に導き出されることになる。\n\n一方、大塚の『物語消費論』を参照し 2001年に出版された『動物化するポストモダン』の中で、東はキャラクターを欲望の対象あるいは結節点として捉えている。「物語消費」に対して提起される「データベース消費」においては、手塚の記号論的な観点を踏襲し、キャラクターは「萌え要素」の集合体として捉えられる。例えば、特定の髪の色や髪型といった個別の記号的要素が、ある特定の性格のタイプなり行動のパターンなりと紐づけられ、キャラクターを鑑賞するものはその特定の記号に対して「萌える」という感情的・情動的反応を行う。このような鑑賞あるいは消費の形態に必要なのは、キャラを構成する記号とその意味の組み合わせを列挙したデータベースであり、作品世界といった大きな物語ではない（東, 2001, 42-47, 50-58）。\n\nしかし、東がキャラクターを消費する主体が世界とどのように関わるかを検討していないというわけではない。『ゲーム的リアリズムの誕生』では、キャラクターを複眼的な主体を立ち上げる契機として捉えている。東はノベルゲームと呼ばれる物語を文字情報として読むことを中心としたゲーム作品の中には、作品世界内で物語が何度も繰り返される特徴があることを指摘している。「スーパーマリオ」のような何度も挑戦できるゲーム的設定を有することで、これらノベルゲーム作品の中で、主人公は同じ物語を少しずつ違う立場や視点から何度も生き直す。東は、このようなキャラクターが何度も死を繰り返し生き直すことで到達する独特の現実感覚を「ゲーム的リアリズム」と呼び、写生文学的リアリズムとは別の現実に対する認識のあり方を強調した。ゲーム的リアリズムを体現した文学作品の中では「キャラクターがメタ物語的な結節点として与えられているがゆえに、あらゆる物語に対して別の物語への想像力が半ば自動的に開かれてしまう」（東, 2007, 125）のである。\n\n大塚と東はそれぞれ異なる立場から、鑑賞者がキャラクターを通してどのように作品世界あるいはそこに表現される現実と向き合うかを議論した。大塚はリアリズムと戦後民主主義的価値観を倫理的審級として強調しキャラクターの向こう側に現実があるべきことを重視し、東はキャラクターの複製的な性質を媒介することによって単一の視点の位置に還元できない複眼的な世界との関係のあり方を模索している。本稿はこれらの立場の優劣を議論するものではない。大塚と東はともに作品というものが存在することを前提としてその上で鑑賞者とその作品世界との関わりを論じているが、本稿が注目するのは作品世界の境界線を超えて我々の日常生活の中にキャラクターが氾濫しているという事実である。現にキャラクターがマーケティングや宣伝の道具として利用され日本社会に氾濫しているという事実は、主体・キャラ・世界の関係性をめぐる議論を作品の外部にひらくことを要請する。\n\nこの観点からは、伊藤の「キャラ」と「キャラクター」の二分法は、キャラクター文化の理解に資するとともに、そのマーケティングや宣伝の道具としての有用性をも明らかにしている。キャラクターの図像的側面が物語内的一貫性から切断できることが、「キャラが間テクスト的に環境中に遊離し、偏在すること」を可能にしており、だからこそマーケティングや宣伝に利用することができる。2.5次元舞台においては舞台上のキャラクターを演じる俳優はもとの作品世界全体を呼び出すことを企図しており、ここでは大塚が描いたようにキャラクターを通して「世界」が立ち現れていると言える。一方、マーブルチョコレートに添付された鉄腕アトムのシールは『鉄腕アトム』の作品世界全体やその中でのアトムの喜怒哀楽の全てを呼び起こすことを目的としてはいない。2.5次元舞台と比べた場合、ここでは東の「萌え要素」の喚起力と同種のメカニズムが機能する余地が大きい。仮に消費者が物語の作品世界全体を味わうことだけを目的とするならば、その消費者はマーブルチョコレートには目もくれず漫画の単行本を所有することだけに喜びを見出すだろう。「萌え」ではないとしても、アトムの固有の図像的魅力が消費者を惹きつけているのだ。\n\nこのように考えると、伊藤のあいまいさを残したキャラの定義が深い洞察を伴っているものに見える。「多くの場合、比較的に簡単な線画を基本とした図像で描かれ、固有名で名指されることによって（あるいは、それを期待させることによって）、「人格・のようなもの」としての存在感を感じさせるもの」（伊藤, 2005, 126）という記述は、キャラの図像とそれが喚起するなんらかの人格や感情的・情動的状態との不可分性を示唆している。アトムのイメージが商業的に流用されるとき、それを鑑賞する主体になんらかの「「人格・のようなもの」としての存在感を感じさせる」からこそ、マーケティングや宣伝にキャラクターが多用される。\n\n平面的なキャラクターのイメージが常になんらかの感情・情動を喚起することは、アニメの聖地巡礼、既存の漫画やアニメキャラクターを使った地域振興、日本全国で見られるゆるキャラの採用といった現象を考える際に示唆的であろう。漫画やアニメの舞台となった土地を訪問する観光の形態は聖地巡礼と呼ばれ、現在では地域振興のための手段として注目されている。しかし、漫画やアニメ作品の中で現実に存在する場所が取り上げられるというインデックス性がこの聖地巡礼を引き起こしている点で、キャラクターのメカニズムとは齟齬が生じる。だからこそ、日本各地で設立されている漫画やアニメのキャラクターの銅像は、その銅像が作者の出生地であるといった現実とのか細いつながりに頼る形で、漫画やアニメのキャラ図像が喚起する情動を観光客誘致の手段として使っている。ゆるキャラの場合はキャラクターの造形の中にその土地を示す記号を導入することで、キャラを土地に繋ぎ止めている。いずれの場合にしても、それらを何らかの形で具体的な土地とのインデックス的なつながりを作りながら、キャラが必然的に喚起する感情・情動が利用されている。\n\nだとすると、キャラクター文化自体は原理的には地域に対する関心を引き起こさない。漫画やアニメのキャラクターの像を見に訪れる観光客は、ブロンズ像というキャラの図像によって喚起されるもの――大塚のシナリオであれば作品世界全体を、東のシナリオであれば記号的に喚起される感情・情動を――消費しているのであり、実際の観光地が作品の中に出現する場合を除いて観客は地域振興を仕掛ける側が売り込んでいる土地を見ているわけではない。ふるさと納税制度のようにさまざまな商品が並んでいて欲望を喚起するが、納税者は返礼品を提供する「ふるさと」に興味を持っているわけではないことと同じである。\n\n本稿はコンテンツ・ツーリズムや地域振興の具体的な方法を検討することを目的としてはいないが、仮にキャラクター文化をこれらに利用しようと考えるのであれば、主体がキャラクターとの間に持っている感情的・情動的関係を、主体と振興しようとする土地との関係に変換するメカニズムを考える必要がある。だとすると、問題はやはり平面と主体の関係なのである。東の「萌え」はこのような主体と平面の関係を記述するひとつの用語である。本稿を執筆している 2022年時点では「萌え」はさほど使用されないが、「エモい」、「推し」、「尊い」といったイメージとの感情的・情動的関係性を定義する言葉は多数出現している。これらの用語はイメージが主体に対して喚起する感情に注目した概念であることからわかるように、キャラクター文化においては対象と主体とがどのような関係を結ぶかが問題となる。\n\n\n英語圏の映画理論における3次元空間の優位\n\n平面的対象とそれを鑑賞する観客主体の関係は、英語圏の映画研究においては観客とスクリーンの関係として議論されている。しかし、英語圏の映画研究においては、日本語でのキャラクターの議論とは異なり、平面性や無時間性には劣位が与えられている。日本のキャラクター論との比較のために、まずはこの点を確認しよう。\n\n映画は 19世紀末に技術が完成し、20世紀初頭に見せ物として利用され、ハリウッド映画産業の国際的な覇権の拡大とともにアメリカ合衆国が生み出した独自の芸術形式と見做されるようになった。他のより古くから存在する芸術形式に対して映画を芸術として確立するために、映画というメディウムに固有の芸術的特性が何かが検討された。その有力な答えの一つはカメラが現実をそのまま映しとることである。カメラという機械の目が人間の意図とは関係なく、世界をありのままに空間的な広がりと時間的持続を伴って記録できることが称揚され、これが映画学におけるリアリズムの基礎となっている (Stam, 2000, 72-83; 角井, 2021, 76-77)。もちろんこのように映画の特性を規定することは20世紀のある時点までの実践に過ぎないが、この映画的リアリズムという規範からは三次元的間が重視され、漫画やアニメのキャラクターは平面的で無時間的なものとして一段低く見積もられる。\n\n映画研究が精神分析を取り入れる過程を見ると、英語圏の映画学における三次元空間への偏重は理解されよう。映画理論はジャック・ラカンの精神分析理論を導入し、観客主体が平面的なスクリーンを通して作品世界に没入するプロセスを理論化してきた。この主体形成のメカニズムは精神分析の用語を借用して「縫合」理論と呼ばれる。その理路は次のようになる。あるショットに対して想像的に同一化した観客は、このショットを撮っている全能の存在――「不在の他者」――が全体をコントロールしているのではないかと不安を抱く。だが、このショットに続く切り返しショットがそのショットを撮る位置に誰もいないことを露わにする。このショットと切り返しショットの連続によって、観客は映画に「縫合」され、主体となるという理屈である (Oudart, 1989, 45-57; Dayan, 1974, 22-31)。精神分析における諸々の概念は関係論的ではあっても物質的に空間的ではない。この関係的概念を具体的な現実的な空間を重視する映画的リアリズムにひきつけた点が映画理論における「縫合」理論の要点となっている。つまり去勢不安が具体的な三次元空間状における「不在の他者」の占める位置へと翻訳され、ショットの連続によって「不在の他者」が存在しないことを示すことで、この不安を解消している。\n\n縫合理論の影響を受けたフェミニズム映画理論においては、三次元空間の優位に加えて、二次元的な平面性の劣位が明確に表れている。例えば「物語映画と視覚的快楽」の中でローラ・マルヴィが定式化した「男性のまなざし」を見てみよう。「男性のまなざし」とはハリウッド映画において、男性主体が女性を性的対象としてまなざす構造を持っており、観客たちは映画の観客となることで異性愛体制を内面化するという議論である。観客がスクリーン平面上に映し出されたイメージを通してそのような規範を受け入れる過程は次のように説明される。ハリウッド映画の中での自由に動き回ることができる男性主人公は精神分析で言うところの「想像界的」な快楽を体現している。観客はこの男性主人公に同一化することで、物語の作品世界内に没入することができる。作品世界内での男性主人公の欲望の眼差しとそれと重ね合わされるカメラの眼差しを通して、観客はこの異性愛秩序を受け入れる(マルヴィ, 1998, 129-135)。この論理の中で女性の身体は男性の性的欲望の眼差しの対象としての固定した平面的イメージとして描きだされる。\n\nお馴染みの女性の足のクロースアップ（例えばディートリッヒの）、もしくは顔のクロースアップ（ガルボの）もまた別の性愛の様式を物語の中に統合する。クロースアップにより断片化された身体の部分は、物語が必要とするルネッサンス的な遠近法の空間と画面上の奥行きの錯覚を無効にしてしまう。身体の断片は画面を平面的なものに変え、物語的な現実らしさよりはむしろ切り抜き絵か肖像的な肌合いをもたらしてしまうのである。(マルヴィ, 1998, 132)\n\nここに三次元の空間の優越と二次元の平面の劣位を読み取ることは容易だろう。個別の映画作品は物語として「ルネッサンス的な遠近法の空間と画面上の奥行き」を要請し三次元の空間を有している。しかし、その物語の中で、クローズアップにより女性の身体は断片化され、平面的な「現実らしさよりはむしろ切り抜き絵か肖像的な肌合い」のものにされてしまう。この静的なイメージとしての女性身体が観客のまなざしをとらえるものとなり、「その途端、呪物崇拝化が起こり、去勢不安を隠蔽しながら視線を凍結し観客を固着し、観客が自分の目前にある画像から距離をとるのを全面的に防いでしまう」(マルヴィ, 1998, 139) のだ。ここでマルヴィは、男性主体が女性のイメージに囚われた状態を「距離をとるのを全面的に防いでしまう」と空間的比喩で表現していることも興味深いが、「凍結」や「固着」といった運動性を欠いた静止した状態として描写していることも重要である。映画が時間芸術でありかつ三次元の空間性を重視するというリアリズム的前提のもとでは、運動を捉えることに対する肯定的評価が必然的に導かれる。その反作用として、マルヴィは運動性を欠いた非時間的なイメージを劣位に置く修辞を駆使している。\n\nマルヴィの男性のまなざしの議論は広範な影響を与え、多くのフェミニズム映画理論家が彼女の議論の瑕疵を指摘した。例えば、ジョアン・コプチェクが指摘しているように、縫合理論は主に「私の機能を作るものとしての鏡像段階」の議論を参照しているが、後にラカンはその議論を大幅に修正している (コプチェク, 1998, 29-58)。しかし本稿が注目したいのは、映画理論における縫合の議論がリアリズム的な前提によって精神分析を具体的な三次元空間の問題に議論を縮減し、結果として出現した二次元的な平面性を低く評価する論理がキャラクターの理解にどのように貢献するかである。\n\nマルヴィの「視線を凍結し観客を固着し、観客が自分の目前にある画像から距離をとるのを全面的に防いでしまう」という記述は、ここまで述べてきた日本のキャラクター論における主体とキャラクターのイメージとの関係を描き出しているようにも読める。ある欲望のあり方へと固着させてしまうと言う点では、ハリウッド映画の中の断片化された女性身体のイメージと、東が「萌え要素」の集合体として描き出す日本のキャラクターは類似したものである。こういった喚起力があるからこそ、スタインバーグがキャラを切り出した理路のようにアニメのシールが魅力を発散するし、コンビニやスーパーマーケットでキャラクターが添えられた商品は後をたたない。しかし、ハリウッド映画の中で三次元の空間性と対比する中で平面のイメージを論じるマルヴィの理論を、そのまま日本の漫画やアニメのキャラクターに適用することは妥当だろうか?\n\n\n分配的領域と脱一点透視図法的主体\n\nトーマス・ラマールの『アニメ・マシーン』(2009 年) がこの問いに関連する重要な議論を行っている。同書はアニメを制作する際のマルチプレーン装置の構造に注目し、ハリウッド映画的な奥行き方向の運動性を持った一点透視図法的な視覚の体制である「シネマティズム」に対して、日本のアニメの特徴である奥行き方向の運動性を欠いた複数の平面間の関係性の美学としての「アニメティズム」を対比させたものである。したがって、キャラクター論がラマールの主要な関心というわけではない。しかし、三部構成の本書の第三部において、CLAMP原作の『ちょびっツ』を題材にアニメにおける「縫合」の問題を取り扱っている。\n\nラマールは映画の編集慣例に則って作られるアニメにおいては、縫合はある程度まで発生するが、最終的に縫合は破綻することを議論している (ラマール, 2013, 349-354)。これはラマールが平面同士の関係性の美学を強調していることから必然的に導かれる結論である。縫合理論は、一点透視図法を実現する装置であるカメラという物理的機構から導き出されるリアリズム的規範を経由させて、精神分析という非物質的メカニズムを空間化した理論であり、ラマールが論じるアニメーションの技術的物質的特性はこれと異なる。複雑な立体的構造物を平面的に開いた展開図を見る時に、それを見るものは平面の各部分ごとの構造や仕組みを合成することで全体の出来事を理解するが、これがアニメの平面的美学で起こっている意味作用だ。ラマールはこのようなアニメの認知的メカニズムが発生する場を「分配的領域」(ラマール, 2013, 148-149, 179-182, 328-331) と呼ぶ。分配的領域において、一点透視図法が想定する単一の点としてではない主体の認知が立ち上がるというのが、アニメにおける観客とイメージとの関係である。もちろんアニメは映画の慣習や文法に則って制作されるため一定程度縫合的なメカニズムは発生するが、物質的な三次元空間の実在に依拠してある特定の点としてのまなざしの主体を立ち上げるメカニズムである縫合が、アニメにおけるイメージと観客主体の関係を規定しているわけではない。\n\nとはいえ、ラマールはアニメの中でイメージが主体を形成するメカニズムが存在しないと言っているわけではない。視覚的モデルの代わりに力学におけるアトラクターとコーペレーターという議論を導入してこれを説明している (ラマール, 2013, 329)。ラマールによると、アトラクターとは「ある力学的システムがそれに向かって発展していく集合」であり、それは点でも曲線でも多様体でもフラクタル構造でもありうる。例えば振動する振り子は摩擦を受けていれば十分な時間が経過したのちにある一点で静止する。この静止する一点が点アトラクターである。コーペレーターとは、「アトラクターに向かう発展に関与する機能」である。その上で、ラマールは次のように両者の関係を論じている。\n\n多平面的なアニメ・イメージの平板化と結びついた分配的な領域という文脈では、萌え要素がアトラクターとして機能する。アトラクターは、諸要素が脱階層化されて分配される領土上で顕著となる萌え要素である。とすれば、相互作用の担い手であるオタクはコーペレーターである。情動的な環状回路や循環経路がコーペレーターとアトラクター、すなわち人を惹きつける萌え要素とオタクとをつなぐ。コーペレーター（あるいはインターアクター）は、その領域内にある、単なるもう一つの要素という以上のものであり、一つの視る位置以下のものである。それは、安定した視る位置や主体ではない。コーペレーターは、アトラクターとの関係で諸要素を統合し差異化する機能である。オタク・コーペレーターの小さな世界や小さな物語は、領域内に分配され密封された諸要素の相互作用を通じて創発する複雑なパターンなのだ。(ラマール, 2013, 329)\n\nここでラマールはおそらく厳密に力学的な意味でアトラクターとコーペレーターという単語を用いてはいない。アニメの分配的領域において「萌え要素がアトラクターとして機能」し「相互作用の担い手であるオタクはコーペレーターである」と言っていることから、画面上に配置された記号的萌え要素とオタクの鑑賞者のような、イメージと主体の関係の表現であると考えてよいだろう。ここで、注意すべきはアトラクターと相互作用を行うコーペレーターは分配的「領域内にある、単なるもう一つの要素という以上のものであり、一つの視る位置以下のものである」ことだ。このように言うことで縫合理論や男性のまなざし論が想定しているような「安定した視る位置や主体」とは異なることを強調している。ラマールは一点透視図法的な主体を立ち上げることを避けつつ、しかし同時に人間とイメージの間の関係性を定式化しようとしている。\n\nその意味で、ラマールの議論はここまでの主体とイメージをめぐる議論の系譜に並ぶものである。ラマールは東の「データベース消費」の議論を踏襲しており、オタク・コーペレーターは記号的萌え要素によって刺激され発火するオタク主体の中の個々の感情的・情動的反応と理解することは可能であろう。だとすると、スタインバーグが議論したアトムのシールをアトラクター、それらを収集し家具や冷蔵庫に貼り付ける子供をコーペレーターと考えることもできる。このとき、アトムのシールを家庭内に貼り付ける子供はシールと室内を統一的にまなざす一点透視図法的視点ではなく、アトムのシールという「アトラクターとの関係で諸要素を統合し差異化する機能」を有しただけの存在である。同時に、ラマールの議論はマルヴィの議論とも意外なほどに近接している。クローズアップによって断片化された女性の身体の平面的イメージというアトラクターに対して、欲望するコーペレーターは異性愛男性の規範を内面化した観客の反応と理解することもできる。マルヴィが前提としていた三次元の優越のもとでは、クローズアップによって断片化された女性身体のイメージは「観客が自分の目前にある画像から距離をとるのを全面的に防いでしま」い、「物語が必要とするルネッサンス的な遠近法の空間と画面上の奥行きの錯覚を無効にしてしまう」という危機を招くものであるが、ラマールの「分配的領域」には劣位の二次元性という発想は存在しない。\n\n以上のことから、アニメにおいて縫合――すなわち作品世界への没入――が十分に機能しないという議論は、別の言い方をすると、キャラクターの目による世界観を通して作品世界全体を鑑賞する大塚的なモデルの機能不全を示している。このことは日本におけるキャラクターの受容の現実をよく反映していると言える。例えば、「倍速視聴」（稲田, 2022）と呼ばれる映像作品を早送りで特定のシーンだけ注目して鑑賞する実践は、作品世界の全体性に注目せず瞬間瞬間のアトラクターによって刺激される快楽の充足を優先した鑑賞あるいは消費のあり方である。これは、東が言うところの、物語の全体性から乖離して個別的な「萌え」要素に反応するだけで、「問主体的な（引用者注 : 複雑な欲望の）構造が消え、各人がそれぞれ欠乏-満足の回路」（東, 2001, 127）に閉塞した状態である「動物化」が現実化していると言うこともできるだろう。\n\n\n平面と遊ぶ主体\n\n主体がイメージによって刺激される動物に過ぎないのかという問いの裏側には、英語圏におけるメディア化した資本主義社会の中で市民の主体的な政治参加が可能なのかという問いがあり、多くの論者が参加すなわち主体の能動性を強調する議論をしている。例えば、池田太臣によれば、アクセル・ブランスは Web 2.0の環境下で、コンテンツの生産者と消費者の区別が曖昧となった状況を「プロデュセイジ(produsage)」と呼んでいる。プロデュセイジは「さらなる改良を追求する、共同的で持続的な、既存のコンテンツの構築と拡張」と定義され、「プロデュセイジの環境においては、ユーザーが作り上げていくコンテンツ生産の過程は、生産者/利用者という区別が重要性を持たず、コンテンツを共有する利用者は、同時に生産者でもある」（池田, 2013, 107-119）とされている。同様の発想は岩渕功一の「プロジューマー(prosumers, producer-consumers)」と「アプロリーダー (approreaders, appropriator-readers)」にも見られる(Iwabuchi, 2010, 87-96)。カルチュラル・スタディーズのオーディエンスの能動性を評価する傾向が、ウェブ 2.0の技術的環境の中で浮上したものであり、したがってヘンリー・ジェンキンズの「参加型文化」(Jenkins, 1992; ジェンキンズ, 2021)とも轍を一にしている。\n\nこういった議論とはかなり様相が異なるが、大塚や東もイメージを通して主体がどのように現実と関わるかという問題意識を共有している。大塚の物語消費と東のデータベース消費を対比し、なぜ「二次創作」という生産活動が「消費」と呼ばれてきたのかを論じた永田大輔の議論がこの点を理解する助けとなる（永田, 2022, 321-337）。大塚は、同じ「世界」をそれぞれの「趣向」として表出しているだけであるという意味で、小さな物語を作り出す二次創作は「生産」ではなく「消費」であるとしている（永田, 2022, 330）。したがって、永田が言うように「大塚が「物語消費論」をマーケティングに過ぎないというのは、彼が行う自己卑下などではなく、文字通りの意味でそうした概念なのである」（永田, 2022, 331）。永田は消費社会の中でオーディエンスの二次創作的生産行為が結局は物語全体を管理する製作者の掌の上で踊らされているだけであり、本当の意味では生産ではないという大塚の問題意識に光を当て直した。永田が指摘している通り、大塚が漫画の描き方講座などを展開し教育に注力しているのは、二次創作という消費にとどまるのではなく自分自身の作品を作り出せることを市民社会にとって重要なことだと考えているからだ（永田, 2022, 334）。\n\nもちろん、ユートピア的にあらゆる種類の二次創作を市民的参加や能動性の発露とみなし肯定的に評価することはできない。しかし、ファン研究は一般的に、商品の消費を後々のより主体的な参加のための第一歩目として重視する傾向がある。例えば、英語圏におけるスラッシュ・フィクションや日本におけるやおいの二次創作は、少なくとも 1970年代から 1980年代の状況においては、男性向けに作られるコンテンツを改変することで女性たちが自分達の欲望を表現する道筋を作った (Jenkins, 1992, 205)。こういった二次創作が原作のコンテンツ提供者によって促進される消費の一形態であるのも事実だが（ジェンキンズ, 2021, 155-169; 大塚, 2018）、同時に、実際に二次創作活動が後の作家を養成する母体となったことも否定できない。\n\n永田が言うように「まんが・アニメ文化をめぐる具体的でローカルな実践記述が必要」（永田, 2022, 335）であり、その一つの事例としてコスプレは重要である。コスプレとは、フィクション作品の登場人物の衣装や髪型を模倣し、登場人物になりきる文化実践である（貝沢, 2018, 57-73）。コスプレ実践と主体の関わりについて田中東子は次のように述べている。\n\n自分自身を別のキャラクターに扮装させることを通じて行使されるこの顕示のための手段は、まったく風変わりな自己の提示方法でもある。自分自身の身体を使いながら、けれども自分そのものを他者に印象づけるのではなく、「キャラクター」という共通の記号を身にまとうことで「私」という自己を打ち消して約分してしまうのだから。その意味でコスプレは匿名化の装置でもある。「オリジナルな自己」を打ち消しつつ目立つ格好をできるという両義牲があるのだ。[…] 着脱可能な「レイヤー化」するアイデンティティの獲得。（田中, 2009, 36-37）\n\nコスプレは平面的なイメージとしてのキャラクターをなんらかの形で利用し「私」という主体を立ち上げる複雑な文化実践である。キャラクターのイメージを身にまとい「着脱可能な「レイヤー化」するアイデンティティ」が獲得されるとき、マルヴィ的なシナリオとは異なる複雑な自己とイメージの関係が展開される。異性愛規範を強化する男性のまなざしと異なって、田中はコスプレイヤーたちの中に女性が多く、彼女たちが男性キャラクターを演じることが支配的な規範を撹乱する可能性を指摘している（田中, 2009, 39-41）。田中は、消費をするときにのみ市民として認めることを「ショッピングモール公共圏」として批判した議論をひいて、女性たちによるコスプレを新しい生きられた DIY文化として捉え直そうとしている。\n\nキャラクターという他者の平面的イメージを纏うコスプレは、自己も複層化させながら、同時に現実の生活で対面する困難と折り合いをつけ対抗する方法となりうる。例えば、東南アジアのイスラム教国家であるマレーシアとインドネシアでは、ヒジャブを漫画やアニメのキャラクターの髪色に合わせるヒジャブ・コスプレが実践されている。そうすることで、ムスリム女性たちがイスラム教の規範の中に留まりつつ自己表現をしている可能性が指摘されている (Yamato, 2020)。また、北米ではコスプレをする際には必然的にエスニシティーの問題が可視化されることになり、「レースベンディング (racebending)」と呼ばれる文化実践が見られる (Kirkpartick, 2019)。レースベンディングとはもともとメディアコンテンツの制作者が役の人種を変更することを批判する用語で、ハリウッドで非白人の役に白人をあてることを意味する「ホワイトウォッシュ」とほぼ同義で使われていた。しかし、#blackwash というハッシュタグと共にアニメや漫画のキャラクターを黒人として描き直すという文化実践も出現し、レースベンディングは主流のメディアにおける人種表象をマイノリティーが自己の生活にひきつける改変をも意味するようになった。小柄なアジア人であるブルース・リーが映画の中で大柄な白人男性を倒すことが 1970年代のアメリカ都市部のエスニック・マイノリティーの若者を勇気づけたように、漫画やアニメのキャラクターのイメージが現代の若者のアイデンティティ政治に取り入れられている (Ongiri, 2002)。ヒジャブ・コスプレやレースベンディングといった文化実践の中では、キャラクターのイメージが素朴に同一化や欲望の対象とされるのではなく、操作・改変可能な平面的な図像として捉えられ、それを身に纏い遊ぶことで複雑な主体を作り出し、また社会との関係を変化させているのである。\n\n\n結論\n\n本稿はまず日本におけるキャラクター文化がその記号的な図像としての平面性をもっており、結果的にトランスメディア的に社会の中に拡散し浸透してきたことを指摘した。この平面性に対して人間主体がどのような関係を持っているのか、また平面性の向こう側に現実の世界がどのように立ち現れるのかを、日本における大塚英志や東浩紀の議論と英語圏の映画理論を参照して概観してきた。永田大輔による二次創作の中に生産と消費の要素が混在していることを指摘した整理を通過することで、主体と平面的イメージとの間に同様の能動性と受動性の混在した複雑な関係性が出現することを指摘した。キャラクターのイメージを纏うコスプレという文化実施は、まさにそのようなイメージの利用を通して社会と交渉し主体を形成する試みである。\n\n\nデータ可用性\n\n本論文には関連データがない。",
"appendix": "参考文献\n\nDayan D: The Tutor-Code of Classical Cinema. Film Quarterly. Oakland:University of California Press; 1974; 28(1): 22–31.\n\nBramesco C: Feels Good Man: the disturbing story behind the rise of Pepe the Frog. The Guardian.2020 Aug 31.Reference Source\n\nIwabuchi K: Undoing Inter-national Fandom in the Age of Brand Nationalism. Vol. 5. . Minneapolis: Mechademia. Minneapolis:University of Minnesota Press;2010; pp. 87–96.\n\nJenkins H: Textual Poachers: Television Fans and Participatory Culture. New York:Routledge;1992.\n\nKirkpartick E: On [dis]play: Outlier resistance and the matter of racebending superhero cosplay. Transformative Works and Cultures. 2019; 29. Publisher Full Text htReference Source\n\nNozawa S: Characterization. Semiotic Review. 2013; 3.Reference Source\n\nOngiri AA: “He wanted to be just like Bruce Lee”: African Americans, Kung Fu Theater and Cultural Exchange at the Margins. J. Asian Am. Stud. 2002; 5(1): 31–40. Publisher Full Text\n\nOudart J: Cinema and Suture. Cahiers du Cinema, 1969-1972: The Politics of Representation. Cambridge:Harvard University Press;1989; pp. 45–57.\n\nRich M: A Morning Surprise for Japan: Shinzo Abe as Super Mario. New York Times;2016 Aug 22.Reference Source\n\nStam R: Film Theory: An Introduction. Blackwell;2000.\n\nSteinberg M: Anytime, Anywhere: Tetsuwan Atomu Stickers and the Emergence of Character Merchandizing. Theory Cult. Soc. 2009; 26: 113–138. Publisher Full Text\n\nYamato E: Self-identification in Malaysian Cosplay. Transformative Works and Cultures. 2020; 34. Publisher Full Text Reference Source\n\n東 浩紀: 動物化するポストモダン:オタクから見た日本社会.講談社;2001.\n\n東 浩紀: ゲーム的リアリズムの誕生:動物化するポストモダン 2.講談社;2007.\n\n池田 太臣: 共同体、個人そしてプロデュセイジ:英語圏におけるファン研究の動向について.甲南女子大学研究紀要甲南女子大学;2013年3月; 第49号. : 107–119.\n\n伊藤 剛: テヅカ・イズ・デッド:ひらかれたマンガ表現論へ.NTT出版;2005.\n\n稲田 豊史: 映画を早送りで観る人たち:ファスト映画・ネタバレ:コンテンツ消費の現在形.光文社;2022.\n\n岩下 朋世: 少女漫画の表現機構:ひらかれたマンガ表現史と「手塚治虫」.NTT出版;2013.\n\n大塚 英志: 定本物語消費論.角川書店;2001.\n\n大塚 英志: キャラクター小説の作り方.講談社;2003.\n\n大塚 英志: アトムの命題:手塚治虫と戦後まんがの主題.Kadokawa;2009.\n\n大塚 英志: 大政翼賛会のメディアミックス:「翼賛一家」と参加するファシズム.平凡社;2018.\n\n岡本 健: アニメ聖地巡礼の観光社会学:コンテンツツーリズムのメディア・コミュニケーション分析.法律文化社;2018.\n\n貝沢 明華: 現代コスプレの分析:キャラクターに近づく写真画像状の身体. ポスト情報メディア論.岡本 健, 松井 広編.ナカニシヤ出版; 2018; 57–73.\n\nコプチェク ジョアン: わたしの欲望を読みなさい:ラカン理論によるフーコー批判. 梶理和子, 下河辺美知子, 鈴木英明, 村山敏勝訳. 青土社. 1998.\n\n小山 昌宏: anime/animationにおける原形質性の再考察:アニメーションにおけるanima概念は有効であり得るか? 日本記号学会編, アニメ的人間:インデックスからアニメーションへ. 新曜社. 2022; 22–45.\n\nジェンキンズ ヘンリー: コンヴァージェンス・カルチャー:ファンとメディアがつくる参加型文化. 渡部宏樹, 阿部康人, 北村紗衣訳. 晶文社. 2021.\n\n須川 亜紀子: 2.5次元文化論:舞台・キャラクター・ファンダム.青弓社;2021.\n\n角井 誠: アンドレ・バザン—「不純な映画」の時代の批評家」. 堀潤之, 木原圭翔編. 映画論の冒険者たち. 東京大学出版会.2021; 74–85.\n\nスタインバーグ マーク: なぜ日本はメディアミックする国なのか. 中川譲訳, 大塚英志監修. Kadokawa. 2015.\n\n田中 東子: コスプレという文化.成実 弘編. コスプレする社会:サブカルチャーの身体文化.せりか書房; 2009; 24–55.\n\n永田 大輔: 「二次創作」はいかなる意味で「消費」 であるのか: 大塚英志の消費論を中心に.日本研究. 国際日本文化研究センター.2022; 65: 321–337.\n\n細馬 宏通: 溶けるチーズ考:「原形質性」の微視的分析と逆アニメーション学. 日本記号学会編. アニメ的人間:インデックスからアニメーションへ. 新曜社. 2022; 117–133.\n\nマルヴィ ローラ: 視覚的快楽と物語映画.岩本 憲, 斉藤 綾, 武田 潔編. 「新」映画理論集成1 : 歴史・人種・ジェンダー. フィルムアート社; 1998; 126–166.\n\nラマール トーマス: アニメ・マシーン : グローバル・メディアとしての日本アニメーション. 藤木秀朗,大崎晴美訳. 名古屋大学出版会. 2013."
}
|
[
{
"id": "163899",
"date": "24 Mar 2023",
"name": "Daisuke Nagata",
"expertise": [
"Reviewer Expertise 文化社会学、映像文化論、社会学、メディア論、アニメーション研究"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n総論 本論は日本発のマンガ・アニメのキャラクター・イメージの拡散を素材に(1)日本で練り上げられてきた議論を整理したうえで、欧米のフィルムスタディーズの議論とトマス・ラマールの議論を接続させつつ論じ、そこで「主体」と平面的な対象の関係という議論の視点を提示したこと、（2）大塚らの議論を基礎としてカルチュラル・スタディーズで問題となってきたアクティブ・オーディエンスをめぐる議論の文脈でいかなる可能性がキャラクター論にあるのかをコスプレなどの具体的な文献をめぐる研究を媒介とさせつつ論じている。 そうした点で非常に野心的な論考であるといえるが、系譜の異なった複数の議論を接続させていることから、(1)と(2)の内部と(1)と（2）の接続のそれぞれについて方法・結論・研究設計に関わる形でいくつか明確化させた方がよいように思われる。\nフィルムスタディーズと東らの議論の接続に関して (1)のパートで最も気になった点として対象と主体の関係こそが重要だという結論が前半で出されており、そこから映画研究の知見を接続させているが、基本的には東の議論のパラフレーズにとどまっているところが多いようにも一見すると見えてしまうことである。その接続自体に一定の意義があることはわかるのだが、その接続を経たことによって、キャラクター文化が拡散し我々の社会に根差すという事態に対して東の議論の知見がどのように変わりうるのかという点についてもう少し明確にしうるのではないだろうか。 読んでいる段階で東の議論の整理がある程度明確であるからこそ、ある程度答えが、出ているように思えてしまい、接続させること意義を途中で見落としてしまう印象がある。 この解決方法としては二つの方向性があるように思われる。それは東の議論の限界や不明確に見える点をもう少し明示化して答えるという方向性である。もう一つの方向性は先に（須川等の議論を紹介したあとに）映画を事例にした主体と対象の関係の議論を紹介し、そのうえで東の議論を解釈しどこまでが映画と主体の解釈の問題として論じられ、どこで息詰まるのかを論じたうえでラマールにつなげるという方向性も存在するように思う。それぞれご検討いただきたい。\n本筋の議論に必要な議論の絞り込みに関して もう一つ、本論の議論の核は主体と対象世界の関係論であるはずなのでその意義をより明確にさせるパートを中心にした方がよいように思う。そのために例えば伊藤剛のキャラ論はこの分野の重要研究ではあるが、本論のキャラに人々はどのようにかかわるのかという問いの視点から考えたときには迂遠な説明である印象が否めないため、もう少し縮減した説明することで意義が明確となりやすいと思われる。また、必須ではないが伊藤のキャラクター論と主体の関係を論じるうえでは足立加勇 2020「人間の表象としてのキャラクターとファンのコンテクストとしてのキャラクター――消費者集団の社会活動が生み出すキャラクターの二面性」(永田大輔・松永伸太朗（編）『アニメの社会学――アニメファンとアニメ制作者たちの文化産業論』ナカニシヤ出版）が参考になると思われる。 また原形質の議論も重要であるが本筋とは外れるため必要があるのか疑わしい説明であるように思う。ここの流れで重要なのは本論の問いが「人々がキャラクターイメージが力を持って人を動員するメカニズム自体の検討」である以上、キャラクター文化が偏在すると同時に我々がそれを同じキャラクターとして享受可能であり、萌えて楽しむことができるのはなぜかという問いを投げかけて、キャラクターの問題を（平面の）対象と人間主体との関係として捉え返す必要があることが提示されることにあるはずだからである。\n情動論とアクティブオーディエンスの関係について 後半部分のラマールの整理から「平面と遊ぶ主体」までの接続（要するに(1)と(2)の接続）の問題についても少し唐突な印象を感じた。動物に過ぎないのかと主体の能動性の問題の記述が唐突に感じるし、この問い自体は例えば東の動物化などでダイレクトに接続されているものではない（のちにつなげようとした議論が存在したのは事実だと思うが）。一案として動物化論と英語圏のアクティブオーディエンスとの接続をするために「平面と遊ぶ主体」の例えば～からの部分とこういった～の段落の部分を入れ替えるなどすると両者の接続がさせやすいのではないだろうか。 本論の問いはA（良きにしろ、悪しきにしろ）「人々がキャラクターイメージが力を持って人を動員するメカニズム自体の検討」とB「キャラクターの拡散」の双方を射程に入れたものである。だが、最後の節では「悪しきにしろ」ではない形でいかなる形で対象世界と主体の関係は可能なのかという点に踏み込んでいるように見える。それ自体は論者の立場としては重要だと思うが、その立場に踏み込むことが明示されないまま議論が進んでいる印象があるので議論の移行点が明示される必要があるのではないだろうか。\n・足立加勇 2020「人間の表象としてのキャラクターとファンのコンテクストとしてのキャラクター――消費者集団の社会活動が生み出すキャラクターの二面性」(永田大輔・松永伸太朗（編）『アニメの社会学――アニメファンとアニメ制作者たちの文化産業論』ナカニシヤ出版\n\n本研究は明確かつ正確に提示されたものであり、最新の文献を引用していますか。 はい\n\n研究設計は適切で学術的価値がありますか。 一部該当\n\n方法と分析について第三者による再現が可能となるよう十分な詳細が提示されていますか。 一部該当\n\n（該当する場合は要回答）統計分析および解釈は適切ですか。 対象外（統計を使っていない\n\n結果の基礎となるソースデータはすべて入手可能で再現性を十全に保証していますか。 ソースデータは不要\n\n結論は結果により妥当な裏付けを得ていますか。 一部該当",
"responses": [
{
"c_id": "10266",
"date": "13 Oct 2023",
"name": "Kohki Watabe",
"role": "Author Response",
"response": "永田大輔様 査読の労をとっていただきお礼申し上げます。丁寧かつ建設的な査読コメントで大変参考になりました。以下、ご指摘いただいた主要な点についてどのように改稿したか、簡単に応答いたします。 【議論の絞り込みについて】 ・「原形質性」についてはおっしゃるとおり議論の本筋からは外れるので、大幅にカットしました。 ・伊藤剛のキャラクター論については、確かに議論全体の流れからすると確かに迂遠だとおもいましたので、彼のキャラクター論全体ではなく本稿の焦点である「キャラ」の部分に絞り込んだ引用をするように整理しました。 ・ご教示いただいた足立加勇氏の論考はおっしゃる通り重要な論点を提示しているものですので、本稿に引用しました。 【フィルムスタディーズと東らの議論の接続に関して】 ・初稿の段階では東の議論とラマールの議論の差異が明示されていないというのは、自分では気づかなかった点で、指摘されて大変納得しました。この点ご指摘いただいて大変ありがたいです。 ・ご提案いただいた改稿方針2つのうちの前者の方針に従い、「分配的領域を見る脱一点透視図法的主体」と題する節の終わりに長めの段落を追加し、東とラマールを対比して整理しました。 【情動論とアクティブオーディエンスの関係について】 ・ご指摘の中で私の議論を整理していただき、その内容によって私の理解も深まりました。ありがとうございます。 ・前述の東の議論を整理する中で、最後の「平面と遊ぶ主体」の節との接続もクリアになり、ご提案いただいた段落の入れ替え等の修正と合わせて、大幅に内容を改稿しました。"
}
]
},
{
"id": "189344",
"date": "18 Aug 2023",
"name": "Hiroshi Morishita",
"expertise": [
"Reviewer Expertise ポピュラー･カルチャー研究"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n総論 本論文は、近年の日本で書かれてきたマンガ・アニメのキャラクター論を概観し、その上でそれを、特に欧米における映画研究やファン研究など、関連する他分野にて培われてきた議論と接続することを試みたものである。この作業を通じては、「キャラクター・イメージが力を持って人を動員するメカニズム自体」（p.3）を議論の俎上に載せることが意図されている。最終的には、トーマス・ラマール『アニメ・マシーン』（2009年）を経由しながら、欧米系の映画理論の主張とは異なる、「平面的なイメージとしてのキャラクターと鑑賞する主体との間に発生する複雑な関係性」（p.3）を明らかにし、受け手の実践が持ち得る可能性に注意を促している。 論旨は明快である上、さまざまな研究領域を横断・整理している本論文は、今後のキャラクター研究の発展にも資するものである。その意味で十分に価値があるものであることは間違いないが、種々の研究を接続する形で議論が紡がれているため、独自の知見に乏しいように感じられる部分があることは否めない（これについては、すでに永田も、前半部分について「東の議論のパラフレーズにとどまっているところが多いようにも一見すると見えてしまう」（p.13）と指摘している）。先行研究の著者の想定とは異なる形でその議論が持ち得る可能性を探っていることをわかりやすく示しておけば、こうした点は多少なりとも軽減されるのではないか。 「大塚と東はともに作品というものが存在することを前提としてその上で鑑賞者とその作品世界との関わりを論じているが、本稿が注目するのは作品世界の境界線を超えて我々の日常生活の中にキャラクターが氾濫しているという事実である」（p.6）と、筆者は述べている。この比較は正確だが、彼らの著作そのものの方向性が筆者の問題関心とは異なることには、もう少し言葉を費やしてもよいだろう。大塚はもちろん、東の『ゲーム的リアリズムの誕生』（2007年）も、小説が読まれる環境それ自体が持つ効果を重視する「環境分析」的な読解によってさまざまなキャラクター小説やゲームを論じるものである。つまり、キャラクターそれ自体をフラットに分析するものではなく、本質的には詩学ないし作品論というべきものだろう。筆者が、作品批評や文化批評、作品論などとはちがう形でのキャラクター論の構築を図っているということと、その積極的な意義とは、この節（「平面の向こう側」）において今以上に強調されてよい。\n「キャラクター論における平面性」に関して その上で、以下では個別の議論に触れておきたい。 「キャラクター論における平面性」の節では、「キャラクターが比較的簡単な線画として平面的に図像化されていることが、そのトランスメディア的拡散を可能にしている」（p.5）と結論づけられているが、もう少し慎重な記述が必要ではないだろうか。これに関しては、永田も挙げていたが、やはり足立加勇「人間の表象としてのキャラクターとファンのコンテクストとしてのキャラクター――消費者集団の社会活動が生み出すキャラクターの二面性」（永田大輔、松永伸太朗編『アニメの社会学 アニメファンとアニメ制作者たちの文化産業論』ナカニシヤ出版、2020年）が重要だろう。 この論考で、足立は、初音ミクなどの例を挙げ、伊藤のいう「キャラ」が、特に消費者の行為によって形づくられたコンテクストによって創出されるものであることを示している。集団内での合意が重要である以上、論理的には、「比較的簡単な線画」ではない形で造形されているキャラクターであっても、トランスメディア的に拡散することは十分に可能である。例えば、アニメ『鉄腕アトム』（1963-66年）と並ぶ1960年代の日本を代表するキャラクターコンテンツとして、『ウルトラマン』（1966-67年）等、怪獣や巨大ヒーローが登場するものがある。実写作品である以上、怪獣の体表などのディテールは本来かなり細かいものではあるが、それらもまたソフトヴィニール製の人形などの形で、スタインバーグの挙げるアトムのシールの場合と同様に、子どもたちの生活に浸透していった。つまり、キャラクターが「比較的簡単な線画」で造形されていることは、送り手や受け手のあいだでの合意形成を容易にするものではあるが、それ自体が「トランスメディア的拡散を可能に」する必須の条件ではない。そのような可能性も考慮に入れる必要があるだろう。\n「平面と遊ぶ主体」に関して 総論の項で述べたとおり、本論文は終盤にて、キャラクターを用いた受け手の実践に、「複雑な主体を作り出し、また社会との関係を変化させ」（p.11）る可能性を見出している。先行研究の読み替えと精緻化から一歩進んで、論者自身の価値判断が展開されているといえよう。 このように自らの見解を提示するにあたり、筆者は、二次創作を「生産」ではなく「消費」であると見なす大塚の見解を取り上げつつ、「実際に二次創作活動が後の作家を養成する母体となったことも否定できない」（p.11）と、これを退けている。筆者のスタンスははっきりしているが、このように論じるのであれば、現在のいわゆる「オタク文化」におけるプラットフォームを通じた動員に関する議論にも踏みこむべきではないか。現在の大塚は、必ずしも学術的な論考に限らない形で、しばしばこうした問題を検討しているからである。 大塚は、角川歴彦のもとでプラットフォームに応じて最適化したヴァリアントを生成する形でのメディアミックス展開が成立したと位置づけている。現在のKADOKAWAも、「ユーザーのコンテンツ制作を誘発し回収するシステム」としてこの延長上にある、というのが彼の分析である。その上で彼は、物語を生成するシステムそのものがだれかに管理される事態そのものに警鐘を鳴らす（『メディアミックス化する日本』イースト・プレス、2014年、p.35）。現在のマンガやアニメ、ゲームなどでは、「ファン活動そのもの」が「エコサイクルとして組み込」まれることが前提となっており、同人誌活動を伴わない場合でも、「アニメーションの舞台の聖地巡礼など、参加者の創造的能力に応じて段階的に用意され、拡張している点で特徴的である」（『シン・モノガタリ・ショウヒ・ロン 歴史・陰謀・労働・疎外』星海社、2021年、p.136）。 こうした大塚的な立場に立つならば、二次創作活動がのちの作家の母体となっていたとしても、プラットフォームによる動員と搾取という問題は揺るがないことになる。また筆者は、田中東子「コスプレという文化」（2009年）を引きながら、「「私」という主体を立ち上げる複雑な文化実践」（p.11）としてコスプレを捉え直しているが、おそらく2009年当時と現在とでもすでに状況は異なっているだろう。コスプレという文化が広がるにつれてDIY性が後退し、「参加者の創造的能力に応じて段階的に用意され」た「参加」の手段のひとつとなり、「ショッピングモール公共圏」に回収されている部分もあるはずである。 いうまでもなく大塚の立論に従う必要はないが、その主張に触れているにもかかわらず、プラットフォームの問題に立ち入らないのはいささかフェアではないように思われる。キャラクター論を精緻化する作業を通じて、東の「動物化」という指摘や大塚の倫理的な批判を乗り越える形で受け手の文化実践の意義を浮かび上がらせることができれば、本論文の意義もより鮮明になるだろう。\n誤字・脱字 以下は単純なミスの指摘である。確認・修正されたい。 p.3 「方法」の節の上から5行目：「伊東」→「伊藤」 p.6 上から3行目：「強調しすることで」→「強調することで」 p.7 下から7行目：「映画的リアリズムという規範からは三次元的間が重視され」→「映画的リアリズムという規範からは三次元的空間が重視され」？\n・足立加勇「人間の表象としてのキャラクターとファンのコンテクストとしてのキャラクター――消費者集団の社会活動が生み出すキャラクターの二面性」永田大輔、松永伸太朗編『アニメの社会学 アニメファンとアニメ制作者たちの文化産業論』ナカニシヤ出版、2020年、pp.204-220 ・大塚英志『メディアミックス化する日本』イースト・プレス、2014年 ・大塚英志『シン・モノガタリ・ショウヒ・ロン 歴史・陰謀・労働・疎外』星海社、2021年\n\n本研究は明確かつ正確に提示されたものであり、最新の文献を引用していますか。 はい\n\n研究設計は適切で学術的価値がありますか。 はい\n\n方法と分析について第三者による再現が可能となるよう十分な詳細が提示されていますか。 はい\n\n（該当する場合は要回答）統計分析および解釈は適切ですか。 対象外（統計を使っていない\n\n結果の基礎となるソースデータはすべて入手可能で再現性を十全に保証していますか。 ソースデータは不要\n\n結論は結果により妥当な裏付けを得ていますか。 はい",
"responses": [
{
"c_id": "10267",
"date": "13 Oct 2023",
"name": "Kohki Watabe",
"role": "Author Response",
"response": "森下達様 今回は査読をお引き受けいただき誠にありがとうございます。論文の細部まで読んでいただき、私が十分に議論しきれなかった部分もフォローするコメントをいただき大変感謝しております。以下、ご指摘の内容への応答を簡単にコメントいたします。 【大塚・東の作品論との対比について】 ・ご指摘のとおり本稿はキャラクターのトランスメディア的拡散が焦点で、大塚・東の作品論的関心の持ち方とは立ち位置が異なるものです。 ・ご教示いただいた足立加勇氏の論考はこの立場の違いを明示するのに大変参考になる論考でしたので、本稿で参照いたしました。 【「比較的簡単な線画」でなくてもトランスメディア的拡散が起こることについて】 ・この点はご指摘のとおりで、「比較的簡単な線画」はトランスメディア的拡散が起こるための「十分条件」ではありません。 ・「平面的キャラクターのトランスメディア的拡散」の節の最後に一段落加筆し、この点について留保をつけました。 【新しい文化的実践が資本主義的プラットフォームに組み込まれることについて】 ・この論点は初稿の段階でうまく言語化できていなかったのですが、森下様のご指摘によって、論点が明確になりました。 ・ご指摘の通り（1）プラットフォームの力は無視できないこと、（2）新しい文化的実践もプラットフォームに組み込まれてDIY性が後退すること、は現実に起きていることであり、これらを過小評価することはできないと考えています。 ・その上で、これらの論点を加え、「平面と遊ぶ主体」の節を大幅に改稿いたしました。"
}
]
}
] | 1
|
https://f1000research.com/articles/12-191
|
https://f1000research.com/articles/12-1325/v1
|
12 Oct 23
|
{
"type": "Research Article",
"title": "Enteric-coating film effect on the delayed drug release of pantoprazole gastro-resistant generic tablets",
"authors": [
"Mosab Arafat",
"Molham Sakkal",
"Mohammad F. Bostanudin",
"Othman Abdulrahim Alhanbali",
"Priya Yuvaraju",
"Rami Beiram",
"Bassem Sadek",
"Amal Akour",
"Salahdein Aburuz",
"Mosab Arafat",
"Molham Sakkal",
"Mohammad F. Bostanudin",
"Othman Abdulrahim Alhanbali",
"Priya Yuvaraju",
"Rami Beiram",
"Bassem Sadek",
"Amal Akour"
],
"abstract": "Background: Enteric coating films in acidic labile tablets protect the drug molecule from the acidic environment of the stomach. However, variations in the excipients used in the coating formulation may affect their ability to provide adequate protection. This study is the first to investigate the potential effects of coating materials on the protective functionality of enteric coating films for pantoprazole (PNZ) generic tablets after their recall from the market. Methods: A comparative analysis was conducted between generic and branded PNZ products, using pure drug powder for identification. The in vitro release of the drug was evaluated in different pH media. The study also utilized various analytical and thermal techniques, including differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier-transform infrared (FTIR), and confocal Raman microscopy. Results: The in vitro assessment results revealed significant variations in the release profile for the generic product in acidic media at 120 min. DSC and TGA thermal profile analyses showed slight variation between the two products. XRD analysis exhibited a noticeable difference in peak intensity for the generic sample, while SEM revealed smaller particle sizes in the generic product. The obtained spectra profile for the generic product displayed significant variation in peaks and band intensity, possibly due to impurities. These findings suggest that the excipients used in the enteric coating film of the generic product may have affected its protective functionality, leading to premature drug release in acidic media. Additionally, the presence of polysorbate 80 (P-80) in the brand product might improve the properties of the enteric coating film due to its multi-functionality. Conclusions: In conclusion, the excipients used in the brand product demonstrated superior functionality in effectively protecting the drug molecule from acidic media through the enteric coating film, as compared to the generic version.",
"keywords": [
"Enteric Coating Film",
"Pantoprazole",
"In vitro Drug Release",
"Analytical Techniques",
"Differential Scanning Calorimetry",
"Thermogravimetric Analysis",
"Generic Drug",
"Polysorbate 80."
],
"content": "Introduction\n\nEnteric coating films play a crucial role in pharmaceutical formulations as they are specifically designed to provide protection from premature releases of the drug molecule in acidic media.1,2 This protective function is particularly essential for drugs that are susceptible to degradation in acidic conditions, such as erythromycin,3 ampicillin,4 and penicillin G antibiotics,5 as well as certain proton pump inhibitors class of drugs, including omeprazole,4 Pantoprazole sodium sesquihydrate (PNZ),6 and esomeprazole.5,7 By forming a protective barrier, enteric coating films ensure the drugs reach their intended site of action intact.5,7 Moreover, enteric coating films also serve to prevent local irritation of the stomach mucosa caused by certain acidic drugs,8,9 including NSAIDs, like diclofenac10 and valproic acid.9 This feature is particularly important for enhancing patient tolerance and reducing potential side effects.8–10\n\nEnteric-coated properties for tablets are commonly achieved through the use of various polymers and additives.11–13 Anionic polymers containing carboxyl groups are frequently employed to achieve the desired enteric effects.14 These polymers are insoluble under low pH conditions but exhibit solubility in intestinal fluid as the pH increases due to the ionization of acidic functional groups, resulting in polymer swelling.11,14 Common examples of anionic polymers used for enteric coating include cellulose acetate,15 polyvinyl acetate,16 hydroxypropyl methylcellulose,17,18 and methacrylic acid copolymers.11–13 Additives play a crucial role in polymer formulations, enhancing mechanical properties,19 modifying film permeability,19 facilitating film formation,12 and improving processing.12,20 Several commonly used additives serve these purposes effectively. For instance, plasticizers like Polysorbate 80 (P-80),21 tributyl citrate,22 and diethyl phthalate23 increase film flexibility, reduce brittleness, and influence drug release by minimizing crack formation.12,24 Anti-adherent materials, such as Talc25,26 and Glyceryl monostearate,27 are employed to reduce film tackiness and prevent substrate agglomeration.12,28 Additionally, surfactants like P-80,29 sorbitan monooleate,30 and sodium dodecyl sulfate31 are utilized to emulsify water-insoluble plasticizers, improve substrate wettability, and stabilize suspensions, thereby enhancing the overall properties of the enteric coat film.12,29\n\nGeneric drugs are manufactured by pharmaceutical companies in accordance with FDA.32,33 These regulations mandate that generic drugs have the same active ingredients, dosage form, strength, and route of administration as their brand-name counterparts and must be bioequivalent.26,32,34 However, certain variations in excipients are permitted.35,36 Although generic drugs are generally considered bioequivalent, some enteric-coated generic drugs have shown compromised functionality in protecting the drug molecule, resulting in premature drug release in simulated acidic media at physiological pH,37–39 such as omeprazole enteric-coated capsules,39 diclofenac enteric-coated tablets,38 lansoprazole enteric-coated tablets,40 and PNZ enteric-coated tablets.37\n\nIn this study, PNZ enteric-coated tablets were chosen as the model generic drug for comparison with the branded one, which was used as a reference. The generic product of PNZ was selected due to the reported issues that led to its recall from the local market. The chemical name of PNZ is Sodium 5-(difluoromethoxy)-2-(3,4-dimethoxy-2-pyridinyl)methyl)sulfincyl]-1H-benzimidazole sesquihydrate.41 It is primarily used as an anti-ulcer agent to treat duodenal and gastric ulcers.11,42 PNZ is classified as a class III drug according to the Biopharmaceutics Classification System (BCS), which indicates high solubility and low permeability.43,44 PNZ has a molecular weight of 432.4 g/mol11 and a melting point of 149-150°C.11,45 It is highly soluble in water,46 slightly soluble in chloroform,11 and practically insoluble in n-hexane.11 PNZ has a pKa value of 3.55 and a LogP value of 2.11.47 PNZ is a drug that is susceptible to degradation in the acidic environment of the stomach.48 therefore, commercially available enteric-coated tablets or capsules of PNZ are used to avoid the drug molecule degradation in acidic environments, ensuring its effectiveness.37,49\n\nSeveral research studies have reported a reduction in the function of the enteric coating film, attributed to multiple possible factors.2,50–52 Therefore, maintaining the integrity of the enteric coating film primarily relies on the type and quantity of polymers and additives used for the film coating, as well as the manufacturing process.2,53 Several research studies have emphasized the importance of analyzing and evaluating the quality and functionality of enteric-coated medications using a range of analytical and thermal techniques.37,39,45 For instance sesquihydrate PNZ generic medication showed a different thermal profile than monohydrate PNZ when subjected to differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA).45 Fourier transforms infrared (FTIR) and Raman spectroscopy also revealed a significant difference in the spectra between monohydrate and sesquihydrate forms of PNZ drug molecule.45 In another study, premature drug release from enteric-coated generic PNZ tablets was observed in acidic media during in vitro dissolution evaluation.37 Furthermore, scanning electron microscopy (SEM) and X-ray diffraction (XRD) examinations demonstrated the absence of enteric coating on some granules of generic omeprazole capsules.39 These findings emphasize the importance of selecting suitable type and amount of ingredients to formulate the enteric coating film, as well as implementing an appropriate manufacturing process.\n\nTherefore, the aim of this study was to find out the effect of coating film materials on the protection of PNZ drug molecules in acidic pH media. Both the brand and generic products of PNZ were utilized to compare any possible differences, with the brand product serving as the reference. Hence, the pure powder of PNZ was used for the drug identification process. To achieve these objectives, a range of analytical and thermal techniques, including DSC, TGA, XRD, SEM, FTIR, and Confocal Raman Microscopy, were used. Additionally, the in vitro drug release rate was evaluated in different pH media. To the best of our knowledge, no prior studies have been conducted on generic PNZ after has been recalled from the local market.\n\n\nMethods\n\nThe generic product of PNZ and the brand product of PNZ were ordered from Boots Pharmacy (Dubai, UAE). The pure powder of PNZ was purchased from Sigma Aldrich (St. Louis, MO, USA).\n\nThe disintegration characteristics for both branded and generic tablets of PNZ were evaluated using the fully automated disintegration instrument (PTZ Auto EZ, Hainburg, Germany). The procedure was performed using 0.1 N hydrochloric acid as the disintegration medium for a duration of 1 h. The temperature was maintained at 37 ± 0.5°C and the specific disintegration time of each tablet was recorded. The expectation was that all six tablets from each product would disintegrate within the predetermined time frame.\n\nThe drug release of branded and generic products of PNZ was evaluated using the Dissolution Apparatus 2 model Dis 8000 (Copley Scientific, Nottingham, UK) under controlled conditions. The dissolution was carried out at a constant temperature of 37 ± 0.50C and a stirring speed of 75 rpm. During the incubation process, three different media with a volume of 900 mL were used, each with a pH value of 1.2, 5, and 6.8. At two time intervals, 60 and 120 min, a sample of 5 mL was taken from each vessel and replaced with an equal volume of distilled water. All collected samples were filtered to eliminate any unwanted particulate matter and diluted with distilled water. The drug concentration in each sample was measured through ultraviolet spectrophotometry analysis at a wavelength of 290 nm. To ensure the accuracy and reliability of the results, each product involved six samples (n=6).\n\nDSC-60 Plus instrument (Shimadzu, Kyoto, Japan) was utilized to analyze the thermal profile for the pure powder of PNZ, the brand product of PNZ, and the generic product of PNZ. a precise amount of 3-5 mg powder was weighed and transferred into sample pans for each product. The analysis was conducted under controlled conditions, where the samples were scanned over a temperature range of 25-350°C at a rate of 10°C per min while being exposed to a continuous flow of nitrogen at a rate of 100 mL/min. The resulting data was collected and processed using the Lab Solutions TA software. To ensure the statistical significance of the results, the experiment was repeated six times for each product, resulting in a total of six samples (n=6).\n\nThe Thermal Gravimetric Analysis (TGA) of the three samples was carried out using the TGA-50 instrument (Shimadzu, Kyoto, Japan). For each sample, an accurate amount of 10-15 mg powder was weighed and loaded into an alumina pan for analysis. The analysis was performed by scanning the samples over a temperature range of 0°C to 600°C at a rate of 15°C per min, while being exposed to a continuous flow of nitrogen at a rate of 50 mL per min. The Lab solutions TA Thermal Analysis Workstation software was used to closely monitor and regulate the analysis process. To ensure the statistical significance of the results, the experiment was repeated six times for each product, resulting in a total of six samples (n=6).\n\nThe crystalline structure for the pure powder of PNZ, the brand product of PNZ, and the generic product of PNZ were determined using XRD 6100 (Shimadzu, Kyoto, Japan). XRD patterns were collected for the tablets and a reference standard by scanning 2θ over a range of 10° to 80° at a rate of 2° per min.\n\nThe JSM-6010PLUS/LA scanning electron microscope (JEOL, Tokyo, Japan) was used to examine the morphological characteristics for the pure powder of PNZ, the brand product of PNZ, and the generic product of PNZ. To prepare the samples for examination, a small amount was affixed to the specimen holder stub via double-coated adhesive carbon tape. Prior to the 20-kilovolt test, the sample was coated with a layer of gold for 10 min in a vacuum environment using the Cressington sputter coater 108 autos. After applying the gold coat, the sample was positioned on the sample stage and examined using the SEM In Touch Scope software version 2. The process was carried out with precision to ensure the quality of the analysis.\n\nThe Fourier Transform Infrared spectra for the three samples were recorded using a Thermo Nicolet Nexus 670 spectrometer (GMI, Ramsey, USA). To facilitate the measurement process, each sample was separately mixed with dry Potassium Bromide at a ratio of 1:100 and subsequently compressed into pellets. The transmittance of the samples was measured within a range of 4000 cm-1 to 450 cm-1, with the spectra obtained from 32 scans. To ensure the accuracy and reliability of the data, the results were then processed using the OMNIC 9 software.\n\nThe Raman spectra of the pure powder of PNZ, the brand product of PNZ, and the generic product of PNZ were obtained using the Confocal Microscope Raman/PL System (NOST, Daejeon, Korea). The samples were placed on a glass slide and subjected to a 5s laser exposure using a 20X objective lens to perform Raman mapping. The Raman shift range of each sample was scanned, spanning from 0 cm-1 to 4000 cm-1, and the corresponding counts were recorded. The RAON-SPEC program was then utilized to analyze the obtained samples.\n\nThe mean values of the determined variables were compared using the Independent Sample T-test for statistical analysis of variance. If p < 0.05, the differences were considered significant. The Statistical Package for Social Science (SPSS) Version 26 was used for the analysis.\n\n\nResults\n\nThe drug released from the branded and generic product of PNZ exhibited only slight differences (p > 0.05) in the first hour in the three different pH dissolution media, as presented in Figure 1.78 However, Figure 2 revealed a significant difference (p < 0.05) in the percentage of drug released between the two products in the pH 5 media after 120 min. The drug release exceeded 10% in the acidic media, which was not in compliance with the United States Pharmacopeia (USP) specifications for enteric-coated tablets.37 In contrast, the brand product PNZ complied with the USP specifications for drug release in acidic media.37 These findings were further supported by the disintegration results, whereas the generic tablet disintegrated in the acidic media, while the branded tablet demonstrated resistance to the same media.\n\nValues are expressed as means ± S.D. (n=6).\n\nValues are expressed as means ± S.D. (n=6).\n\nFigure 3 demonstrates the thermal profiles for the pure powder of PNZ, the brand product of PNZ, and the generic product of PNZ. Slight difference in the endothermic peak temperature corresponding to the melting point between two products of PNZ (p > 0.05) were observed. The generic product had the highest recorded endothermic peak temperature at 164.29°C, as compared to the brand product which exhibited an endothermic peak of 161.74°C. However, the energy absorbed was greater for the brand product at nearly 51.65 J/g and 49.52 J/g for the generic product.\n\nFigure 4 represent the thermal profile obtained by TGA for the pure powder of PNZ, The brand product of PNZ and the generic product of PNZ. slight differences were observed among the TGA results of the two samples (P > 0.05). The weight loss for all samples occurred mainly in two stages, with a lower (Tonset) observed for the generic product compared to the brand product in both stages. In the first stage, the brand product had a (Tonset) of 140.44°C, and the generic product had a (Tonset) of 120.00°C. In the second stage, the (Tonset) values were 379.08°C, and 351.08°C for brand product, and generic product, respectively. The total weight loss for the two samples was slightly higher for the generic product (84.06 %) compared to the brand product (81.58%).\n\nFigure 5 represents the crystalline atomic arrangement of the three samples and shows a clear pattern in their diffraction analysis. Although the peak positions of the three samples were similar, the intensity of the peaks varied between the generic and branded PNZ products. The generic sample exhibited lower peak intensity values compared to the branded sample. The main peaks were observed at 2θ angles of 13°, 14°, 16°, 21°, 39°, and 44°. The differences in peak intensity between the generic and branded products may suggest some variations in the crystalline form of the drug powder in the generic product.\n\nThe SEM in Figure 6 displays three images: a) the generic product of PNZ, b) the brand product of PNZ, and c) the pure powder of PNZ. These images provide detailed information on the surface morphology, particle size, and shape of the three samples. The pure powder of PNZ and the brand product of PNZ exhibited similar particle sizes, ranging from 10-20 um. In contrast, the generic product of PNZ had a particle size range of 5-10 um. Upon closer examination of the SEM images, it was observed that the pure powder exhibited clear and smooth particle surfaces, whereas the brand product of PNZ and the generic product of PNZ displayed a coarse surface.\n\nCaliper indicates 5-20 μm. Images were obtained under x850-5000 - magnifications operating at 20 kV.\n\nThe FTIR spectra, presented in Figure 7, provide essential qualitative data for the generic product of PNZ by illustrating the bands that correspond to the functional groups of the chemical structures shown in Figure 8. The characteristic bands in the fingerprint regions below 1500 cm-1 demonstrate a similar wave number for the three samples, with less intensity noted for the generic product compared to the other two samples. For example, the C-O stretching vibration is represented by a medium-sharp peak at 1100 cm-1 wave number.\n\nThe diagnostic region for the three samples shows almost similar peak positions, with variations in intensity for the generic product of PNZ. The three spectra exhibit the following band positions: N-H bending vibration (secondary amine) at 3400 cm -1, C-H aromatic stretching at 3100 cm -1, carbonyl functional group at 1700 cm-1, and N-H bending vibration at 1589 cm-1 wave number.\n\nThe spectra profile of the pure powder of PNZ, the brand product of PNZ, and the generic product of PNZ are presented in Figure 9. It was observed that the three spectra had several similar peaks at the same Raman shift, with varying intensities. These peaks mainly corresponded to the functional groups of the PNZ molecule, as shown in Figure 8. The main peaks were demonstrated in Table 1, which included the attributed functional group and intensity for the three different samples.\n\n\nDiscussion\n\nTo our knowledge, the current study was the first of its kind to highlight the various possible effects of coating material on the protective functionality of enteric coating films for PNZ generic tablets after their recall from the market, using a range of analytical and thermal techniques.\n\nThe premature drug release in acidic media for the generic product, compared to the branded product, suggests a weaker resistance of the enteric coating film in the generic tablet.37,54,55 Extensive literature indicates that various factors contribute to diminishing the protective functionality of the generic tablet in acidic media.37,56–58 Among these factors, the type and amount of excipients used in the enteric coating film have been identified as the primary ones. According to the medication leaflets, both the generic and branded products contain common excipients such as hypromellose, povidone K25, titanium dioxide, yellow iron oxide, propylene glycol, and methacrylic acid ethyl acrylate copolymer (1:1). However, P-80 is present only in the enteric coating film of the branded product.\n\nThe presence of P-80 in the enteric coat formulation for the brand product of PNZ is presumed to play a crucial role in preventing premature drug release in acidic conditions. This effect is attributed to the plasticizing properties of P-80, which enhance the integrity of the enteric coating film.49,59 This finding aligns with several previous research studies that have demonstrated how the addition of P-80 to the enteric coating improves the smoothness and continuity of the film, ultimately preventing cracking in acidic conditions.59–61 In contrast, the generic product of PNZ does not contain P-80 in its enteric coat formulation, potentially contributing to the premature drug release in acidic media.59 These findings are consistent with previous studies that have shown that the presence of P-80 in enteric coat formulations can enhance the ability of the enteric coat in protecting the tablet from the premature drug release in acidic conditions.59,62\n\nThe DSC thermal analysis profile of the branded and generic products provides valuable information about their respective thermal behaviors. The slight difference in the melting points between the two products indicates the presence of the same drug molecule in both samples, as they fall within the same range for the pure powder of PNZ melting point.26,63,64 However, a slight decrease in the area under the curve for the generic product may indicate the presence of some impurities.63–65 These findings are consistent with several previous research studies that have shown a reverse proportional relationship between the presence of impurities in drug formulations and the corresponding area under the curve in DSC analysis.63,64 Another factor that could be contributed to the slight variation is the absence of P-80 as a plasticizer in the generic product of PNZ, potentially leading to a higher melting point.66–69 the presence of a plasticizer in the brand product of PNZ may have slightly lowered its melting point by enhancing flexibility and elasticity.66–69 These findings align with previous studies that have shown a decrease in the melting point of a formulation upon the addition of a plasticizer.68–70\n\nThe TGA results support the DSC findings. The absence of a plasticizer in the generic tablet may have slightly affected the thermal behavior of the polymer used in the binder, resulting in a higher weight loss during TGA.66,69 Furthermore, the presence of the plasticizer in the brand tablet may have increased the thermal profile of the polymer in the binder and prevented the onset of weight loss at lower temperatures, leading to a lower weight loss during TGA.66,69,71 Overall, these results may demonstrate the possible influence of impurities and P 80 on the thermal behavior of the samples.\n\nThe XRD results obtained from the three samples provide valuable information on the crystallite structure, size, and degree of crystallinity of the drug particle. The similarity in the position of the peak for the two products suggests that both the brand and generic products contain the same crystalline structure.72 The observed difference in peak intensity between the pure powder of PNZ and the other two samples might be attributed to the absence of excipients in the pure powder of PNZ.69,71 This finding was supported by the smooth surface displayed for the pure powder by SEM, whereas the surface of the generic and brand product of PNZ was coarse due to the existence of excipients.73 The higher peak intensity observed for the brand product compared to the generic product may indicate a more ordered crystal structure for the branded product.69,72 Our results are inconsistent with previous studies, which showed almost similar peak positions for the PNZ drug molecule.74\n\nThe FTIR spectra for both the generic and brand products showed similarities in the band positions when compared to the reference pure powder, suggesting that there was no interference between the drug molecule and the excipients used in both products and confirming the presence of the PNZ drug molecule in both.60,75,76 However, differences in band transmittance were observed between the generic and brand samples, which could be attributed to the presumed presence of impurities in the generic PNZ product.55,76–77 These findings are consistent with previous literature that reported no alteration in the band position for PNZ in the formulation, except for the band transmittance.55 Raman spectra for all three samples showed comparable results to the FTIR, further supporting the concept that the differences observed in the FTIR spectra of the generic and brand products might be due to the presence of impurities.55,76\n\n\nConclusion\n\nIn conclusion, this study highlights the functionality role of the coating materials in the formulation of enteric-coated PNZ generic tablets. It was observed that the variation in the excipients used in the enteric coating of generic products of PNZ affected its protection functionality, leading to premature drug release in acidic media. On the other hand, the brand product showed superior functionality in protecting the drug molecule in acidic media, which might be attributed to the presence of P-80 as a plasticizer and emulsifier in the enteric coating film alongside anionic polymer. Also, the presence of impurities was obvious in the generic product of PNZ. The number of analytical and thermal techniques used in this study provided valuable insights into the differences between the generic and brand products of PNZ. Overall, the findings of this study have significant implications for the development of enteric-coated generic drugs and emphasize the importance of selecting suitable coating materials.",
"appendix": "Data availability\n\nFigshare: Enteric-Coating Film Effect on the Delayed Drug Release of Pantoprazole Gastro-Resistant Generic Tablets. https://doi.org/10.6084/m9.figshare.23979114.v1. 78\n\nThis project contains the following underlying data:\n\n- Data_01_SEM (F1000R).pdf\n\n- Data_4_Xray.pdf\n\n- Data_3_Xray.pdf\n\n- Data Prepared for Statistical Analysis of Generic and Brand PNZ_4a.pdf\n\n- Dissolution release assessment for PNZ_5a.pdf\n\n- Statistical Analysis of Generic and Brand Product Release in Different pH Media_6a.pdf\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nWe extend our sincere thanks to Al Ain University and United Arab Emirates University for providing the necessary lab facilities and invaluable support for this research study.\n\n\nReferences\n\nMaderuelo C, Lanao JM, Zarzuelo A: Enteric Coating of Oral Solid Dosage Forms as a Tool to Improve Drug Bioavailability. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nBouchoul B, Benaniba MT, Massardier V: Thermal and Mechanical Properties of Bio-Based Plasticizers Mixtures on Poly (Vinyl Chloride). Polímeros. 2017; 27: 237–246. Publisher Full Text\n\nGorajana A, Garg S, Koh P, et al.: Formulation Development and Dissolution Rate Enhancement of Efavirenz by Solid Dispersion Systems. Indian J. Pharm. Sci. 2013; 75: 291–301. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFawcett TG, Gates-Rector S, Gindhart AM, et al.: A Practical Guide to Pharmaceutical Analyses Using X-Ray Powder Diffraction. Powder Diffract. 2019; 34: 164–183. Publisher Full Text\n\nAlyami H, Dahmash E, Bowen J, et al.: An Investigation into the Effects of Excipient Particle Size, Blending Techniques and Processing Parameters on the Homogeneity and Content Uniformity of a Blend Containing Low-Dose Model Drug. PLoS One. 2017; 12: e0178772. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGonzalez D, Golab JT, Kaduk JA, et al.: Crystal Structure of Pantoprazole Sodium Sesquihydrate Form I, C 16 H 14 F 2 N 3 O 4 SNa(H 2 O) 1.5. Powder Diffract. 2020; 35: 53–60. Publisher Full Text\n\nSeçilmiş Canbay H, Doğantürk M: Compatibility Studies of Sildenafil with Different Excipients by Using TGA, DSC, XRD and FTIR. Celal Bayar Üniversitesi Fen Bilim. Derg. 2019; 15: 401–407. Publisher Full Text\n\nMonajjemzadeh F, Hassanzadeh D, Valizadeh H, et al.: Compatibility Studies of Acyclovir and Lactose in Physical Mixtures and Commercial Tablets. Eur. J. Pharm. Biopharm. 2009; 73: 404–413. PubMed Abstract | Publisher Full Text\n\nEbrahimi S, Sipaut CS: Synthesis of Hydroxyapatite/Bioglass Composite Nanopowder Using Design of Experiments. Nanomaterials. 2022; 12: 2264. PubMed Abstract | Publisher Full Text | Free Full Text\n\nArafat M, Sakkal M, Bostanudin MF, et al.: Enteric-Coating Film Effect on the Delayed Drug Release of Pantoprazole Gastro-Resistant Generic Tablets. [Dataset]. figshare. 2023. Publisher Full Text"
}
|
[
{
"id": "249483",
"date": "20 Mar 2024",
"name": "Jiyauddin Khan",
"expertise": [
"Reviewer Expertise Extremely interested in Research Oriented Works of Pharmaceutical Technology (Drug Development",
"Dosages form Design",
"Drug Delivery and Novel Drug Delivery Systems) related to Controlled-release/ Sustained-release Matrix Formulations etc. Beside these interests",
"also I am highly interested in Clinical Trials / Bio-equivalence Studies",
"Halal Pharmaceuticals & Cosmeceuticals etc."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nREVIEWER COMMENTS: A & B\n(A). The manuscript entitled “ENTERIC-COATING FILM EFFECT ON THE DELAYED DRUG RELEASE OF PANTOPRAZOLE GASTRO-RESISTANT GENERIC TABLETS” was reviewed prudently, and it was felt that this type of research work contributes to the pharmaceutical science in terms of developing several solid dosage forms.\nThis manuscript is well written scientifically & grammatically. On a scientific ground, the idea of the manuscript is novel and significant. The paper contains new information that is adequate to justify publication but suggests some minor revisions to the manuscript. Overall, the manuscript is good and well-written.\n(B). A few minor corrections are suggested, and comments to the authors are listed below.\nScientific Comment & Suggestions:\n1. The introduction part is too general; it is required to write up some more if possible. I suggest elaborating on the strength of the concern area will be a more comprehensive approach than describing the general contents.\n2. The literature review given in the manuscript is substantial, with considerable planning, methodical searches, and attention to detail. The information covered in the process has provided valuable input for the research.\n3. The research methodology in the manuscript has covered all study design, data, & statistical analysis, as well as ethical considerations.\n\n4. Results and discussions are presented and comply with the manuscript, which required fitting with the aims and objectives of the research work. The discussion of research is done extensively and is appropriately compared with other research findings, etc.\n5. The research findings of the current research works are concluded properly, if possible, can be concluded with appropriate recommendations, and further suggestions etc.\n6. I verified that all the references given are cited in this manuscript. However, the formatting of the references requires multiple citation formats (APA, Harvard, MLA, and Chicago manual style). The date of reference should be mentioned, and the internet citations are changed periodically. I request that you please follow only one citation format and apply it to all.\n\n7. The figure and table are properly placed in the correct location according to their descriptions.\nGeneral Comments:\nI do accept that as we all are non-English speakers the language proficiency will always be a barrier to maintain the standards. Therefore, I suggest the candidate do thorough language editing for this manuscript.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "249484",
"date": "08 Apr 2024",
"name": "Goutam Kumar Jena",
"expertise": [
"Reviewer Expertise Nanotechnology",
"novel drug delivery systems",
"polymeric nanoparticles and Nano structured lipid carriers"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript \"Enteric-coating film effect on the delayed drug release of pantoprazole gastro-resistant generic tablets\" was found to be interesting. The authors are investigating the effects of enteri-coating effect on the delayed drug release of pantoprazole gastro-resistant generic tablets and compared with the reference standard and concluded that the excipients used in the brand product demonstrated superior functionality in effectively protecting the drug molecule from acidic media through the enteric coating film, as compared to the generic version. The data presentation and results section are good but the discussion section needs to be improved by citing more.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1325
|
https://f1000research.com/articles/12-1324/v1
|
12 Oct 23
|
{
"type": "Case Report",
"title": "Case Report: An infant with agenesis of the corpus callosum (AgCC) with normal developmental milestones",
"authors": [
"Varsha Lamture",
"Prajwal Lamture",
"Yeshwant Lamture",
"Varsha Lamture",
"Prajwal Lamture"
],
"abstract": "Background: Agenesis of the corpus callosum (AgCC) is a unique and rare brain malformation that can have long-term effects on the cognitive and neurological development of those affected. Individuals with AgCC must undergo regular neuropsychological screening to secure conceivable problems and diagnose and tackle them at the appropriate times. Case report: This case is of a male-term infant born through vaginal delivery to a primigravida mother. Antenatal history was insignificant. Fetal Ultrasonography (USG) done at 24 weeks of gestation showed AgCC. The risk factor was explained to the parents, but they wanted to continue the pregnancy. The infant was delivered at term gestation and weighed 2500 gm. The baby was discharged from the hospital and was advised for follow-up. On follow-up, milestones were normal. Magnetic resonance imaging (MRI) of his brain at 24 months during follow-up showed total AgCC. Surprisingly, milestones were not delayed for his age, so he was advised to screen for neurocognitive in the subsequent follow-up. Discussion: AgCC is typically diagnosed through antenatal MRI or genetic testing, but it may be isolated in cases where no additional anomalies are present. It is also associated with various hereditary syndromes, and prenatal diagnosis through Ultrasonography (USG) can be performed between 18 and 22 weeks of gestation to identify features suggestive of AgCC so that early intervention can be done. Though we do not have exact treatment, supporting treatment is equally important to combat further complications. Conclusions: Despite diagnostic tools for AgCC, many physicians are not familiar with the neurological and cognitive features of AgCC, which can lead to delayed management and treatment. Therefore, medical professionals must receive education and training on this condition to manage individuals with AgCC and receive the most supportive care they need.",
"keywords": [
"Cerebral malformations",
"Intellectual disability",
"Neurocognitive development",
"Neuropsychological testing",
"genetic background"
],
"content": "Introduction\n\nAgenesis of the corpus callosum (AgCC) is a rare brain disorder presented as total absence or isolated agenesis. The worldwide incidence rate is 0.5 per 10000 live births, while the prevalence has been estimated to be as high as 230 in 10,000 for children with developmental issues.1 Corpus callosum is a collection of nerve fibers that helps connect two cerebral hemispheres, which is important for communication. It controls movements, cognitive skills, and power of sight. It develops around 70-74 days of gestation and completes about 100 to 115 days.2 The exact cause is not known, but there are links to ingestion of alcohol during pregnancy, phenylketonuria, Chiari 2 malformation, genetic factors like Apert syndrome, Joubert syndrome, X-linked like Aicardi syndrome.3\n\nIt's true that despite the connection between agenesis and associated issues with AgCC, the range of neurological assessment can vary significantly from normal to severe.4 This demonstrates that developmental problems can present in various ways, and it's crucial to have a comprehensive understanding of each case.\n\nPatients who have isolated AgCC with no cognitive dysfunction initially can develop neurological disorders later in life as cognitive demands increase with age. Regular neuropsychological screening is highly recommended for individuals with AgCC. This can help identify any underlying problems associated with AgCC and ensure they are addressed promptly. With a comprehensive understanding of each case, it's possible to address developmental issues in various ways and ensure that the appropriate interventions are put in place as needed.\n\nWhile there is no cure for AgCC, early diagnosis and symptomatic treatment can help prevent complications.5 This includes physiotherapy, occupational therapy, and speech therapy. It is crucial that individuals with AgCC receive empathetic care and adequate counseling toward the family to ensure future care.\n\n\nCase report\n\nA full-term male newborn delivered vaginally was brought to the present center. Their birth weight was 2.5 kg. The mother was primigravida, with no history of consanguineous marriage, no history of abortion, or congenital anomalies in the family. The antenatal and postnatal history was not significant. Fetal Ultrasonography (USG) was done at 24 weeks of gestation, which showed signs of AgCC (Figure 1).\n\nThe risk factor was explained to the parents, but they wanted to continue the pregnancy. A postnatal cranial ultrasonography scan showed complete AgCC. MRI (magnetic resonance images) show complete callosal agenesis (Figure 2). The occipitofrontal circumference was at the 95th percentile, and general and systemic examination was normal.\n\nAfter a 10-day stay in the hospital, the baby was advised to return after a month for a routine checkup and immunization. The mother was explicitly advised to keep a notebook for recording the date of noticing new developmental milestones, which were checked during each follow-up visit. Hearing screening and eye examination were done at two months, which was normal. Genetic and metabolic screening were not performed as the parents were not willing. On follow-up, the infant's head circumference and domains of development were noted: neck holding at three months, sitting without support at seven months, standing with support at 9month, and walking alone at 15 months. Fine motor development, reaching objects with both hands at four months, pincer grasp at 12 months of age. Personal and social understanding included a social smile for two months, recognizing their mother at three months, Language had a syllabus at nine months,1-2 meaningful words at 12 months, and vision and hearing were normal for his age.\n\nHis brain's magnetic resonance imaging (MRI) was repeated at 24 months of age and showed total AgCC. His pattern of postnatal growth and neurocognitive development was normal. During the medical examination, he was alert, aware, oriented, and asymptomatic. His Language was normal for his age, and gross and fine milestones were according to age. Intelligent quotient (I.Q.) done, found to be 1 which is within the normal IQ range at this age (1 to 10). Blood tests were taken for liver function, kidney function test, serum electrolytes, vitamin B12, and folic acid, which showed a normal range. We planned a similar blood test every six months of his visit. Neurologist appointments will be taken every two months during his visits to the hospital.\n\n\nDiscussion\n\nAgenesis of the corpus callosum (AgCC) is a congenital disability in the brain where the corpus callosum is missing or partially missing. It can occur alone or with other brain and extracranial malformations. AgCC is associated with many factors, such as intrauterine injury or infection, ingestion of alcohol during pregnancy, or genetic syndromes like Dandy-Walker syndrome, Andermann syndrome, and autosomal dominant, recessive, and X-linked. AgCC can develop neurological and cognitive disorders later in life, so it is crucial that individuals with AgCC undergo regular neuropsychological screening to ensure timely identification and address of potential issues. Physicians and medical professionals should receive education and training on this condition to provide individuals with AgCC the care and support they need to thrive. While there is no specific treatment for AgCC, early diagnosis and symptomatic treatment can help prevent complications. It is essential that individuals with AgCC receive empathetic care and adequate counseling for their families to ensure future care.6\n\nIn a recently published case report, Pierre-Kahn et al. evaluated the guideline that agenesis of the corpus callosum (AgCC) is considered isolated when antenatal MRI or genetic tests do not indicate additional anomalies. This guideline was assessed in the case study context, highlighting the importance of regular neuropsychological screening and empathetic care for individuals with AgCC.7\n\nIt's interesting to note that AgCC can be associated with various congenital syndromes related to different exposures and genetic disorders, as Tomasch J et al. discussed in their findings, which were not seen in the present study.8 Fetal alcohol syndrome (FAS) was found by Mattson SN et al. to be a significant non-genetic congenital cause of AgCC in their study, which was not seen in the present case report.9\n\nThe study by Santo S, D'antonio F et al. revealed that Ultrasonography (USG) performed during the 18-22 weeks of gestation could detect features indicative of AgCC. It's fascinating to see how technology has advanced to the point where such diagnoses can be made early on in a pregnancy. It's crucial to detect such anomalies as early as possible to ensure the best possible outcome for the child. USG was done in the present case report, similar to the above study.10\n\nIt has been shown in a study conducted by Yakovlev PI et al. that patients with isolated AgCC and normal intelligence could significantly benefit from early detection of neurocognitive anomalies. They may improve their independence and compensate for deficits by receiving timely rehabilitative strategies. This information was considered and followed in the present case report, which suggests that Ultrasonography performed between 18 and 22 weeks of gestation could potentially diagnose features indicative of AgCC and have significant implications for diagnosing and managing this condition.11\n\nIt's worth noting that individuals with AgCC may encounter challenges when integrating or interpreting social and emotional information, as demonstrated in a study conducted by Brown WS, Paul LK, et al. However, the present case report did not show any such difficulties. Instead, it highlighted the vital role of early detection and timely rehabilitative measures in enhancing independence and compensating for deficits in patients with isolated AgCC and normal intelligence.12\n\nIndividuals with isolated primary AgCC typically have a favorable functional outcome, with minimal impact on their overall cognitive capacity, as Fischer M et al. demonstrated in their study, similar to a present case report. However, there are still disabilities consistently observed in isolated cases, such as difficulties with abstract reasoning, problem-solving, and category fluency, which require follow-up. This was an essential consideration in our case report when advising patients' relatives during follow-up.13\n\n\nConclusion\n\nIt's crucial for medical professionals to be aware of AgCC, a disorder that can cause various disabilities. Although rare, it's essential to recognize the clinical presentation of AgCC to ensure early diagnosis and proper intervention to prevent complications.\n\n\nConsent\n\nWritten informed consent was taken from the father of the patient.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReference\n\nMihrshahi R: The corpus callosum as an evolutionary innovation. J. Exp. Zool. B Mol. Dev. Evol. 2006 Jan 15; 306B(1): 8–17. PubMed Abstract | Publisher Full Text\n\nJeret JS, Serur D, Wisniewski KE, et al.: Clinicopathological findings associated with agenesis of the corpus callosum. Brain and Development. 1987; 9(3): 255–264. Erratum in: Brain Dev 1987;9(5):567. PubMed Abstract | Publisher Full Text\n\nHatten ME: Central nervous system neuronal migration. Annu. Rev. Neurosci. 1999; 22: 511–539. Publisher Full Text\n\nFreytag E, Lindenberg R: Neuropathologic findings in patients of a hospital for the mentally deficient. A survey of 359 cases. Johns Hopkins Med. J. 1967 Dec; 121(6): 379–392. PubMed Abstract\n\nChiappedi M, Bejor M: Corpus callosum agenesis and rehabilitative treatment. Ital. J. Pediatr. 2010 Sep 17; 36: 64. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStroustrup Smith A, Levine D: Appearance of an interhemispheric cyst associated with Agenesis of the corpus callosum. AJNR Am. J. Neuroradiol. 2004; 25: 1037–1040.\n\nPierre-Kahn A, Hanlo P, Sonigo P, et al.: The contribution of prenatal diagnosis to the understanding of malformative intracranial cysts: state of the art. Childs Nerv. Syst. 2000 Nov; 16(10-11): 618–626. Publisher Full Text\n\nTomasch J: Size, distribution, and number of fibres in the human corpus callosum. Anat. Rec. 1954 May; 119(1): 119–135. PubMed Abstract | Publisher Full Text\n\nMattson SN, Riley EP: A review of the neurobehavioral deficits in children with fetal alcohol syndrome or prenatal exposure to alcohol. Alcohol. Clin. Exp. Res. 1998 Apr; 22(2): 279–294. Publisher Full Text\n\nSanto S, D'Antonio F, Homfray T, et al.: Counseling in fetal medicine: agenesis of the corpus callosum. Ultrasound Obstet. Gynecol. 2012 Nov; 40(5): 513–521. Publisher Full Text\n\nYakovlev PI, Lecours A-R: The phylogenetic cycles of regional maturation of the brain.Minkowski A, editor. Regional Development of the Brain in Early Life. Oxford: Blackwell; 1967; p. 3–70.\n\nBrown WS, Paul LK: The Neuropsychological Syndrome of Agenesis of the Corpus Callosum. J. Int. Neuropsychol. Soc. 2019 Mar; 25(3): 324–330. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFischer M, Ryan SB, Dobyns WB: Mechanisms of interhemispheric transfer and patterns of cognitive function in acallosal patients of normal intelligence. Arch. Neurol. 1992 Mar; 49(3): 271–277. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "296026",
"date": "13 Jul 2024",
"name": "Kranthi Marathu",
"expertise": [
"Reviewer Expertise Neuroradiology",
"AI"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall well written paper,\n\nThe case report did not mention the parents' ages, even though maternal age is a recognized risk factor.\nThe discussion could be expanded to cover the developmental and neuropsychological abnormalities identified in cases of primary isolated Corpus Callosal Agenesis. It should also include the various risk factors identified for this condition.\nThe conclusion should provide a summary based on the findings of your case, along with suggestions for the readers.\nThe references cited in the article are old, with the most recent being from 2019. Add the latest available literature. can include this latest article [Ref-1].\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1324
|
https://f1000research.com/articles/12-1321/v1
|
12 Oct 23
|
{
"type": "Research Article",
"title": "Factors associated with scientific production citations in dentistry: Zero-inflated negative binomial regression and hurdle modelling",
"authors": [
"Pablo Alejandro Millones-Gómez",
"Carlos Alberto Minchón-Medina",
"David Yeret Rodríguez-Salazar",
"Jorge Gustavo Alonso Delgado-Caramutti",
"Alejandro Valencia-Arias",
"Pablo Alejandro Millones-Gómez",
"Carlos Alberto Minchón-Medina",
"David Yeret Rodríguez-Salazar",
"Jorge Gustavo Alonso Delgado-Caramutti"
],
"abstract": "Background: The global scientific literature in dentistry has shown important advances in the field, with major contributions ranging from the analysis of the basic epidemiological aspects of prevention to specialised results in the field of dental treatments. The present investigation aimed to analyse the current state of the scientific literature on dentistry hosted in the Web of Science database. Methods: The methodology included two phases in the analysis of articles and indexed reviews in all thematic areas. During the first phase, the following variables were analysed: scientific production by the publisher, the evolution of scientific output published by publishers, the factors associated with the impact of scientific production, and the modelling of the impact of scientific production on dentistry. During the second phase, associations, evolutions, and trends in the use of keywords in the scientific literature in dentistry were analysed. Results: The first phase shows that scientific production in dentistry will increase between 2010 and 2021, reaching 12,126 articles in 2021. Publishers such as Wiley and Elsevier stand out, but Quintessence Publishing has the most citations. Factors such as pages, authors, and references influence the number of citations. Phase 2 analyzes trends in the dental literature using the WoS database. Topics such as \"dental education\", \"pediatric dentistry\", and \"pandemic\" stand out. The intersection of technology and dentistry and the importance of evidence-based education are highlighted. Conclusions: In conclusion, the study shows that the most studied topics include the association of dental education and the curriculum, the association of pediatric dentistry with oral health, and dental care. The findings show that more recently emphasised topics also stand out, such as evidence-based dentistry, the COVID-19 pandemic, infection control, and endodontics, as well as the need for future research to expand current knowledge based on emerging topics in the scientific literature on dentistry.",
"keywords": [
"bibliometric",
"dentistry",
"scientific production",
"pandemic",
"infection control",
"Dentistry",
"Research methods",
"Information / Knowledge Management"
],
"content": "Introduction\n\nScientific or research activity has often been evaluated based on different bibliometric indicators. Bibliometrics is a set of mathematical and statistical methods used to analyse and measure the number and quality of books, articles, and other forms of publications. Through bibliometrics, we can gain an understanding of scientific productivity and thus quantify scientific production; additionally, we can recognise which authors, journals, institutions, or even countries are most interested in the generation of knowledge about a topic.1 Quality indicators allow for the evaluation of the impact of researchers, institutions, or the scientific community, for example journal impact factors, crown indicators, and the hindex (or Hirsch index) and its variants.2,3 In addition to indicators measuring volume and quality, some bibliometric analyses also examine the structure that, according to García-Villar and García-Santos,3 allows for an appreciation of different aspects of scientific cooperation and thematic alliance. These indicators facilitate a more holistic, detailed, and useful understanding of the scientific information housed in specialised databases.4\n\nThis analysis encompasses not only the visibility, relevance, and impact of the articles but also considers aspects of prestige.5 These standardised indicators in all disciplines, for which there is great interest,6 are calculated by using the data available in international databases,7 thus addressing some research gaps. As the current scientific community has become increasingly competitive and global, and as digital technology has emerged in conjunction with the rapid evolution of journals acting as platforms for the dissemination of data and other digital objects,8 editorial excellence has become an overarching goal.9\n\nThe creation of new indicators has been particularly important as journals are evolving rapidly and becoming platforms for the dissemination of data, methods, and other digital objects. The quality of the articles submitted to dental and scientific journals, plagiarism, attempted duplication, and sometimes fraudulent results are all challenges publishers and publishing companies must face.10 In addition, one of the main challenges for the editors of scientific journals is the analysis of self-citations, which also affects aspects associated with scientific impact.11 Hence, it is important for publishers to understand scientific production and its impact.\n\nA series of factors are associated with problems in scientific production and its impact, including the lack of resources for developing research, poor preparation of the manuscripts sent to journals, limited access to quality literature in scientific databases, conflicts in relation to publication, and limitations in the journal review process; therefore, it is necessary to be aware of these limitations and to monitor them to achieve a better representation in the thematic areas of scientific journals.12–15\n\nA review of research indexed in some search engines such as PubMed reveals that the number of publications has doubled over the last two decades globally, as evidenced by Godín.4 The reach of a research field, the extent to which publications are concentrated, and the characteristics of citations are fundamental considerations in carrying out bibliometric analyses. In addition, factors such as variations in the frequency of publication of articles by topic indicate different research priorities at a global level, as in the case of research on epidemiological trends and changes in the practice of dentistry.16 Over the last 30 years, scientific production in dentistry, while maintaining a similar structure in terms of the represented specialties, has varied both in terms of qualitative and quantitative research models and in its geographical distribution17; moreover, it has been recognised that these factors are distinctly important for the advancement of science and that a small number of studies stand out.18\n\nThe increase in the number of scientific publications is an important aspect to consider in bibliometric analyses in various fields, such as dentistry. In some cases, these analyses have only described trends.19,20 Indeed, some analyses have indicated that there were trends21; that there was no clear trend22; that the increase in the number of publications was linear,23 polynomial,24 or exponential25; or that its trends followed a discontinuous regression pattern.26 This information will guide researchers in dentistry when they make decisions about which journal to publish in and therefore to which publisher they should submit their article.\n\nThe number of times scientific papers are cited in other studies is a reflection of their quality. However, this factor does not distinguish whether the citation has a positive or critical connotation.27 In addition, some authors point out that the number of citations should not be considered a sufficiently nuanced or solid quality measure if it is used in isolation.28\n\nScientometrics experts analyze the reasons for the lack of citations in certain articles. Articles without citations are typically authored by a single individual, which may suggest that they offer less comprehensive information. These articles tend to have fewer references and are generally shorter in length.29\n\nThe analysis of the number of citations or noncitations for articles published in journals around the world involves the consideration of important aspects. First, factors that affect the highest number of citations must be considered. In dentistry, various factors have been studied: years since publication,30,31 number of pages,30 type of article,29,32 topic covered in the article,30,33 journal,2,31–33 number of authors,2,33 and number of references,2 among others. Second, it is concerning for researchers and journals not to be cited, and there are various reasons why an article is not cited, for instance, the article’s topic might be highly specialized and irrelevant to current research, or the distribution and accessibility of the publication might be restricted, hindering other researchers from discovering and citing it as a reference.34 It has been recommended that noncitation rates should be made available for all journals.35 These factors are of interest for the present study.\n\nA third factor has been considered to explore the question of citations. In dentistry, linear regression models,20 Poisson regression models,31 and negative binomial regression models2,32,33 have been used to identify the factors associated with the number of citations; in particular, negative binomial regression models have been used in the presence of overdispersion in the number of citations.34 However, these models, by themselves, do not allow the study of the factors impacting the number of citations and noncitations, whereas zero-inflated negative binomial regression models and double fence models do have this capability as part of bibliometric36 or computer science37 studies.\n\nHence, the present investigation aimed to analyse the current state of the scientific literature on dentistry hosted on the Web of Science (WoS) database. The models’ scientific production in journals is classified by publisher using discontinuous regression models. The factors associated with citations and noncitations of scientific articles in dentistry published in the WoS are determined using zero-inflated negative binomial regression models and double fence models. In addition, a differentiated analysis of the main keywords is carried out to account for the activities taking place in the field and the thematic evolution of that field.\n\nIn this study, some research questions were formulated to achieve objectives and guide a discussion. The research questions are as follows:\n\nRQ1: What statistical model does scientific production on dentistry follow in the main publishing houses?\n\nRQ2: What are the factors associated with the citation of scientific production in dentistry?\n\nRQ3: What are the main clusters that define conceptual associativity in dentistry?\n\nRQ4: How have themes covered in the scientific literature on dentistry evolved?\n\nRQ5: What keywords have emerged and been increasingly used in the dentistry scientific literature?\n\n\nMethods\n\nThe present study is based on a bibliometric-computer analysis36,37 of scientific articles in dentistry during the period 2010-2022 that were published in journals across the world and extracted from the WoS database. The analysis includes the evolution of scientific production over time, the factors associated with articles in dentistry being cited and not cited, and regression models for the selection of factors.\n\nThe data for the present investigation were retrieved from the WoS database in August 2022; the search criteria was “dentistry”, and the search was limited to the latest articles published in journals. The total number of articles was 110,269, with 9,034 published in 2022. The files were downloaded in Excel to extract study variables such as the total number of citations (TCitations), number of pages (NPages), year of publication (Year), number of years between the time of publication and 2022 (PYears), number of authors (Nauthors), and number of references (Nreferences); the journal’s publisher was also downloaded as a variable. The name of the publisher was recorded if it was one of the top 10 in a list that was developed later, and the rest were classified into the “other” category.\n\nThe bibliometric information downloaded contained the study variables, but it was necessary to resort to text separation functions with the Excel function “Text in columns” to quantify these variables. The work was carried out by two specialists of regression models.\n\nTo analyse the obtained information, the methodological design involved two phases: first, statistics were used to evaluate scientific production and extract important indicators, such as the main publishers, the annual production, as well as evaluate the scientific impact based on the previously obtained variables.\n\nThe annual scientific production on dentistry in the WoS between 2010 and 2022 was used to unveil the top 10 publishers, whose average production from 2010 to 2021 was compared using the analysis of variance (ANOVA) and Tukey’s test in the Statistical Package for Social Sciences (SPSS) in version 28. Likewise, for the same period, the annual trend in the number of publications on dentistry was evaluated using discontinuity regression models, a method applied to dental visit copayments.38 These models showed that scientific production increased in any given year with some discontinuity in the trend. When the associated parameter was not significant, it was reduced to a regression model by sections. The modelling was performed in Excel.\n\nThe impact of the publications was measured by the number of citations the articles received or by the occurrences of noncitation. The program used to select these factors was Stata 16, and the z test was used to count the models with the significance set at p < 0.05. The analysis of the impact included 76,641 of the 110,269 articles, which were downloaded for the period from 2010 to August 2022 and covered the 10 publishers in the ranking. The program used to estimate the models was Stata 16. Overdispersion in the Poisson model was evaluated using the Lagrange multiplier test; moreover, the standard negative binomial regression model was evaluated through the likelihood ratio (LR) test for the α parameter (if α = 0, there is no overdispersion).39\n\nThe counting models used were the zero-inflated negative binomial regression model and the hurdle model, which allowed us to analyse both the number of citations and noncitations for each article.36,37 The dependent variables were the total number of citations and noncitations per article, and the independent variables were the number of pages, year of publication, number of authors, and number of references in each article. The editors working within the top 10 journals in which the articles were published constituted a categorical independent variable, and the BioMed Central (BMC) editorial board was used as a reference. The choice of a zero-inflated model versus a standard model was made using the Vuong test, and the Akaike criteria (AIC) and Bayesian (BIC) approach were used to choose the best model.39\n\nSubsequently, in the methodological design, there was a second phase of bibliometric analysis, and once the statistical analysis of the main journals was advanced, the evaluation of the impact and of the annual scientific productivity focused mainly on the materialisation of the analysis of the keywords derived from the scientific activity.\n\nDuring this process, an exclusion criterion that allows the content analysis of the main scientific articles that are available in the field was chosen so that, of the total number of articles selected for the first phase in the methodological design, 1,000 articles were used as a filter. Moreover, at the time the present research was conducted, these articles accounted for the highest total number of citations and were considered the main references in the field.\n\nOnce the extraction of the thematic analysis of the main articles was carried out, the main network was analysed to determine the co-occurrence of keywords, allowing for an understanding of the elements of thematic associativity. We also conducted an analysis of the validity and frequency of the keywords so that consolidated or increasingly used keywords were extracted as well as the keywords emerging within the research field. Finally, an analysis of the thematic evolution was carried out based on the main keywords for each research year based on the selected articles.\n\nTo execute the analysis of the main network and determine the co-occurrence of keywords in the scientific body, the free access software VOSviewer was used, while the analysis of the increasingly used and emerging words as well as the thematic evolution was carried out using the office automation tool Microsoft Excel. This phase in the methodological design was completed collectively by all of the authors of the present research with the purpose of reducing biases in the results and jointly treating the disagreements found until convergence was attained. To increase the level of replicability and further detail the methodology, Figure 1 presents a summary of the methodological design used in the research.\n\nTcitations: total of citations, Npages: number of pages, Pyears: publication years, Nauthors: number of authors, Nreferences: number of references.\n\nFigure 1 Alt Text. The figure provides a concise overview of the methodological design employed in the research, encompassing the analysis of co-occurring keywords using VOSviewer, tracking emerging words and thematic evolution through Microsoft Excel®, and collaborative author involvement for minimizing biases and achieving consensus.\n\n\nResults\n\nIn accordance with the nature of the methodological design, Phase 1 of the results is presented in this section. This phase involved a rigorous analysis of the scientific output published by each publisher as well as this output evolved within the time window selected for the extraction of articles. The analysis also included the factors associated with the impact of scientific output.\n\nFigure 2 shows the evolution of scientific production in dentistry during the period 2010-2021 through polynomial models of discontinuous regression and regression models according to the selection in the top 10 main publishers.\n\nSource: Published by publishers in the field of dentistry.\n\nFigure 2 Alt Text. Figure illustrates the scientific production trend in dentistry from 2010 to 2021 using polynomial models of discontinuous regression and regression models for the top 10 main publishers.\n\nThe WoS database is a platform composed of a large collection of databases from all disciplines of knowledge organised by the British-American company Clarivate Analytics.40,41 In 2016, the scientific production in the WoS changed to an estimated 2,377 articles (t = 14.1, p = 0.000). During the first period—2010-2016—the growth curve was concave, with the number of articles barely exceeding 8,000 per year; however, the growth curve was convex for the period between 2017 and 2021, with more than 10,000 articles/year and R2 = 99.9%. The scientific citation indexing service is based on the online subscription Book Citation Index (BKCI), which is part of WoS and is maintained by Clarivate Analytics. The BKCI provides analytic services for academic and scientific research data and was, in a limited manner, part of the WoS Core Collection for 14 years until 2017. Since 2018, it has become a perpetually maintained database.42 In 2018, the complementary tool Kopernio, an extension for browsers that saves time and allows direct access to the best articles available in PDF format, was acquired by Clarivate Analytics, revolutionising access to articles from anywhere in the world.43\n\nThe curves corresponding to Wiley’s activities are concave in each section. In the first section, the production is practically stable without a linear trend (p = 0.211 > 0.05) or quadratic trend (p = 0.211 > 0.05). However, in the second section, the linear trend increases (p = 0.029 < 0.05), and the quadratic trend is not evident (p = 0.690 > 0.05) and R2 = 92.7%.\n\nLike that of the WoS, the curve corresponding to Elsevier’s activities is concave and convex, showing a discontinuity of 550 articles/year (t = 2.85, p = 0.029) and R2 = 94.3%. The activities of Quintessence Publishing are shown to have slightly changed during the 2015-2022 period compared to the 2010-2014 period, with R2 = 83.8%. In this regard, a linear model would have presented an increasing annual trend of approximately 13 articles/year (t = 4.11, p = 0.002 < 0.05) and R2 = 62.9%.\n\nThe regression models for scientific production published in the WoS and Elsevier are discontinuous regression models with leaps in 2017, and those corresponding to Wiley and Quintessence Publishing are reduced to regression models by sections.\n\nThe curve for the Churchill Livingstone publishing house shows a difference in the number of publications between the periods 2010-2014 and 2015-2021, ascending in the first and descending in the second. The number of publications by Springer Nature can be divided into the 2010-2016 and 2017-2021 periods; both periods exhibit positive growth in those numbers but changes are more intense in the second period. The number of articles published by MOSBY-ELSEVIER declines in 2012 and experiences a slow recovery thereafter. Activities in the other top 10 publishers fluctuate, with a stable number of publications or small increases throughout the study period. It is important to note that the number of articles to be published in 2022 by these publishers is predicted to be lower than expected, as shown in the trend analysis. The models used for the number of publications produced by these publishers were not estimated.\n\nThe annual scientific production on dentistry published in journals made up the top 10 categories during the period 2010-2022, as shown in Table 1. The number of published articles increased from 6,850 in 2010 to 12,126 in 2021 at a rate of 440 articles/year, with great changes between 2016 and 2017, when the number of published articles reached 2,330 articles over one year. The trend in the number of articles published by publishers, in some cases, shows very similar patterns. As of 2022, some journals still had not published related publications.\n\nThe quantity of published journal articles is merely one of numerous factors taken into account when assessing publishing companies such as Wiley in rankings, as illustrated in this study. This parameter, while vital, is only a component of a larger set of metrics and criteria utilized to evaluate the academic and scientific significance, influence, and importance of publishers. Publishers strive to enhance their image by increasing the number of publications and ensuring their quality and relevance. Besides, several other factors, such as article citation frequency, impact on the scientific community, and journal accessibility, also determine their rankings.\n\nIn general, the average number of citations per article was 13.4 ± 23.79, with a maximum of 1,621 citations; noncitations reached 12.08%. On the one hand, citations are the basis of the SCImago Journal Rank (SJR) index that ranks journals, and noncitations also represent an indicator for the quality of the researchers, articles, journals, and now publishers. On the other hand, the average number of pages was 7.61 ± 2.84, the average number of authors was 5.19 ± 2.59, the average number of references was 31.63 ± 16.15. These results are also important for authors to consider when producing scientific articles in dentistry.\n\nThe number of citations for the articles published in journals owned by the top 10 publishers and the factors associated with these articles are shown in Table 2.\n\nIn addition, in the UK, for example, the UK Research and Innovation (UKRI) suggests that impact factors should not be used to indicate quality and should be ignored, as should other journal metrics.44\n\nIn terms of the average number of citations, Sage Publications, Inc. stands out with 23.2 ± 45.9 citations and a maximum of 1,040; however, results show 13.6% noncitations.\n\nQuintessence Publishing Co., Inc. shows the maximum number of citations (1,621), followed by Springer Nature, with 1,407 citations. However, the former also shows the second highest noncitation rate (15.5%) after BMC (15.8%) as well as the maximum number of pages (124 pages) and references (612) per article. The maximum number of authors was found in an article published by Elsevier (131 authors).\n\nOn the one hand, Poisson’s model assumes that the mean is equal to the variance, but Table 1 indicates that the standard deviation (square root of the variance) is greater than the mean of the total number of citations per article. The presence of overdispersion is assumed to be evident. The presence of overdispersion was identified using the Lagrange multiplier test in the Poisson regression model (LR value = 15263275, p = 0.000 < 0.05) and confirmed by the likelihood ratio test in the negative binomial regression model (chibar2(01) = 8.8e+05, p = 0.000 < 0.05). The presentation of the results estimated for these models is omitted. However, these findings justify the discarding of Poisson’s regression model since resorting to alternative models was necessary.\n\nOn the other hand, according to Table 2, the percentages of noncitations for the articles published in the top 10 journals are within the range of 6.0-15.8%, suggesting a high occurrence of noncitations. Because the average number of citations is 9.4 citations per article, the probability of an article not being cited is 0.008%; this probability becomes very small (practically zero) as the average number of citations increases. In these circumstances, zero-inflated models are justified.\n\nThe zero-inflated negative binomial regression model and negative binomial hurdle regression model estimated for citations and noncitations are shown in Tables 3 and 4, respectively. The models do not show the results corresponding to the BMC publisher because that publisher constitutes the reference category; moreover, the regression coefficients establish the differences between BMC and the other publishers.\n\nWith respect to citations, the negative binomial regression model (Table 3) indicates that the number of pages (p < 0.001), the number of years since the article was published (p < 0.001), the number of authors (p < 0.001), and the number of references used (p < 0.001) contribute favourably to increasing the number of citations per article since the regression coefficients are positive. Regarding the publishers, in comparison with BMC, the publishers with the highest number of articles being cited were Wiley (p < 0.001), Elsevier (p < 0.001), Mosby-Elsevier (p < 0.001), and Sage Publications, Inc. (p < 0.001) but also Springer Nature (p < 0.05); moreover, those with the fewest citations were Quintessence Publishing Co., Inc. (p < 0.001) and Wb Saunders Co-Elsevier Inc. (p < 0.001). These results reflect that the factors have a favourable effect and that the differences between the publishers seeking to achieve a higher number of citations improved the h-index among dental researchers when adjusting for the other factors.\n\nIn reference to the zero-inflated model, that is, the model without citations, the factors under study contributed to the decrease in the number of publications, which is explained by the negative regression coefficient.\n\nSome journals are known to limit the number of authors per article, especially when the topic covered in the articles does not justify the presence of numerous authors. Each publisher makes decisions in this regard.\n\nThe negative zero-inflated binomial regression model, on the one hand, confirms the presence of overdispersion by testing the likelihood ratio (chibar2(01) = 8.1e+05 and p = 0.000 < 0.05); on the other hand, the information criteria provide AIC = 531 580.4 and BIC = 531 848.5.\n\nThe hurdle regression model, which is presented in Table 4, also establishes the positive effect of these factors on the impact of scientific publications compared to the zero-inflated negative binomial regression model in both the direction and the magnitude of the effect. Likewise, the hurdle model confirms the differences in the number of article citations in the different journals compared to BMC; the model also shows where there are no differences. The similarity of the effect of the factors and the differences between the publishers are also maintained with respect to the percentage of citations, with the exception of the logistic model that did not show differences in the number of citations in Elsevier’s journals compared to those in of BMC (p > 0.05). The confirmation of the factors through this model shows that the factors under study are as important in evaluating both the number of citations and noncitations.\n\nIn the evaluation of the goodness of fit for the negative binomial regression model, Hurdle provides the values AIC = 531 390.6 and BIC = 531 658.8 as information criteria. It is important to note that when estimating this model, it is necessary to create artificial variables to represent the publishers.\n\nBased on the assumption that a model with lower AIC and BIC values is better, Hurdle’s model is slightly more suitable than the negative zero-inflated binomial regression model; moreover, adducing a criterion of parsimony to decide otherwise may limit the choice of which model should be adopted in articles in dentistry. However, the findings show that both models will be useful when selecting robust factors associated with citations and noncitations in the dental field.\n\nBetween 2010 and 2021, there were differences among the publishers’ average output, according to ANOVA (F = 107.191, p = 0.000). Wiley was the publisher with the most publications (1,938 ± 256 articles/year), followed by Elsevier (1,221 ± 257 articles/year); there were significant differences between these major publishers and other publishers, according to Tukey’s test.\n\nWith a portfolio of 1,600 journals in various scientific categories, Wiley is the world’s leading publisher. Elsevier’s journals lead in the field of medicine and health sciences.45 These articles published by these publishers differ in the average number of times they are cited (F = 136.03, p = 0.000) as well as in the number of pages (F = 616.8, p = 0.000), the number of years since publication (F = 420.39, p = 0.000), number of authors (F = 286.59, p = 0.000), and number of references used (F = 382.64, p = 0.000).\n\nThe publishers for which they articles show a lower percentage of noncitations than BMC were Wiley (p < 0.001), Springer Nature (p < 0.001), Mosby-Elsevier (p < 0.001), Sage Publications Inc. (p < 0.001), Elsevier (p < 0.05), Churchill Livingstone (p < 0.05), and Pergamon-Elsevier Science Ltd. (p < 0.05). In contrast, articles published by Quintessence Publishing Co., Inc., exhibit a higher percentage of noncitations (p < 0.001), a result that is adjusted for the effect of other factors.\n\nBased on the nature of the methodological design, results from Phase 2 are presented here. These results provide a rigorous analysis of the scientific output published by publishers; the results also show trends in the scientific output published by publishers within the time window selected for the extraction of articles and based on the factors associated with the impact of scientific production.\n\nThe materialisation of the bibliometric analysis also allowed for an exhaustive analysis of the keywords associated with the scientific literature on dentistry so that the output covered in the literature, its associations, and the scientific trends represented can be understood. Therefore, Figure 3 presents the main keyword co-occurrence network in dentistry research that can be found in the WoS database; this figure allows us to identify relational and associative factors for keywords through clusters for an understanding of thematic affinities.46\n\nFigure 3 Alt Text. The Figure depicts the main keyword co-occurrence network in dentistry research from the WoS database, revealing thematic relationships and trends based on rigorous analysis of scientific output and impacts in Phase 2 of the methodological design.\n\nThe main thematic cluster in red shows that “dental education” is a central concept. This concept is associated mainly with other keywords such as “paediatric dentistry”, “curriculum”, and “undergraduate”, which add important elements to the analysis; for example, it includes the idea of learning paediatric dentistry through cutting-edge educational models such as the flipped classroom47 and virtual reality simulations.48 Moreover, this approach allows for a rigorous analysis of the basic components that must be understood in the curricula of paediatric dentistry, as studied by Kaur et al.49 in the Australian educational context.\n\nThe green thematic cluster is the second most relevant in terms of dentistry scientific production. On the one hand, results show that the concept of “paediatric dentistry” is also associated with other terms such as “children”, “oral health”, and “dental care”. These terms have generally been associated with shaping the scientific literature in terms of the dental needs of children who have special health needs, as described in studies that have analysed the dental characteristics of paediatric oncology patients, for example in Brazil.50,51\n\nOn the other hand, there is an association between the green cluster and the yellow thematic cluster, which accounts for concepts such as “evidence-based dentistry” and “knowledge”.\n\nIndeed, academia has expanded the knowledge, attitudes, behaviours, and practices of oral health professionals based on evidence-based dentistry. According to Rawat et al.,52 this approach has improved the clinical experience of dental professionals. The approach has allowed researchers to improve their decision-making in relation to treatment safety; it has also increased treatments’ success rate. However, other authors have suggested that this success may be due to the development of robust and specialised educational programs that use evidence-based dentistry to allow dentists to improve their knowledge and skills.53\n\nIn turn, this cluster also presents an important association with the purple thematic cluster, which accounts for overall essential concepts of health today, such as “stress” and “anxiety”; indeed, students of dentistry experience great psychoemotional burdens and high rates of anxiety. These concepts affect the dental system, including behaviours such as bruxism or cheek biting, which are important oral health problems.54,55 This issue is of interest not only to dental students but also to general dentistry practitioners and specialists in paediatric dentistry, as shown in the context of Iran.56\n\nFinally, the blue thematic cluster includes important concepts such as “pandemic”, “infection control”, “endodontics”, and “infection”, which have become relevant in the scientific literature on dentistry in recent years. This cluster aids in the analysis of specific situations in the context of the COVID-19 pandemic; for example, it helps in assessing the risk mental health workers have had of contracting the virus, showing that it has been considerably low because of intensive triage and comprehensive preventive measures57; moreover, the cluster shows the effectiveness of blended learning in dentistry, specifically in endodontics, in the pandemic-induced context of isolation.58\n\nSubsequently, the analysis of the conceptual evolution of the scientific literature on dentistry is shown in Figure 4, which presents the most frequent and investigated keyword in each year during the time window included in the database. In that sense, it is clear that the trends in dentistry research at the beginning of the previous decade already revealed the interest of academics, researchers, and oral health professionals for paediatric dentistry, with “paediatric” being the most researched concept in 2010, time in which important advances were made on the topic. For example, in the study by Poletto and Junior,59 one of the key review articles in the field, the authors concluded that the previous literature provided little conclusive scientific evidence, specifically in the Brazilian scientific literature, a context in which the prevalence of alveolar bone loss was also studied in children considered healthy and treated in private paediatric dentistry clinics.60 Moreover, it is evident that this concept has dominated the literature since that year, constituting the most researched term in 2012 and 2019, which further indicates the relevance of the topic.\n\nFigure 4 Alt Text. The figure showcases the conceptual evolution of dentistry's scientific literature, highlighting the most frequently explored keyword for each year within the specified database timeframe.\n\nMoreover, dental education has been a central issue in the research field, and it was the most investigated concept for the year 2015, when important contributions were made. For example, Musa, Bernabé and Gallagher61 studied the main motivations of Malaysian students for studying dentistry based on psychometric methodologies and the robust statistics of a confirmatory factor analysis. In addition, dental education has been the area of interest of the greatest number of studies in 2022, where the topic has been addressed in terms of state-of-the-art technologies, such as the implementation of standardised patient methodologies that allow students to develop communication skills, deeper diagnostic reasoning, and critical thinking.62\n\nIn conjunction, it is evident that for 2020 and 2021, the priority in research was associated with the COVID-19 pandemic, and the term “pandemic” was the most studied concept in the scientific literature on dentistry. Some studies covered aspects associated with fears, eating habits, and perceptions of oral health,63 and general evaluations of the impact of the pandemic on dentistry were made in specific contexts such as the Czech Republic, as evidenced in Schmidt et al.64 These results contribute to the analysis of and debate on communication management during the current pandemic, a time during which dentistry has clearly emerged as a field in which research must be developed in consideration of international collaboration. The results for the last three years allow us to infer that the pandemic is an aspect that can propose new directions for research in this field.\n\nFinally, terms of keyword analysis for the scientific activity in dentistry that has been indexed in the WoS database are shown in Figure 5. From a Cartesian plane, this figure compares the frequency of keywords with the year in which they were used as a measure of validity. Therefore, there are a total of four quadrants: quadrant I includes the most frequent and current concepts; quadrant II plots the least frequent and most current concepts; quadrant III includes the least frequent and the least current concepts; and finally, quadrant IV shows the most frequent concepts that are less current in the scientific literature.\n\nFigure 5 Alt Text. This figure displays a keyword analysis of indexed scientific activity in dentistry from the WoS database. Using a Cartesian plane, the figure illustrates the frequency of keywords against the year of usage, categorizing concepts into four quadrants based on frequency and recency. Quadrants I-IV depict varying combinations of frequency and currency in the scientific literature.\n\nTherefore, quadrant IV, by positioning the concepts most frequently used for years showing a low average use, represents the terms whose use has declined in the research field; these terms only include “oral health”, which was previously key in stratifying the population for preventive dental care programs.65\n\nIn a less prominent position, quadrant III groups the current concepts used the least frequently in the research field. This quadrant provides a general panorama for concepts that are not very prominent in the immediate future of dental research, noting terms such as “prevention”, “forensic”, “ethics”, “public health”, “dental caries”, and “restorative”. This phenomenon may indicate that researchers have already explored these topics in great depth or that there has been a constant evolution in the areas and/or the terms addressed; this scenario is reflected in the use of “forensic” in dentistry, which is currently related to the study of dental DNA, involving the use of prosthetic devices in recognition procedures, or to the issue of identification from the oral microbiota.\n\nOn the other hand, quadrant II includes those keywords that, although they are among the least frequently used in dentistry research, are among the most current, being categorised as emerging keywords. Among these main emerging keywords in the scientific literature on dentistry, there are research methodologies such as “bibliometrics”, which has been used in studies such as Paschoal et al.’s,66 one of the most cited articles on the application of lasers in dentistry; also emerging is “infection control”, which in recent years was investigated by Kızılcı et al.67 in relation to the level of knowledge that dental students should have regarding the factors that influenced the spread of the COVID-19 pandemic; and “digital” has also emerged, referring to the implementation of new technologies such as artificial intelligence in the dental context to improve medical diagnoses and patient care.68 Emerging keywords are related to new technologies and new conditions, although they can also reflect the continuous development of an existing technology. The term “digital” can be associated with different concepts that involve not only artificial intelligence but automation, virtual reality and augmented reality, and 3D printing and robotic dentistry, among others.\n\nLikewise, in terms of the specific analysis of the concept of the COVID-19 pandemic, future research must not explicitly focus on the analysis of that disease but understand that the post-pandemic context is already being discussed. Therefore, greater prominence will be given to the themes derived from this historical context, such as the application of new technologies, which were recently mentioned, and the response to the Industry 4.0 context or the Fourth Industrial Revolution.\n\nFinally, quadrant I, which relates the most frequent and current use of concepts, is considered to account for the growing use of concepts on the subject; this quadrant includes the concepts that are the most prominent and relevant to the scientific literature on dentistry. It also includes the term “dental students”, who have been studied from different perspectives. For example, the effectiveness of e-learning classes in contexts such as Pakistan has been analysed69 in a study in which the authors drew conclusions about the level of dissatisfaction generally perceived among students, revealing problems related to the use of new technologies. In addition, the keyword “education” was identified, where important contributions to dental practice have been generated, as evidenced in studies that have evaluated the quality of the educational system’s services for dental students based on a validated psychometric model such as SERVQUAL and on variables such as educational sector, country, gender, and year.70 Finally, the concept of “paediatric” has emerged, referring to paediatric dentistry in which new approaches have made it possible to understand the role of new technologies such as cone-beam computed tomography; studying factors, including the degree of awareness; and knowledge of correct use.71 The scientific production centered on students is focused on their skills and experiences that contribute to problem solving and lifelong learning; this research has focused on students’ performance in building meaning based on previous experiences and new information.\n\n\nDiscussion and conclusions\n\nCurrently, a commercial strategic reorientation is taking place among the main academic publishers regarding a more democratic access to knowledge through open-access and alternative payment structures. However, an increase in the control of the academic infrastructure, which has been geared towards generating income, can strengthen the power of publishing houses, causing some researchers or institutions to be marginalised.72\n\nAccording to Posada and Chen,72 some of the largest academic publishers use a set of elements, resources, or necessary services that allows their development within the publishing industry, which can generate a dependency known as oligopoly.72,73 Such is the case for Taylor & Francis, one of the main academic publishers globally that engaged in content acquisitions between 2013 and 2015. However, according to our results, this trend does not appear to be relevant for the 10 main publishers during the 2010-2021 period in terms of scientific production in dentistry.74\n\nWith respect to Elsevier and Wiley, the disproportionate ownership is evident in 2013, the year in which together with Springer, Taylor & Francis and Sage monopolised more than half of the total articles published.72 According to the findings of the present study, although the line showing Wiley’s activities is concave in each time period, during the first period (2010-2016), Wiley exhibited essentially stable production with no linear (p = 0.211 > 0.05) or quadratic trends (p = 0.211 > 0.05). However, during the second period, the linear trend increased (p = 0.029 < 0.05), and the quadratic trend was not evident (p = 0.690 > 0.05), R2 = 92.7%.\n\nElsevier, which has integrated new products vertically into the life cycle of academic knowledge production, has created greater dependence on its products by offering greater convenience and by integrating these products into the decision-making process in universities; these universities must be up to date or improve their situation by acquiring Elsevier’s services. Elsevier generates income by owning data and, as a result, by promoting high-impact journals, a practice in which Wiley and Francis & Taylor have also engaged.72 According to our findings, the curve showing Elsevier’s behaviour is concave–convex, similar to that of the WoS, with a discontinuity of 550 articles/year (t = 2.85, p = 0.029) and R2 = 94.3%. The data shows that Quintessence Publishing slightly changed its behaviour during the 2015-2022 period compared to the 2010-2014 period, with R2 = 83.8%. In this regard, a linear model would have exhibited an increasing annual trend of approximately 13 articles/year (t = 4.11, p = 0.002 < 0.05) and R2 = 62.9%.\n\nThe number of studies published in recent decades shows has trended upward. For example, five publishers accounted for more than 20% in 1973, increasing to 30% in 1996, 50% in 2006, and 53% in 2013. In 2013, 47% of all articles were distributed by three publishers. The production of the publishing house Reed-Elsevier has increased 1.5-fold since 1990, accounting for 24.1%. The production of the Springer Nature publishing house increased 2.9-fold, accounting for 11.9% of articles, and that of the publishing house Wiley-Blackwell increased 2.2-fold, accounting for 11.3%. In contrast, the number of publications by the American Chemical Society decreased by 5%, accounting for 3.4%; finally, the production of the Taylor & Francis publishing house increased 4.9-fold, reaching 2.9% of all publications.47\n\nLuchilo75 indicated that for the year 2015, in the publishing market, the four leading publishers concentrated a considerable number of journals; these publishers are Springer Nature (2,987 journals), Elsevier (3,057 journals), Wiley (2,339 journals), and Taylor & Francis (2,105 journals). According to the present study, among the 10 publishers with the highest number of publications in terms of dentistry scientific output, 333 were found in Springer Nature, 1,072 were found in Elsevier, and 1,847 were found in Wiley; the number of publications for Taylor and Francis was not included in the table.\n\nFereira et al.76 reviewed the output included in dentistry journals in the 2015 edition of the Journal Citation Reports in the category “Dentistry, Oral Surgery & Medicine”. Among the publishing houses that support these journals, the American publisher Wiley-Blackwell was the most represented, controlling 24 of the 91 journals identified, followed by Elsevier with 10 journals and Quintessence Publishing Co. with the same number. These results coincide with those found in the present investigation in terms of scientific production; indeed, between 2010 and 2022 (August), Wiley hosted 24,125 publications, Elsevier hosted 14,790, and Quintessence Publishing Co., Inc., hosted 7,592. Likewise, Luengo’s results showed that, out of the 10 main journals publishing research in dentistry, Wiley-Blackwell published five, Elsevier Science published four, and Sage Publications published one.\n\nThe results of the bibliometric analysis on dental caries, which is one of the most prevalent oral diseases worldwide,77 with abundant research addressing this issue in various fields of dentistry, developed from the analysis of academic production from 2014 to 2018 in the WoS. This issue has shown to follow a linear growth pattern with a low slope, suggesting a near saturation point.78 Moreover, the analysis carried out on the same database regarding scientific production in dentistry coincides with the present research because it shows a concave growth curve during the first period of 2010-2016. However, during the second period, 2017-2021, the curve is shown to be convex, which means that the topic is not approaching a saturation point.\n\nBased on the results obtained in the present study, it is important to consider specific aspects, such as those studied by Li et al.,79 who analysed the format in the structure and the policy pertaining to the relevant publishing houses in relation to the selection of articles in an easy, rapid way that is more relevant to readers, hence promoting a more efficient indexing of research. Compared to a highly structured format, the Introduction, Methods, Results, and Discussion (IMRandD) format was used more frequently and was required to be used in the abstracts of randomised controlled trials (RCTs) and systematic reviews (SRs) in the field of dentistry.\n\nThe factors associated with the citations of scientific production in dentistry indexed in Scopus suggest some explanatory variables, such as the aspects related to the evolution of scientific production by the editor. Within these aspects, the number of pages, authors and references used were important. Moreover, the analysis of associations, and the evolution and trends in the main studies include the study of the association of thematic groups, the evolution of scientific approaches, and the validity and frequency of keywords. These studies provide evidence on which the scientific community can focus in relation to dentistry to increase its scientific production by concentrating on strategies that generate good results.\n\nA total of 110,269 articles published in WoS journals were reviewed. Although this volume is large, it must be recognised that this study constitutes only a partial vision because other databases have not been included. On the one hand, the analyses carried out include different numbers of articles, which could confuse readers; however, it was strictly necessary, as the annual scientific production selected could not include the year 2022, which is not published until the third of that month. The factor analysis did include all of the studies, and it was evident that the 9,034 articles published in 2022 contained current bibliometric information. On the other hand, comparing journals was expected for the analysis of impact factors; however, editorials were considered for technical reasons, and the journals were part of more than one scientific category. Moreover, when a good article was not accepted in a journal based on field or category, suggestions for other journals were received from the same publisher. Finally, the bibliometric analysis includes 1,000 more recent articles because these contain information on emerging issues from the point of view of journals and therefore publishers. Perhaps these results constitute valid reasons for the authors, but not for the readers.\n\nThe study includes modelling in the bibliometric analysis. First, for a demonstration through statistical tests rather than subjective appraisals, the great growth in scientific production in dentistry is shown through discontinuous regression models. Changes in the timing of production are shown through regression models by sections, and these models are adaptable to biometric analyses on emerging issues in various scientific areas or categories. Moreover, this study retrieves factors related to the positive impact (citations) or lack thereof (noncitation) of articles published in dentistry. Authors and journals may take these results into consideration to improve their bibliometric metrics and thereby increase the prestige of the editors while guiding them in making decisions about editorial policies. Finally, bibliometric analysis provides information on emerging issues that authors should consider regarding the acceptance of their articles in WoS journals using classical and current methodologies.\n\nAdditionally, although it is true that the factors associated with the citations of scientific production in dentistry are similar to those used for other health disciplines, we recognise that some factors can be differentiated, such as those base research topics, since dentistry focuses on diagnosis, the treatment and prevention of diseases and the conditions of the dental system. Other health disciplines may focus on different areas of the human body or methodological aspects of research. Although there is a wide variety of research methodologies addressed in health disciplines, some may be more common in dentistry. The existence of specialised magazines that publish scientific articles have framed dentistry. Moreover, some health disciplines have superior means of dissemination for research results compared to dentistry, which affects the output in that field.\n\n\nConclusions\n\nOur results show that the trend in the dentistry scientific output published by the main publishers is discontinuous in regression models. The main factors associated with the citation and noncitation of scientific output in dentistry are shown to be the editors working at these journals, the number of pages in the articles, the year of publication, the number of authors and the number of references. in the article, according to zero-inflated negative binomial regression and Hurdle models. The main clusters that define the conceptual associativity on dentistry are the red and green clusters, where the red cluster puts in relation concepts associated with the design of university curricula in paediatric dentistry, and the green cluster puts in relation elements associated with oral health in children. The thematic evolution in the scientific literature on dentistry shows that there have been changes since the first investigations on paediatric oral health; indeed, investigations in recent years have focused on the analysis of the subject during the pandemic period and on the importance of dental education. Finally, the main keywords that have been increasingly used within the scientific body in dentistry are “dental students”, “education”, and “paediatrics”, while the top emerging keywords are “digital”, “pandemic”, “anxiety”, and “infection control”. Further research in this important area is needed.",
"appendix": "Data availability\n\nZenodo: Factors Associated with Scientific Production Citations in Dentistry: Zero-inflated Negative Binomial Regression and Hurdle Modelling, https://doi.org/10.5281/zenodo.8387311. 80\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nGarcés-Giraldo LF, et al.: Tendencias en el uso del marketing digital en el sector turismo: una perspectiva bibliométrica. Revista Ibérica de Sistemas e Tecnologias de Informação. 2022; E50: 631–643.\n\nAllareddy V, Allareddy V, Rampa S, et al.: Global dental research productivity and its association with human development, gross national income, and political stability. J. Evid. Based Dent. Pract. 2015; 15: 90–96. PubMed Abstract | Publisher Full Text\n\nGarcía-Villar C, García-Santos JM: Bibliometric indicators to evaluate scientific activity. Radiologia. 2021; 63: 228–235. 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}
|
[
{
"id": "235646",
"date": "25 Mar 2024",
"name": "Carolina Caleza Jimenez",
"expertise": [
"Reviewer Expertise Paediatric dentistry"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article is very interesting. The data analysis is very complete with two phases, with sufficient details and adequate statistical analysis.\nIt would be interesting to highlight the role of universities in providing publications to students or young researchers. The conclusions respond to the questions formulated to achieve the objectives, although they should be more cautious in the statements.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "293804",
"date": "05 Jul 2024",
"name": "Brenda Yuliana Herrera Serna",
"expertise": [
"Reviewer Expertise Oral epidemiology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for the manuscript. It is interesting and provides an enriching overview. Given the broad search strategy, the volume of findings is to be expected. The statistical analysis is relevant and shows the application of diverse tools for the practice of dental research and education. Although WOS is a comprehensive database, it would be appropriate to state why it is the only one used. There are many other data that are extracted from this type of analysis, such as the most productive countries, institutions and researchers. The 10 most cited articles is also an important source of information. These are only suggestions, and do not interfere with the review.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1321
|
https://f1000research.com/articles/11-1529/v1
|
19 Dec 22
|
{
"type": "Brief Report",
"title": "Prediction of self-efficacy in recognizing deepfakes based on personality traits ",
"authors": [
"Juneman Abraham",
"Heru Alamsyah Putra",
"Tommy Prayoga",
"Harco Leslie Hendric Spits Warnars",
"Rudi Hartono Manurung",
"Togiaratua Nainggolan",
"Heru Alamsyah Putra",
"Tommy Prayoga",
"Harco Leslie Hendric Spits Warnars",
"Rudi Hartono Manurung",
"Togiaratua Nainggolan"
],
"abstract": "Background: While deepfake technology is still relatively new, concerns are increasing as they are getting harder to spot. The first question we need to ask is how good humans are at recognizing deepfakes - realistic-looking videos or images that show people doing or saying things that they never actually did or said generated by an artificial intelligence-based technology. Research has shown that an individual’s self-efficacy correlates with their ability to detect deepfakes. Previous studies suggest that one of the most fundamental predictors of self-efficacy are personality traits. In this study, we ask the question: how can people’s personality traits influence their efficacy in recognizing deepfakes? Methods: Predictive correlational design with a multiple linear regression data analysis technique was used in this study. The participants of this study were 200 Indonesian young adults. Results: The results showed that only traits of Honesty-humility and Agreeableness were able to predict the efficacy, in the negative and positive directions, respectively. Meanwhile, traits of Emotionality, Extraversion, Conscientiousness, and Openness cannot predict it. Conclusion: Self-efficacy in spotting deepfakes can be predicted by certain personality traits.",
"keywords": [
"deepfake detection",
"deepfake recognition",
"self-efficacy",
"personality",
"traits"
],
"content": "Introduction\n\nOne of the biggest threats and disruptions to privacy and democracy in this digital age is deepfake technology. A ‘deepfake’ or synthetic media, is a video editing technology that manipulates and mimic a person’s facial expressions, mannerisms, voice, and inflections based on a large amount of data of other people to create a hyper-realistic video depicting them doing or saying things that never happened (Westerlund, 2019).\n\nThe current consensus is that the average human’s ability in recognizing deepfakes is similar to the machines (Vitak, 2022). However, the result seems to vary depending on their own confidence and belief in their cognitive abilities. Some studies suggest that some individual differences determine if a person is good at recognizing deepfakes or not (Shahid et al., 2022). In this study, we will look at the relationship between personality traits and people’s efficacy in recognizing deepfakes.\n\nThe HEXACO personality model describes six facets of personality structures: Honesty-humility, Emotionality, Extraversion, Agreeableness, Conscientiousness, and Openness to experience (Lee & Ashton, 2009; unpublished report). Multiple studies in various contexts have shown that personality traits influence an individual’s self-efficacy (Lodewyk, 2018).\n\nThe Honesty-humility dimension reflects an individual’s fair-mindedness, modesty, and cooperation. A person with high Honesty-humility might not think they are good at recognizing deepfakes, regardless of their true ability while an individual with low Honesty-humility might be biased in their ability in recognizing a deepfake.\n\nEmotionality reflects an individual’s degree of anxiousness, fearfulness, and sentimentality - the experience of anxiety in response to life’s stressors. To overcome this anxiety, the sense of being able to recognize deepfakes is important to reduce that anxiety. One way to become less anxious is to appreciate deepfakes as a “cultural technology” (Cover, 2022) that contains artistic and creative values. People with high Emotionality may be more motivated to use deepfakes as an \"antidote\" from the pressures of everyday life, so they have higher efficacy to detect them, not to be avoided but as potential things to be used according to their interests (technology appropriation; see Prayoga & Abraham, 2017)\n\nExtraversion reflects an individual’s degree of sociability. Individuals high in Extraversion might have higher self-efficacy due to their higher social esteem, boldness, and familiarity. Van der Zee et al. (2002) found that extroverts are friendly and less formal in their interactions with others. This is closely connected with emotion recognition (part of emotional intelligence) which affects the success of negotiations. By using the paradigm of the social construction of technology (Kwok & Koh, 2021), humans are parties who \"negotiate\" with technology to better recognize the technology, including deepfakes, and can adapt it to not become victims of technology—or misappropriate technology for evil interests—but rather agents who utilize technology to improve humanity and prevent harm posed by technology (such as deepfakes).\n\nAn Individual’s degree of cooperation, tolerance, flexibility, and patience is reflected in the Agreeableness dimension. More agreeable people are at a larger risk for security, and social engineers (like deepfake designers) specifically target Agreeableness attributes like benevolence and compliance.\n\nConscientiousness reflects precisions, cautiousness, and a degree of self-control. Individuals with higher Conscientiousness thread might have higher self-efficacy in recognizing deepfakes. This is in line with the hypothesis of Köbis et al. (2021) that increasing Conscientiousness will make people motivated to invest cognitive resources to detect deepfakes, thereby enhancing their capacity to recognize truth and decreasing their desire to spread false information.\n\nOpenness reflects the willingness to experience new things and is associated with lower risk aversion. Research by Uebelacker and Quiel (2014) shows that open people don’t create suitable coping mechanisms because they misjudge their vulnerability to being a target of social engineering (like deepfake designers).\n\n\nMethods\n\nThere is only one data collection stage and there is no exposure in this study.\n\nThis present study was initially approved by the Bina Nusantara University Research Committee, vide Letter of Approval No. 042/VR.RTT/VI/2021, strengthened with Letter No. 127/VR.RTT/VI/2022. The ethical decree is stated in Article 1 Paragraph 2 of the Letter.\n\nWritten informed consent was obtained from all participants of this study, which included consent for the research procedure to be carried out and for the publication of this article containing anonymized, analyzed, and interpreted data.\n\nThe eligibility criteria of the samples were young adults aged 18–25 years (Generation Z), which, according to a YouGov survey, is an age group who are concerned about a deepfake video of themselves going viral online (Help Net Security, 2022; unpublished report). The participants of this study were 200 young adults (139 women, 61 men; M = 22.06 years old; SD = 1.98 year) who came from a non-Western country, Indonesia, and were recruited using a convenience sampling technique. The number of sample came from a calculation using the Sample Size Calculator (Calculator.net, 2022), with the following parameters: Confidence level of 95%, population size of 68,662,815 and population proportion of 27.94% - which was the total population of generation Z in Indonesia (Widi, 2022; unpublished report), as well as a margin of error of 6.3% - which is still in the range of 4–8%, the acceptable one (Cork Institute of Technology, 2020; unpublished report).\n\nThe research was conducted for 6 months from planning, participant recruitment, to data analysis. The research location is in Indonesia in an online setting for 3 months, namely 1 May to 31 July 2022. There is only one data collection stage. There was no exposure or treatment because the research was not an experimental study. The research was a cross-sectional study, so no follow-up procedure was applied.\n\nParticipants filled out an electronic questionnaire consisting of demographic data and two scales, namely HEXACO Personality Traits (as the predictors) and Self-efficacy in recognizing deepfake (as the criterion variable). The design of this study was predictive correlation.\n\nTo measure self-efficacy in recognizing deepfakes, the authors constructed a self-efficacy measuring tool based on Bandura’s theory (1977) which is combined with ways to detect deepfakes taken from an unpublished report (Johansen, 2020). The introductory question was: \"How sure are you that you can recognize or detect the presence of non-original or unnatural or unnatural elements (e.g. because it has been EDITED/MANIPULATED) from every image, photo, sound, and video you encounter?\" Examples of items were: (1) I feel able to see abnormal eye movements; (2) I feel that I recognize awkward faces, e.g. if someone’s face is pointing in one direction and the nose is pointing the other way; (3) I feel able to see any inappropriate skin tone in a video; (4) I am confident of being able to recognize when a person’s face does not seem to convey the emotion that should be in line with what the person is supposed to say. There were six answer choices, ranging from \"Feeling Very Incompetent\" (scored 1) to \"Feeling Very Capable\" (scored 6).\n\nTo measure personality traits, this study used the short version of HEXACO-PI-R (60 items) (Lee & Ashton, 2009) with a scoring key. The response option ranged from “Strongly Disagree” (scored 1) to “Strongly Agree” (scored 6). The author translated the measuring tool into Indonesian.\n\nThe underlying data (Abraham & Alamsyah, 2022a) and complete questionnaire (Abraham & Alamsyah, 2022b) are openly available.\n\n\nResults\n\nDemographically, some participants were residents of DKI Jakarta province (N=90) which is the capital of Indonesia. In addition, other participants were residents of the Java Island (non-DKI Jakarta; N=86); Sumatera Island (N=21); and the rest (N=3) came from East Kalimantan, North Maluku, and West Nusa Tenggara provinces.\n\nThe psychometric properties and descriptive statistics of the variables are shown in Table 1. The results of this study indicate that the residuals are normally distributed (Figure 1) and all HEXACO personality dimensions are negatively correlated with self-efficacy in recognizing deepfakes; except for Agreeableness, which positively correlated (see Table 2). However, the results of the regression analysis with F(6,199)=13,295, p=0.000, R2=0.292, showed that only Honesty-humility and Agreeableness were able to predict the efficacy (see Table 3). No difference was found between women and men, t(198)=−0.120, p=0.904, in terms of self-efficacy.\n\n* p <0.05,\n\n** p <0.01,\n\n*** p <0.001\n\nTable 3 shows the unadjusted (B) and adjusted (β) estimates for each predictor of which the potential confounders are the personality traits dimensions other than the focused predictor.\n\n\nDiscussion\n\nThis study found that the personality trait of Honesty-humility had negative predictive correlation with self-efficacy in recognizing deepfakes, β=-0.255, t(193)=-2.491, p<0.05 (Table 3). “Persons with very high scores on the Honesty-Humility scale avoid manipulating others for personal gain, feel little temptation to break rules, are uninterested in lavish wealth and luxuries, and feel no special entitlement to elevated social status” (Lee & Ashton, 2009, para 1). A person’s Honesty-humility trait do not want to engineer others but, ironically, this trait makes them vulnerable to being manipulated by others (Ternovski et al., 2021), including deepfakes, especially in the context of political greediness. It can drive higher errors for the trait in recognizing deepfakes, opening vulnerabilities in security and political integrity.\n\nThis study found that Emotionality cannot predict self-efficacy in recognizing deepfakes, β=-0.029, t(193)=0.332, p>0.05 (Table 3). Austin and Vahle (2016) found that Emotionality—a trait that is positively correlated with empathy and social engagement—can predict the dimensions of Enhance (providing support and reassurance as interpersonal emotion management strategies) and Divert (the practice of using humor and pleasure pursuits to lift the spirits of others) of the Managing the Emotion of Others Scale (MEOS). This means that the Emotionality dimension is also positively correlated with the emotional intelligence needed to recognize deepfakes. Yang et al. (2022) emphasized the pivotal role of emotional intelligence in improving artificial intelligence technology so that it becomes a useful deepfake in the context of clinical encounters. By knowing that deepfakes themselves are increasingly being prepared with elements of emotional intelligence, then recognizing deepfakes also requires a better one; and this intelligence can actually be found in people with higher Emotionality. However, individuals high in Emotionality might be less confident in their own ability to accurately recognize deepfakes, as they might consider more factors and doubt themselves more (Thompson, 1998). With this uncertain direction, it is not surprising that no predictive power of Emotionality was found on self-efficacy.\n\nThis study found that Extraversion is a personality trait that cannot predict self-efficacy in recognizing deepfakes, β=0.003, t(193)=0.044, p>0.05 (Table 3). Hosler et al. (2021) put forward that detecting deepfakes is actually recognizing unnatural displays of emotion in voices and faces. Emotion apparently plays a central role in recognizing deepfakes because emotion is a higher-level semantic construct—which is difficult to counterfeit up to now—that could offer hints for detection. In an unpublished report, Kill states that emotion recognition is an ability that is honed in someone with a high extraversion trait (2021). However, Extraversion is also found to be positively correlated with excitement-seeking and a lower preference for consistency (Uebelacker & Quiel, 2014) - whereas “pairwise self-consistency learning” (Zhao et al., 2021, p. 15023) is needed to recognize deepfakes. Therefore, the effects of Extraversion traits appear to cancel out of each other resulting in no predictive correlation with the self-efficacy.\n\nThis study found that the Agreeableness trait can predict self-efficacy in recognizing deepfakes; however, not as hypothesized, the direction was found positive – not negative, β=0.309, t(193)=4.090, p<0.05 (Table 3). People with high Agreeableness are eager to cooperate and reach a compromise with others (Lee & Ashton, 2009). One of the good “others” in the context of deepfake recognition or detection is the “wisdom of the crowds” (Groh et al., 2022), which Surowiecki (2004) defines as “the collective intelligence that arises when our imperfect judgments are aggregated”. Agreeing with (or high Agreeableness to) the collective intelligence should reduce the chance of falsely recognizing deepfakes, including its algorithm attempts that present visual obstructions such as misalignment, partial occlusion, and inversion.\n\nThis study found that Conscientiousness was not able to predict self-efficacy in recognizing deepfakes, β=-0.079, t(193)=-0.798, p>0.05 (Table 3). Although deepfake recognition requires conscientious characteristics such as prudence and a sense of responsibility, Lawson and Kakkar’s (as cited in Sütterlin et al., 2022) research recently found that Conscientiousness is partially correlated with belief in conspiracy and conservatism - making it less efficacious in recognizing deepfakes.\n\nThis study found that Openness was not able to predict self-efficacy in recognizing deepfakes β=-0.028, t(193)=-0.312, p>0.05 (Table 3). In an unpublished report, Jin (2020) found that values of Openness to change do not correlate with the perceived ethical implications of deepfakes (e.g., \"These videos can uncontrollably deceive and influence many people\", p. 24). In addition, contrast with the certain direction of the influence of Agreeableness and Honesty-humility on the self-efficacy; the direction of the Openness prediction is ambiguous. On the one hand, Openness is related to the low ability to recognize deepfakes. It is because Openness was found to be positively correlated with cognitive ability (Curtis et al., 2015; Rammstedt et al., 2016), but cognitive abilities encourage more protective online behavior, indicated by more interest in discussing how people who use deepfakes manipulate their audiences - rather than developing ability to apply scepticism on the authenticity of videos (Ahmed, 2021). On the other hand, there is a logic in favor of Openness as a buffer to prevent vulnerabilities from being manipulated by social engineering. For example, Eftimie et al. (2022) associated Openness with cognitive exploration tendencies which, based on their study, will stimulate responsible behavior including security best practices - which in the context of this study is deepfake recognition.\n\nThe limitation of this research is the use of non-probability sampling with limited generalizability. Nevertheless, this study has implication for the development of psychoinformatics - a branch of psychology that explains attitudes, competencies, and behavior in using information technology. Further research is suggested to implement random sampling and experimental methods to ensure a causal–not only predictive–relationship between personality traits and deepfakes detection self-efficacy.",
"appendix": "Data availability\n\nZenodo: Dataset of Prediction of Self-efficacy in Recognizing Deepfake based on Personality Traits. https://doi.org/10.5281/zenodo.7357400 (Abraham & Alamsyah, 2022a).\n\nThe project contains the following underlying data:\n\n- Dataset of Prediction of Self-efficacy in Recognizing Deepfake based on Personality Traits.xlsx (Raw data)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nZenodo: Questionnaire of Prediction of Self-efficacy in Recognizing Deepfake based on Personality Traits. https://doi.org/10.5281/zenodo.7413517 (Abraham & Alamsyah, 2022b).\n\nThe project contains the following extended data:\n\n- Questionnare-HEXACO and Self-efficacy.docx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAbraham J, Alamsyah H: Dataset of Prediction of Self-efficacy in Recognizing Deepfake based on Personality Traits. [Data set]. Zenodo. 2022a. Publisher Full Text\n\nAbraham J, Alamsyah H: Questionnaire of Prediction of Self-efficacy in Recognizing Deepfake based on Personality Traits. Zenodo. [Extended data].2022b. Publisher Full Text\n\nAhmed S: Fooled by the fakes: Cognitive differences in perceived claim accuracy and sharing intention of non-political deepfakes. Personal. Individ. Differ. 2021; 182: 111074. Publisher Full Text\n\nAustin EJ, Vahle N: Associations of the Managing the Emotions of Others Scale (MEOS) with HEXACO personality and with trait emotional intelligence at the factor and facet level. Personal. Individ. Differ. 2016; 94: 348–353. Publisher Full Text\n\nBandura A: Self-efficacy: Toward a unifying theory of behavioral change. Psychol. Rev. 1977; 84(2): 191–215. PubMed Abstract | Publisher Full Text\n\nCover R: Deepfake culture: The emergence of audio-video deception as an object of social anxiety and regulation. Continuum. 2022; 36(4): 609–621. Publisher Full Text\n\nCurtis RG, Windsor TD, Soubelet A: The relationship between Big-5 personality traits and cognitive ability in older adults – a review. Aging Neuropsychol. Cognit. 2015; 22(1): 42–71. PubMed Abstract | Publisher Full Text\n\nEftimie S, Moinescu R, Răcuciu C: Spear-phishing susceptibility stemming from personality traits. IEEE Access. 2022; 10: 73548–73561. Publisher Full Text\n\nGroh M, Epstein Z, Firestone C, et al.: Deepfake detection by human crowds, machines, and machine-informed crowds. Proc. Natl. Acad. Sci. 2022; 119(1): e2110013119. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHosler B, Salvi D, Murray A, et al.: Do deepfakes feel emotions? A semantic approach to recognizing deepfakes via emotional inconsistencies. Proceedings of the 2021 IEEE/CVF Conference on Computer Vision and Pattern Recognition Workshops (CVPRW). 2021; 1013–1022. Publisher Full Text\n\nKöbis NC, Doležalová B, Soraperra I: Fooled twice: People cannot detect deepfakes but think they can. IScience. 2021; 24(11): 103364. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKwok AO, Koh SG: Deepfake: A social construction of technology perspective. Curr. Issue Tour. 2021; 24(13): 1798–1802. Publisher Full Text\n\nLodewyk KR: Associations between trait personality, anxiety, self-efficacy and intentions to exercise by gender in high school physical education. Educ. Psychol. 2018; 38(4): 487–501. Publisher Full Text\n\nPrayoga T, Abraham J:Technopsychology of IoT optimization in business world.Lee I, editor. The Internet of things in the modern business environment. IGI Global;2017; (pp. 50–75). Publisher Full Text\n\nRammstedt B, Danner D, Martin S: The association between personality and cognitive ability: Going beyond simple effects. J. Res. Pers. 2016; 62: 39–44. Publisher Full Text\n\nShahid F, Kamath S, Sidotam A, et al.: “It matches my worldview”: Examining perceptions and attitudes around fake videos. CHI '22: Proceedings of the 2022 CHI Conference on Human Factors in Computing Systems,. 2022; 255: 1–15. Publisher Full Text\n\nSurowiecki J: The wisdom of crowds: Why the many are smarter than the few and how collective wisdom shapes business, economies, societies, and nations. Doubleday & Co.;2004.\n\nSütterlin S, Lugo RG, Ask TF, et al.:The role of IT background for metacognitive accuracy, confidence and overestimation of deep fake recognition skills.Schmorrow DD, Fidopiastis CM, editors. Lecture Notes in Computer Science (subseries Lecture Notes in Artificial Intelligence, Augmented Cognition). Springer;2022; 13310. : 103–119. Publisher Full Text\n\nTernovski J, Kalla J, Aronow PM: Deepfake warnings for political videos increase disbelief but do not improve discernment: Evidence from two experiments. OSF [Preprint]. 2021. Publisher Full Text\n\nThompson RA: Emotional competence and the development of self. Psychol. Inq. 1998; 9(4): 308–309. Publisher Full Text\n\nUebelacker S, Quiel S: The social engineering personality framework. Proceedings of the 2014 Workshop on Socio-Technical Aspects in Security and Trust. 2014, July; 24–30. Publisher Full Text\n\nVan der Zee K, Thijs M, Schakel L: The relationship of emotional intelligence with academic intelligence and the Big Five. Eur. J. Personal. 2002; 16(2): 103–125. Publisher Full Text\n\nWesterlund M: The emergence of deepfake technology: A review. Technol. Innov. Manag. Rev. 2019; 9(11): 39–52. Publisher Full Text\n\nYang HC, Rahmanti AR, Huang CW, et al.: How can research on artificial empathy be enhanced by applying deepfakes? J. Med. Internet Res. 2022; 24(3): e29506. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhao T, Xu X, Xu M, et al.: Learning self-consistency for deepfake detection. Proceedings of the 2021 IEEE/CVF International Conference on Computer Vision (ICCV). 2021; 15023–15033. Publisher Full Text"
}
|
[
{
"id": "160499",
"date": "10 Feb 2023",
"name": "Sandra Grinschgl",
"expertise": [
"Reviewer Expertise Human-technology interaction",
"personality psychology",
"cognitive psychology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary: This article deals with a highly relevant topic - the identification of deepfakes. The authors investigated potential predictors of the self-reported ability to detect deepfakes, namely individuals’ personality traits based on the HEXACO model. While the traits honesty-humility and agreeableness were indeed shown to be predictors for self-reported ability to identify deepfakes, emotionality, extraversion, conscientiousness and openness were not. A higher honesty-humility was related to a lower self-reported ability to detect deepfakes whereas a higher agreeableness was related to a higher self-reported ability to detect deepfakes.\nI think this is an interesting article on a very acute topic, however, I think it would benefit from some revisions. I outline my concerns below.\nMajor comments:\nRegarding the clear and accurate presentation of the authors’ work: In my opinion, the introduction is lacking an elaborate justification for testing the HEXACO traits as potential predictors of the (self-reported) ability to detect deepfakes. Why might especially those traits act as predictors? The authors could, for instance, argue that typical personality traits might also be relevant when it comes to the application of other artificial intelligence technologies (e.g., robots). For a reference on this behalf see Matthews et al. (2021)1.\n\nThe introduction does not end with clear hypotheses, thus, to me it is unclear whether this research was exploratory or confirmatory.\n\nTable 1: Why was the number of items reduced for the HEXACO traits? What does “after validation” refer do? This choice of method might potentially influence the interpretation of results.\n\nI think the discussion would benefit from a paragraph that focuses on the bigger picture in which the results can be placed. For instance, it could be discussed what conclusions we can draw from the study findings when it comes to the increasing distribution of deepfakes. What might be the “optimal” personality to not fall for deepfakes? Also, I think the authors should discuss how self-reported abilities in detecting deepfakes might be related to actual abilities in detecting deepfakes. This seems especially relevant as individuals’ self-estimation is not always accurate (e.g., above-average effect, Dunning-Kruger effect).\n\nMinor comments:\n\nPage 3: “The current consensus is that the average human’s ability in recognizing deepfakes is similar to the machines (Vitak, 2022).” I’m not sure what this exactly means. Does it mean that artificial intelligence technologies analyzing videos/pictures are as good as humans in identifying deepfakes from real videos?\n\nOnly within the methods section it became fully clear to me that the authors did not actually measure participants’ ability to detect deepfakes but rather participants’ self-reported ability to do so. I would recommend the authors to refer to “self-reported efficacy in recognizing deepfakes” already from the beginning of their article (and in the abstract) to avoid any confusion.\n\nFigure 1: I guess this graph shows the residuals for the multiple regression model. Please clearly state this in the figure description and corresponding manuscript text.\n\nPlease report an effect size with the t-Test statistics on gender differences.\n\nI think especially the discussion could need some language-editing. Every paragraph starts with “This study found” which does not induce an optimal reading flow.\n\nRegarding reproducibility: Data of this study are already openly available (great!). I would suggest that the authors also make their analyses scripts available.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Yes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "162152",
"date": "20 Feb 2023",
"name": "Dilrukshi Gamage",
"expertise": [
"Reviewer Expertise Computational social science",
"deepfakes social implications"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall, the objective of this brief report is to find out the personality traits that affect the efficacy of spotting deepfakes.\n\nIs the work clearly and accurately presented and does it cite the current literature?\nSince some of the literature cited are unpublished reports, I am not sure of the credibility. Since those were absorbed to the main study, this is pretty questionable.\nIs the study design appropriate and does the work have academic merit?\nAs mentioned in the introduction, the authors have taken the personality traits HEXACO from an unpublished report in 2009. I am curious what the authors consider other personality traits and also why did not cite any peer reviewed article with verified and validated factors. On the other hand, introduction does not provide a smooth understanding to why such model was selected and how others have conducted such explanations.\n\nAre sufficient details of methods and analysis provided to allow replication by others?\nMethods were illustrated in a very awkward pattern, for example at once I was not sure doing such a sample size for what- the method of data collection, it took a while to understand that this is a questionnaire, and authors' explanation of other statements made this bit complicated than a straight forward mention.\n\nThe survey questionnaire was unclear - as I understand it's a 6 point Likert scale, but I am not sure if the authors show any deepfake video before the question asked, and if so what are those.\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nThe authors were not clear upfront about their analysis structure or procedure. I believe this was not pre-registered as well. In the results Authors explain the regression analysis and also correlation coefficient of the variables (personality traits), but due to the fact that this was not explain or mentioned as hypothesis, it is not clear the objective of the results and the strategy it provide to show the evidence.\nAre all the source data underlying the results available to ensure full reproducibility?\nData seems to be available.\nAre the conclusions drawn adequately supported by the results?\nThe authors do not provide any concrete conclusions as per se but, the discussion is somewhat leaning toward their conclusions.\n\nBut I have many issues with the way the study is conducted and how authors could claim statement as follow - “Honesty-humility trait do not want to engineer others but, ironically, this trait makes them vulnerable to being manipulated by others (Ternovski et al., 2021), including deepfakes, especially in the context of political greediness.” ---> how did you think of political context, because the study did not support any assumption? Did you ask this question?\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Partly\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-1529
|
https://f1000research.com/articles/12-1316/v1
|
11 Oct 23
|
{
"type": "Research Article",
"title": "Measurement of medication adherence among type II diabetes patients attending primary healthcare facilities in Morocco.",
"authors": [
"Arraji Maryem",
"Al Wachami Nadia",
"Iderdar Younes",
"El Moubchiri Chaimaa",
"Mourajid Yassmine",
"Boumendil Karima",
"Bouchachi Fatima Zahra",
"Guennouni Morad",
"El Khoudri Noureddine",
"Barkaoui Mohamed",
"Mohamed Chahboune",
"Al Wachami Nadia",
"Iderdar Younes",
"El Moubchiri Chaimaa",
"Mourajid Yassmine",
"Boumendil Karima",
"Bouchachi Fatima Zahra",
"Guennouni Morad",
"El Khoudri Noureddine",
"Barkaoui Mohamed",
"Mohamed Chahboune"
],
"abstract": "Background: The aim of this study was to assess medication adherence among Moroccan patients with type 2 diabetes. Methods: To achieve this objective, a quantitative cross-sectional study was conducted among patients with type 2 diabetes in Morocco. The General Medication Adherence Scale (GMAS) was used to measure medication adherence in this target population. The study received ethical approval from the Moroccan Association for Research and Ethics. Results: A total of 284 patients were included in the study. Among them, 90.30% of type 2 diabetes patients demonstrated high adherence to their medication treatment, while 5.30% were considered to have moderate adherence and only 4.40% showed partial adherence. However, when the cumulative evaluation of medication adherence towards antidiabetic drugs was conducted, the results confirmed an adherence rate of approximately 95.78%. Conclusions: The study's findings revealed a high level of medication adherence among type 2 diabetes patients. To sustain these encouraging results, it will be crucial to maintain and value the efforts made by healthcare professionals involved in the care of these patients.",
"keywords": [
"Medication adherence",
"type 2 diabetes",
"oral antidiabetic drugs",
"Morocco."
],
"content": "Introduction\n\nChronic diseases are physical or even mental conditions that restrict the daily activities of patients, persist for at least a year, and require ongoing medical treatment.1,2 In 2014, in the United States, 60% of people were affected by chronic conditions, including heart diseases, cancer, and diabetes, while 42% were affected by other chronic illnesses.3 Non-communicable diseases have a significant impact on mortality and result in substantial economic burdens, further increasing healthcare expenditures globally. Statistical data have highlighted that annual healthcare expenditures associated with heart diseases and strokes combined reached 199 billion US dollars,4 and healthcare expenditures related to diabetes were estimated at 237 billion US dollars in 2018 according to the American Diabetes Association. Global epidemiological statistics indicate a significant increase in the number of individuals with diabetes mellitus (DM), making this chronic condition a leading cause of mortality and morbidity worldwide.5 Additionally, alongside genetic predispositions, it is crucial to mention the essential role of modifiable factors, such as a sedentary lifestyle and an unhealthy diet, which are fundamental predictors of this chronic disease, the prevalence of which continues to rise.6 This epidemic has become a major dilemma for global public health services, with 425 million people confirmed to have DM in 2017; this alarming number could reach 693 million by 2045.7 Indeed, DM stands as the most well-known chronic disorder of the endocrine system. It is noteworthy that improving medication adherence can effectively minimize the economic and health imbalances caused by this DM. For instance, a 10% improvement in treatment adherence among diabetic patients could lead to annual savings of around $450 per affected individual.8,9 Thus, the study of medication adherence is valuable in the effort to mitigate the economic and health burden imposed by this disease. In Morocco, the situation remains alarming, with DM being one of the most common metabolic diseases, recording over 1.4 million cases in 2013, according to the International Diabetes Federation. It should be noted that the number of diagnosed type 2 diabetics each year at primary healthcare institutions. The PHI is 23,761, with 14,479 (66%) in urban areas, compared to 9,282 (34%) in rural areas. Meanwhile, the number of diabetics receiving care within the same facility shows a figure of 1,033,999, with 324,382 (31%) in rural areas and 709,617 (69%) in urban areas, according to statistics from the Moroccan Ministry of Health and Social Protection in 2021.10 Medication adherence is defined as the extent to which a person's behavior regarding medication intake aligns with the recommendations agreed upon with their healthcare professional.11 Nevertheless, various studies have noted that non-adherence to medications is a common issue among different patient populations.12,13 In this regard, poor adherence can lead to unfavorable outcomes that could worsen the patient's health, result in additional healthcare costs, and even impact their quality of life.12,14,15 Consequently, this constitutes a major public health problem with adverse implications for treatment goals, particularly among patients suffering from chronic diseases.16 The objective of this study was to assess the level of medication adherence among type 2 diabetic patients who attend primary healthcare institutions in Morocco. To our knowledge, no study has been conducted in this direction so far due to the lack of validated tools specifically designed for the Moroccan context to measure this crucial component. Hence, this recent work is essential as it aims to quantitatively measure adherence using the General Medication Adherence Scale (GMAS), which has been recently translated and validated exclusively for the first time in Morocco.17 Through this scale, we were able to assess medication adherence within our study population.\n\n\nMethods\n\nThe study protocol received approval from RB00012973 Moroccan Association for Research and Ethics IRB #1 [09/REC/22]. Patients were informed about the study and its objectives; they then provided their informed consent to participate via verbal communication. We chose to use verbal consent because we initially identified that a significant portion of our patients were illiterate. In our sample, 78.50% of them cannot read or write. This is why we opted for oral consent from our patients to participate in the study.\n\nThis cross-sectional study was conducted face-to-face from July 1st to August 1st, 2023, at primary healthcare facilities in Morocco that provide curative and preventive care programs to individuals with chronic diseases. Study participants were adults aged 18 and above, presenting with prediabetes and/or confirmed diabetes, with or without other concurrent conditions, and who had been on antidiabetic treatment for at least one month prior to their inclusion in the study. Patients planning to undergo surgical intervention, pregnant women, and those with acute illnesses requiring urgent medical treatment were excluded from the study. To address issues of reading and comprehension, particularly for illiterate patients, all subjects provided informed consent through verbal communication.\n\nA total of 284 participants were selected from the registry of the primary healthcare facility.\n\nIn the context of our study aiming to measure medication adherence among patients with type 2 diabetes (T2DM), we employed the General Medication Adherence Scale (GMAS), which was translated and transculturally validated exclusively within the Moroccan context.17 The scale was originally developed in the Urdu language in December 2017 by Naqvi et al.18 To translate the instrument from English to Moroccan Arabic, we followed the standard operational procedure of the World Health Organization (WHO).19 This Moroccan Arabic version of GMAS was translated and validated among Moroccan patients with T2DM, and the results demonstrated that this version met the validity criteria for most of the studied psychometric parameters.\n\nThe GMAS is a self-assessment tool consisting of 11 items, with a maximum score of 33. A score ≤ 10 indicates poor medication adherence, a score between 11-16 indicates low adherence, 17-26 indicates partial adherence, 27-29 indicates good adherence, and 30-33 indicates high adherence. This adherence is further subdivided into three constructs:\n\nPatient Behavior-Related Non-Adherence (PBNA): Items 1-5.\n\nNon-Adherence Related to Comorbidities and Medication Burden (ADPB): Items 6-9.\n\nNon-Adherence Related to Costs (CRNA): Items 10-11.\n\nThe Cumulative Classification of Overall Medication Adherence (dichotomous) is distributed as follows:\n\n≥ 27 indicates medication adherence.\n\n≤ 26 indicates medication non-adherence.\n\nInitially, two translators, native speakers of Moroccan Arabic with proficiency in English, performed the translation of the scale. This led to the creation of two versions of the GMAS in Moroccan Arabic at this stage. Both versions were then presented to a panel and examined in terms of conceptual and cultural equivalence. These two versions were harmonized to create a single version in Moroccan Arabic, which was formulated and adopted at this stage. The research team assigned a reviewer proficient in both English and Arabic to develop a back-translation of the measurement instrument. In this way, any discrepancies between the translated and back-translated versions were addressed at this stage. The final version of the GMAS in Moroccan Arabic was tested on 20 subjects. No difficulties were encountered, and the Moroccan Arabic version of the GMAS was deemed satisfactory.\n\nIn order to adapt the original English version of the GMAS tool to Moroccan culture, certain terms were added, replaced, or even rearranged. This process helped develop a version understandable for patients with type 2 diabetes, thus overcoming constraints and ambiguities related to intercultural differences.\n\nAs for assessing the reliability of the translated GMAS tool, it was tested twice on 20 patients through questionnaires containing the 11 items, administered at a 15-day interval. This time frame was sufficiently long to avoid any influence on the responses provided in the first administration. Reproducibility is considered \"good\" when the intraclass correlation coefficient (ICC) exceeds 0.4,20 and internal consistency among different items was estimated using Cronbach's alpha (α) value, which is considered satisfactory for values above 0.7. The response rate to all items was used to evaluate the instrument's acceptability. Thus, the measurement tool was translated and transculturally validated, and it met the majority of psychometric parameters.17\n\nThe collected data were entered and analyzed using the IBM SPSS software, also known as “Statistical Package for Social Sciences,” version 20 (SPSS Inc., Chicago, IL, USA). Demographic data were presented using frequency counts (N) and percentages (%). Statistical tests were chosen based on the data distribution. The Shapiro-Wilk test was used to check data normality.21 For non-parametric data, the chi-square test (χ2) and Spearman's correlation (ρ) were used to identify any association between patient characteristics and treatment adherence. Significant associations were indicated by p-values below 0.05 and correlation coefficients within the range of (-1.0 and +1.0).\n\n\nResults\n\nA total of two hundred eighty-four patients with T2DM participated in the study, with a mean age of 58.24 ± 13.827 years, ranging from 29 to 91 years. Slightly over half of the patients (53.20%) were female, 65.50% were married, and a large majority of participants (78.50%) were illiterate. Most patients were unemployed (91.50%). Almost all patients had medical coverage, primarily provided by the Medical Assistance Program (RAMED), representing 82.81% of all insured individuals (Table 1).\n\nApproximately 40.50% of participants were on a single antidiabetic medication, with the most common being metformin 1000 mg (37%). Hypertension was the most notable comorbidity (43.70%), followed by dyslipidemia (37.70%). The duration of diabetes diagnosis ranged from 6 to 10 years for 37.70% of subjects; 58.80% reported practicing self-monitoring of their blood glucose, and 58.8% indicated receiving education about their diabetes (Table 2).\n\nInformation Patient responses for each item of the GMAS scale (Table 3) confirmed that almost all patients exhibited high medication adherence (N=257, 90.50%), and none of the patients in our target population had low or poor adherence (Table 4). The assessment of medication adherence based on different constructs of the scale confirms that 100% of participants had poor adherence in relation to the PBNA construct (Table 5). The cumulative classification of overall medication adherence shows that 95.78% (N=272) are classified as adherent to medication treatment (Table 6).\n\n\nDiscussion\n\nDocumenting medication adherence is crucial for evaluating treatment outcomes in the case of chronic conditions, with type 2 diabetes being a prime example. One of the most practical methods to measure medication adherence involves the use of a self-reporting tool.22,23 For this study, we chose the GMAS tool, which we translated and transculturally validated for the first time in Morocco in 2023.17 Our results demonstrated medication adherence of 95.78%. Among diabetic subjects, 90.30% exhibited high adherence, 5.30% had good adherence, and 4.40% showed partial adherence. Our study aligns with the 2020 study conducted by Naqvi et al for translating the GMAS tool into Arabic in Saudi Arabia,24 which revealed that the majority of patients had high adherence (42.60%), while 19.10% exhibited good adherence, 32.60% showed partial adherence, 4.30% had low adherence, and a small minority (1.40%) had poor adherence. Similarly, our findings are in harmony with the 2022 study by Allaham et al in the United Arab Emirates,25 using the same GMAS tool, which also confirmed high adherence of 78.57%. Our results are also consistent with the study conducted by Lasut et al in Riyadh, Saudi Arabia26 in 2022, using the same measurement scale on elderly individuals. The majority of patients demonstrated high adherence (64.90%), while 21.30% exhibited good adherence, 13.30% showed partial adherence, and a minimal proportion (0.50%) reported low adherence. This alignment is also seen in the Sudanese study by Mahmoud et al in 2021,27 where 69% showed high adherence, 8.80% had good adherence, 11.40% exhibited partial adherence, and 0.80% had poor adherence. The Vietnamese study by Nguyen et al in 2021,28 focusing on the translation and transcultural validation of GMAS, concluded that officers had a high adherence rate of 91.70%, while traders had a low adherence rate of 43.80%. Patients with an income between three and five million exhibited a significant cumulative non-adherence rate (≤ 26) of 69.25%. A recent 2023 study in Faisalabad, Pakistan,29 demonstrated that cognitive-behavioral therapy significantly improved medication adherence in patients with T2DM. For instance, high adherence increased from 7.41% to 37.04%, good adherence increased from 11.12% to 44.45%, partial adherence decreased from 46.15% to 11.12%, and low adherence decreased from 22.23% to 7.41%. Additionally, the study by Sendekie et al in northwest Ethiopia30 in 2022, using the GMAS tool, found that 76.90% of participants had low adherence. Our results contradict the findings of the study by Naqvi et al in Saudi Arabia31 in 2019, where GMAS validation in English showed that 17.55% of patients had high adherence, 25.10% had good adherence, 49.70% had partial adherence, 5.80% had low adherence, and 1.80% had poor adherence. For the study by AlQarni et al. in 2019 in Khobar, Saudi Arabia,32 the data revealed that a little over one-third, 35.80%, of patients were adherent to medication treatment across the three constructs. Among them, half of the patients, 50.90%, exhibited high adherence in the PBNA construct. Furthermore, for the ADPB construct, just under half of the patients, 47.20%, showed high adherence in this regard. Concerning the last CRNA construct, more than half of the subjects, 54.70%, demonstrated high adherence at this level. Although the Vietnamese study conducted by Pham et al. in 202233 found that adherence to the PBNA construct was high in 41% of cases, good in 24.40%, partial in 24.60%, low in 7.60%, and poor in 2.40%. For the ADPB construct, adherence to treatment was high in 51.30%, good in 27.20%, partial in 17.50%, low in 2.90%, and even poor in 1.10%. Regarding the last ADPB construct, adherence levels were high in 53.10%, good in 22.50%, partial in 21.60%, low in 1.50%, and even poor in 1.30%.\n\nThe present study has some limitations. For instance, the degree of medication adherence was measured through a self-assessment scale completed by patients, which could influence responses and lead to underestimation or overestimation of adherence levels. Despite this limitation, this study is considered the first of its kind to fill the existing gap in the literature concerning factors influencing medication non-adherence in the same target population.\n\n\nConclusions and recommendations\n\nOur study revealed that type 2 diabetic subjects exhibited high medication adherence using the Moroccan GMAS tool (GMAS-M), which has previously demonstrated validity, reliability, and satisfactory psychometric parameters. Its concise and easy-to-understand format allows patients to complete it independently, making it a valuable tool for measuring medication adherence levels among patients with chronic diseases, as well as for identifying potential barriers to adherence. We recommend its use in other chronic diseases.\n\n\nAuthor Contributions\n\nARRAJI Maryem: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing\n\nAL WACHAMI Nadia: Data Curation, Methodology\n\nIDERDAR Younes: Resources, Software\n\nEL MOUBCHIRI Chaimaa: Formal Analysis, Investigation\n\nMOURAJID Yassmine: Investigation, Methodology\n\nBOUMENDIL Karima: Project Administration, Resources\n\nBOUCHACHI Fatima Zahra: Validation, Visualization\n\nGUENNOUNI Morad: Resources, Software, Supervision, Validation\n\nEL KHOUDRI Noureddine: Visualization, Writing – Original Draft Preparation\n\nBARKAOUI Mohamed: Supervision, Validation\n\nCHAHBOUNE Mohamed: Data Curation, Formal Analysis, Funding Acquisition, Methodology, Project Administration, Validation, Visualization",
"appendix": "Data availability\n\nDue to the fact that open posting of data on a repository was not included in the study information sheet at the time the survey was done, data access will be granted once users have consented to the data sharing agreement and provided written plans and justification for what is proposed with the data. Data access may be obtained by submitting a request to the authors at Hassan First University of Settat, Higher Institute of Health Sciences, Laboratory of Sciences and Health Technologies, Settat 26000, Morocco.\n\n\nReferences\n\nCenter for Disease Control and Prevention (CDC): About Chronic Diseases.2019. (accessed 01 August 2023). Reference Source\n\nNaqvi AA, Hassali MA, Rizvi M, et al.: Development and Validation of a Novel General Medication Adherence Scale (GMAS) for Chronic Illness Patients in Pakistan. Front. Pharmacol. 2018 Oct 9; 9: 1124. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRaghupathi W, Raghupathi V: An Empirical Study of Chronic Diseases in the United States: A Visual Analytics Approach. Int. J. Environ. Res. Public Health. 2018 Mar 1; 15(3): 431. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBenjamin EJ, Virani SS, Callaway CW, et al.: Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation. 2018 Mar 20; 137(12): e67–e492. PubMed Abstract | Publisher Full Text\n\nWorld health organization (2016) global report on diabetes. Geneva, Switzerland: World health organization; (accessed on 02/08/2023 at 3:00 PM). Reference Source\n\nZheng Y, Ley SH, Hu FB: Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat. Rev. Endocrinol. 2018 Feb; 14(2): 88–98. Publisher Full Text\n\nCho NH, Shaw JE, Karuranga S, et al.: IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract. 2018 Apr; 138: 271–281. PubMed Abstract | Publisher Full Text\n\nKennedy-Martin T, Boye KS, Peng X: Cost of medication adherence and persistence in type 2 diabetes mellitus: a literature review. Patient Prefer. Adherence. 2017 Jun 30; 11: 1103–1117. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHuang YM, Shiyanbola OO, Chan HY, et al.: Patient factors associated with diabetes medication adherence at different health literacy levels: a cross-sectional study at a family medicine clinic. Postgrad. Med. 2020 May; 132(4): 328–336. PubMed Abstract | Publisher Full Text\n\nministère de la santé et de la protection sociale Direction de la Planification et des Ressources Financières, Division de la Planification et des Etudes, Service des Etudes et de l’Information sanitaire.2021.\n\nWorld Health Organization (WHO): Adherence to long-term therapies: evidence for action.2003. (accessed 01 August 2020). Reference Source\n\nNguyen TM, La Caze A, Cottrell N: What are validated self-report adherence scales really measuring? a systematic review. Br. J. Clin. Pharmacol. 2014 Mar; 77(3): 427–445. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlQarni K, AlQarni EA, Naqvi AA, et al.: Assessment of Medication Adherence in Saudi Patients With Type II Diabetes Mellitus in Khobar City, Saudi Arabia. Front. Pharmacol. 2019 Nov 8; 10: 1306. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGehi AK, Ali S, Na B, et al.: Self-reported medication adherence and cardiovascular events in patients with stable coronary heart disease: the heart and soul study. Arch. Intern. Med. 2007 Sep 10; 167(16): 1798–1803. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSokol MC, McGuigan KA, Verbrugge RR, et al.: Impact of medication adherence on hospitalization risk and healthcare cost. Med. Care. 2005 Jun; 43(6): 521–530. Publisher Full Text\n\nHaynes RB, Ackloo E, Sahota N, et al.: Interventions for enhancing medication adherence. Cochrane Database Syst. Rev. 2008 Apr 16; 2: CD000011. Publisher Full Text\n\nMaryem A, Younes I, Yassmine M, et al.: Translation, cultural adaptation and validation of the General Medication Adherence Scale (GMAS) in moroccan patients with type-2 diabetes. BMC Nurs. 2023 Sep 4; 22(1): 302. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNaqvi AA, Hassali MA, Rizvi M, et al.: Development and Validation of a Novel General Medication Adherence Scale (GMAS) for Chronic Illness Patients in Pakistan. Front. Pharmacol. 2018 Oct 9; 9: 1124. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organisation Regional Office of Africa: Standard Operating Procedures For AFRO Strategic Health Operations Centre (AFRO SHOC).2014. 2014. (accessed 01 Jully 2023). Reference Source\n\nAuquier P, Robitail S: Validation d’un questionnaire de qualité de vie. Qualitéde vie et dermatologie. Montrouge: John Libbey Eurotext; 2001; 13.\n\nShapiro SS, Wilk MB: An analysis of variance test for normality (complete samples). Biometrika. 1965; 52: 591–611. Publisher Full Text\n\nNaqvi AA, Hassali MA: Limitations in contemporary self-reported medication adherence questionnaires: the concept and design of the General Medication Adherence Scale (GMAS) originating from a developing country. Curr. Med. Res. Opin. 2019 Jan; 35(1): 1–2. PubMed Abstract | Publisher Full Text\n\nForbes CA, Deshpande S, Sorio-Vilela F, et al.: A systematic literature review comparing methods for the measurement of patient persistence and adherence. Curr. Med. Res. Opin. 2018 Sep; 34(9): 1613–1625. PubMed Abstract | Publisher Full Text\n\nNaqvi AA, Mahmoud MA, AlShayban DM, et al.: Translation and validation of the Arabic version of the General Medication Adherence Scale (GMAS) in Saudi patients with chronic illnesses. Saudi Pharm. J. 2020 Sep; 28(9): 1055–1061. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAllaham KK, Feyasa MB, Govender RD, et al.: Medication Adherence Among Patients with Multimorbidity in the United Arab Emirates. Patient Prefer. Adherence. 2022 May 6; 16: 1187–1200. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLasut D, Nugroho HSW, Winarko W: Medication Adherence Among Geriatric Patients with Chronic Diseases [Letter]. Patient Prefer. Adherence. 2022 Aug 29; 16: 2353–2354. Publisher Full Text\n\nMahmoud MA, Islam MA, Ahmed M, et al.: Validation of the Arabic Version of General Medication Adherence Scale (GMAS) in Sudanese Patients with Diabetes Mellitus. Risk Manag. Healthc Policy. 2021 Oct 9; 14: 4235–4241. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNguyen TH, Truong HV, Vi MT, et al.: Vietnamese Version of the General Medication Adherence Scale (GMAS): Translation, Adaptation, and Validation. Healthcare (Basel). 2021 Oct 29; 9(11): 1471. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAbbas Q, Latif S, Ayaz Habib H, et al.: Cognitive behavior therapy for diabetes distress, depression, health anxiety, quality of life and treatment adherence among patients with type-II diabetes mellitus: a randomized control trial. BMC Psychiatry. 2023 Feb 3; 23(1): 86. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSendekie AK, Netere AK, Kasahun AE, et al.: Medication adherence and its impact on glycemic control in type 2 diabetes mellitus patients with comorbidity: A multicenter cross-sectional study in Northwest Ethiopia. PLoS One. 2022 Sep 21; 17(9): e0274971. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNaqvi AA, AlShayban DM, Ghori SA, et al.: Validation of the General Medication Adherence Scale in Saudi Patients With Chronic Diseases. Front. Pharmacol. 2019 Jun 4; 10: 633. Publisher Full Text\n\nAlQarni K, AlQarni EA, Naqvi AA, et al.: Assessment of Medication Adherence in Saudi Patients With Type II Diabetes Mellitus in Khobar City, Saudi Arabia. Front. Pharmacol. 2019 Nov 8; 10: 1306. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPham ST, Dam CV, Duong CX, et al.: Medication Adherence of Vietnamese Outpatients with Chronic Diseases during the COVID-19 Pandemic. Trop. Med. Infect Dis. 2022 Jun 13; 7(6): 101. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "276928",
"date": "29 May 2024",
"name": "Chun Wai Chan",
"expertise": [
"Reviewer Expertise Primary care"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntroduction: Background, rationale and objective of the study were adequately described.\nMethods: Cross-sectional design is appropriate for prevalence study. Sample size calculation is missing. GMAS is adequately described. I am confused with the translation and validation part – Did the authors describe the study conducted by Arraji et al or they conducted the translation and validation again themselves? If they described the previous study then can omit most of the information, just describe the relevant statistical results showing the validity of the previous study will do.\nResults: The tables describing the frequency of independent and dependant variables were listed, but there is no statistical analysis on the associated factors. Table 5 description isn’t in English.\n\nDiscussions: The authors listed many other studies with the similar results, but did not mention the reasons why the adherence rates were high. Missing the discussion on the associated factors.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
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https://f1000research.com/articles/12-1316
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https://f1000research.com/articles/12-1315/v1
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11 Oct 23
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{
"type": "Research Article",
"title": "Total cholesterol effect after consumption of tomato juice alone and in combination with extra virgin olive oil. A nine-day pilot study in hypercholesterolemic patients",
"authors": [
"Giuliana Del Castillo Vidal",
"Michelle Lozada-Urbano",
"Doris Miranda",
"Oriana Rivera-Lozada",
"Christian Mejia",
"Jaime Yáñez",
"Giuliana Del Castillo Vidal",
"Doris Miranda",
"Christian Mejia"
],
"abstract": "The objective was to determine the effect of lycopene on the total cholesterol levels in patients with hypercholesterolemia at a hospital in Lima in 2018. The type of study was quantitative, and the design was analytical, longitudinal and prospective. The sample consisted of patients with hypercholesterolemia treated at the department of Nutrition of Sanidad de la Policia Nacional del Perú. Tomato juice containing lycopene was administered through a preparation based on tomato juice with olive oil, which was macerated for an average of 8 hours before being consumed. A total of 70 subjects were recruited; however, a total of 50 patients finished the study protocol. 21 received tomato juice with olive oil (TOO), 14 patients only received tomato juice (TJ), and 15 only had nutritional counseling regarding the low-calorie diet (LCD). According to this study, the tomato juice and olive oil preparation, as well as the diet, were related to differences on cholesterol measurement. These recommendations can help to lower cholesterol in patients.",
"keywords": [
"lycopene",
"hypolipidemic agents",
"hypercholesterolemia",
"tomato",
"olive oil"
],
"content": "Introduction\n\nThe ideal cardiovascular health is determined by the absence of tobacco, body mass index <25 kg/m2, physical activity and, according to current guidelines, untreated total cholesterol <200 mg/dL, untreated blood pressure <120/<80 mm Hg and fasting blood glucose <100 mg/dL.1 The American Heart Association recommends maintaining total cholesterol values at no more than 200 mg/dL, while values higher than 240 mg/dL are considered high. The optimal high-density lipoprotein (HDL) and LDL levels are considered to be at least 60 mg/dL and not more than 100 mg/dL, respectively.2\n\nThe use of lycopene has been reported to reduce blood cholesterol in the range of 30 to 60 mg/dL (a 25 to 30% reduction) in patients with initial levels of 250 to 300 mg/dL.3 Lycopene is a strong antioxidant, which prevents oxidative stress of LDL cholesterol molecules, and helps prevent atherosclerosis and benefits cardiovascular health.4,5 The antioxidant function of lycopene has been reported to be twice as active as β-carotene’s.6 Lycopene acts synergistically with other components7–12 and is transported by lipoproteins in the plasma and then distributed to different organs.13 In humans, lycopene has been reported to have a bioavailability of 10-30%, which is influenced by biological and other lifestyle factors such as age, gender, hormonal status, body composition, blood triglyceride levels, smoking, and alcohol consumption.5\n\nPharmacological treatment through statins has been reported to be effective in reducing low-density lipoprotein (LDL) cholesterol by up to 60%, but can lead to adverse events such as muscle complications and an increased risk of diabetes.14 Statins have been reported to improve the lipid profile in both genders, but higher improvements observed in women older than 70 years old.15 An advantage of consuming lycopene through tomatoes is that it shows no adverse effects over statins, and has been reported to lower blood pressure.16 These results strengthen the practice of including tomatoes in individualized and nutritional strategies for treating cardiovascular diseases.17,18 There is not a universally established dose of lycopene that is considered healthy, but it has been reported that including at least one tomato per day in our diet decreases the risk of cardiovascular disease due to its antioxidant effect.15 In the terms of servings of tomato, it has been reported that one serving is equivalent to half a cup of tomato sauce for spaghetti, a quarter cup of tomato paste or puree, or a medium tomato.19 Tomatoes are rich in antioxidants20 such as lycopene21–24 and other bioactive compounds such as flavonols, flavanones and hydroxycinnamic acids,4,8–12,25–28 and a preparation rich in antioxidants has been reported to contribute for the prevention of cancer and other noncommunicable diseases.29–37 Longitudinal studies in men have shown that those who consumed ten servings per week of cooked tomato products had one-third less risk than men who ate less than two servings per week.38 Tomato lycopene has been found to have a hypocholesterolemic effect, and the effect has been proposed to be related to inhibition of cholesterol synthesis.39 Furthermore, tomato lycopene has been used as adjuvant treatment for arterial circulation disorders including angina pectoris and myocardial infarction.3 Other studies suggest that lycopene may influence the reduction of the risk of other cancers, including colon, rectum, and breast cancer.19 The effects of tomato products and lycopene supplementation have shown positive effects on blood lipids, blood pressure, and endothelial function.18\n\nThe combination of olive oil and tomato lycopene has been reported to decrease the risk of coronary heart disease by improving the serum lipid profile compared to a diet rich in carbohydrates, low in fat and rich in lycopene.40 Also, the consumption of tomato products with olive oil has been reported to improve the antioxidant activity of plasma.41 The antioxidant and hypocholesterolemic activity of the phenolic extracts of virgin and extra virgin olive oil has been reported while protecting HepG2 liver cells from hydrogen peroxide induced oxidative stress by reducing intracellular reactive oxygen species (ROS) and lipid peroxidation levels.42 Olive oil has also been reported to modulate the low-density lipoprotein receptor (LDLR) pathway causing a reduction in plasma levels of LDL cholesterol and the oxidation of these lipoproteins.42 Therefore, diets rich in monounsaturated fatty acids promote the formation of compounds with antiaggregating and vasodilating action.43–45\n\nIn developing countries such as Peru there is limited access to adequate and timely access to pharmaceutical treatment for cardiovascular diseases.46 The incidence of cardiovascular risk in Peru surpasses an average of 41% in people older than 15 years, being higher (43.5%) in urban areas but lowed in rural areas (31.2%).47 The prevalence of hypercholesterolemia in Peru is 19.6% in adults over 20 years of age and the population having high levels of triglycerides and LDL is approximately 15% and 13%, respectively.48,49\n\nFurthermore, Peru has a considerable consumption of medicinal plants35 and it is easier in some instances to implement nutritional and lifestyle intervention or recommend the adjuvant treatment with a fruit, vegetable or medicinal plant.50–53 The use of tomato lycopene alone and in combination with olive oil offers a plausible acceptable adjuvant treatment to reduce cholesterol levels in the Peruvian population. Therefore, we designed an intervention study to determine the effect in cholesterol levels after at least 9 days of consumption of tomato juice alone and in combination with olive oil accompanied with usual diet in comparison with a low-calorie diet (1000 calories) in 50 70 patients in a hospital in Lima, Peru.\n\n\nMethods\n\nAnalytical study with a longitudinal and prospective design, quantitative type. Figure 1 shows the three treatments the study patients received, (1) tomato juice + olive oil and usual diet; (2) tomato juice (3) low calorie diet (1000 kcal).\n\nA total of 70 patients were recruited; however, a total of 50 patients finished the study protocol. Patients with the diagnosis of hypercholesterolemia who were treated in the Nutrition service at a Department of Nutrition of Sanidad de la Policia del Perú (hospital based in Lima, Peru). Convenience sampling was used to allow representative samples to be obtained from the population of patients in medical consultation from June to November 2018 and who met the inclusion criteria.\n\nThe inclusion criteria were patients older than 18 years old with a diagnosis of hypercholesterolemia of both genders in a hospital in Lima that were not receiving pharmacological treatment. The patients were previously diagnosed with hypercholesterolemia based on their medical history. The patients that accepted to be part of the study were referred to a nutritionist appointment and a confirmatory cholesterol measurement was performed. The hospital (Sanidad de la Policia del Perú) uses the definition of the American Heart Association for high cholesterol when the total cholesterol levels are above 240 mg/dL.54\n\nThe exclusion criteria were the use of pharmacological treatment for hypercholesterolemia or any pharmacological treatment, which may produce synergistic or antagonistic effects with cholesterol. Another exclusion criteria were history of food allergy to some of the components of the interventions.\n\nPatients were randomized into the three intervention groups at the time of their initial clinic visit. The patients that met the inclusion criteria were explained about the study and the objectives and were requested to sign the informed consent. Then, the patients were requested to return the following day for baseline measurement of total cholesterol in blood and for anthropometric measurements (weight, height, BMI and waist circumference). Total cholesterol was measured using a colorimetric enzymatic method, as previously described.55\n\nThe tomato juice and olive oil were prepared with approximately 420 grams of peeled ripe tomatoes, whose pulp with seeds was liquefied and with the addition of approximately 18 mL of extra virgin olive oil. It was mixed for one more minute until obtaining a homogeneous mixture. This was macerated for eight hours at room temperature. This preparation was made by the nutritionist in charge of patient care and was consumed in the office.\n\nThe tomato juice was prepared with approximately 420 grams of fresh and ripe tomatoes, from which the skin was removed, the pulp along with the seeds were blended without any additives. It was stored at room temperature for eight hours before being consumed in the office. This preparation was made by the nutritionist in charge of patient care.\n\nThe type of food preparation was selected because it has been previously reported that the use of olive oil can generate a biocompatible microemulsion containing lycopene that exhibit good solubility in aqueous and non-polar media and can enhance the health promoting properties of both lycopene and olive oil.56 The tomato variety utilized in our study was organic Milano Perseo, which has been reported to contain 219.95 ± 1.76 μg lycopene per gram of tomato57; therefore, the tomato juice preparations averaged approximately 92.38 ± 0.74 mg of lycopene.\n\nA plan of one thousand calories was provided by the nutritionist in charge of patient care. A list of food exchanges for the day was given to the patients based on the World Health Organization (WHO) energy and protein requirements.58 The low-calorie diet was consumed by the patients in their homes without supervision.\n\nThe first group of patients consumed tomato juice + olive oil, which was prepared by the nutritionist the day before (eight hours before) and was delivered to the patients in the hospital in the morning while fasting. This was performed for nine consecutive days.\n\nTo the second group, the nutritionist gave tomato juice without olive oil, which was also prepared the day before and consumed in the hospital in the morning while fasting. This was performed for nine consecutive days.\n\nThe third group of patients did not drink tomato juice or tomato juice + olive oil, they consumed a detailed plan of 1000 calories that was prepared by themselves at home.\n\nThe duration of the study treatment for nine days was based on previous studies that have evaluated similar tomato treatments and their effect in cholesterol levels and endothelial function for periods of time between seven days and 14 days. For instance, Stangl et al. evaluated the effect of tomato products on endothelial function after administration of 70 g of tomatoes containing 46.2 mg of lycopene for 7 days to healthy non-smoking postmenopausal women.59 Another study delivered 70 g tomato paste containing 33.3 mg of lycopene for 14 days to evaluate endothelial dynamics and plasma total oxidative status in healthy subjects.60\n\nTo control protocol adherence, the patients who consumed the hypocaloric diet were called by telephone by the nutritionist in charge of patient care to follow-up if they prepared the proposed nutritional plan.\n\nThere was no control diet, the reason is because the patients were referred from the doctor’s care with a reference sheet to be attended by the nutritionist. At that moment they entered a list to be randomized and they were assigned to one of the three treatment groups. Because of their hypercholesterolemia diagnosis, the patients needed a nutritional plan that required changes in the usual diet. Therefore, having a control diet based on their usual diet was not appropriate because of the need of proper timely care.\n\nDescriptive statistics (central tendency and dispersion measures) were used. The variables were described according to the type of preparation or diet received. Because cholesterol is a quantitative variable, the normality test was performed, and Shapiro Wilk was used since the population was less than 50 patients. The test for homogeneity of variances was observed to see if the results adjust or not to a normal model. It was proposed to apply a contrast of equality of means for two independent samples with the Student’s T test. Statistical significance was determined with p-values < 0.05. The results were analyzed in the statistical package SPSS, version 23.\n\nParticipants received an explanation about the study objectives and procedures. It was explained that their identity and the results obtained from the laboratory were protected at all times, and that if they decided to leave the study, they could do so at any time they chose. Once they voluntarily accepted to participate, they signed the informed consent form. The study protocol was approved by the institutional ethics committee for health research of the Universidad Norbert Wiener (# 0014-2018).\n\n\nResults\n\nA total of 70 patients were recruited; however, a total of 50 patients finished the study protocol. Out of these, 21 received tomato juice with olive oil (TOO) and their regular diet; 14 patients received only tomato juice (TJ) and regular diet; and 15 had only nutritional counseling regarding the 1,000-calorie diet (LCD). The average age in the first (TOO) group was 53.48, in the second (TJ) group 54.13, and in the third (LCD) group, it was 52.60 years.\n\nThe initial body mass index (BMI) for two of the TOO and TJ groups showed the level of overweight (BMI ± SD) (29.53 ± 3.15 kg/m2 and 29.26 ± 4.73 kg/m2 respectively); and for group LCD (30.59 ± 3.46 kg/m2), it had a value corresponding to obesity. Furthermore, there were no statistically significant differences in the initial cholesterol measurements nor the anthropometric measurements (weight, height, BMI and abdominal circumference) between the treatment groups.\n\nThe BMI on Day 9 exhibited a slight increase in all the treatment groups, which correlated to a slightly higher body weight even though the abdominal circumference measurements in all the treatment groups were lower; however, all these differences were not statistically significant.\n\nThe baseline cholesterol levels in the three groups were in the range of 219.90 and 264.04 mg/dL, which were considered elevated. However, the cholesterol levels on Day 9 were reduced to values lower than 200 mg/dL that were considered normal (Table 1).\n\nIt was determined that the cholesterol values at baseline (CHOL1) and at the end of the study (CHOL2) do not have a normal distribution, therefore, the medians were compared using non-parametric tests: Kruskal Wallis and Wilcoxon. In Table 2, the differences of the CHOL2-CHOL1 level were analyzed to verify if the cholesterol levels were reduced with the diet, effectively. It was determined that there were significant differences (p< 0.05) in cholesterol levels within each type of intervention.\n\nThe CHOL 1 value at the start of the intervention was checked with the Kruskal Wallis test to verify whether the cholesterol values were the same in all groups. It was determined that at baseline patients had similar cholesterol level (p>0.05). Then, the CHOL 2 level at the end of the intervention was analyzed and it was found that there were no significant differences (p>0.05) between the type of diet (see Table 3).\n\n* Test de Kruskal Wallis.\n\n\nDiscussion\n\nThe patients who consumed tomato juice and olive oil were 53.48 years old on average and had a BMI of 29.53 (overweight) and final cholesterol of 145.56 md/dL. Patients who consumed tomato juice were 54.13 years old on average and had a BMI of 29.26 (overweight) and final cholesterol of 118.35 md/dL, and patients who consumed only their diet were 52.60 years old on average and had a BMI of 30.59 (obesity) and final cholesterol of 139.00 md/dL. The distribution of cholesterol before and after the intervention in the three groups: tomato juice and olive oil (TOO), tomato juice (TJ) and low-calorie diet (LCD), shows the same distribution among the categories and there were no statistical differences.\n\nThe benefits of diets rich in tomatoes for the cardiovascular system have been linked to plasma carotenoid concentrations. It has been reported that all lycopene isomers significantly increased in subjects consuming tomato juice (TJ) with oil, reaching maximum concentration at 24 h. LDL and total cholesterol decreased significantly six h after TJ consumption with oil, which was significantly correlated with an increase in trans-lycopene and 5-cis-lycopene, respectively.61 Lycopene has been reported to be a potentially useful compound to prevent and treat cardiovascular diseases and cancers because of its antioxidant capacity.62 Salazar Lugo showed that the consumption of tomato juice for six weeks decreased total cholesterol and LDL cholesterol, being more effective in patients with hyperlipidemia,63 which correlates with our results.\n\nThe consumption of diets containing olive oil and rich in lycopene for 9 days have been reported to decrease the cholesterol levels by improving the lipid profile compared to diets rich in carbohydrates, low in fat and rich in lycopene.61,64 The consumption of tomatoes with olive oil improves the antioxidant capacity of plasma.41 Although the measurement of antioxidant activity was not the objective of this study, it was observed that the serum lipid profile measured by cholesterol did change. The results show that a significant difference was found between the first and second measurements in the tomato juice and olive oil (TOO) preparation, while no difference was observed for the tomato juice (TJ) preparation. The low-calorie diet (LCD) showed differences between the first and second cholesterol measurements, but no differences between groups were observed.\n\nRecent studies have reported that patients supplemented with tomato were associated with significant reductions in LDL cholesterol, IL-6, and flow-mediated dilation.20,61,64 Tomato consumption also had positive effects on blood pressure and endothelial function, while lycopene intake has been classified as a preventive and non-pharmacological therapeutic measure for different types of diseases.65 The dose of lycopene needed to obtain health benefits has not yet been agreed upon, and most epidemiological studies have shown the consumption of seven to ten servings per week of lycopene source foods, equivalent to five to ten mg/day of lycopene, seem to have positive effect.66 It is important to note that based on previous lycopene quantification (219.95 ± 1.76 μg lycopene per gram of tomato),57 our tomato juice preparations could average approximately 92.38 ± 0.74 mg of lycopene. Tomato juice preparations, rich in lycopene, combined other synergistic foods such as olive oil have been reported. For instance, tomato juice made with 420 g of tomatoes and macerated for more than 8 hours with the 18 mL of extra virgin olive oil, have been reported to increase the content of relevant phytochemicals such as lycopene, chlorogenic acid, caffeic acid and ferulic acid, lutein and zeaxanthin67 and vitamin C. Tomato also contains various flavonoids such as quercetin, rutin, naringenin that possess antioxidant effects and health related benefits.68,69 Likewise, the consumption of olive oil improves the absorption of lycopene from tomato preparations,70,71 and extra virgin olive oil provides an excellent amount of vitamin E,72 which is scarce in food and has a high anti-oxidant capacity.73 Extra virgin olive oil consumption has been reported to provide a cardioprotective effect by reducing total cholesterol and LDL, because of its high monounsaturated fat content.74\n\nThe main limitation is that the sample size was small, and it can only be considered as a pilot study. There was no evaluation of tomato maturity, phytochemical content nor physicochemical and organoleptic evaluation of the tomatoes and extra virgin olive oil used. Only total cholesterol was quantified, and no information was obtained from the HDL or LDL cholesterol or any other cardiovascular relevant biochemical parameter. Future research should be performed with a better and more detailed characterization of the food preparations and for longer periods of administration.\n\n\nConclusions\n\nThere was an effect on the measurement of cholesterol with the preparation of tomato juice and olive oil as well as the low-calorie diet. These recommendations would support patients with cardiovascular disease and dyslipidemia. The found information would support the creation of individualized nutritional strategies involving lycopene-rich products such as tomatoes in patients with cardiovascular disease and dyslipidemia.",
"appendix": "Data availability statement\n\nThe data presented in this study is too large to be feasibly hosted by a F1000Research-approved repository. The data presented in this study is part of multiple studies to be published. All necessary data required for a reader or reviewer is presented in the study.\n\n\nAcknowledgments\n\nTo the Dirección de la Investigación of the Universidad Peruana de Ciencias Aplicadas for the support provided to carry out this research work through the UPC-EXPOST-2023-2.\n\n\nReferences\n\nLloyd-Jones DM, Hong Y, Labarthe D, et al.: Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s strategic Impact Goal through 2020 and beyond. Circulation. 2010 Feb 2; 121(4): 586–613. eng. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nCruz Bojórquez RM, González Gallego J, Sánchez CP: Propiedades funcionales y beneficios para la salud del licopeno. Nutr. Hosp. 2013; 28: 6–15.\n\nRao AV, Shen H: Effect of low dose lycopene intake on lycopene bioavailability and oxidative stress. Nutr. Res. 2002 2002/10/01/; 22(10): 1125–1131. Publisher Full Text\n\nChaudhary P, Sharma A, Singh B, et al.: Bioactivities of phytochemicals present in tomato. J. Food Sci. Technol. 2018 2018/08/01; 55(8): 2833–2849. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang S, DeGroff VL, Clinton SK: Tomato and soy polyphenols reduce insulin-like growth factor-I-stimulated rat prostate cancer cell proliferation and apoptotic resistance in vitro via inhibition of intracellular signaling pathways involving tyrosine kinase. J. Nutr. 2003 Jul; 133(7): 2367–2376. eng. PubMed Abstract | Publisher Full Text\n\nLoke WM, Proudfoot JM, McKinley AJ, et al.: Quercetin and its in vivo metabolites inhibit neutrophil-mediated low-density lipoprotein oxidation. J. Agric. Food Chem. 2008 May 28; 56(10): 3609–3615. eng. PubMed Abstract | Publisher Full Text\n\nVazquez-Martin A, Fernández-Arroyo S, Cufí S, et al.: Phenolic secoiridoids in extra virgin olive oil impede fibrogenic and oncogenic epithelial-to-mesenchymal transition: extra virgin olive oil as a source of novel antiaging phytochemicals. Rejuvenation Res. 2012 Feb; 15(1): 3–21. eng. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRocchetti G, Senizza B, Giuberti G, et al.: Metabolomic Study to Evaluate the Transformations of Extra-Virgin Olive Oil’s Antioxidant Phytochemicals During in vitro Gastrointestinal Digestion. Antioxidants (Basel). 2020 Apr 6; 9(4). Epub 20200406. eng. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBartella L, Di Donna L, Napoli A, et al.: High-throughput determination of vitamin E in extra virgin olive oil by paper spray tandem mass spectrometry. Anal. Bioanal. Chem. 2019 May; 411(13): 2885–2890. eng. PubMed Abstract | Publisher Full Text\n\nBouymajane A, Oulad El Majdoub Y, Cacciola F, et al.: Characterization of Phenolic Compounds, Vitamin E and Fatty Acids from Monovarietal Virgin Olive Oils of “Picholine marocaine” Cultivar. Molecules. 2020; 25(22): 5428. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCovas MI, Nyyssönen K, Poulsen HE, et al.: The effect of polyphenols in olive oil on heart disease risk factors: a randomized trial. Ann. Intern. Med. 2006 Sep 5; 145(5): 333–341. eng. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "230745",
"date": "15 Feb 2024",
"name": "Phakkharawat Sittiprapaporn",
"expertise": [
"Reviewer Expertise Neurosciences"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReview Results\nManuscript entitled: Total cholesterol effect after consumption of tomato juice alone and in combination with extra virgin olive oil.\nI am really appreciative of this study and enjoy reading this manuscript. However, there are some concerns where more details need to be declared, as follows:\nPopulation and sampling: The authors mentioned that “Convenience sampling was used to allow representative samples to be obtained from the population of patients in medical consultation from June to November 2018.”\nQuestion: Please kindly explore the meaning of scientific convenience sampling.\nEthical aspect: The authors mentioned that “The study protocol was approved by the institutional ethics committee for health research of the Universidad Norbert Wiener (# 0014-2018)”.\nQuestion: Please kindly indicate the date, month, and year of the EC approval.\nAssignment and variables: The authors mentioned that “Patients were randomized into the three intervention groups at the time of their initial clinic visit.\nQuestion: How were participants randomized? Please kindly explain.\nPreparation of tomato juice; tomato juice + olive oil and low-calorie diet:\nQuestion: References are really needed to support the preparation.\nLimitations: The authors insisted that “The main limitation is that the sample size was small, and it can only be considered as a pilot study.\nThus, the authors cannot mention the following in the conclusion part: “There was an effect on the measurement of cholesterol with the preparation of tomato juice and olive oil as well as the low-calorie diet. These recommendations would support patients with cardiovascular disease and dyslipidemia.”\nAfter revising this manuscript and returning it to review, it might be appropriate for approval.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
},
{
"id": "217460",
"date": "11 May 2024",
"name": "Victoria Valls-Belles",
"expertise": [],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntroduction: - Does not mention the clinical practice guidelines for cardiovascular risk (ATP II and ATP III). - The bibliography is not very current (2 articles from 2021; 3 from 2022 and 1 from 2023, when there are many, including one of mine published in 2023 on tomato lycopene and extra virgin olive oil) - The introduction is weak, without clear concepts or going deeper into the topic.\nMaterial and methods: - They take 50 patients, both sexes. Age > 18 years old and has an average age of 53.48 +/-13.12. They have to put the age range. - The groups are poorly planned and missing. In addition, what does the 1000 kcal group do that does not cover the minimum requirements (basal metabolism)? - Few patients per group and with great variability between patients. - The tomato juice is left to macerate for 8 hours at room temperature, very bad. What happens to the oxidations that occur? It has to be prepared at the moment. Also, I don't think they prepare it at 24 hours to give it at 8 hours. - Experiment time too short, 9 days. Without prior dietary study. - A group with only oil is missing.\nResults: - 50 people over 18 years old and they all have practically the same BMI. - After 9 days, they have < body weight ????? (even if it is insignificant) - Abdominal circumference decreases????? (Not significant) - Cholesterol is reduced, practically, by 50% with a P=0.331. I don't believe this cholesterol drop - Only determined, BMI, waist circumference and cholesterol levels. No HDL or LDL, at least.\nWith a simple determination of cholesterol (its results have been known for many years) they intend to publish a work that does not meet any requirements. Furthermore, I believe, it has not passed any ethics committee.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1315
|
https://f1000research.com/articles/12-1314/v1
|
11 Oct 23
|
{
"type": "Study Protocol",
"title": "A study to assess the efficacy of print and digital health communication media tools (HCMT) in rural and urban communities.",
"authors": [
"Sushim Kanchan",
"Abhay Gaidhane",
"Abhay Gaidhane"
],
"abstract": "Background: Existing studies have described the potential of either digital or print media for health information in one discipline. Both media are excellent tools for disseminating information, promoting social awareness, and offering in-depth healthcare information thereby being considered as leading health communication media tools. Hence, this study aims to assess and compare the effectiveness of print and digital media in various aspects of health communication in rural and urban populations. Methodology: A cross-sectional population survey will be conducted in rural and urban areas, using a semi-structured, pre-tested questionnaire, which includes socio-demographic variables, media usage patterns, perception, and health behavior change from health information via both media. The study population size will include 342 individuals in the age group of 21 to 60 with minimum qualification of matriculation. Study implications: Our research will help to understand which media are more effective at reaching different populations and can help choose appropriate communication channels for health promotion efforts, develop more effective interventions, and identify potential disparities in access to health information and resources.",
"keywords": [
"HCMT (Health communication media tool)",
"print media",
"digital media",
"health information",
"health communication",
"mass media"
],
"content": "Introduction\n\nHealth communication via mass media (digital, electronic, and print) is an emerging field for health information, education, and promotion among communities. However, the advanced platforms of the Web 2.0 (internet platform) age have accelerated the battle against the print media, changing the nature of communication, including health-related communications.1 Despite being more available and accessible health information channels, these modern digital media have discrete information, so somewhere the authenticity is being lost. On the other hand, print media believes to maintain health information’s reliability and credibility,2 which is why the printing channels still exist. Similarly, electronic media (e-media) is an integral aspect of today’s era, and health care is no exception.3 For example, the electronic health record in a healthcare organization,4 mobile health (mhealth) contact tracing, and telemedicine are new faces of the health system.5\n\nAlthough it has also been apparent that not all of these media interventions for health-related reasons are successful.6 For instance, sources may be effective in increasing patient awareness, but persistent use of print or digital media did not seem to persuade doctors,1 and the problem of self-expertise has gotten worse.7 Concerns also exist regarding news reports that are sufficiently erroneous or deceptive due to poor reporting or complete falsification.8 Therefore, efficient use and the role of health communication media tools must be understood and further explored. Our study aims to know how capable these media (print and digital) are for health communication in various aspects.\n\nThe study will compare and analyze the performance of print and digital health communication media in both rural and urban communities, considering a range of relevant aspects like user engagement, beliefs, and behavioral change to gain comprehensive insights into their efficacy across sociodemographic variables. Understanding the capabilities of media tools in specific contexts can be helpful in the selection and utilization of appropriate media channels to maximize the reach and impact of health messages, bridge the gap in health communication and contribute to reducing health disparities and developing tailored communication strategies.\n\nThe purpose of this research paper is to assess the effectiveness of print and digital media as health communication tools in urban and rural communities.\n\n\n\na) Primary objective:\n\ni. To assess the usage of print and digital health communication media tools among individuals in rural and urban communities.\n\nii. To compare the perceptions of individuals in rural and urban communities for print and digital health communication media tools.\n\niii. To explore the impact of print and digital health communication media tools on health behavior changes among individuals in rural and urban communities.\n\nb) Secondary objective:\n\ni. To determine the association between population type and their consumption pattern, beliefs, and health behavior in response to health information acquired through the media.\n\n\nMethods\n\nA community-based cross-sectional study will be conducted during a 6-month survey from March 2023 to November 2023. A face-to-face interview will be conducted using a semi-structured, pre-tested questionnaire regarding how various media are used for health-related reasons, their reliability and accessibility, and changes in rural and urban populations’ health behavior using the mobile app ONA data kit. A minimum of 6-7 visits will be required to collect all the data, with each subject receiving a 10-minute survey and sign a consent form.\n\nThe current study will be conducted in the field practice area of the community medicine department under the Datta Meghe Institute of Higher Education and Research (DMIHER) for the rural population and urban population in the Wardha district.\n\nThe study participants will be a population of age 21- to 60-year-olds with minimum qualification of matriculation in urban and rural areas of Wardha.\n\nIndividuals who have agreed to engage in the study will make up the study’s participants. A person will be excluded if they have a history of neuropsychiatric disorders, are physically challenged, have less education than a high school graduate (matric), and refuse to give their consent. After the initial visit, if a particular property is found to be locked, and after two additional attempts to contact the eligible residents, they will be eliminated from the study.\n\nVariables\n\nDependent variables\n\nEfficacy of health communication media tools (print and digital)\n\nIndependent variables\n\n• Sociodemographic variable (age, sex, education, and population type: rural/urban,)\n\n• Type of media preferred (print media, digital media)\n\n• Frequency of media consumption (daily, weekly, monthly, rarely, never)\n\n• Perception of accessibility and trustworthiness of print media for health-related information\n\n• Perception of accessibility and trustworthiness of digital media for health-related information\n\n• Influence of print media and digital media on health behavior\n\nData tool (Ona.io): Validated structured questionnaire will be created in ona.io (Odk- questionnaire).\n\nTo ascertain the effectiveness of print and digital health communication tools on members of rural and urban communities, the tool consists of a structured interview questionnaire that is semi-structured and close-ended. We modified a previously validated questionnaire6,9–11 and prepared self-made questionnaire to compile both- print and digital media users about their viewpoints on capabilities of providing health information via both media as communication tool. The second author, a public health expert, evaluated and approved the final questionnaires.\n\nThe questionnaire consists of 17 multiple-choice questions divided over 4 sections (Table 2)2: Sociodemographic information,1 Media Usage/Media consumption habit,3 Perceptions of Health Communication Media Tools and4 Effect of Health Communication Media Tools on Health Behavior. The questionnaire will include questions in English. For Marathi regional language speakers, a translator will be present during survey time for explaining questions to participants. A pilot study with a sample size of 33 participants was completed using the final set of questionnaires, and the full sample size was calculated because the standard data for sample size computation for both print and digital media together, were not readily available.\n\nData sources are presented in Table 1.\n\n\n\n1. Age\n\n2. Sex\n\n3. Education\n\n4. Population type: Urban/Rural\n\n\n\n1. The type of media being preferred for health information.\n\n2. Frequency of media consumption for health information.\n\n\n\n1. The accessibility and\n\n2. credibility of health information in print and digital media.\n\n\n\n1. The effect of health information acquired through various media outlets on health behavior like\n\na. influence decision-making,\n\nb. engagement in preventive measures and\n\nc. information-sharing tendencies.\n\nThe study will be conducted using simple random sampling. A list of all rural areas under the field practice area of the community medicine department under the Datta Meghe Institute of Higher Education and Research (DMIHER) will be prepared and will be numbered using a random number generator, created in an Excel spreadsheet using the formula =RAND (). Once the list will be randomly sorted, the first two or three rural areas will be selected. The same process of selection will be performed for urban areas. The data will be entered into MS Excel, and descriptive statistics, including frequency and percentages, will be presented using a table and graph. Chi-square test will be performed to determine the association between category variables.\n\nRecall bias: Participants may have difficulty in accurately recalling their exposure to print and digital health communication media tools or their health-related behaviors. Shorter recall periods will be used to address the bias, meaning that instead of asking participants to recollect events over a long period of time, researchers can utilize shorter recall periods to reduce memory errors.\n\nResponse bias: Participants’ responses to the questionnaire may be influenced by social desirability bias, where they provide answers, they believe are socially acceptable or expected. In order to counteract this bias, an anonymity and secrecy approach will be used. Through this method, we can guarantee participants’ anonymity and confidentiality and provide a secure setting in which they can respond honestly without worrying about criticism or social ramifications.\n\nSelection bias: There could be a risk of selection bias if the participants in the study are not representative of the larger population in rural and urban communities. Random sampling techniques will be used to help eliminate selection bias by guaranteeing that every member of the population has an equal chance of being included in the study.\n\nThe sample size was decided after calculating the pilot study on 33 samples.\n\nThe estimated proportion with absolute precision: n≥Z21−α/2×p1−pd2\n\nAlpha (α): 0.05\n\nEstimation error (p): 0.666\n\nEstimation error (d): 0.05\n\nThe minimum sample size needed: 342\n\nData will be entered into MS Excel software and analyzed using SPSS version 22 (RRID:SCR_002865). The descriptive statistics (frequencies and percentages) for sociodemographic information, popular media, frequency of media consumption, accessibility, credibility, influence of media in health-related decisions, and information-sharing tendencies of health information related data will be used. Chi-square will be employed to measure the association between sociodemographic variables and their choice of health communication media tool.\n\nExpected outcomes\n\nMedia preference: The study may reveal that digital media tools are more frequently used and preferred by individuals in both rural and urban communities compared to print media tools.\n\nReach and accessibility: The research may demonstrate that digital media tools have a broader reach and higher accessibility compared to print media tools in both rural and urban communities. Digital platforms may provide a more convenient and readily available source of health information for individuals in diverse locations.\n\nPerceived credibility: The study may reveal that print media are more trustworthy for health information as compared to dispersed digital information.\n\nInfluence on decision-making: The study could reveal that both print and digital media tools have a significant influence on individuals’ health-related decision-making processes in a positive way.\n\nBehavior change: The findings may indicate that individuals exposed to print and digital media tools are more likely to engage in positive health behaviors like adopting healthier lifestyles, seeking preventive healthcare measures, or adhering to recommended treatment plans.\n\nDemographic differences: The findings may reveal that younger individuals and those with higher educational backgrounds are more likely to utilize digital media tools and exhibit greater behavior changes compared to older individuals and those with lower educational backgrounds.\n\nKey results\n\nThe findings can be used to determine the preferred media tool (print or digital) and levels of interaction of print and digital media among people in urban and rural locations, based on factors like accessibility and perceived legitimacy. This might entail ideas for combining print and digital media tools, tailoring messages for audiences, utilizing preferred media platforms, or removing obstacles to media access. Thus, the study can help policymakers, public health organizations, and healthcare practitioners establish policies and standards for successful health communication projects and use media channels cost-effectively.\n\nLimitations\n\nOne limitation of the study is that it will not accurately provide information about the frequent health topics covered in the media and accuracy of these health information. People with qualifications below matriculation are omitted, thus their familiarity with health information is not examined. A further omission from the study is any discussion of the effectiveness of various types of print media (such as newspapers, posters, books, etc.) and digital media (such as social media and the internet) in rural and urban populations.\n\nDissemination\n\nThe results will be published in relevant indexed journals.\n\nStudy status\n\nThe piloting of the data collection tool was done. Recruitment of final study participants is scheduled in the coming months.\n\n\nDiscussion\n\nIt has been proposed that the use of social networking sites to share credible health information can assist physicians in fulfilling their professional obligation to transmit pertinent information to patients, colleagues, and the public, as well as assist members of the public in properly contextualizing the findings of health-related current events.12 Similar studies by Belt et al. in 2013 found that one in four people would interact with their doctor through social media, and it is anticipated that this figure will rise. As a result, healthcare professionals ought to investigate new Internet communication channels and encourage patient interaction.6\n\nThe study conducted by Fatimah et al. in North Toraja society in 2021 shares a perspective on the choice of printed communication media, such as books and magazines, as a source of knowledge on reproductive health. He calculated that print media garners 57.39% of preferences, followed by websites (27.8%) and social media (14.78%).13 Online medical education can be an effective method for medical students14 and an informative and communicative data source for health researchers.15\n\nThe public’s perceptions of health-related concerns can be influenced by the mass media by stressing specific aspects of its coverage, such as the origins of issues, the availability of solutions, as well as post-disease treatment, and precautions. According to a 2021 study by Ghosh et al. on how reversible current procedures give women greater contraceptive options than opting for permanent therapies that restrict their capacity to bear children, the media effectively emphasizes and raises awareness of voluntary contraceptive use in India. The decomposition analysis’s findings revealed that media exposure boosted the utilization of reversible advanced treatments by 14%.16 The digital tool has the potential to increase the frequency with which sexual health is discussed in primary care, notably by nurses, leading to an improvement in patient satisfaction, 2010 research by Macdowall et al.17 Similarly, the results and analysis of the survey conducted by Pandey and Kumar in 2020 indicate that print media has been crucial in raising awareness of the pandemic Coronavirus Disease (COVID-19), supporting the idea that the media may be a useful tool in times of national emergency.18\n\nBased on the findings of these previous studies, our planned study seeks to expand the understanding of the role of communication media in the healthcare context by focusing on the efficacy and impact of both print and digital health communication media in rural and urban communities. While the existing studies have shed light on various aspects of media’s influence on health-related information dissemination and public perception, our study aims to contribute by directly comparing the performance of print and digital media across diverse population types, thereby offering valuable insights into enhancing health communication strategies.\n\nWith the written consent of the head of the relevant institution, data collection will happen at a time that is convenient for instructors and rural and urban community members. The institutional ethics committee of the Datta Meghe Institute of Higher Education and Research (DMIHER) has approved the research proposal with the approval number DMIHER (DU)/IEC/2023/623. Before beginning our study, we will also obtain written informed consent and notify the participants of its purpose. We will make sure the interviewee has privacy and feels comfortable throughout the interview.",
"appendix": "Data availability\n\nNo data is associated with this study as this is a study protocol.\n\nZenodo: A study to assess the efficacy of print and digital health communication media tools (HCMT) in rural and urban communities, https://doi.org/10.5281/zenodo.8238040. 19\n\nThis project contains the following extended data:\n\n- Questionnaire\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nI acknowledge the support of Mr. Laxmikant Umate, Statistician, Datta Meghe Institute of Higher Education and Research.\n\n\nReferences\n\nChou WYS, Hunt YM, Beckjord EB, et al.: Social Media Use in the United States: Implications for Health Communication. J. Med. Internet Res. 2009 Nov 27 [cited 2022 Dec 6]; 11(4): e1249. Publisher Full Text Reference Source\n\nIndhumathi P: A STUDY ON EFFECTIVENESS OF PRINT MEDIA NEWSPAPERS AMONG THE CONSUMERS IN VELLORE CITY.2019; 9: 2394.\n\nShinde: Use of e-media among pediatric dental professionals and postgraduate students in pediatric dentistry during COVID-19.[cited 2023 Jun 2]. Reference Source\n\nPure: A Review on Association between Electronic Health Record use and Quality of Patient Care.[cited 2023 Jun 2]. Reference Source\n\nParmar: Utilizing digital technology in the public health system during an epidemic.[cited 2023 Jun 2]. Reference Source\n\nde Belt THV , Engelen LJ, Berben SA, et al.: Internet and Social Media For Health-Related Information and Communication in Health Care: Preferences of the Dutch General Population. J. Med. Internet Res. 2013 Oct 2 [cited 2023 May 30]; 15(10): e2607. Publisher Full Text Reference Source\n\nShakeel S, Nesar S, Rahim N, et al.: Utilization and Impact of Electronic and Print Media on the Patients’ Health Status: Physicians’ Perspectives. J. Pharm. Bioallied Sci. 2017 [cited 2022 Dec 16]; 9(4): 266–271. PubMed Abstract | Publisher Full Text | Free Full Text\n\nArsenijevic J, Tummers L, Bosma N: Adherence to Electronic Health Tools Among Vulnerable Groups: Systematic Literature Review and Meta-Analysis. J. Med. Internet Res. 2020 Feb 6; 22(2): e11613. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYoon S, Wee S, Lee VSY, et al.: Patterns of use and perceived value of social media for population health among population health stakeholders: a cross-sectional web-based survey. BMC Public Health. 2021 Jul 5 [cited 2023 Jul 11]; 21(1): 1312. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIftikhar R, Abaalkhail B: Health-Seeking Influence Reflected by Online Health-Related Messages Received on Social Media: Cross-Sectional Survey. J. Med. Internet Res. 2017 Nov 16 [cited 2023 May 30]; 19(11): e382. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIttefaq M, Seo H, Abwao M, et al.: Social media use for health, cultural characteristics, and demographics: A survey of Pakistani millennials. Digit Health. 2022 Apr 5 [cited 2023 May 30]; 8: 205520762210894. Publisher Full Text | Free Full Text\n\nKanchan S, Gaidhane A, Kanchan S, et al.: Social Media Role and Its Impact on Public Health: A Narrative Review. Cureus. 2023 Jan 13 [cited 2023 Jun 4]; 15(1). Publisher Full Text Reference Source\n\nFatimah JM, Null A, Bahfiarti T: Media communication and youth reproductive health, North Toraja District. Gac. Sanit. 2021; 35 Suppl 2: S112–S115. PubMed Abstract | Publisher Full Text\n\nPotdar: Quality and effectiveness of online medical education during COVID-19 outbreak: Perception of medical students in Delhi NCR region.[cited 2023 Jun 2]. Reference Source\n\nDol J, Tutelman PR, Chambers CT, et al.: Health Researchers’ Use of Social Media: Scoping Review. J. Med. Internet Res. 2019 Nov 13; 21(11): e13687. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGhosh R, Mozumdar A, Chattopadhyay A, et al.: Mass media exposure and use of reversible modern contraceptives among married women in India: An analysis of the NFHS 2015-16 data. PLoS One. 2021; 16(7): e0254400. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMacdowall W, Parker R, Nanchahal K, et al.: ‘Talking of Sex’: Developing and piloting a sexual health communication tool for use in primary care. Patient Educ. Couns. 2010 Dec 1 [cited 2022 Dec 5]; 81(3): 332–337. PubMed Abstract | Publisher Full Text Reference Source\n\nPandey H, Kumar S: Role of Print Media in Spreading Awareness on Coronavirus Disease (COVID-19). Xian Jianzhu Keji Daxue XuebaoJournal Xian Univ. Archit. Technol. 2020 Apr 28; XII: 5203.\n\nKanchan S: A study to assess the efficacy of print and digital health communication media tools (HCMT) in rural and urban communities. [dataset]. Zenodo. 2023. Publisher Full Text"
}
|
[
{
"id": "321994",
"date": "03 Oct 2024",
"name": "Kavita Thapliyal",
"expertise": [
"Reviewer Expertise Digital Twin",
"Chatbot XAI",
"AI & Neurodegenerative Treatment",
"Social Media & Health Communication",
"Cyber Phycology",
"GHRM",
"Cross Culture Management"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nMerits: The well written article is aptly relevant to the study of disseminating public health information through print and digital media platforms. Primary and Secondary objectives are also well defined. Methodology of cross sectional population design is also appropriate with a semi structured and pre tested questionnaire making it flexible for qualitative inputs while having a quantitative approach. The age group, qualification and demographics provide a uniform base for desired output, with Department of DMIHER further validating the study.\n\nLimitations & Scope of Improvement : I feel a Longitudinal design would have given better output against a cross sectional design giving accurate behavior changes. The area of study has limited scope of study in lieu of minimum qualification, general accessibility, self reporting bias, sample size justification, data collection, timeframe with digital platform and net availability. Add more relevant referencing to make it a enriching read.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
},
{
"id": "311654",
"date": "07 Oct 2024",
"name": "Debdutta Bhattacharya",
"expertise": [
"Reviewer Expertise Health Communication",
"One Health",
"AMR",
"Microbiology",
"Public Health"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe study protocol presents a valuable investigation into the effectiveness of health communication media in rural and urban communities. However, it is essential to provide detailed information about the Mobile App ONA data kit used for data collection, including its reliability, functionality, and user experience, to enhance the transparency and credibility of the research methodology.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1314
|
https://f1000research.com/articles/12-1313/v1
|
11 Oct 23
|
{
"type": "Research Article",
"title": "Policy analysis on municipal solid waste management in Dhaka South City Corporation, Bangladesh: A qualitative study",
"authors": [
"Tangila Sultana",
"Nafiul Azim",
"Faridah Akuju",
"Taufique Joarder",
"Nafiul Azim",
"Faridah Akuju",
"Taufique Joarder"
],
"abstract": "Background: Inadequate and improper municipal solid waste (MSW) management is one of the significant reasons behind the environmental deterioration in Bangladesh. The projected daily waste generation for 2025 in Dhaka City is 47,665 tons, half of which remains uncollected despite door-to-door community-based waste collection. There are few studies on MSW management in Bangladesh, most focusing on household-level waste management, measurement of the amount of MSW, etc., but none applied a political economy lens to examine the policy issues related to MSW management. This study aimed to explore the context, actors, and processes regarding MSW management of policies in Dhaka City, Bangladesh, applying the policy-triangle-framework. Methods: This study adopted an exploratory qualitative approach, and document reviews and key informant interviews were conducted from September 2016 to January 2017. Results: We found that the issue of MSW slowly entered the policy documents starting with the Sixth-Five Year Plan (2011-2015), with some earlier sporadic policy initiatives. Due to its being a relatively new concept, stakeholders still lack the expertise to tackle the issue leading to donor dependence. MSW management demands multi-stakeholder involvement, which, in turn, depends on multi-ministerial and -departmental coordination, which is chronically deficient. MSW policies, like most other social policies, demand citizen involvement, without which both policy formulation processes and their proper implementation are compromised. Conclusion: In order to overcome these policy challenges, the technical and financial capacity of the stakeholders for MSW management should be enhanced, high-level multi-ministerial coordination needs to be strengthened, and citizen empowerment and engagement must be ensured at every step of the MSW policy cycle.",
"keywords": [
"Solid waste",
"policy",
"waste management",
"environmental protection",
"pollution"
],
"content": "Introduction\n\nSolid waste materials have a low content of liquid and are occasionally hazardous. Solid waste generation has increased in developing countries with urbanization and rising population growth. Improper solid waste management has become a threat to public health in developing countries as it negatively affects the quality of life of people.1 Management of municipal solid waste (MSW) is an important aspect of environmental sanitation, which is necessary for promoting good health and quality of life. The necessity of MSW management is also reflected in the four sustainable development goals (SDGs). SDG 3 aims at ensuring healthy lives and well-being; SDG 6 promotes clean water and sanitation; SDG 11 ensures inclusive, safe, resilient, and sustainable cities; and SDG 13 takes action against climate change and its impact.2 However, managing MSW is a major challenge worldwide, particularly in rapidly expanding urban areas of low- and middle-income countries (LMICs).3\n\nMSW management is a complete process covering all the functional elements from waste generation to disposal. This process involves the identification, reduction, storage, collection, transfer and transport, reuse and recycling, and effective treatment and disposal of MSW in accordance with the best principles of management, economics, engineering, public health, conservation, aesthetics, and other environmental conditions, including all administrative, financial, legal, planning, and engineering functions involved in the total spectrum of problem-solving options.4 MSW risk factors include organic contents of waste (e.g., blood, body fluids, animal body parts, fecal matter) or inorganic contents (e.g., hazardous chemicals, heavy metals, greenhouse gases, and pressurized gas containers).5 The disposal of solid waste is a major problem and an urgent issue that contributes to air, water, and land pollution. The accumulation of uncollected MSWs on roads and in open spaces is detrimental to public health.6 Improper management of MSW can contaminate water and is a source of air pollution; the pollutants may include methane, carbon dioxide, benzene, and cadmium, which can cause severe bodily harm.7\n\nBangladesh is a developing country experiencing rapid economic expansion. However, the industrialization and urbanization of this country’s economic growth are degrading its environment. Inadequate and improper MSW management is one of the significant contributors to the environmental deterioration in Bangladesh. Nowadays, MSW management is a crucial issue in urban Bangladesh. In 2012, the total waste generated in Bangladesh was around 22.4 million tons per year or 150 kilograms per capita per year.8 The capital city of Bangladesh, Dhaka, generated 6448.373 tons of MSW per day (0.57 per capita per day) in 2016-2017.9 Despite door-to-door community-based waste collection, half of the total MSW in Dhaka City remains uncollected.10 The MSW trend in Dhaka is alarming, and the projected daily waste generation for 2025 is 47,664 tons.11\n\nIn recent years, various innovative approaches have been introduced globally for MSW management. Some Asian countries have substantially improved their MSW management systems. For example, neighboring India has developed mechanical composting technology and bio-methanation for biodegradable MSWs that can act as a renewable energy source.12 Unfortunately, like many other developing countries, Bangladesh is still far behind in taking long-term strategies for MSW management. The major obstacles behind the poor MSW management in Dhaka city are rapid industrialization, unplanned urbanization, a dearth of sufficient budget, limited efficient human resources, poor use of technology, and negligence of the community.13–15 There are few studies on MSW management in Bangladesh, most with a focus only on household-level waste management. Some studies measured the amount of MSWs16,17 while others examined MSW management from systems and policy perspectives.18–21 However, no study applied a political economy lens to examine Bangladesh’s policy issues related to MSW management. Therefore, this study aimed to explore the available policies, including the contents, context, actors, and processes regarding MSW management of policies in Dhaka City, Bangladesh, applying the policy triangle framework.22 This article focuses on the policy triangle’s context, actors, and processes, as the policy contents have been extensively covered in other studies.9,19\n\n\nMethods\n\nThe study adopted an exploratory qualitative approach. Data were generated through document reviews and key informant interviews (KIIs) conducted from September 2016 to January 2017.\n\nFor the retrospective policy analysis, the policy analysis triangle framework22 (Figure 1) was used; the constructs of which are:\n\n• Content means the substance of the policies.\n\n• Context is the influencing factors of the policy, such as political, social, and cultural factors.\n\n• Actors are organizations, government institutions, and individuals who play a significant role in the policy processes.\n\n• Process is the action of the actors through which the policies are implemented.\n\nDocument review\n\nThe reviewed documents included published reports, research or evaluation articles, guidelines, strategic white papers, and policy documents. The academic databases Scopus, Web of Science, and PubMed were searched using terms such as “municipal solid waste management,” “Dhaka South City Corporation,” and “Bangladesh.” The Bangladesh Waste Management Board and the Dhaka South City Corporation’s official website were consulted as government registers and databases pertaining to waste management. The websites of international organizations such as the World Bank, United Nations Develop Program (UNDP), and Asian Development Bank (ADB), as well as local organizations and NGOs such as Waste Concern and WMAB, were investigated. In addition to examining the reference lists of identified documents, additional sources, including government publications, policy memoranda, conference proceedings, and grey literature, were considered. Utilizing pertinent keywords, subject headings, and Boolean operators (e.g., AND, OR) were utilized to refine search results. To determine if a document met the inclusion criteria, we reviewed the document fully. Multiple evaluators participated in the screening process, evaluating each record and report independently. Consensus meetings were conducted to resolve any disagreements and ensure that documents were consistently included. Multiple reviewers were involved in accumulating data from reports, and they worked independently to extract pertinent information. When clarification or additional information was required, attempts were also made to contact the study’s investigators to obtain the necessary information. Documents related to medical wastes were excluded because these require specialized treatment, and their processing and disposal are distinct from MSW in general. At the beginning of the review, the research team compiled a preliminary list, which was supplemented by suggestions from the key informants and reference tracking of published articles. The relevant parts of the policy documents written in Bengali were translated into English. The list of documents reviewed is provided in Table 1.\n\nKey informant interviews (KIIs)\n\nInitially, the sampling method was purposive, with the snowball technique added as the interviews progressed. The interviews were conducted from 18th to 20th December 2017. The KIIs were conducted using a semi-structured interview guideline supplemented by qualitative probing. Eight SWM officials from the Dhaka South City Corporation (DSCC), the Department of Environment (DoE), and the Japan International Cooperation Agency (JICA), with at least one year of working experience, were included in the study. A breakdown of the key informants is provided in Table 2.\n\nMembers of the research team conducted all face-to-face interviews at the respondents’ offices in their preferred language. The majority of responses were given in Bangla, the local language, while others preferred English. The interviews were recorded using a digital audio recorder with the respondents’ permission. Additionally, handwritten notes were taken to prevent data loss in case of technical error. Following the interview, respondents were requested to introduce the research team to their colleagues and other relevant officials involved with the policy processes. The average duration of the interview was half an hour. Based on the suggestions and recommendations from the primary sets of key informants, we interviewed officials from JICA and DoE.\n\nAfter the interview, two research assistants transcribed the data into English within 24 hours of data collection. Data familiarization was done through repeated readings. A priori codes were prepared before the data collection. A quotation from each transcription was used to cluster and compose the data display matrix in order to identify the policy analysis framework components. Prior to the data collection, a set of priority codes was developed, and information was entered into each code. During the data familiarization process, which consisted of reading and rereading the transcripts, additional subcodes and inductive codes were determined. Finally, thematic analysis was done using a manual coding technique. Texts were organized across the following themes: i. Policy Context, ii. Policy Actors and iii. Policy Processes. Quotations were extracted to substantiate the thematic analysis. To increase validity, the first and the last authors independently coded the two transcripts, calibrated the coding according to the codebook’s definitions, and consulted whenever any confusion occurred.\n\nAs the study was a master’s thesis, no individual ethical approval number was provided. Instead, an interim board of reviewers, consisting of members from the regular IRB of the BRAC James P Grant School of Public Health, reviewed all the students’ thesis proposals, provided necessary comments, and approved the proposals for data collection after ensuring that ethical issues were adequately addressed. Permission from DSCC authorities and written informed consent from all the respondents were taken, and the study’s purpose, potential benefits, and risks were explained. Confidentiality and anonymity were maintained, and interviewees possessed the right to withdraw from the interview at any time.\n\n\nResults\n\nDuring the independence of Bangladesh, there was no policy on environmental issues. The Planning Commission of the Government of Bangladesh (GoB) started the First Five-Year Plan of Bangladesh (1973-1978) without any sectoral chapter on the environment. This trend continued until the Third Five-Year Plan of Bangladesh (1985-1990). The first mention of the environment is found in the Fourth Five-Year Plan of Bangladesh (1990-1995), ‘Environment and Sustainable Development,’ not as a sectoral chapter but as an introductory macro chapter. The environment found a place for the first time as a sectoral chapter in the Sixth Five-Year Plan (2011-2015). Since then, Bangladesh’s government policy documents have included objectives, timelines for proposed activities, and budgetary allocations for MSW. Apart from the Five-Year Plans, an ordinance of environmental pollution control was a valuable step in the 1980s toward prioritizing environmental protection nationally.23–27 The National Environmental Policy, approved in 1992, was a pioneering framework to express the government’s commitment to environmental issues.27–30 Thereafter, establishing the Department of Environment Pollution Control (DEPC) was an important sequence for promoting environmental protection in the country. The latest initiative at the time of data collection was drafting the National SWM Regulations, which was published in 2021. A key informant said,\n\n“We are working on the SWM regulations, which are at their final stage. We will leapfrog on its implementation as soon as we finalize the document. This will be a big achievement regarding SWM policies in Bangladesh.” KII 5\n\nMeanwhile, important initiatives for the MSW management in Dhaka were taken by Japan International Cooperation Agency (JICA) in 2005. In 2010, the DoE developed the National 3R Strategy for Waste Management with support from the United Nations Centre for Regional Development (UNCRD) and the Ministry of Environment of the Government of Japan. After certain improvements in SWM, JICA developed another four-year plan. After completing that project in 2017, they began a new project for the next fifteen years to enhance the MSW sector in Bangladesh, particularly in the capital city. A key informant from DSCC said,\n\n“JICA is helping us through different projects on MSW, mainly through technical support. There is a contract between the Bangladesh government and the Japanese government, and as a part of this, they have taken a project for the next 15 years.” KII 6\n\nThe major policy events related to MSW in Bangladesh since its independence are shown in the timeline (Figure 2).\n\nBangladesh’s main actors in relation to MSW policy-making are the Ministry of Environment, Forest and Climate Change (MoEFCC), the Department of Environment (DoE), and the Planning Commission. Other relevant ministries, consultants, bureaucrats, and environmental NGOs like the Forum of the Environmental Journalists of Bangladesh (FEJB), Bangladesh Centre for Advanced Studies (BCAS), Association of Development Agencies of Bangladesh (ADAB), International Union for Conservation of Nature (IUCN), and Coastal Area Resource Development and Management Association (CARDMA) have been involved in MSW management. JICA has been providing funding and technical support for the last decade. Additionally, JICA advocated for policy development, especially the National SWM Regulations. The DoE under the MoEFCC is primarily responsible for initiating policy processes, such as developing the primary draft and finalizing the version of the policies that are suitable for publication. As such, the DoE organized formal meetings with the cabinet, other pertinent ministries, and relevant stakeholders in developing the National SWM Regulations. A key informant said,\n\n“We [JICA] provide donations per the government’s request. We not only provide donations but also provide support like technical cooperation, knowledge and skills, technology, etc. Although we do not create policies, our work with the government generates demand for new policies on MSW management.” KII 4\n\nHowever, in regard to implementing the policies, the key informants named the Ministry of Local Government, Rural Development and Cooperatives (MoLGRD&C) as the primary stakeholder. The city corporations, under the jurisdiction of MoLGRD&C, are responsible for MSW management. The capital city of Dhaka is divided into two city corporations, and our study area’s MSW management was the responsibility of the DSCC. A respondent said,\n\n“We [DoE] drafted the National SWM Regulations, which the MoLGRDC will engage the DSCC to implement, along with other local government entities. So, it’s not only MoEFCC’s business; MSW management involves many stakeholders from policy formulation to implementation.” KII 7\n\nMSW management requires multisectoral collaboration. DoE under the MoEFCC is entrusted with policy-making related to SWM. On the other hand, MSW management is the responsibility of the city corporations, such as the DSCC. MoLGRD&C is a large ministry that oversees city corporations, with multiple responsibilities, ranging from organizing local government elections to providing primary healthcare to urban residents. Health-related issues pertaining to MSW fall under the Ministry of Health and Family Welfare’s (MoHFW’s) jurisdiction. These ministries are unable to prioritize their coordination with other ministries due to their diverse responsibilities. A key informant said,\n\n\"DSCC’s work should be done by DSCC without interference from the agencies that do not share the pain. There is very weak coordination between the ministries. This creates tension and hinders our workflow.\" KII 8\n\nDue to the relatively recent occurrence of rapid urbanization, GoB agencies lack the technical expertise to address MSW challenges. MSW is a complex issue involving climate change, environmental pollution, waste management technologies, management approaches, health problems, and governance. Aligning different dimensions of MSW is too complicated for the GoB to manage by itself and therefore, it depends on bilateral and multilateral agencies for technical support, which is prone to rendering the GoB donor dependent. A respondent said,\n\n“The [MSW management] process is sluggish and often influenced by international agencies. This is because this problem demands multidisciplinary expertise, which is often deficient in Bangladesh.” KII 2\n\nMSW management demands large landfill sites, incinerators, recycling plants, dump trucks, storage and treatment tanks, etc. As Bangladesh is a populous country, finding adequate space, especially in urban areas, presents a significant challenge. Furthermore, the chronic funding shortage leads to deficient equipment and logistics support for MSW management. Reflecting on this issue, a key informant said,\n\n\"We need to change the aged transport. Secondly, we need to arrange more secondary transfer stations because, currently, we put waste in open containers here and there, and sometimes inside a room. Thirdly, we don’t have any field to dump the waste. In general, there is a severe shortage of both space and equipment for MSW management.\" KII 1\n\nPublic policies in Bangladesh are usually formulated by a ‘top-down’ approach, hardly involving the community, civil society, and national and international NGOs. This issue is even more pronounced in Bangladesh’s MSW management, as there is insufficient public attention to this issue. Since this issue has traditionally been away from public discussion, ensuring people’s awareness and spontaneous participation is a challenge. Highlighting the importance of citizen participation, a key informant said,\n\n“Cleaners clean all the drains and roads by 6 AM, but as soon as people open the markets around 9 AM, they start dumping the waste in the road again. So, without the help of citizens, we can’t achieve our goal of clean Dhaka.\" KII 3\n\n\nDiscussion\n\nOur qualitative policy analysis found that the issue of MSW gradually integrated into Bangladesh’s policy documents beginning with the Sixth Five-Year Plan (2011-2015),30 with sporadic policy initiatives occurring prior to that. Due to its being a relatively new concept, there is still a lack of expertise in GoB to tackle the issue. This may put our policy-makers and implementers in a position of reliance on donors. Secondly, MSW management demands multi-stakeholder involvement. This depends on proper coordination among different relevant ministries and departments that report to them. Lack of coordination is a chronic problem in many LMICs, including Bangladesh. Thirdly, MSW policies, like most other social policies, require citizen involvement. Inadequate community engagement threatens both the formulation and implementation of MSW-related policies. These major findings from the policy analysis have been summarized in the figure (Figure 3).\n\nDonor dependence may prevent decision-makers from deciding what is best for the local population in terms of MSW management. Donors frequently adhere to a prescribed format disregarding the local culture and priorities. A study on strengthening the health research system in Africa identified donor dependence vis-à-vis local capacity as a factor inhibiting health improvements.31 Another example, from South Asia, is Pakistan, where reproductive, maternal, neonatal, and child health progress was slow despite a high volume of overseas development assistance. This calls for developing local capacity and coming out of donor dependence.32 In contrast to Cambodia and Sierra Leone, where development partners expanded their influence through both technical assistance and financing, in Uganda, their contribution to post-conflict reconstruction was primarily limited to financing. This enabled the Ugandan government to regain the lead coordination role over various actors more rapidly than other such post-conflict countries.33 Buse,34 based on his seminal work on donor control over aid coordination in Bangladesh, proposed the solution, albeit time-consuming, to be the enhancement of capacity and improvement of governance systems.\n\nMSW management is a multidisciplinary endeavor demanding additional coordination, while lack of coordination among ministries and departments is a hallmark of LMICs.31,33 Participants of a study on the public perception of the COVID-19 pandemic management in Bangladesh expressed concern about a lack of coordination among different government authorities, which manifested itself in several ways, including the imposition of a lockdown in rural areas without making arrangements for the patients to be transported to the health facilities in the city, the designation of several hospitals as COVID-19 dedicated institutions without allocating the necessary resources, and the involvement of private hospitals in the delivery of care without allowing them to test patients for COVID-19 upon admission.35 Similar coordination issues exist in the implementation of MSW management in Kathmandu, Nepal.36 Despite all evidence in favor of the need for a coordinated response to MSW management, there is no specific guideline on the responsibility of different stakeholders in this regard for Bangladesh. Coordination approaches should be extended beyond government agencies, to include civil society, academia, media, development partners, and eventually citizen bodies.\n\nCitizen engagement is crucial not only in MSW policy formation but also in awareness raising in its proper application. According to a study on MSW in Hong Kong, community members are frequently not involved in the design and implementation process, nor are implementers trained in public participation. In the same study, public awareness and participation have been asserted as one of the driving forces of MSW management.37 It is now well known that understanding and considering the local context and local voices are necessary for effective changes to MSW management. In a study from Thailand, community consultations on MSW generated a multitude of innovative recommendations, such as hosting MSW training programs in the locality to increase awareness, engaging local students in awareness building, donating recyclable waste to religious sites (e.g., temples in Buddhist-majority Thailand), etc.38 Citizens must be empowered and involved not only in MSW-related policy formulation but also in its implementation and evaluation.\n\nConducted as a low-budget student thesis under time pressure, this study failed to interview representatives of many key stakeholders of MSW management in Dhaka City, including the MoLGRD&C, which is the mother ministry of the implementing agency, DSCC. Secondly, given the qualitative nature of the study, the findings of this study cannot be generalized statistically. Finally, since we conducted all interviews during office hours, most respondents rushed during the interview and often the interviews had to be shortened.\n\nDespite the limitations, due to the dearth of policy-relevant research on MSW in Bangladesh, this small-scale qualitative research generated some important policy recommendations and identified research needs. The GoB must strive to improve the MSW management capacity both technically and financially, and eventually overcome donor dependence. Acknowledging the multidisciplinary nature of the issue, a high-level multi-ministerial coordination body should be formed for MSW management. Citizen bodies must be engaged in every step of the MSW policy cycle, i.e., from issue identification to policy monitoring and evaluation.39 Further implementation research and evaluation are needed to identify the optimum implementation strategies for MSW management in Dhaka City.\n\n\nConclusions\n\nSolid waste generation has increased gradually and consistently in Bangladesh with urbanization and population growth in the last few decades. MSW management is an important aspect of environmental sanitation necessary for promoting good health and quality of life. Despite recent technological advancements in MSW management, policy integration of these technologies is still at an early stage in Dhaka City, one of the fastest growing megacities in the world with a population of 22.6 million.40 Our policy case study analysis, which included DSCC as a case, revealed that the GoB lacks the expertise to tackle MSW due to the relative novelty of the concept in the country’s policy landscape, resulting in donor dependence. From policy formulation to implementation and risk mitigation, it is a challenge to ensure proper coordination among different stakeholders. Community engagement, both at the policy level and awareness to cooperate in MSW management, is indispensable. Despite the limited nature of the study (an exploratory student project for a master’s thesis), the study generated some important policy lessons such as the need for the technical and financial capacity of GoB for MSW management, high-level multi-ministerial coordination, and citizen empowerment and engagement throughout the MSW policy cycle.",
"appendix": "Data availability\n\nHarvard Dataverse: Policy analysis on municipal solid waste management in Dhaka South City Corporation, Bangladesh: a qualitative study. https://doi.org/10.7910/DVN/FXEMSC. 41\n\nThis project contains the following underlying data:\n\n- KII 1 (Waste Management Officer I)\n\n- KII 2 (Engineer I)\n\n- KII 3 (Engineer II)\n\n- KII 4 (Waste Management Advisor I)\n\n- KII 5 (Planning Officer I)\n\n- KII 6 (Waste Management Officer II)\n\n- KII 7 (Planning Manager I)\n\n- KII 8 (Engineer III)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgments\n\nThe study was conducted under the Urban Wash program at the BRAC James P Grant School of Public Health, BRAC University, Dhaka, Bangladesh. 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}
|
[
{
"id": "224490",
"date": "27 Nov 2023",
"name": "Atiq Zaman",
"expertise": [
"Reviewer Expertise Waste Management and Circular Economy"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe submitted article, \"Policy analysis on municipal solid waste management in Dhaka South City Corporation, Bangladesh: A qualitative study,\" appears to be interesting. However, based on the current submission, the article fails to provide insight into the policy intervention. There are several significant methodological flaws in the research that need to be addressed before indexing. The following points help understand the issues:\nThe study lacks the identification of research problems by conducting a comprehensive literature review and identifying knowledge gaps.\n\nThe introduction provides a very brief background, but the literature review of existing policies and regulations is missing, given that the study claims to focus on analyzing Dhaka’s MSW management through the political economy lens.\n\nOne significant methodological flaw is the lack of applying a systematic approach in reviewing and updating the data from its initial research, conducted in 2017, over five years old. The use of Dhaka South City Corporation for data search is incorrect; only Dhaka City Corporation should have been used since DSCC and DNCC are relatively new.\n\nNo mention is made of how many scholarly articles have been found in the database search and the findings of those articles.\n\nA list of 15 regulatory policies is listed without any further critical analysis of how these regulations address waste management issues and the scope of their application.\n\nThere is no description of the semi-structured interview questions, which may be a key contribution to the article. It is unclear whether separate questions were used for different stakeholders or if the same questions were applied to all of them.\n\nAs a policy analysis article, it lacks crucial exploratory findings from the policy intervention, and the list needs to be updated based on recent developments. Moreover, the analysis lacks the key aspects of the policy and how they support/mandate better management or restrict pollution from waste.\n\nThe results only provide a few direct quotes without further explanation and interpretation of the greater management and policy implications.\n\nThe proposed 'Capacity-Coordination-Community' (CCC) framework for MSW Policy seems like an add-on rather than derived from the results presented in the result section. Significant improvement is needed to link it with the data and CCC framework.\n\nVarious grammatical corrections are needed.\nOverall, the article fails to present knowledge gaps and a clear methodological approach in conducting, collecting, and analysing data (both primary and the review of policies) and presenting to develop the proposed framework and draw conclusions.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "10664",
"date": "30 Nov 2023",
"name": "Taufique Joarder",
"role": "Author Response",
"response": "Dear Reviewer, We would like to express our sincere gratitude for your insightful comments and suggestions on our manuscript, \"Policy analysis on municipal solid waste management in Dhaka South City Corporation, Bangladesh: A qualitative study.\" Your feedback is invaluable to us, and we appreciate the time and effort you have invested in reviewing our work. We acknowledge that our research, originally conducted as a master's thesis, has certain methodological limitations due to constraints in time, resources, and the technical expertise and experience of the student. These limitations have been acknowledged in the manuscript. Despite these, we decided to publish the article to contribute to the existing knowledge base as much as possible. The exclusion of a literature review on existing policies was intentional. The initial literature review was conducted prior to the thesis in 2017, during which many policy-related contextual issues have since changed. We have cited more updated policy content published elsewhere (reference numbers 9 and 19) to avoid duplication of efforts. As our research was not a systematic review, we employed a focused literature review supplemented by other literature and document search techniques. We agree that using \"Dhaka City Corporation\" instead of \"Dhaka South City Corporation\" for keyword search would have been more appropriate. However, we ensured no document uniquely related to \"Dhaka City Corporation\" was left out of our review through our non-systematic search. As this was not a systematic review, we did not track or report the actual number of scholarly articles consulted. The critical analysis of the 15 documents was not reported in this article for the reasons explained above. We felt it was more beneficial to refer to existing and updated policy content analyses that are already published, and we have referred to those articles in our manuscript. We concur that the inclusion of research tools would have been beneficial. As the journal did not request us to upload these, we did not include them. However, we will contact the journal to request permission to upload these tools. We appreciate your other comments and agree with most of them. As we mentioned earlier, most of the limitations you rightly pointed out are attributable to the constraints of this being a master's thesis. Once again, we would like to express our profound gratitude for your valuable feedback. We believe that your comments will significantly improve the quality of our work. Best regards."
}
]
},
{
"id": "224477",
"date": "14 Dec 2023",
"name": "Tumpa Hazra",
"expertise": [
"Reviewer Expertise Waste management and Environmental Engineering"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a well written paper however following things need clarification: 1) Please check the result \"The MSW trend in Dhaka is alarming, and the projected daily waste generation for 2025 is 47,664 tons\" how the value 6448.373 ton of 016-2017 became almost 8 times just in 6 -7 years? 2) State the basis of selecting sampling sizes. Out of the 8 official interviewed 6 are of same department and one each from other two organisations. So reliability of the study should be added\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10828",
"date": "22 Mar 2024",
"name": "Taufique Joarder",
"role": "Author Response",
"response": "Dear Reviewer, Thanks for your thoughtful comments. Here are responses to your queries. Response to the first question: The volume of waste produced daily in Bangladesh has shown a consistent annual increase since 1991. In 1991, urban areas of the country generated approximately 6,493 tons per day of municipal solid waste. However, by 2005, this figure had more than doubled, reaching 13,330 tons per day. Subsequently, in 2014, it is estimated that Bangladesh produced 23,688 tons of waste per day in its urban areas. Simultaneously, the total urban population of Bangladesh has experienced significant growth, escalating from 20.8 million in 1991 to 32.76 million in 2005 and further to 41.94 million in 2014, owing to rapid urbanization. Projections suggest that the total urban population could surge to as high as 78.44 million by 2025, with an associated waste generation of 47,000 tons per day. Evidently, there exists a direct correlation between increased waste production and a burgeoning urban population. Notably, since 2005, the rate of change in daily waste generation has outpaced the rate of population growth, attributable to a heightened average daily per capita waste generation rate. Source of Information: Bangladesh Waste Database, 2014 The quantity of solid waste generated in urban areas of Bangladesh stands at approximately 25,000 tons per day, equivalent to 170 kg per capita per year. Dhaka city alone contributes a quarter of the entire urban waste in the country. Projections indicate that total urban solid waste could escalate to 47,000 tons per day by 2025, fueled by population growth and an increase in per capita waste generation. In 1995, the per-person average generation of urban solid waste was 0.49 kg/person/day, but this figure is anticipated to rise to 0.60 kg/person/day by 2025. Data on waste collection efficiency in various urban areas varies between 37 percent and 77 percent, averaging at 55 percent. Source of Information: The Daily Star: Newspaper Response to the second question: Our sampling method employed a snowball approach, where samples were chosen based on individuals' engagement in the process and the willingness of respondents to allocate their time for participation. This served as the foundation for the sampling strategy in our study. This coupled with the resource and time constraints contributed to the sampling limitations which we acknowledged in the Discussion section of our manuscript."
}
]
}
] | 1
|
https://f1000research.com/articles/12-1313
|
https://f1000research.com/articles/12-1112/v1
|
06 Sep 23
|
{
"type": "Research Article",
"title": "Knowledge and awareness of stroke in the United Arab Emirates: a cross-sectional study of the general population",
"authors": [
"Feras Jirjees",
"Hala Al-Obaidi",
"Muna Barakat",
"Zelal Kharaba",
"Husam AlSalamat",
"Zainab Khidhair",
"Yassen Alfoteih",
"Eyman Eltayib",
"Sara Mansour",
"Souheil Hallit",
"Diana Malaeb",
"Hassan Hosseini",
"Hala Al-Obaidi",
"Muna Barakat",
"Zelal Kharaba",
"Husam AlSalamat",
"Zainab Khidhair",
"Yassen Alfoteih",
"Eyman Eltayib",
"Sara Mansour",
"Souheil Hallit",
"Hassan Hosseini"
],
"abstract": "Background: The study aimed to assess stroke knowledge among the general population in the United Arab Emirates (UAE) and determine the factors associated with stroke awareness among people. Methods: A cross-sectional study was conducted in the UAE between September and November 2021. The general population has self-administered an online bilingual survey (Arabic and English) distributed via social media platforms. The questionnaire covered general knowledge about stroke risk factors, consequences of stroke, and responding to somebody with acute stroke attack.\n\nResults: A total of 545 surveys were completed, with more than half of the participants being female (58.5%), married (55.4%) and employed (59.4%). The majority were less than 50 years old (90.5%) and had a university degree (71.0%). Many of the participants (70.8%) had a good general knowledge of stroke; however, around 20% of the participants were able to recognize all symptoms and risk factors of stroke. The most common sources of stroke-related information were the internet/social media (53.6%). Females were better able to correctly identify at least one stroke symptom and outcome than males (p=0.008). University education has significantly affected participants' ability to identify early stroke symptoms (p=0.001) correctly. In addition, diabetic people were more likely to recognize at least one stroke outcome than non-diabetic people (p=0.039). Conclusions: The knowledge of stroke was good among highly educated people and females. However, the awareness of all stroke risk factors, symptoms, consequences and risk factors was inadequate among the general population of the UAE. Thus, there is still a gap between recognition of the relevant stroke and taking action among people.",
"keywords": [
"Stroke",
"Knowledge",
"risk factor of stroke",
"source of information",
"UAE"
],
"content": "Introduction\n\nStroke is a major cause of mortality, morbidity and a leading cause of disability worldwide. The incidence of stroke increases in parallel to age, the prevalence of chronic cardiovascular disease and unhealthy lifestyle.1,2 Stroke is a health condition that describes a disruption of the blood supply to the brain and thus has devastating health consequences resulting from oxygen starvation and brain cellular damage.3 This damage might lead to paralysis, speech and communication problems, cognitive and memory problems, and death.4\n\nAccording to World Stroke Organization, stroke has already become a worldwide epidemic and the prevalence rate of stroke reaching around 13.7 million people by the year 2021, and approximately 40% of them are going to die because of the stroke. The data also urged for action as the statistics indicate a rise to 6.7 million expected annual deaths if no actions were taken.5,6\n\nPrevention is a key to reducing the burden of stroke, with joint efforts required at the individual and community levels. People’s knowledge and stroke awareness are essential for primary stroke prevention and timely access to stroke treatments, including acute reperfusion therapies (such as thrombolysis and mechanical thrombectomy). However, a lack of awareness of stroke among population in many countries has been highlighted.7–10 Generally, knowledge of risk factors and warning signs in the general population is consistently inadequate or poor.11,12\n\nThe UAE is a fast growing developing country where the last country report on the population number reaching nearly ten million.13 In addition, the UAE is a youth country where 65% of the people are between (25-54 years old).14 There has been about a 40-times increased in country’s population in the past four decades, plus the disparity in education, beliefs, and cultural practices has posed many challenges for shaping population-based public health strategies.15,16 The increased population has also been associated with an increase prevelance of several non-communicable diseases such as diabetes, asthma, cardiovascular diseases, and cancer.17–19 However, stroke is considered among the top killer diseases in the country. It is located just behind the ischemic heart diseases and road injuries, where the number of deaths between 1990–2019 has changed by 105%.20\n\nAlthough there were several calls from national media and practitioners regarding the importance of enhancing awareness among residents in the UAE regarding stroke, only a few available published data have been assessed the awareness level and knowledge among residents in the UAE.20 In a recent study carried out by a group of researchers in one city (the emirate of Sharjah) to assess the knowledge of the stroke among adult residents, data revealed that around 25% of people were misdescribed the disease.21 Another study that evaluated the knowledge of stroke in the Gulf Cooperation Council (GCC) confirmed a poor level of knowledge among GCC communities and urged stroke educational campaigns.22\n\nThere are multifactorial aspects of importance in this study. The high prevalence of the disease, the level of stroke knowledge of the public in the country, the level of ignorance of symptoms among the people, and the scarcity of data available for healthcare professionals and health strategists that may help develop programs to increase stroke awareness among the population including rapid response when faced with a case of stroke, which may also help focus on people with poor knowledge of stroke. The current study aimed to assess stroke knowledge among the general population in the UAE and determine the factors associated with stroke awareness.\n\n\nMethods\n\nThe study received ethical approval from the research ethics committee (REC-21-03-20-01) at the University of Sharjah, UAE. All participants agreed to participate in the study by selecting “I agree” on the electronic informed consent form before filling out the questionnaire. All methods were performed in accordance with the relevant guidelines and regulations or declaration of Helsinki.\n\nThe Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies was adopted and followed as a protocol for conducting this study.23 A cross-sectional observational study was conducted in the UAE between September and November 2021 using an anonymous online survey from the general population. The survey has been developed using the general principles of good survey design.24 An online survey25 was created on Google Forms and distributed via social media applications (WhatsApp and Facebook); through sent it to public general groups in WhatsApp and posted the survey several times in many public pages in Facebook, after obtaining approval from the administrators of these pages. Participation in this study was voluntary, and participants over 18 years old were eligible. Those with a history of stroke were excluded. The survey was self-administered and took approximately ten minutes to complete. The survey was bilingual: Arabic and English. As the Arabic language is the native language of the Emirati citizens and also of the Arabs living in the UAE. The English language survey was conducted for non-Arabic speakers who consist a large ratio of the population in the UAE. A bilingual committee composed of three pharmacy academics translated the English version of the questionnaire into Arabic. An English-speaking translator subsequently performed a back translation and any discrepancies were resolved with the help of the original board. Eight people (authors) and two academic members reviewed the questionnaire and then underwent a five-person pilot test to ensure the clarity of the questions. Then, the questions were modified based on their feedback.\n\nThe first section of the questionnaire covered the socio-demographic data. The second section assessed the overall knowledge about stroke and evaluated awareness about stroke risk factors, consequences of stroke, and response when facing somebody with a stroke attack. Moreover, it examined knowledge of early warning signs: participants were awarded one point per correct answer to the above statements. The third section identified sources of information related to stroke among the participants.\n\nThe target sample size was estimated to be 384 participants. The number was based on the Raosoft® software sample size calculator,26 for the minimal sample size needed for an unlimited population size using a confidence interval of 95%, a standard deviation of 0.5 and a margin error of 5%.\n\nThe data collected27 were analyzed using the Statistical Package for the Social Sciences (SPSS) version 25.0. Continuous variables were presented as mean ± standard deviation (SD) and 95% confidence interval (CI). Categorical and ordinal variables were presented as frequencies and percentages. Binary logistic regression was performed to identify factors associated with the ability to automatically answer one or more stroke risk factors, one or more warning signs, one or more consequences, and to seek an emergency room once a stroke had developed. Variables with p < 0.2 in the bivariate analysis were included in the regression analysis. The results were presented as odds ratios (OR) and 95% CI. Statistical tests were two-tailed and had a statistical significance of p < 0.05.\n\n\nResults\n\nA total of 593 surveys were collected from the general population; 48 surveys were excluded because of incomplete responses or refusal to participate. As a result, 545 participants were included in the final study analysis.\n\nMore than half of the respondents were females (58.5%), married (55.4%) and employed (59.4%). The majority were less than 50 years (90.5%), non-UAE citizens (73.0%) and held a university bachelor’s degree or above (71.0%). Regarding their medical status, hypertension (12.1%) and dyslipidemia (11.7%) were the most reported comorbid conditions. Moreover, more than half of the respondents (58.3%) stated being only slightly aware of stroke, and one-third (33.8%) knew about stroke from family members or relatives who had this disease before. The demographic characteristics of the respondents are presented in Table 1.\n\n* Missing values for employment status (n = 5).\n\nMany respondents (70.8%) recognized the brain as the primary organ affected by a stroke. In comparison, less than half (42.9%) perceived it as a preventable disease (Figure 1A). As for early stroke symptoms, only 21.3% of participants were able to recognize all symptoms of a stroke. The most often recognized symptoms were sudden difficulty speaking/understanding speech (78.0%), loss of consciousness/fainting (73.8%) and sudden dizziness (71.4%) (Figure 1B). When asked about possible risk factors, only 22.2% of participants were able to identify all stroke risk factors. The most three frequently identified risk factors were high blood pressure (90.3%), stress (79.3%) and old age (68.1%) (Figure 1C). Most participants (77.4%) and (75.6%) reported that stroke might lead to functional/movement problem and cognitive/memory problems, respectively. In addition, many participants (70.2%) reported that stroke might lead to long-term disability (Figure 1D).\n\nOnly 21.1% of the respondents believed they do not have good knowledge about stroke and its effects. However, the majority of the participants (82.7%) were curious to have more information related to stroke, including symptoms, emergency signs and responses when facing someone with a stroke attack and the consequences of the stroke. In addition, the majority of participants (94.9%) believed that the role of the family is essential in providing care to a patient with stroke at an early stage. In addition, more than half of the participants (54.7%) believed that stroke disease could make patients’ lives unhappy.\n\nThe most common sources of stroke-related information reported by participants were internet/social media (53.6%), followed by healthcare professionals (38.5%) and family/relatives (31.4%) (Figure 2).\n\nIn the bivariate analysis, females were better able to significantly identify at least one correct stroke symptom than males (92.8% vs. 85.8%, p = 0.008). Moreover, participants with higher levels of education (university level) correctly identified early stroke symptoms compared to those with lower educational levels (92.8% vs. 82.9%, p = 0.001), as demonstrated in Table 2.\n\n* For the variable income level, n = 99 preferred not to answer this question.\n\nRegarding stroke consequences, females compared to males (89% vs. 82.3%, p = 0.025) and those with diabetes compared with having no history of diabetes were more likely to recognize at least one consequence of stroke (97.4% vs. 85.4%, p = 0.039). Compared to UAE citizens, non-UAE citizen showed significantly higher recognition of stroke consequences (88.7% vs. 79.6%, p = 0.006) (Table 2).\n\nFor the response to acute stroke symptoms, none of the studied characteristics were significantly associated with the correct action which is taking patients to the hospital responded to acute stroke symptoms.\n\nWhen considering the identification of at least an early stroke symptom as the dependent variable, the multivariable analysis showed that females versus males and university compared to school level of education had significantly higher odds (OR of 1.9 and 2.5, respectively). In addition, those with low and medium incomes versus meager incomes were significantly associated with early symptoms identification (OR of 2.5 and 3.1, respectively) (Table 3).\n\n* Reference.\n\nWhen considering the identification of at least one consequence of stroke as the dependent variable, females versus males and those with non-UAE citizens versus UAE citizens had significantly higher odds (OR of 1.9 and 2.1, respectively) (Table 3). Regarding the correct response to acute stroke symptoms as the dependent variable, smokers versus non-smokers were more likely to respond by taking the patient to the hospital (OR of 1.5).\n\n\nDiscussion\n\nA study to assess stroke knowledge among the general UAE population was conducted. More than half of the participants were female and employed. The majority were less than 50 years old and had a university bachelor’s degree or higher. Good general knowledge of stroke was reported in more than two-thirds of the participants. However, just over 20% of the participants recognized all of the symptoms of stroke and were able to identify all of the stroke risk factors.\n\nIn 2019, a study by Karkout et al. reported an average to low level of knowledge about stroke among the adult population in the UAE.21 Although the majority of our study participants could identify the brain as a typical stroke-affected organ, they were unable to recognize all symptoms and risk factors associated with stroke. However, they identified at least four symptoms, five risk factors, and three-stroke consequences. Visual issues and severe headaches were the least detected signs and symptoms of stroke in the Karkout et al. study.21 At the same time, African American race, female gender, and advanced age were the least identified risk factors for stroke.21 Because more than half of the study population identified all information, risk factors, symptoms, and consequences related to stroke, our stroke health literacy outcome measures are higher than similar literature.28–31\n\nIn our study, 99.8% of participants identified at least one risk factor related to stroke. In comparison, previous studies have reported 98.1% among 573 participants in Jordan,9 85.4% (n = 5391) to 97.8% (n = 551) in Lebanon,10,32 76.2% among 822 participants in Australia,28 76.2% among 609 participants in Iraq,33 59.6% among 2,884 participants in Spain,34 and 8.6% among 4,671 in Benin of West Africa.35 Conversely, other previous studies have demonstrated poor knowledge of stroke risk factors and symptoms in the general population.7,36,37 High blood pressure, hyperglycemia, obesity, renal dysfunction, and hyperlipidemia are all risk factors for stroke, according to the American Heart Association’s latest update for 2021, with a further (47%) attributed to behavioral risk factors like sedentary behavior, smoking, and an unhealthy diet.38 With percentages reaching 50%, hypertension, psychological stress, old age, hypercholesterolemia, smoking, heart disease, physical inactivity, and obesity were the most recognized risk factors for stroke in our study. Unlike a previous Sharjah study in 2019, which found that hypertension (87.0%), hypercholesterolemia (72.6%), obesity (62.3%), and hyperglycemia (59.2%) were the most commonly identified risk factors in the study.21 This demonstrates a more confident tendency among our study participants to recognize stroke risk factors. Furthermore, participants in several studies conducted in Jordan, Saudi Arabia, Lebanon, Iraq, and Morocco reported that hypertension and stress were main risk factors for stroke, at different levels.9,10,32,33,39,40 Diabetes Mellitus was somewhat less recognized by our study participants, despite being one of the most frequent modifiable risk factors for stroke (49.7%). This finding has been observed in other investigations in Jordan, Iraq and Morocco.9,33,40\n\nWith regard to stroke symptoms, participants in our study expressed a high percentage recalling at least one stroke symptom (89.9%) compared to studies in Jordan (95.5%),9 Iraq (76.2%),33 Portugal (74.2%),41 Norway (70.7%),42 Canada (69.5%),43 Oman (68.0%),44 Korea (65%),45 Lebanon (68.2%),10 and Benin of west Africa (4.9%).35 In contrast to our study, only (23%) of participants in a prior 2007 study among GCC countries, including the UAE, identified at least one sign or symptom connected to stroke, which is still a low percentage.22 Sudden difficulty speaking or understanding speech was the most frequently reported stroke symptom in our study (78.0%) with same symptom reported in previous studies in Jordan (92.3%),9 Iraq (88.0%),33 China (65.2%),46 Saudi Arabia (63.8%),39 Ireland (54%),11 and Australia (14.2%).28 However, in Omani (65%) and Nigerian (24.4%) populations, sudden weakness on one side of the body was the most prevalent stroke symptom were reported.44,47\n\nIn terms of their attitudes toward stroke, less than half of the participants in our study (23.9%) were encouraged to go to a hospital as soon as possible after a stroke was detected, with no strong correlation to their socio-demographic characteristics. In a recent large study in China involving 3,051 adults, this phenomenon of paradoxical behavior toward seeking immediate medical help was recognized, with around (25%) of participants who recognized at least one of the stroke symptoms in the stroke action scenario not indicating that they would call an ambulance.46 Nevertheless, previous studies emphasized the need for immediate medical care for stroke patients.35,43,48,49 In Oman, 73% of participants reported they would immediately go to the hospital emergency if they suspected a stroke.44 However, percentages from international studies may vary, with only 47% claiming they would go to a hospital if they were suspicious of a stroke.50 In a previous study in Jordan using the same evaluation measure, participants who were well educated, employed, or diagnosed with diabetes expressed a readiness to take a patient to the hospital as soon as possible if they suspected a stroke.9 Such discrepancies necessitate a more in-depth examination to address knowledge gaps in our study population. It is self-evident that a greater understanding of the implications of a stroke would necessitate timely treatment.\n\nUntil 2008, a systematic analysis linked the female gender to a superior overall understanding of stroke risk factors and symptoms.36 In our study, adequate knowledge about risk factors was not attributed significantly to any socio-demographic characteristics, but learning about stroke symptoms was attributed significantly to female gender and advanced education while learning about consequences of stroke was attributed significantly to female gender and nationality of participants. In another study, the male gender was found to be a predictor of increased knowledge.47 Previous research has found no consistent gender correlations in favor of such differences in knowledge of stroke’s risk factors, symptoms, or consequences, so whether there are gender-specific variations in knowledge remains debatable and would require further in-depth causality analyses.49,51,52 On the other hand, women are more knowledgeable, show a greater interest in health issues, and spend more time looking for information than men.53\n\nIn terms of stroke information resources, the internet and social media were regarded as the most relied on among participants, followed by healthcare professionals and family and/or relatives. However, in studies in Jordan and Iraq, the sequence of the sources of information are similar but the percentages of participants are different.9,34 This is concerning since publicly available health information on social media may not be evidence-based and is frequently misunderstood by the general public.40,54,55\n\nFinally, although the levels of awareness and knowledge related to stroke and risk factors among the people of the UAE were high compared with many studies among people in the region and the world, these levels were still not sufficient. Practically, many of the risk factors associated with stroke are relatively high among the people in the UAE such as smoking, diabetes, cardiovascular diseases, non-healthy lifestyle.56–59 Therefore, organizational health literacy is needed to target individuals with inadequate personal health knowledge related to stroke among the UAE population through systematic, credible, evidence-based, and accessible health awareness tools. Further research on a national scale could confirm more representative findings of the UAE population.\n\nThere are some drawbacks to this study that can be identified. First, the study tool (online survey) requires technical requirements (access to internet and mobile/computer), and reading ability, hence the representation of the population may be compromised. Second, information bias connected to on-demand resource accessibility can jeopardize answer credibility. Third, selection bias associated with the snowball collection technique could be an issue, as there is no guarantee for random selection. Unmeasured variables or responses to variables directly or indirectly connected to stroke could cause residual confounding bias. Furthermore, using an online survey rather than a face-to-face meeting puts the study data’s trustworthiness and authenticity in danger. The online poll includes questions relevant to the UAE and a detailed description of the target population and inclusion criteria in the title and invitation message. Given the COVID-19 pandemic’s restriction measures, such a methodology was the best alternative.\n\n\nConclusions\n\nAlthough the general UAE population has a high level of personal health literacy when it comes to stroke risk factors, symptoms, and consequences, recognition of all stroke symptoms, risk factors, and consequences were low, and there is still a gap between recognizing a stroke-related event and taking immediate action. Better knowledge of many stroke elements was associated with higher education levels and the female gender.",
"appendix": "Data availability\n\nOpen Science Framework: Underlying data for ‘Knowledge and awareness of stroke in the United Arab Emirates: A cross-sectional study of the general population’, https://www.doi.org/10.17605/OSF.IO/DV6FS. 27\n\nThis project contains the following underlying data:\n\n- Raw Data.xlsx 27\n\nOpen Science Framework: Extended data for ‘Knowledge and awareness of stroke in the United Arab Emirates: A cross-sectional study of the general population’, https://www.doi.org/10.17605/OSF.IO/DV6FS. 25\n\nThis project contains the following extended data:\n\n- Stroke Awareness Questionnaire - UAE.docx 25\n\nOpen Science Framework: STROBE checklist for ‘Knowledge and awareness of stroke in the United Arab Emirates: A cross-sectional study of the general population’, https://www.doi.org/10.17605/OSF.IO/DV6FS. 23\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nKatan M, Luft A: Global Burden of Stroke. Semin. Neurol. 2018; 38(2): 208–211. Publisher Full Text\n\nKalache A, Aboderin I: Stroke: the global burden. Health Policy Plan. 1995; 10(1): 1–21. Publisher Full Text\n\nCoupland AP, Thapar A, Qureshi MI, et al.: The definition of stroke. J. R. Soc. Med. 2017; 110(1): 9–12. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNational Health Service (NHS): Causes of Stroke.2019. Reference Source\n\nKrueger-Young N, Maude S: World Stroke Day 2021 – Action taken within minutes can save lives.2021. Reference Source\n\nGBD 2019 Diseases and Injuries Collaborators: Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020; 396(10258): 1204–1222. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHickey A, O’Hanlon A, McGee H, et al.: Stroke awareness in the general population: knowledge of stroke risk factors and warning signs in older adults. BMC Geriatr. 2009; 9: 35. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJuyeon OH, Hyun Young K, Young Seo K, et al.: Variation in Knowledge of Stroke Warning Signs by Age and Presence of Conventional Risk Factors. J. Cardiovasc. Nurs. 2022; 37(2): 177–183. PubMed Abstract | Publisher Full Text\n\nBarakat M, AlSalamat H, Jirjees F, et al.: Factors Associated with Knowledge and Awareness of Stroke Among the Jordanian Population: A Cross-Sectional Study. F1000Res. 2021; 10: 1242. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMalaeb D, Dia N, Haddad C, et al.: Factors associated with knowledge and awareness of stroke among the Lebanese population: A cross-sectional study. F1000 Res. 2022; 11(425): 425. Publisher Full Text\n\nNicol MB, Thrift AG: Knowledge of risk factors and warning signs of stroke. Vasc. Health Risk Manag. 2005; 1(2): 137–147. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJones SP, Jenkinson AJ, Leathley MJ, et al.: Stroke knowledge and awareness: an integrative review of the evidence. Age Ageing. 2010; 39(1): 11–22. PubMed Abstract | Publisher Full Text\n\nReview, WP United Arab Emirates Population 2022 (Live).2022. Reference Source\n\nLoney T, Aw TC, Handysides DG, et al.: An analysis of the health status of the United Arab Emirates: the ‘Big 4’ public health issues. Glob. Health Action. 2013 Feb 5; 6: 20100. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGMI: United Arab Emirates Population Statistics 2022.2022. Reference Source\n\nIHME: United Arab Emirates (How is the population forecasted to change?).2019. Reference Source\n\nIbrahim O, Jirjees F, Mahdi H: Barriers affecting compliance of patients with chronic diseases: A preliminary study in United Arab Emirates (UAE) population. Asian J. Pharm. Clin. Res. 2011; 4(2): 42–45.\n\nAlnakhi WK, Mamdouh H, Hussain HY, et al.: The Socio-Demographic Characteristics Associated with Non-Communicable Diseases among the Adult Population of Dubai: Results from Dubai Household Survey 2019. Healthcare (Basel). 2021; 9(9): 1139. PubMed Abstract | Publisher Full Text | Free Full Text\n\nThe United Arab Emirates’ Government portal: Chronic diseases and natural disorders.2023.Reference Source\n\nCleveland Clinic Abu Dhabi: Reducing The Number Of Strokes Key Healthcare Goal For The UAE Say Doctors.2018. Reference Source\n\nKarkout RA, Shamaa O, Al Ammour ST, et al.: Knowledge about stroke among adults in Sharjah, United Arab Emirates. Int. J. Res. Med. Sci. 2019; 7(7): 3632. Publisher Full Text\n\nKamran S, Bener AB, Deleu D, et al.: The level of awareness of stroke risk factors and symptoms in the Gulf Cooperation Council countries: Gulf Cooperation Council stroke awareness study. Neuroepidemiology. 2007; 29(3-4): 235–242. PubMed Abstract | Publisher Full Text\n\nOpen Science Framework: STROBE checklist for ‘Knowledge and awareness of stroke in the United Arab Emirates: A cross-sectional study of the general population’.Publisher Full Text\n\nBolarinwa OA: Principles and methods of validity and reliability testing of questionnaires used in social and health science researches. Niger. Postgrad. Med. J. 2015; 22(4): 195–201. PubMed Abstract | Publisher Full Text\n\nOpen Science Framework: Extended data for ‘Knowledge and awareness of stroke in the United Arab Emirates: A cross-sectional study of the general population’.Publisher Full Text\n\nRaosoft®: Software sample size calculator.2004. Reference Source\n\nOpen Science Framework: Underlying data for ‘Knowledge and awareness of stroke in the United Arab Emirates: A cross-sectional study of the general population’.Publisher Full Text\n\nSug Yoon S, Heller RF, Levi C, et al.: Knowledge of stroke risk factors, warning symptoms, and treatment among an Australian urban population. Stroke. 2001; 32(8): 1926–1930. PubMed Abstract | Publisher Full Text\n\nPancioli AM, Broderick J, Kothari R, et al.: Public perception of stroke warning signs and knowledge of potential risk factors. JAMA. 1998; 279(16): 1288–1292. PubMed Abstract | Publisher Full Text\n\nCroquelois A, Bogousslavsky J: Risk awareness and knowledge of patients with stroke: results of a questionnaire survey 3 months after stroke. J. Neurol. Neurosurg. Psychiatry. 2006; 77(6): 726–728. PubMed Abstract | Publisher Full Text | Free Full Text\n\nReeves MJ, Rafferty AP, Aranha AA, et al.: Changes in knowledge of stroke risk factors and warning signs among Michigan adults. Cerebrovasc. Dis. 2008; 25(5): 385–391. PubMed Abstract | Publisher Full Text\n\nKhalil HM, Lahoud N: Knowledge of stroke warning signs, risk factors, and response to stroke among Lebanese older adults in Beirut. J. Stroke Cerebrovasc. Dis. 2020; 29(5): 104716. PubMed Abstract | Publisher Full Text\n\nAl-Obaidi H, Khidhair Z, Jirjees F, et al.: Factors associated with knowledge and awareness of stroke in the Iraqi population: a cross-sectional study. Front. Neurol. 2023; 14: 1144481. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSegura T, Vega G, López S, et al.: Public perception of stroke in Spain. Cerebrovasc. Dis. 2003; 16(1): 21–26. Publisher Full Text\n\nAgbetou Houessou M, Hountada H, Yahouédéou B, et al.: Knowledge of Stroke Risk Factors and Signs in Parakou, a Northern City of Benin in West Africa. Cerebrovasc. Dis. 2021; 50(1): 88–93. Publisher Full Text\n\nStroebele N, Müller-Riemenschneider F, Nolte CH, et al.: Knowledge of risk factors, and warning signs of stroke: a systematic review from a gender perspective. Int. J. Stroke. 2011; 6(1): 60–66. Publisher Full Text\n\nNicol MB, Thrift AG: Knowledge of risk factors and warning signs of stroke. Vasc. Health Risk Manag. 2005; 1(2): 137–147. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVirani SS, Alonso A, Aparicio HJ, et al.: Heart Disease and Stroke Statistics-2021: A Report From the American Heart Association. Circulation. 2021; 143(8): e254–e743. PubMed Abstract | Publisher Full Text\n\nAlluqmani MM, Almshhen NR, Alotaibi RA, et al.: Public Awareness of Ischemic Stroke in Medina city, Kingdom of Saudi Arabia. Neurosciences. 2021; 26(2): 134–140. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKharbach A, Obtel M, Achbani A, et al.: Level of Knowledge on Stroke and Associated Factors: A Cross-Sectional Study at Primary Health Care Centers in Morocco. Ann. Glob. Health. 2020; 86(1): 83. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDuque AS, Fernandes L, Correia AF, et al.: Awareness of stroke risk factors and warning signs and attitude to acute stroke. Int. Arch. Med. 2015; 8: 195. Publisher Full Text\n\nSundseth A, Faiz KW, Rønning OM, et al.: Factors related to knowledge of stroke symptoms and risk factors in a Norwegian stroke population. J. Stroke Cerebrovasc. Dis. 2014; 23(7): 1849–1855. Publisher Full Text\n\nRioux B, Brissette V, Marin FF, et al.: The Impact of Stroke Public Awareness Campaigns Differs Between Sociodemographic Groups. Can. J. Neurol. Sci. 2022; 49(2): 231–238. Publisher Full Text\n\nAl Shafaee MA, Ganguly SS, Al Asmi AR: Perception of stroke and knowledge of potential risk factors among Omani patients at increased risk for stroke. BMC Neurol. 2006; 6: 38. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKim JS, Yoon SS: Perspectives of stroke in persons living in Seoul, South Korea. A survey of 1000 subjects. Stroke. 1997; 28(6): 1165–1169. PubMed Abstract | Publisher Full Text\n\nLuan S, Yang Y, Huang Y, et al.: Public knowledge of stroke and heart attack symptoms in China: a cross-sectional survey. BMJ Open. 2021; 11(1): e043220. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWahab KW, Okokhere PO, Ugheoke AJ, et al.: Awareness of warning signs among suburban Nigerians at high risk for stroke is poor: a cross-sectional study. BMC Neurol. 2008; 8: 18. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHawkes MA, Gomez-Schneider MM, Dossi DE, et al.: Stroke Knowledge in the EstEPA Project, a Population-Based Study. J. Stroke Cerebrovasc. Dis. 2021; 30(2): 105471. PubMed Abstract | Publisher Full Text\n\nPark MH, Jo SA, Jo I, et al.: No difference in stroke knowledge between Korean adherents to traditional and western medicine - the AGE study: an epidemiological study. BMC Public Health. 2006; 6: 153. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJones SP, Jenkinson AJ, Leathley MJ, et al.: Stroke knowledge and awareness: an integrative review of the evidence. Age Ageing. 2010; 39(1): 11–22. PubMed Abstract | Publisher Full Text\n\nKoçer A, Ince N, Koçer E, et al.: Factors influencing treatment compliance among Turkish people at risk for stroke. J. Prim. Prev. 2006; 27(1): 81–89. PubMed Abstract | Publisher Full Text\n\nPontes-Neto OM, Silva GS, Feitosa MR, et al.: Stroke awareness in Brazil: alarming results in a community-based study. Stroke. 2008; 39(2): 292–296. Publisher Full Text\n\nHorch K, Wirz J: Nutzung von Gesundheitsinformationen [People’s interest in health information]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2005; 48(11): 1250–1255. PubMed Abstract | Publisher Full Text\n\nSuarez-Lledo V, Alvarez-Galvez J: Prevalence of Health Misinformation on Social Media: Systematic Review. J. Med. Internet Res. 2021; 23(1): e17187. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWaszak PM, Kasprzycka-Waszak W, Kubanek A: The spread of medical fake news in social media–the pilot quantitative study. Health Policy Technol. 2018; 7(2): 115–118. Publisher Full Text\n\nBarakat M, Jirjees F, Al-Tammemi AB, et al.: The era of e-cigarettes: A Cross-sectional study of vaping preferences, reasons for use and withdrawal symptoms among current e-cigarette users in the United Arab Emirates. J. Community Health. 2021; 46(5): 876–886. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMahdi H, Hassan Y, Aziz N, et al.: Diabetes knowledge and practice in Malaysian and the United Arab Emirates diabetic patients. Res. J. Pharm. Biol. Chem. Sci. 2013; 4(3): 653–665.\n\nMezhal F, Oulhaj A, Abdulle A, et al.: High prevalence of cardiometabolic risk factors amongst young adults in the United Arab Emirates: the UAE Healthy Future Study. BMC Cardiovasc. Disord. 2023; 23: 137. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShehab A, Bakir S, Sabbour H, et al.: Prevalence of Cardiovascular Risk Factors and 10-Years Risk for Coronary Heart Disease in the United Arab Emirates. Curr. Diabetes Rev. 2023; 19(3): e210422203892. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "204545",
"date": "26 Sep 2023",
"name": "Javedh Shareef",
"expertise": [
"Reviewer Expertise Clinical Pharmacy Practice"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors made a good attempt in carrying out the research related to knowledge and awareness of stroke in the UAE.\n\nDid the author checked the reliability and validity of the study questionnaire?\n\nThe author has mentioned that the google forms of the questionnaire was distributed through WhatsApp and Facebook. Will there be a possibility of bias if the study participants discuss or share the questions with their friends for right answers. What measures have been taken by the author to avoid this bias?\n\nThe sample size of the study was estimated to be 384 participants, however we could see that 545 participants were included in the study. Need justification for selecting more number of participants in the study or else the author need to recalculate the sample size.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10355",
"date": "11 Oct 2023",
"name": "Feras Jirjees",
"role": "Author Response",
"response": "Dear Reviewer Thank you immensely for your insightful comments and recommendations. Comment (1) Did the author checked the reliability and validity of the study questionnaire? Answer / The following statement added to the methods section: The questionnaire was structured similarly to a survey developed and validated in a published study among the general population in Jordan in all aspects that covered knowledge of the stroke with the exception of sociodemographic factors such as economic status due to the discrepancy between the two countries (9). The mentioned survey has been developed using the general principles of good survey design (24)”. In addition, reliability test was conducted before the study began. The following statement added to the methods section: “The reliability of the questionnaires was tested among 12 subjects during the pilot study to detect any difficulties in understanding the topic and meaning of the questions. The Cronbach's alpha value for the items in the second section related to assessing comprehensive knowledge about stroke, stroke risk factors, and stroke consequences was (α = 0.73)”. Comment (2) The author has mentioned that the google forms of the questionnaire was distributed through WhatsApp and Facebook. Will there be a possibility of bias if the study participants discuss or share the questions with their friends for right answers. What measures have been taken by the author to avoid this bias? Answer / This type of bias is a concern when using this type of data collection tool. Therefore, participants were asked at the beginning of the survey in the “invitation letter” to answer the survey based on their knowledge, without discussing or asking questions related to the survey with anyone, to avoid any relevant bias. Comment (3) The sample size of the study was estimated to be 384 participants, however we could see that 545 participants were included in the study. Need justification for selecting more number of participants in the study or else the author need to recalculate the sample size. Answer / A larger sample size (n=545) than the minimum requirement (n=384), based on sample size calculation, has been chosen for the current study. This decision is often made to improve the validity of the study. The reasoning behind larger sample size are to increased generalizability as a larger sample size can provide more representative data, and then making it easier to generalize study findings to a broader population. Also, it will improve statistical power with a better chance of detecting real effects or differences if they exist. In addition, it reduced sampling error and enhanced confidence in results to increase the confidence in the study's findings. Best regards"
}
]
},
{
"id": "204544",
"date": "28 Sep 2023",
"name": "Hadeer Akram Abdulrazzaq Al-Ani",
"expertise": [
"Reviewer Expertise Clinical Pharmacy",
"Public Health",
"Pharmacogenetics",
"and Biostatistics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI want to congratulate the authors of this study for their excellent work and achievement in implementing and publishing the present study. I have several points that are required to be edited and corrected.\nSeveral sentences are required to be rephrased to be clear to the readers, especially in the abstract.\n\nIn methodology, please write about the questionnaire's validity procedure and reliability outcomes.\n\nIn the statistical analysis (Methodology ): What do you mean by “Variables with p < 0.2 in the bivariate analysis”? Why did you select the cutoff equal to 0.2? Please justify and support the sentence with a reference.\n\nFigure 1 is blurred. Please try to find a clear image.\n\nPlease be consistent with the background of Table 2.\n\nTable 3, please add columns of the df and confidence interval. The readers like to see the validity of outcomes.\n\nIn Table 3, please correct the level of high income (High (>2K)). Also, justify why the income increase of the early symptoms identified is not significant.\n\nIn the Discussion, please be consistent in writing the following sentence: “In comparison, previous studies have reported 98.1% among 573 participants in Jordan, 85.4% (n = 5391) to 97.8% (n = 551) in Lebanon, 76.2% among 822 participants in Australia, 76.2% among 609 participants in Iraq, 8.6% among 4,671 in Benin of West Africa”.\n\nPlease add future work.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10358",
"date": "11 Oct 2023",
"name": "Feras Jirjees",
"role": "Author Response",
"response": "Dear Reviewer I greatly appreciate your valuable feedback and suggestions. Comment (1) Several sentences are required to be rephrased to be clear to the readers, especially in the abstract. Answer / Some corrections have been made in the manuscript which is heighted in track changes mode. Comment (2) In methodology, please write about the questionnaire's validity procedure and reliability outcomes. Answer / The following statement added to the methods section: The questionnaire was structured similarly to a survey developed and validated in a published study among the general population in Jordan in all aspects that covered knowledge of the stroke with the exception of sociodemographic factors such as economic status due to the discrepancy between the two countries (9). The mentioned survey has been developed using the general principles of good survey design (24)”. In addition, reliability test was conducted before the study began. The following statement added to the methods section: “The reliability of the questionnaires was tested among 12 subjects during the pilot study to detect any difficulties in understanding the topic and meaning of the questions. The Cronbach's alpha value for the items in the second section related to assessing comprehensive knowledge about stroke, stroke risk factors, and stroke consequences was (α = 0.73)”. Comment (3) In the statistical analysis (Methodology ): What do you mean by “Variables with p < 0.2 in the bivariate analysis”? Why did you select the cutoff equal to 0.2? Please justify and support the sentence with a reference. Answer / A justification and support the sentence was added to the methods section. Comment (4) Figure 1 is blurred. Please try to find a clear image. Answer / A better figure is provided to replace the current figure. Comment (5) Please be consistent with the background of Table 2. Answer / Done, the table now has a consistent white background. Comment (6) Table 3, please add columns of the df and confidence interval. The readers like to see the validity of outcomes. Answer / Confidence interval data have been added to the table, as required. Comment (7) In Table 3, please correct the level of high income (High (>2K)). Also, justify why the income increase of the early symptoms identified is not significant. Answer / Done for the first part (High (> 25K)). In addition, the clarification of this factor was written in the section. Comment (8) In the Discussion, please be consistent in writing the following sentence: “In comparison, previous studies have reported 98.1% among 573 participants in Jordan, 85.4% (n = 5391) to 97.8% (n = 551) in Lebanon, 76.2% among 822 participants in Australia, 76.2% among 609 participants in Iraq, 8.6% among 4,671 in Benin of West Africa”. Answer / Done, the modifications were made in the manuscript. Comment (9) Please add future work. Answer / The following statement is added to the manuscript (after the conclusion section. “Additional studies at the national level could confirm results that are more representative of the general UAE population. More work is needed to raise awareness among people in the UAE through a structured, reliable, evidence-based and accessible health awareness program to target all people in the UAE especially individuals who do not have sufficient knowledge regarding stroke.” Best regards"
}
]
},
{
"id": "204543",
"date": "02 Oct 2023",
"name": "Doaa Alkhalidi",
"expertise": [
"Reviewer Expertise Areas of research interest include medication safety",
"pharmacovigilance",
"and health services research."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe study is interesting.\n\nThe title is appropriate.\n\nThe written text needs to be revised to ensure that grammatically correct (some mistakes are there).\n\nThe objectives are clearly stated.\n\nIn the abstract (results), it has been mentioned that Many of the participants (70.8%) had a good general knowledge of stroke; however, around 20% of the participants were able to recognize all symptoms and risk factors of stroke. How good level of knowledge has been decided. This has to be explained under the methods section, through the scoring system applied in the data analysis. In addition, it needs to be reflected in the results section.\n\nIt has been mentioned in the \"Study Design and Questionnaire\" section that those with a history of stroke were excluded. The authors need to clarify how the exclusion took place since it is an online survey.\n\nThe authors need to explain the validation process of the developed questionnaire.\n\nHow was the reliability of the questionnaire ensured?\n\nIn the same section, the scoring system applied needs further elaboration. What about the incorrect answers?\n\nIn Table 1, the last variable was about Familiarity with a history of stroke: in the family Personally know someone with stroke, what is the difference between each of them?\n\nIn the Results section, \" Stroke knowledge of the participants\" it has been found that (majority of the participants (82.7%) were curious to have more information related to stroke, including symptoms, emergency signs and responses when facing someone with a stroke attack and the consequences of the stroke), how participants curiosity has been measured through the survey?\n\nThe conclusion is not clearly expressed. It has been mentioned \"general UAE population has a high level of personal health literacy\" But \"stroke risk factors, symptoms, and consequences, recognition of all stroke symptoms, risk factors, and consequences were low\" as a reader, it is recognized as a contradiction. The conclusion needs to be expressed more clearly, and some recommendations need to be suggested by the authors based on their findings.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "10356",
"date": "11 Oct 2023",
"name": "Feras Jirjees",
"role": "Author Response",
"response": "Dear Reviewer Thank you very much for the valuable comments and suggestions. Comment (1) In the abstract (results), it has been mentioned that Many of the participants (70.8%) had a good general knowledge of stroke; however, around 20% of the participants were able to recognize all symptoms and risk factors of stroke. How good level of knowledge has been decided. This has to be explained under the methods section, through the scoring system applied in the data analysis. In addition, it needs to be reflected in the results section. Answer / It is good comment, we change the statement to be many of the participants (70.8%) recognized the brain as the primary organ affected by a stroke. Comment (2) It has been mentioned in the \"Study Design and Questionnaire\" section that those with a history of stroke were excluded. The authors need to clarify how the exclusion took place since it is an online survey. Answer / The following statement added to the method section: “A question was asked whether the participant had ever had a stroke, and if the participant answered yes, the survey was terminated”. Comment (3) The authors need to explain the validation process of the developed questionnaire. Answer / the following statement added to the methods section: The questionnaire was structured similarly to a survey developed and validated in a published study among the general population in Jordan in all aspects that covered knowledge of the stroke with the exception of sociodemographic factors such as economic status due to the discrepancy between the two countries (9). The mentioned survey has been developed using the general principles of good survey design (24).” Comment (4) How was the reliability of the questionnaire ensured? Answer / Sorry for missing this important point, reliability test was conducted before the study began. The following statement added to the methods section: “The reliability of the questionnaires was tested among 12 subjects during the pilot study to detect any difficulties in understanding the topic and meaning of the questions. The Cronbach's alpha value for the items in the second section related to assessing comprehensive knowledge about stroke, stroke risk factors, and stroke consequences was (α = 0.73)”. Comment (5) In the same section, the scoring system applied needs further elaboration. What about the incorrect answers? Answer / If the answer is correct, the participant receives a score of one, and if the answer is incorrect, the participant receives a zero. The statement was mentioned in the method section at the Study design and questionnaire: “participants were awarded one point per correct answer to …”. The analysis was performed based on the correct answers. The participants with scores (i.e. high correct knowledge), and this is shown in Figure 1 and Table 2. For incorrect answers, they did not account in the bivariate and multivariate analysis. Comment (6) In Table 1, the last variable was about Familiarity with a history of stroke: in the family Personally know someone with stroke, what is the difference between each of them? Answer / “History of stroke in the family” means there is a history of stroke in the family, while the “Personally know someone with stroke” means friends or people around them. Comment (7) In the Results section, \" Stroke knowledge of the participants\" it has been found that (majority of the participants (82.7%) were curious to have more information related to stroke, including symptoms, emergency signs and responses when facing someone with a stroke attack and the consequences of the stroke), how participants curiosity has been measured through the survey? Answer / There was a question in the survey that asked about people’s interest in receiving more information related to stroke, including symptoms, emergency signs and responses when facing someone with a stroke attack and the consequences of the stroke. The importance of this question is to assess the needs of the people in the UAE for awareness program and campaign related the topic of the study as a part of health promotion in the country. A statement added to the method section related to that. Comment (8) The conclusion is not clearly expressed. It has been mentioned \"general UAE population has a high level of personal health literacy\" But \"stroke risk factors, symptoms, and consequences, recognition of all stroke symptoms, risk factors, and consequences were low\" as a reader, it is recognized as a contradiction. The conclusion needs to be expressed more clearly, and some recommendations need to be suggested by the authors based on their findings. Answer / Thanks for this comment, a word moderate has been added to the conclusion section. Many participants reported correct answers, with more than 50% correct answers on most items and more than 75% correct answers on several questions. Best regards"
}
]
}
] | 1
|
https://f1000research.com/articles/12-1112
|
https://f1000research.com/articles/12-1307/v1
|
11 Oct 23
|
{
"type": "Research Article",
"title": "Quasi-experimental study on fostering creativity through creative writing in German as a Foreign Language (GFL) in COVID-19",
"authors": [
"Katinka Szabó-Szettele",
"Andrea Kárpáti",
"Andrea Kárpáti"
],
"abstract": "Background: In this paper, creative language teaching and learning will be discussed in the context of subject-based development of creativity that supports learning performance. Although there are several benefits of creative teaching and learning methods, creative writing tasks are not typical in foreign language education. The main focus of this study is developing a creative writing test in GFL education. Methods: The pilot study was implemented in a primary school in Hungary in 2020/2021 and introduces a model to enhance creativity in German as a Foreign Language (GFL) classroom through creative writing tasks. In the pilot experiment, pre- and post-test design was used. Results: Results of the study show that there is significant correlation between creative writing and creative thinking skills, measured with a Language Proficiency Test for Creative Writing Skills and the Test for Creative Thinking/Drawing Development (TCT-DP) by Urban and Jellen (1996). The results indicate that our creative writing skills assessment instrument is valid for measuring creative performance in GFL, however in the development of creative writing we could not prove significant changes in the experimental group, probably because of the online teaching situation during the coronavirus disease (COVID-19) pandemic. Conclusion: Creative writing is an important tool for enhancing divergent thinking and foreign language competence. Through creative writing tasks, students engage with the language more intensively and their creative, imaginative thinking skills develop. For the evaluation of students’ creative texts analytical rubrics have been developed and they proved to be appropriate. However, despite the exciting and thought-provoking exercises, more motivation and criterion-oriented feedback is needed to support the creative learning process in an online learning environment.",
"keywords": [
"creativity",
"creative pedagogy",
"creative writing assessment",
"foreign language education"
],
"content": "Introduction\n\nAlthough there are several benefits of creative pedagogical teaching and learning methods, they are not really valued in schools widely. However, non-traditional pedagogical approaches for creative learning can improve the quality of teaching which impacts the development of student's creativity and learning performance. Non-traditional pedagogical approaches are supported among others through explorative learning, student choice, access to varied materials, problem finding, and problem-solving strategies. In turn, Beauregard (2014) claims that creative activities, such as dance, drama and visual arts, contribute to children's emotional well-being which is crucial for creative self-efficacy.\n\nCreative pedagogies are contemporary educational models based on the redefinition of learning which include creativity as a key component in their concepts. Creative Pedagogy introduced and described by Aleinikov (1989, 2013), Mehlhorn and Mehlhorn (2003) and Lin (2011) aims at the development of the creative potential of the individual and supports the successful acquisition of knowledge. Dezuanni and Jetnikoff (2011) interpret innovative curriculum as part of the creative teaching-learning process, while Selkrig and Keamy (2017) emphasise the role of the teacher linked to the dimensions of creative teaching, teaching creativity and creative learning by Lin (2011). The concept of the Creative Classroom (CCR) advocates the renewal of the learning environment that fully embeds the potential of information and communications technology (ICT) to innovate learning and teaching practices in different educational settings (COM, 2012). Less known are investigations in the field of effectiveness of creative pedagogical practice and intervention. According to the meta-analysis of Scott et al. (2004a, 2004b) practice-oriented interventions embedded in a specific discipline that used thinking skills and included collaborative activities proved to be the most successful way of fostering creativity. Creative educational programmes are developed in several countries (such as the Learn to Think programme in China, the Creative Schools Programme in Ireland, the BIP Schools in Germany), which we can consider applied creative pedagogies.\n\nCreative language teaching and learning offers the possibility of creativity development via cross-curricular interventions. Foreign language (FL) curricula are generally less rigorous than those of science and mathematics, so the FL classroom teachers can adapt topics to the learners' interests and vary them during the lesson. It is also essential for natural language use (Fehér, 2015), which means the use of real content, demonstration of real-life language situations and practices. It includes the use of language compensation strategies through gesticulation, drawing, paraphrasing a word or phrase, which require creativity. According to Woodward (2015), the most important elements to facilitate creative language teaching and learning are: tools for attention-grabbing (for example, listening to a piece of music or playing a game that requires concentration), brainstorming techniques (for example listing objects of a particular colour or beginning with a particular letter), making unusual associations and combinations (for example exploring the relationship between a text and an unrelated picture). Woodward (2015) also stresses the importance of an inspiring, stimulating environment, physical activities and collaboration, rewarding creative expressions and more than one idea, encouraging risk-taking and preferring imagination and visualising.\n\nCreative language learning is also linked to linguistic creativity and the language of ideas, described as the completion of an academic task, no matter how far from the ‘literate’ use of the language it is (Bunch, 2014). According to Bunch and Martin (2021), creative language learning is especially important in the case of students from a wide variety of linguistic backgrounds. In the process of foreign language learning, students should be encouraged to focus on self-expression and mediation of ideas and not the linguistic features of interactions or conversations. “Language creativity” defined as the playful use of language to construct new meaning (Tin, 2011), requires learners to communicate about new meanings and to construct unknown meaning: “The cognitive and linguistic processes learners go through in creative language play tasks can contribute to learners’ language development.” (Tin, 2012:179). Tin (2011, 2012) argues that in a creative language task, language users/learners must somehow innovate and complexify their language, by reanalysing and combining known utterances and structures to create new ideas and forms. He claims that students explore and exploit more syntactically and lexically rich utterances in creative play tasks as compared to non-creative tasks and tasks. In the experiment of Liao et al. (2018), language skills, creativity and motivation of 6–7-year-old Taiwanese primary school students were investigated. The technique of brainstorming was used in the intervention, which involved 256 students and lasted only eight weeks. According to the results, the vocabulary of the pupils increased significantly although the short time frame of the experiment, their creative ability measured by the Torrance Test of Creative Thinking (TTCT) improved (except fluency), and their motivation increased compared to the control group as well.\n\nAccording to the Common European Framework of Reference for Languages (CEFR, 2001) the aesthetic-artistic use of language, which includes poems, songs, stories, creative writing and role-playing exercises is an alternative way in the teaching and learning process, but also important for the FL acquisition and competence. It is widely known that art activities are suggested as a way to support FL learning, however, there is little empirical evidence. According to the research of Ludke et al. (2014) which focuses on the effects of art activities on specific aspects of FL learning, students engaged in singing and song activities improved more on grammatical skills, listening comprehension, conversation/speaking, and intonation and flow speech, different from the group where visual art and drama activities were integrated into FL instruction. However, there were smaller mean differences between the groups for vocabulary and reading skills. The findings of the six week intervention show a stronger benefit of singing activities, although an important limitation of a study is the sample size (N = 45). Another empirical research with pre- and post-test design (Tok and Kandemir, 2015) found that during a four-weeks intervention in seventh grade English language classes of an elementary school in Turkey, students’ achievement in writing skill was increased, however, their attitude to English courses was not. Results indicate that creative writing exercises have a positive effect on writing performance among students at the age of 13–14 years old.\n\nAlthough there are several benefits of developing and writing skills in foreign language learning, textbooks focus on listening, reading and speaking exercises (like practising short dialogues) and include fewer writing tasks. That is why writing skills in language learning are often overlooked, especially creative writing opposed to expository or technical writing. The latter is based on standardised rules and conventions, and performance is easier to assess. On the other hand, there are other problems with writing creatively, namely the lack of experience of how to develop and assess such tasks. Moreover, most teachers and students are not really aware of the importance of creative writing in the development of thinking skills and FL achievement in general.\n\nStudies have shown that creative writing supports language development at all levels. Raimes (1983) claims that writing reinforces the acquisition of grammatical structures, idioms and vocabulary and it encourages students to be adventurous with the language. According to Craik and Lockhart (1972) language learners engage with the language at a deeper level of processing than with most expository texts, they manipulate the language in interesting and sophisticated ways in their attempt to express uniquely personal meanings. Maley (2006) claims that the benefits are noticeable in grammatical accuracy, appropriacy and originality of lexical choice, and sensitivity to rhythm, rhyme, stress and intonation. According to Piazza and Siebert (2008), affective aspects are also important, because writing creatively is considered as a construct which requires such resources as self-discipline, perseverance in the face of difficulties, tolerance of ambiguity, autonomy, willingness to take risks, motivation, self-efficacy, and interest. Lutzker (2015) argues that stories not only shape the imaginative and emotional life of a child, but also the acquisition of language and the development of thought and self. Storytelling and story writing techniques can help to aid the development of these processes, but it requires enough possibilities to practise them.\n\nAssessment techniques\n\nThe assessment of creative writing, like other dimensions of measuring creative performance raises a number of questions. Mozaffari (2013) describes three types of assessment techniques: the first is based on the feature of divergent thinking, the second on the consensus or the common judgement of experts of the field and the third one is based on the main characteristics and attributes of creativity.\n\nThere are debates about the possibility of assessing creative writing in foreign language education and research in this area is scarce. According to Tung (2015), if creative writing as a skill is valued in 21st century education, then valid and reliable assessment methods should be introduced in language art education. Because unless it is resolved, there will be no instructional programmes carried out by teachers and other stakeholders of education which would be effective. He argues, in agreement with other Chinese educators, that the objectives of writing assessments have become more complex, and it also requires creative thinking skills. Among others, Brookhart (2013) suggests that using rubrics for assessing creativity in writing may also clarify criteria or show the continuum of creative performance. Blomer (2011) also argues that rubrics are needed to ensure objectivity in creativity assessment, but their design is difficult. Most foreign language education (FLE) rubrics contain criteria which are irrelevant to creativity (correctness of grammar, punctuation, syntax, etc.), non-creative features like mechanics, organisation and structure or inclusion of all required elements of a story (Mozaffari, 2013). He concludes that the validity of creative writing tests depends also on the theory upon which the tests are based and the criteria they set (Blomer, 2011). However, the rubric seems to be the most appropriate and reliable method to assess creative writing.\n\nCriteria of creative writing assessment\n\nMorris and Sharplin (2013) argue that an optimal analytical marking scheme is needed which can define qualities of creative writing. Analytical rubrics are appropriate to set categories of achievement to describe how far each quality has been achieved. Based on the literature in the field, creative writing includes four major qualities: image, voice, characterization and story (Burroway, 2011; Mills, 2006). Image is a central feature that “evokes one or more of our senses” (Burroway, 2011:15). There are two ways of creating images: the use of significant details (without abstraction, generalisation and judgement) and literary tropes (such as metaphor, simile, personification). According to Burroway (2011), literary figures are powerful tools for writers to create images which appeal to the readers' senses and details allow us to draw our own conclusion about the character. Voice is understood as the use of images to make the diction original and appealing. Voice also involves indirect characterization through significant details that is employed in most types of creative writing: in a short story, novel, poetry, playwriting, nonfiction and fiction. It is implemented through action (what a character does), thought (what a character thinks about his/her surroundings), dialogue (what a character says and how it is said), setting (where and when a character is situated), and symbols (added information about a character). Story is another aspect of evaluating creative writing among the four qualities. It refers to the narrative which puts events in a sequence (Mozaffari, 2013) and provides readers with some information which allows them to draw conclusions about the purpose of the text (Mills, 2006).\n\n\nMethods\n\nInstitutional approval was obtained by the scientific committee of the Eötvös József College (2019/PED01). The school leader, teachers and the students’ parents were provided with written information about the data collection and the purpose of the study and gave their written informed consent.\n\nSince language teaching can differ from school to school, the pedagogical experiment was carried out in one institution with the same curriculum for all classes in one grade. So, for validating the new assessment tool, six German as foreign language (GFL) classes in the fifth–sixth grades of a Hungarian primary school were recruited at the beginning of the school year of 2020/2021. Because of this limitation (the primary school has only three classes in one grade) the sample size (N=99) was relatively small. The students with average socioeconomic status learn German as a second language from the beginning of the school years and are expected to achieve A2–B1 level in the fifth–sixth grades. Language skills were tested among fifth grade students in the previous pilot study before COVID-19 and this school age group proved to be appropriate for creative writing exercises based on their vocabulary and grammar skills.\n\nThe study was designed as a three-month intervention project and was carried out in the second half (March, April, May, June) of the school year of 2020/2021. Quasi-experimental research design with pretest and posttest was used. Besides the participants’ language background and experience, information about language proficiency of the parents was also collected before the intervention. Mastery Motivation in German as a foreign language was also assessed by the Subject Specific Mastery Motivation Questionnaire (SSMMQ), developed in Hungary (Józsa, 2014) to avoid differences between the motivation of the experimental and the control group. The questionnaire has been made available by the author for free use. In the adapted version of the questionnaire 10 Likert-type items were used. Subsequently, the standard German language curriculum for the 12-week period was supplemented with creative writing activities in the classes of the experimental group. Learning outcomes regarding students' creative writing skills in German language class (GLC) and creative thinking skills were assessed through pre- and post-tests. Both instruments were implemented as paper-and-pencil tests in the classroom.\n\nIntroduction of the test measuring creative writing skills in GLC\n\nThe test measuring creative writing skills in GLC consisted of a series of tasks developed specifically for this study. The test was based on divergent thinking components (fluency, flexibility, originality) related to creative writing qualities like describing details, characterization and context. The creative writing test also included visual stimuli: one image with three pictures of a story, one image to describe and one image to complete (Figure 1). The test was improved and after deleting one item it showed good internal consistency (Cronbach’s α = 0.725).\n\nTask 1.\n\nThe Fox and the Raven\n\nA fox sees a raven fly off with a piece of cheese in its beak and settle on a branch of a tree. The fox says: “Good morning, you beautiful raven! What a beautiful bird you are! Let me hear but one song from you that I may greet you as the Queen of Birds.” The raven likes these words very much and opens her mouth to sing. That moment the cheese falls to the ground and the fox grabbed it away.\n\nWhat else could the fox have said to the raven to achieve his goal?\n\nExemplary solutions for Task 1:\n\nDear Raven … please come down. We could divide the cheese in two. / … I have a gift for you. / … please, sing a song for me. / … I bring you to a talent show. It costs only a mere trifle! / … I would like to take a closer look at your feather. / … please come here, I am your dentist.\n\nTask 2.\n\nUse the words below to tell the story using the pictures. You can use as many of the words as you like.\n\nNotes: Task 1 is a retelling of Aesop's famous fable − summarized by Author 1. Task 2 is based on the cartoon story by Mira Faßbender with the title \"Bildergeschichte: Paddelspaß/Picture story: paddling fun\". The image has been reproduced with permission of the publisher from: https://www.persen.de/media/wysiwyg/Zusatzmaterial/23538DA3_Bildergeschichte_Paddelspass.pdf. Task 3 is a worksheet with the figure of a skydiver (created by the Hungarian artist Áron Szabó) to complete and includes a drawing activity. The image has been applied with permission of the artist. Most of the students (N=56) completed the images and compiled a story as well.\n\nlake rowing boat funny duck overturns\n\nExemplary solutions for Task 2:\n\nTwo boys were paddling on the lake. They had fun and the boat turned over. They were really wet, but they found it funny.\n\nMark and Dominik were paddling together because they wanted to get to China. But as Dominik said a terrible joke, Mark laughed so hard, that they fell into the water.\n\nTwo boys wanted to go fishing. When they were far enough, they realized, that there was a gun in the boot. They saw a duck which they wanted to shoot. But Marcus was so scared, that he fell into the water. The other guy wanted to save him, so he jumped after him.\n\nTask 3.\n\nImagine and write down where the parachutist arrives. You can draw it if you like.\n\nAssessment rubrics were used to evaluate creative writing. Assessment criteria for Tasks 1–3 are outlined below (Table 1).\n\nExemplary solutions for Task 3:\n\nThe skydiver lands next to a forest. He is afraid, and he wants to flee but he has to stay there. / The man lands on a field and saw a horse with brown hair. He rides away. /The skydiver ends up at the bus stop. / The skydiver lands in the stomach of a shark. / There were many clouds in the sky and the man could not see well. He landed in a garden. There were animals: two dogs and three cats. He had no idea what to do. /The man lands in a country, where everything is different: there are chocolate trees, houses built from gingerbread, flowers made of gummy bears. There are also cookies hanging from the trees and the sky is made of marzipan. Everywhere are funny dwarfs and fairies.\n\nFor assessing creative thinking skills, the Test for Creative Thinking/Drawing Development (TCT-DP) by Klaus Urban and Hans Jellen (1996) was used, which is a valid, reliable and internationally utilised instrument. The TCT test files were provided by the Visual Culture Research Group of the Corvinus University of Budapest with copyright license. The test sheet contains six figural elements (Figure 2), which are offered for completion, repetition, modification, inclusion and composition (Kárpáti & Gyebnár, 2013). The TCT-DP attempts to capture the qualitative nature of a creative product. It is like a screening instrument for a person's creative activity (Harecker, 2000) and it also represents a sophisticated, multifaceted construct instead of the limited creativity concept of conventional tests that only consider quantitative criteria of divergent thinking (Urban, 2011).\n\nNotes: Test sheets A and B of The Test for Creative Thinking/Drawing Development (TCT-DP) created by Klaus Urban and Hans Jellen (1996) contains six figurative elements (semicircle, dot, large corner, serpentine line, dashed line, small horizontal U shape outside the frame). The elements inspire both figurative and abstract solutions.\n\nThe TCT-DP can be used with children aged six and above. According to Urban (2011), teachers can use it to objectify, supplement and, if necessary, correct their observations, impressions and conclusions about the creative behaviour of their students.\n\nDuring the educational intervention, students of the experimental group received creative writing tasks (Table 2) which included visual stimuli for drawing or handicrafts. They were adapted from a German story writing and drawing book (Rüger & Bauermeister, 1998). Based on the task instruction, the beginning of the storyline was provided along with the drawing stimuli. Students were encouraged to complete the image and they also had to write a short story with 100 words for each task. Due to COVID-19 regulations, the task was administered online.\n\nWhen the creative writing tasks were introduced, the task developer (the first author of this paper) was present and clarified the tasks and the intervention frame. Students could choose from different writing opportunities, and they were asked to work on the stories at home. Before and after the intervention, pre- and post-tests were used, which were scheduled for school hours. The German creative writing test took approximately 45 minutes (the duration of one lesson hour). Students were working in class, where dictionaries were provided. They were also allowed to ask the German teacher, who was walking through the classroom and answering the questions about the necessary vocabulary and phrases. Creative thinking skills were measured by the Test for Creative Thinking/Drawing Development (TCT-DP) by Urban and Jellen (1996), which seemed to be an appropriate measurement tool for 11–12 years old students because it can be solved in a wide variety of drawing styles, and title and text can be added for explanation. The measurement took 15 minutes and most of the students enjoyed drawing very much. Assessment was performed by two experts. The evaluation of the test measuring creative writing skills in GLC was carried out by the same person with professional experience in German language teaching. The evaluation of the TCT−DP tests was carried out by an art teacher. Neither the language teacher nor the art educator is members of the school staff. In the post-test, we used the equivalent versions of the tests and added some questions about the student’s experiences of taking part in the study. For quantitative data analysis, the SPSS statistical software (Version 25) was used. Paired sample t-test and independent sample t-test were used for analysing quantitative variables. Correlation between the variables (creative writing, TCT-DP test results and language background data) was measured by Pearson correlation coefficient. Listwise deletion (complete-case analysis) technique was used to handling missing data.\n\n\nResults\n\nDue to absences on the testing days, the complete data set after post-testing had a total of N≥65 students. Based on results of the adapted SSMMQ (Józsa, 2014), there was no significant difference between the motivation of the experimental and the control group. To compare performances across the two measures (creative writing in German and creative thinking), students’ raw score on each test was converted to a percentage score (Szabó-Szettele, 2023). There was no significant difference in the creative writing performance between the pre- and post-test of the experimental group. The performance of the experimental group did not decrease significantly, unlike the control group. The TCT-DP test showed no significant difference between the two groups. Results are summarised in Tables 3 and 4.\n\nThere are several difficulties in the measurement of creativity which will not be discussed in this paper, but it can be said that results strengthen the opinion that creative thinking skills are potential-like, which means they are relatively constant, and their educational development is time-consuming. It can be concluded that the three month time interval of the experiment was short to enhance creative thinking skills, because assessment results do not reflect any changes in the field. Based on pre- and post-test results, the pilot study shows that there is significant correlation between creative writing and creative thinking skills measured by Pearson correlation coefficient. Correlation is significant at the 0.01 level, which are summarised in Table 5. Language background data was analysed with data about the language knowledge and skills of students’ parents. Pearson product-moment correlation coefficient shows that there is average correlation between the number of years spent on learning the language and the language proficiency level of students’ parents (r = 0.462, p = 0.000). Although some of the students started to learn German as a second language earlier, there was no correlation between the years they spent on learning the language and their FL performance.\n\n\nConclusion\n\nUsing creative writing tasks is not typical in foreign language education, and the participants of the study were not familiar with creative writing, which is not promoted by the FL school book they used. Although several benefits of the teaching and learning method are explained in this study, it is not easy to motivate neither the students, nor the teacher to do creative writing tasks. The correction of such open-ended tasks requires considerable effort, and an open-ended task is considered more complex and thus more difficult. However, students appeared to be interested the first time the author met them and became excited as they saw the tasks with visual stimuli.\n\nThe main focus of this study was developing a creative writing test in GFL, which was carried out successfully. According to our results which show significant correlation (r=0.34 in pre-test, r=0.36 in post-test) measured by Pearson correlation coefficient, the instrument proved to be suitable for measuring creative thinking skills through writing tasks in foreign language education. The creative writing test was developed along of components of creative thinking and some creative writing qualities and also included visual stimuli. The main aspects of the tasks referred to fluency (collecting ideas), flexibility (adding new different elements) and originality (contextualisation, using causality, creating a story with exciting elements and specific narrative). For the adequate evaluation analytical rubrics were used developed specifically for the test described in this study.\n\nTo summarise, our test contributes to the enhancement of creativity through language learning with may concrete recommendations and a valid and reliable assessment instrument which can give teachers feedback on creative language use development and enrich their evaluation practice.\n\nSwitching to online teaching because of COVID-19 situation during the implementation time, was a strong limitation that made the intervention less effective. The author created virtual groups for each class and had contact with the students with the support of the German teacher. Although sending materials regularly, students showed less motivation, and some did not do the tasks appropriately or not at all. Through face-to-face instruction, teaching presence, students became more motivated to complete the tasks.",
"appendix": "Data availability\n\nFigshare: Creative thinking and writing project in FLL. https://doi.org/10.6084/m9.figshare.23553666 (Szabó-Szettele, 2023).\n\nThe project contains the following underlying data:\n\n‐ Dataset_Creative thinking and writing project_2021.xlsx (Students’ raw score, participants’ language background and language proficiency of the parents.)\n\nFigshare: Creative thinking and writing project in FLL. https://doi.org/10.6084/m9.figshare.23553666 (Szabó-Szettele, 2023).\n\nThis project contains the following extended data:\n\n‐ Language Proficiency Test for Creative Writing Skills_by Katinka Szabó-Szettele.pdf\n\n‐ SSMMQ_Hungarian_adapted by Katinka Szabó-Szettele.pdf\n\n‐ SSMMQ_English_adapted by Katinka Szabó-Szettele.pdf\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgments\n\nThe first author would like to acknowledge the support of the school management and thank members of the school staff who participated in the pilot experiment.\n\n\nReferences\n\nAleinikov AG: On Creative Pedagogy. 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}
|
[
{
"id": "214209",
"date": "08 Nov 2023",
"name": "Ida Dringó-Horváth",
"expertise": [
"Reviewer Expertise Language methodology",
"German language and literature",
"digital competences",
"GFL methodic-didactig"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article offers a thorough analysis of the literature on the subject of creative writing in foreign language acquisition and is presented in an understandable manner. It addresses current status of research in this field and identifies relevant studies. The goals of the study, which are mainly to develop and validate a creative writing exam for use in foreign language classrooms, are well-suited for the study's design. The study's scholarly value is demonstrated by its examination of a little-studied topic in foreign language instruction. One issue is that the study's efficacy might have been impacted by the switch to online instruction brought on by COVID-19.\nA follow-up study is therefore necessary, and as creative writing and creative thinking have been found to be strongly correlated, future research may build on this finding and focus in particular on monitoring the development of creative writing.\nEnough information is provided in the text regarding the study's methodology, including how the creative writing exam was created and how the intervention procedure worked. Using and building upon already developed, validated tests (the TCT-DP test and Urban and Jellen, 1996) is a key strength of the study. To encourage replication by others, there is need for improvement in the detailed description of certain study components, such as the assessment rubric.\nHowever the article doesn't go into great detail regarding the precise statistical techniques applied or the outcomes of these studies. The quality of the work would be improved by greater transparency in the statistical analysis and interpretation.\nThe research may provide very useful practical direction for those who wish to incorporate creative writing into their language teaching practice. One of the work's best features in this regard is that it provides adequate evaluation tools—analytical rubrics—for evaluating students' creative writing.\nDespite this, the experimental group's creative writing performance did not significantly change between the pre- and post-test findings. A more thorough statistical analysis and a more in-depth examination of the limitations and implications of the results, however, could reinforce the conclusions. Furthermore, there is a lack of clarity in the text regarding how the results relate to the original study questions and literature review.\nThe discussion of the findings' implications might be expanded upon by asking how the findings can be used to improve teacher training programs, curriculum development, or foreign language instruction. What are the practical implications for teachers?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "233380",
"date": "24 Jan 2024",
"name": "Suzanne Graham",
"expertise": [
"Reviewer Expertise second language education"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an interesting study in an underexplored area. It is generally clearly written.\nI would like to have seen a clearer outlining of what creativity is and how it relates to language learning and why.\nThere is not much detail on the analysis procedures and the statistical tests are rather simple. Would it not have been better to use repeated measures ANOVA? Also, are there not other variables, specifically English language ability, that should have been included as a covariate? p values should be written without leading zeros.\nNevertheless, it is good to see a study exploring this issue. The study needs to be followed up with a larger sample and over a longer period.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1307
|
https://f1000research.com/articles/12-1304/v1
|
11 Oct 23
|
{
"type": "Software Tool Article",
"title": "CIViCutils: Matching and downstream processing of clinical annotations from CIViC",
"authors": [
"María L. Rosano-Gonzalez",
"Vipin T. Sreedharan",
"Antoine Hanns",
"Daniel J. Stekhoven",
"Franziska Singer",
"María L. Rosano-Gonzalez",
"Vipin T. Sreedharan",
"Antoine Hanns",
"Daniel J. Stekhoven"
],
"abstract": "Background: With the advent of next-generation sequencing, profiling the genetic landscape of tumors entered clinical diagnostics, bringing the resolution of precision oncology to unprecedented levels. However, the wealth of information generated in a sequencing experiment can be difficult to manage, especially if hundreds of mutations need to be interpreted in a clinical context. Dedicated methods and databases are required that assist in interpreting the importance of a mutation for disease progression, prognosis, and with respect to therapy. Here, the CIViC knowledgebase is a valuable curated resource, however, utilizing CIViC in an efficient way for querying a large number of mutations needs sophisticated downstream methods. Methods: To this end, we have developed CIViCutils, a Python package to query, annotate, prioritize, and summarize information from the CIViC database. Our package provides functionality for performing high-throughput searches in CIViC, automatically matching clinical evidence to input variants, evaluating the accuracy of the extracted variant matches, fully exploiting the available disease-specific information according to cancer types of interest, and in-silico predicting drug-target interactions tailored to individual patients. Results: CIViCutils allows the simultaneous query of hundreds of mutations and is able to harmonize input across different nomenclatures. Moreover, it supports gene expression data, single nucleotide mutations, as well as copy number alterations as input. We utilized CIViCutils in a study on the bladder cancer cohort from The Cancer Genome Atlas (TCGA-BLCA), where it helped to extract clinically relevant mutations for personalized therapy recommendation. Conclusions: CIViCutils is an easy-to-use Python package that can be integrated into workflows for profiling the genetic landscape of tumor samples. It streamlines interpreting large numbers of variants with retrieving and processing curated CIViC information.",
"keywords": [
"In-silico drug prediction",
"variant prioritization",
"clinical relevance",
"CIViC database",
"API query"
],
"content": "Introduction\n\nIn recent years, next-generation sequencing (NGS) has become one of the main technologies to profile the genetic landscape of tumors, offering unprecedented insights into disease mechanisms, personalized patient care and potential treatment options.1,2 One key aspect in precision oncology is the evaluation of actionable molecular alterations from cancer samples, in order to select promising targeted therapies and to predict the specific response (i.e., beneficial or adverse) of patients to a particular choice of treatment.2 However, the implementation of tailored strategies in routine cancer patient care still remains a challenging task. The wealth of data generated in standard NGS experiments, such as variant calling from whole exome sequencing (WES) or gene expression levels based on bulk RNA sequencing, needs to be interpreted in a meaningful way in order to guide clinical decision-making. Furthermore, clinical interpretation of the observed molecular profile requires an in-depth evaluation of the ever-growing biomedical literature, which is both a time-consuming and complex process that needs to be performed by experts.1,2 Altogether, a manual annotation of the oftentimes hundreds of readouts resulting from high-throughput technologies is challenging due to the amount of curation burden involved.\n\nTo overcome this bottleneck, sophisticated databases have evolved to aid the extraction of clinically relevant and actionable insights from the molecular composition of tumor samples, by enriching the identified aberrations with information such as prognosis or treatment relevance.1 Among those databases, a very popular and highly curated one is the CIViC knowledgebase, a powerful resource for the clinical interpretation of variants in precision oncology.3 This database contains expert-reviewed information about the clinical actionability of cancer genes and their molecular alterations, linking them to disease-specific knowledge about their potential therapeutic, prognostic, predisposing and diagnostic value. CIViC also provides a public application programming interface (API), which allows users to programmatically access and retrieve data from the knowledgebase.3 Nevertheless, sophisticated query tools are still required, on the one hand to enable the efficient simultaneous query of hundreds of variants, which is necessary for analyzing multiple patients in parallel. On the other hand, downstream annotation, prioritization, and summary of CIViC records is still necessary to streamline clinical interpretation. Recently, a Python package called CIViCpy has become available that offers a solution for the first issue of large-scale retrieval and inspection of CIViC records.4 This tool ensures the success of high-throughput queries by leveraging an offline version of the online content that is hosted in the knowledgebase, and it also provides valuable functionality such as coordinate search methods for the precached variants.\n\nDespite these advancements, matching CIViC evidence to observed tumor aberrations in an automated fashion continues to be a challenge. The lookup strategies supported by CIViCpy impose limitations on the type of alterations and attributes that can be found. Moreover, the queries are exclusively coordinate-based, which can be too sensitive in case a particular amino acid change is under consideration; or it can be too restrictive, e.g. in case generally the variants affecting a particular gene are in the focus. For instance, users may wish to fetch evidence from gene expression records (which are coordinate-independent in the database), match variants on the basis of their effect in the downstream proteins rather than their genomic coordinates, or perform position-independent searches for copy number alterations in a gene. Moreover, taking full advantage of the different information available for clinical evidence in CIViC requires intricate prioritization, grouping and filtering of the extracted variant and drug information, which is not supported by CIViCpy. To this end, we implemented CIViCutils, an open-source Python package for rapid retrieval, matching and downstream processing of expert-curated evidence records from CIViC. CIViCutils can be easily incorporated into precision oncology workflows to provide variant-level disease-specific information about treatment response, pathogenesis, diagnosis, and prognosis of genomic aberrations, as well as differentially expressed genes. Convenient features offered by our package include simplified position-independent variant retrieval, subsequent match quality evaluation and prioritization based on cancer types of interest, flexible record filtering, grouping of the extracted experimental findings, and standardized reporting of the final annotations. CIViCutils is intended to facilitate the analysis and interpretation of CIViC information, with particular focus on the context of in-silico drug candidate prediction, enabling custom support during the clinical decision-making process, and in turn contributing to faster analysis turn-around times.\n\nThe package has already been applied in previous studies and analysis workflows,5–7 one of which is the automated annotation of cancer aberrations using WES variant calling data derived from the muscle-invasive bladder cancer cohort of The Cancer Genome Atlas (TCGA-BLCA).8 We use this study to showcase the functionality and use cases of CIViCutils.\n\n\nMethods\n\nCIViCutils is an open-source Python package for extracting, selecting, filtering, prioritizing, grouping and reporting variant-specific clinical information from the expert-curated knowledgebase CIViC3 (see Figure 1). It is primarily intended to be used for supplying clinical annotations to variants and drug pairs. In the following, we provide a basic overview on design choices and output. For detailed information about specific modules, required input files, and source code of CIViCutils we refer to our GitHub repository (see Software availability).\n\nCIViCutils supports as input variant-calling data (SNVs, InDels, and CNVs) and expression data. Note that SNVs and InDels can be processed simultaneously and thus are regarded as a single category “SNV”. After the query of the CIViC knowledgebase, CIViCutils performs variant-specific matching of the provided variants to clinical evidence extracted from the database. A tier-based rating system is used for evaluating the quality of the resulting matches. In addition, the package offers functionality for annotating, aggregating, and filtering the retrieved evidences. Given one or more cancer indications that are of interest to the user, CIViCutils can further annotate data matched from CIViC with labels describing the disease specificity of the evidence. Drug prediction evidences can be aggregated (together with the cancer specificity information) into consensus drug responses. Abbreviations: SNV, single nucleotide variant; InDel, insertion-deletion mutation; CNV, copy number variant; CIViC, Clinical Interpretations for Variants in Cancer.\n\nInput files and CIViC query\n\nThe input for CIViCutils is a list of the genes and their molecular alterations that should be queried in CIViC. The package can handle four different types of information: genomic-based data in the form of single nucleotide variants (SNVs), short insertions and deletions (InDels), and copy number variants (CNVs), as well as gene expression data from differential expression analyses. In the context of CIViCutils, SNVs and InDels are handled together and thus considered as a single category “SNV” (Figure 1). The minimum information required for a CIViCutils query are the gene names, where the specific format and content of the input file depends on the data type at hand and is described in the GitHub repository (see Software availability).\n\nCIViCutils depends on the Python package CIViCpy4 for performing large-volume queries to CIViC, as it leverages its offline access to the knowledgebase to ease the retrieval of the often hundreds of variant records returned from high-throughput queries in standard high-throughput experiments. The query supports three different types of gene identifiers (Entrez symbols, Entrez IDs and internal CIViC IDs), and alternative gene symbols such as aliases or synonyms are also permitted during the search.\n\nTier-based matching of variants\n\nOne core functionality of CIViCutils is its matching framework, which associates specific variants retrieved from CIViC with the input aberrations provided by the user (Figure 1). This step is needed because oftentimes variants from different sources follow different nomenclatures, and in the particular case of CIViC records, they often deviate from the recommended and widely used guidelines by the Human Genome Variation Society (HGVS), and many entries do not even have HGVS expressions available. For this reason, we generate a standardized format for both the CIViC records and the input alterations, dependent on the type of variant being queried in each situation, and making use of HGVS guidelines whenever possible. As for CNVs and differential gene expression data which, to date, do not have any HGVS nomenclature available in CIViC, the matching is exclusively based on a reduced set of expressions known to be commonly used to designate this kind of molecular aberrations. Whenever additional information about the exon location and/or predicted variant impacts of the input SNVs and InDels has been supplied to CIViCutils, these annotations will also be leveraged by our package during the matching of variants. The quality of the resulting variant-specific matches between input and CIViC is assessed through a tier-based rating system (see Table 1). Note that, as a result of the matching framework, more than one CIViC record could potentially qualify and be assigned to the same queried variant.\n\nMatches at the variant level are evaluated through a system of five tier categories, as described below. Categories are listed in descending hierarchical order, i.e. tier 1 matches are prioritized by the package over tier 3 ones. Note that tier 1b is only supported for SNVs/InDels, while tier 2 is not available for differential gene expression data. Abbr.: logFC, log fold-change; SNV, single nucleotide variant; InDel, insertion-deletion mutation; CNV, copy number variant; CIViC, Clinical Interpretations for Variants in Cancer.\n\nAnnotating disease specificity\n\nWhile the variant-specific clinical data returned by CIViCutils can often be considerable in size, as well as very diverse with regard to associated disease information, users frequently rather focus on a particular cancer type or even subtype of relevance during the annotation of their variants. To this end, CIViCutils allows for categorization and prioritization of CIViC data based on the specificity of their cancer indication compared to one or more indications of interest. Relevant keywords can be specified by the user and are used to match disease names of particular significance and simultaneously exclude undesired indications from the CIViC results. In addition, high-level disease names that occur in CIViC (e.g. cancer or solid tumor) can be specified and will serve as a “second-best” alternative during the classification whenever relevant terms are not found. CIViCutils reports records in three categories in descending hierarchical order: cancer type specific (“ct”), when the disease name matches relevant keywords, general cancer type specificity (“gt”), when the conditions for category “ct” are not fulfilled and the disease name matches unspecific high-level terms, and non-specific cancer type (“nct”), when none of the previous conditions are fulfilled.\n\nFiltering clinical data\n\nCIViCutils offers functionality for flexible record filtering at several levels of its annotation workflow (see Figure 1), allowing the possibility to clean-up and to prioritize data. For many purposes it is recommended to filter data retrieved from the CIViC query, e.g. to exclude records that have not yet been expert-reviewed, or to retrieve variants of a specific type such as somatic or germline. Furthermore, it is possible to prioritize and filter variants based on the tiers resulting from the matching framework of CIViCutils (e.g. to select clinical data from the best tier match available, or ignore input aberrations that could not be found in CIViC), as well as based on their annotated cancer type specificity (e.g. to retrieve evidences from the best classification found, or to focus exclusively on records associated with a particular disease of interest).\n\nConsensus drug response predictions\n\nCIViCutils provides a module for further processing and aggregating the predictive evidence annotated from CIViC into so-called “consensus drug responses”. Predictive data correspond to drug-variant interactions that can be used for in-silico prediction of the therapeutic response on the basis of actionable molecular targets. While CIViC contains a substantial number of these records, they can often be complex to interpret and quite diverse concerning content. For instance, even for the same aberration, a multitude of claims might exist across an extensive range of cancers, in turn involving various drug names and different clinical interpretations depending on the given indication. At the same time, the underlying evidence might greatly vary in terms of quantity and quality.\n\nCIViCutils eases the interpretation of this multitude of records by combining them into a single and unanimous response prediction per aberration, and taking into account drug name and cancer type specificity. Clinical data is characterized in the knowledgebase by a combination of evidence direction and clinical significance terms. CIViCutils further interprets these records into a reduced set of expressions relative to the direct therapeutic prediction (“POSITIVE”, “NEGATIVE” or “UNKNOWN”).\n\nIn order to provide the consensus drug response prediction, first the CIViC information is standardized across records, followed by a majority vote of the available evidence (taking into account disease specificity). The consensus reported by CIViCutils is the drug response prediction with the highest number of occurrences across all records available for the therapy, cancer type specificity, and molecular alteration at hand, resulting in one of the following categories: “SUPPORT” (overall the evidence is considered “POSITIVE”), “RESISTANCE” (majority is “NEGATIVE”), “CONFLICT” (unresolved cases with contradicting information) and “UNKNOWN” (prevailing category is “UNKNOWN”, i.e. the predictive value is not known).\n\nOutput file\n\nCIViCutils reports the annotated CIViC information into a new file, using the same layout as the input file of molecular alterations originally provided to the package. New columns are appended that summarize clinically relevant data from the knowledgebase, using an identical human- and machine-readable format regardless of the type of variants at hand.\n\nFor each variant provided to CIViCutils, information about the corresponding records extracted from CIViC is always reported with a single tier classification, rating the accuracy and overall quality of the match. Additional columns contain different aspects of the variant records, including their CIViC Actionability Scores, variant type classifications, and all associated clinical statements on disease diagnosis, prognosis, predisposition and predictive therapeutic response. Individual records are described by their specific combination of cancer indication, evidence direction, clinical significance and evidence level, as well as the publication reviewed by curators to endorse the claim. Publications are referenced using their citation identifiers, namely, PubMed sources and abstracts from the American Society of Clinical Oncology.\n\nIn addition, CIViCutils can aggregate clinical data of the same evidence type and from the same variant match to ease readability. In the first layer of aggregation, records assigned to the same evidence level are reported together under a single statement that lists the different supporting publications. In turn, claims describing the same type of clinical action (i.e. identical combination of direction and clinical significance) are also clustered, followed by the aggregation of evidence associated with identical disease names. Optionally, additional details about the CIViC records can be displayed, such as status in the database or confidence rating, as well as CIViCutils’ disease term information or consensus drug reports.\n\nCIViCutils can be run on a Linux-based or MacOS system and requires Python 3.7, as well as an installation of CIViCpy (instructions are provided on the GitHub repository). Querying a total of 34,039 SNVs/InDels and CNVs called on the whole-exome sequencing data from the TCGA-BLCA cohort required a total of 100 MB memory and 56 minutes.\n\n\nUse cases\n\nIn the following we showcase different aspects of how CIViCutils facilitates the interpretation of molecular data. The examples are based on a previous study that analyzed somatic variants observed in the bladder cancer cohort (TCGA-BLCA) that is part of The Cancer Genome Atlas (TCGA).6,8 In this former study, CIViCutils was applied to a total of 34,039 SNVs/InDels and CNVs found across 412 bladder cancer patients, with the aim of identifying actionable aberrations and a set of the clinically most relevant genes and their corresponding therapies. CIViCutils was applied independently to the annotated variants observed in each tumor sample. The retrieved records were subsequently filtered e.g., in order to remove evidence not yet accepted in the knowledgebase, or data linked to germline variants. With CIViCutils input variants were matched to the available CIViC information on the basis of the best tier category. Next, the matched CIViC evidence was annotated with disease specificity information; “bladder” and “solid tumor” were provided as relevant and unspecific terms to the package, respectively. Based on this information, CIViCutils could further filter the annotated CIViC evidence to only select information from the highest cancer specificity found for every variant and evidence type. Subsequently, all remaining drug prediction data available for the matched variants were processed into consensus drug response predictions. As a result, all records with evidence direction “DOES NOT SUPPORT” were translated into drug response category “UNKNOWN”. Manual curation performed in Krentel et al. proved this type of evidence to have an ambiguous meaning, dependant on the specific context of the underlying data, hence making it difficult to translate into a clearly defined consequence without the review of an expert. Following the same logic, records associated with blank or null (“N/A”) values in their evidence direction and/or clinical significance were also considered to be category “UNKNOWN”.\n\nThe set of 34,039 actionable variants initially supplied to CIViCutils consisted of 13,514 SNVs/InDels (hereafter jointly referred to as “SNVs”) and 20,525 CNVs. The number of input SNVs available per patient spanned from 0 to 574 throughout the cohort, with an overall mean of 33 SNVs, whereas the average number of CNVs was 50, ranging between 0 and 243. Of those, CIViCutils matched CIViC information for 21% and 74% of the actionable SNVs and CNVs, respectively (see Figure 2A). The remaining variants were associated with genes that are not contained in CIViC, and hence were assigned tier 4 by CIViCutils. We refer to the Extended data (section 1) for information on the per-sample number of variants that could be matched to CIViC.9 On average, each SNV could be associated with two different CIViC variant records, whereas for CNVs only one hit was reported per individual alteration. However, overall more CNVs than SNVs could be matched in CIViC. This is due to the fact that CNVs can affect multiple genes (on average 220 genes per CNV for the variants identified in the TCGA-BLCA cohort) in contrast to SNVs that are associated with only one gene. Consequently, the likelihood of a given CNV having CIViC information available for at least one gene is higher than that of a SNV. We refer to Extended data section 3 for an overview of the identified evidence types (“Predictive”, “Prognostic”, “Diagnostic”, Predisposing”) that are available in CIViC for the variants called in the bladder cancer cohort.9\n\n(A) Pie charts show the overall fractions of bladder cancer aberrations which were successfully matched by CIViCutils to clinical data from CIViC. (B) Pie charts illustrate the cohort-based fractions of tiers annotated by CIViCutils for the set of SNVs and CNVs successfully matched in CIViC across the 412 patients. Cancer aberrations found to have exact hits in CIViC are shown in red (tier 1), non-exact variants are represented in dark blue (tier 1b), while yellow and light blue portions illustrate positional (tier 2) and gene-only (tier 3) hits. Note that tier 1b is not available for CNVs. Abbr.: SNV, single nucleotide variant; CNV, copy number variant; CIViC, Clinical Interpretations for Variants in Cancer.\n\nThe matched records were further assigned their highest-ranking tier category (hierarchical order: tier 1 > tier 1b > tier 2 > tier 3) to assess the overall quality of the matches (see Figure 2B). Out of the 2,864 SNVs with clinical data detected across the cohort, 7% were classified as tier 1 (n=208), 46% as tier 1b (n=1,311), and 0.2% as tier 2 (n=5). From the set of 15,192 CNVs that have been successfully matched to CIViC records, 38.7% correspond to tier 1 (n=5,875), and 0.2% to tier 2 hits (n=37). On the other hand, the remaining set of tier 3 aberrations assigned by CIViCutils accounted for 47% (n=1,340) and 61% (n=9,280) of the SNV and CNV hits, respectively. Thus, in both variant types tier 3 represents the largest fraction of alterations. We refer to the Extended data (section 2) for a per-sample analysis of the tier assignment.9\n\nOverall, exact matches were observed more frequently in the CNV set than the SNV one (39% and 7%, respectively). This is likely due to the fact that CNVs are annotated with only a few simple categories (e.g., amplification or gain) that have a higher chance to be matched compared to the complex and diverse annotations available for SNVs. On the contrary, positional matches were rarely observed regardless of the genomic alteration being considered (0.2%), in the case of CNVs, probably due to limited availability of database records fulfilling this classification, while for SNVs, it is more likely that either exact or gene-only hits were found in the database. The conditions defined for tier 1b and tier 3 are much broader and typically easier to fulfill by any variant. Accordingly, many variants match as non-exact hits, e.g., tier 3 hits represent the large majority of the retrieved CIViC matches (61%). Interestingly, tier 1b classifications (non-perfect, but of a particular type or in concrete regions of the gene, e.g., located in specific exons or introns) constitute a large proportion of matches (47%). This type of records supported by CIViCutils would not have been matched with coordinate-based searches, but it is relatively common in the CIViC knowledgebase.\n\nCIViCutils enables the prioritization of variant matches according to disease specificity. Category ct (cancer type specific, in the TCGA-BLCA cohort analysis specified as “bladder cancer”) is the most specific match, whereas gt (general type, unspecific, in our example “solid tumor”) is the second-best match, and nct (non-cancer type specific) corresponds to cancer types differing from the cancer type of interest. Figure 3A illustrates the fraction of ct, gt, and nct matches per patient. As expected, the majority of records do not correspond to the cancer type of interest (as CIViC hosts information across many different cancer types, and only few of them match the ct term). This exemplifies the importance of an annotation of the disease specificity, as the categorization further helps to stratify the most relevant variants for each patient. We refer to the Extended data (section 4) for more information on the different disease types occurring in the nct category and more details on the observed ct and gt matches per sample.9\n\n(A) Boxplots show the patient-based distributions of cancer type specificity labels (ct, gt, nct) reported by CIViCutils per type of genomic alteration, before and after removing tier 3 variants. Each data point (only outliers illustrated) represents the percentage of occurrences of a given disease specificity observed in one bladder cancer sample. (B) Pie charts depict the distributions of disease specificities assigned by the package throughout the TCGA-BLCA cohort, evaluated separately for SNVs and CNVs, before and after tier 3 matches were excluded. The illustrated proportions were derived from the aggregation of sample-based disease counts for every specificity label across the cohort. Abbr.: SNV, single nucleotide variant; CNV, copy number variant.\n\nAdditionally, we analyzed the overall portion of cancer indications retrieved throughout the entire TCGA-BLCA cohort per type of disease specificity and molecular aberration. Figure 3B shows for each disease specificity category the fraction of associated matches, computed per patient and aggregated across the cohort. Thus, the underlying absolute values are per category the total number of occurrences in the cohort. The vast majority of cancers retrieved by CIViCutils were labeled as nct, both in the SNV (95.4%, n=5,521) and CNV (95%, n=11,311) datasets, contrary to the remaining two categories, which overall were seldom reported and showed equivalent percentages for both types of alterations. Roughly 4% of the SNV-based (n=211) and 3% of the CNV-based (n=332) indications were annotated as ct, followed by gt, accounting for 1% (n=53) and 2% (n=266) of the extracted disease names, respectively. Figure 3A and 3B also report the percentages after removing tier 3 variants, to investigate the effect of excluding non-exact matches from the set of variants. Excluding tier 3 records has little effect on the overall results, except that for SNVs no longer the gt category can be observed.\n\nCIViCutils generates consensus drug response predictions for variants matched to CIViC records with predictive evidence, taking into account disease specificity information. Figure 4A shows per sample the number of variants with at least one consensus prediction. On average, treatment response information was reported for 75% of the SNVs and 50% of the CNVs. The percentage of genomic alterations linked to treatment predictions increased when excluding non-exact (tier 3) matches, and is then comparable between SNVs and CNVs (on average 85% and 93%, respectively).\n\n(A) Boxplots illustrate the percentage of variants with drug response predictions across the cohort, before and after tier 3 matches were excluded. (B) Boxplots depict the fractions of unique therapies reported for every sample, classified by their sample-level drug response derived from all the consensus predictions available in each case (“ALL-SUPPORT”, “ALL-RESISTANCE”, “ALL-CONFLICT”, “ALL-UNKNOWN”, “MIXED”). Every data point (only outliers shown) represents the fraction of treatments observed in one patient in the respective response category. Abbr.: SNV, single nucleotide variant; CNV, copy number variant.\n\nFigure S5 (see Extended data, section 59) shows the mean number of response predictions available per variant. On average four entries were available per SNV and three entries per CNV. Per sample and treatment, different consensus prediction categories can be assigned: “ALL-SUPPORT”, “ALL-RESISTANCE”, “ALL-CONFLICT”, “ALL-UNKNOWN” and “MIXED”. In the first four categories, the treatment was consistently associated with the same drug-level prediction (e.g. “SUPPORT” for “ALL-SUPPORT”) across all the evidence records and variants observed in a sample. In the case of treatments classified as “MIXED”, different responses were reported for the same therapy and patient depending on the particular variant being evaluated. As shown in Figure 4B, the most prevalent responses assigned across TCGA-BLCA patients were “ALL-SUPPORT” (64%) and “ALL-RESISTANCE” (23%), which together accounted for over 87% of the therapies predicted on average per tumor. The high number of supporting evidence records goes in line with a known reporting bias for positive experiment results, including positive associations with treatment response.3,10 Importantly, divergent and non-informative response predictions were only rarely reported. Category “ALL-UNKNOWN” was on average annotated for only 6% and 8% of the SNV-based and CNV-based drugs, respectively, followed by “MIXED” therapies, where the mean fractions observed per patient were of 1% for the SNVs and 5% for the CNVs. Only 1% of the annotated therapies were assigned an “ALL-CONFLICT” prediction. These observations are similar when excluding non-exact (i.e., tier 3) variant matches. We refer to the Extended data (section 5) for details on the prediction types observed for individual variants.9\n\n\nConclusions\n\nTo allow comprehensive tumor profiling as a personalized strategy for supporting clinical decision-making in precision oncology short analysis turn-around times and simplified interpretation of the actionable molecular aberrations observed in cancer patients is required. In this context, well-curated knowledgebases such as CIViC, which link aberrations to their potential effect on prognosis and treatment response, are of high importance. Here, we introduced CIViCutils, a user-friendly and open-source Python package for the automated enrichment of tumor aberrations with CIViC information. Our package facilitates the extraction, analysis, and interpretation of expert-reviewed clinical data from the CIViC database. CIViCutils can be easily integrated into clinical workflows for comprehensive tumor profiling and it supports as input genomic aberrations (single nucleotide and insertion-deletion variants, and copy number alterations) as well as gene expression data. The package has been already employed in existing clinical analyses workflows, where it provided real-world clinical decision support.5–7 We foresee continuous package development for additional applications, such as extending the package to support queries from other variant-level clinical databases (e.g. OncoKB11 or ClinVar12).\n\nIn our use case example on analyzing actionable aberrations detected in 412 tumor samples from the TCGA-BLCA study, we show that CIViCutils could retrieve CIViC information for 21% and 74% of the actionable SNVs and CNVs, respectively. While for those records typically a wealth of clinically relevant information is available, this proportion also shows the current general limitation of relying on highly-curated knowledgebases: such high quality and expert curated information is typically not available for thousands of variants but only a subset. Nevertheless, the databases are constantly growing, leading to more frequent hits in the future. Moreover, having reliable information even for a fraction of hits greatly aids the interpretation and reduces the overall burden of prioritizing the clinically relevant results.\n\nWe highlight that using CIViCutils in the future to annotate the WES data from the TCGA-BLCA cohort would likely deliver different results than those described in our study, due to the ever-growing research literature and ongoing manual curation efforts in CIViC. Thus, the success of our package is heavily reliant on such resources becoming extended and more curated over time, with the ultimate goal of overcoming the current challenges of variant interpretation in cancer.",
"appendix": "Data availability\n\nThe original data of the TCGA-BLCA study that is utilized for the use case example in this manuscript is available upon request, details are provided at db GaP: https://dbgap.ncbi.nlm.nih.gov/aa/wga.cgi?page=login\n\nZenodo: Extended data for ‘CIViCutils: Matching and downstream processing of clinical annotations from CIViC’, ‘CIViCutils_Extended_Data’, https://doi.org/10.5281/zenodo.7990876. 9\n\nThis project contains the following extended data:\n\n- 2023-05-31_CIViCutils_extended_data.pdf (contains supplementary figures and results for the example use case).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0)\n\n\nAcknowledgements\n\nThe authors want to acknowledge Roland Seiler and Friedemann Krentel for feedback on relevant features of the CIViCutils package, as well as Matteo Carrara and Anne Bertolini for their support during the testing of parts of the package features.\n\n\nReferences\n\nMateo J, Steuten L, Aftimos P, et al.: Delivering precision oncology to patients with cancer. Nat. Med. 2022 Apr; 28(4): 658–665. Publisher Full Text\n\nBrown NA, Elenitoba-Johnson KSJ: Enabling Precision Oncology Through Precision Diagnostics. Annu. Rev. Pathol. 2020 Jan 24; 15(15): 97–121. Publisher Full Text\n\nGriffith M, Spies NC, Krysiak K, et al.: CIViC is a community knowledgebase for expert crowdsourcing the clinical interpretation of variants in cancer. Nat. Genet. 2017 Jan 31; 49(2): 170–174. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWagner AH, Kiwala S, Coffman AC, et al.: CIViCpy: A Python Software Development and Analysis Toolkit for the CIViC Knowledgebase. JCO Clin. Cancer Inform. 2020 Mar; 4: 245–253. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIrmisch A, Bonilla X, Chevrier S, et al.: The Tumor Profiler Study: integrated, multi-omic, functional tumor profiling for clinical decision support. Cancer Cell. 2021 Mar 8; 39(3): 288–293. PubMed Abstract | Publisher Full Text\n\nKrentel F, Singer F, Rosano-Gonzalez ML, et al.: A showcase study on personalized in silico drug response prediction based on the genetic landscape of muscle invasive bladder cancer. Sci. Rep. 2021 Mar 12; 11(1): 5849. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBertolini A, Prummer M, Tuncel MA, et al.: scAmpi-A versatile pipeline for single-cell RNA-seq analysis from basics to clinics. PLoS Comput. Biol. 2022 Jun; 18(6): e1010097. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRobertson AG, Kim J, Al-Ahmadie H, et al.: Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell. 2017 Oct 19; 171(3): 540–56.e25. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRosano-Gonzalez ML, Sreedharan VT, Hanns A, et al.: CIViCutils extended data. [Dataset]. Zenodo. 2023. Publisher Full Text\n\nFanelli D: Negative results are disappearing from most disciplines and countries. Scientometrics. 2012 Mar; 90(3): 891–904. Publisher Full Text\n\nChakravarty D, Gao J, Phillips SM, et al.: OncoKB: A Precision Oncology Knowledge Base. JCO Precis. Oncol. 2017 Jul; 2017: 1–16. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLandrum MJ, Lee JM, Benson M, et al.: ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018 Jan 4; 46(D1): D1062–D1067. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRosano-Gonzalez ML, Sreedharan VT, Hanns A, et al.: CIViCutils archived source code. Zenodo. [Software]. 2023. Publisher Full Text"
}
|
[
{
"id": "265158",
"date": "06 May 2024",
"name": "Kandarp Joshi",
"expertise": [
"Reviewer Expertise Bioinformatics",
"clinical genomics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nRosano-Gonzalez et al. report a data retrieval tool with added features on annotations that can aid in interpretation of variants. The tool is based on retrieval by CIViCpy and additional algorithm to prioritize variants and assemble information. The tool is described well and use case is explained in detail. There are few minor comments to the authors.\n\n1. Is the query for each feature (variant/CNV) done separately and if so how much time is required per query? Is there a limit on the number of queries that can be made to the server? These details will be helpful for the users. 2. In the use case, authors have reported number of subjects within different tiers. It would be helpful to know the application of the tool to individual samples by knowing the number of samples with just tier1, missing tier1, missing tier1&2 annotations. This will inform specificity and how tool behaves when applied to an individual sample.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": []
},
{
"id": "265160",
"date": "09 May 2024",
"name": "Sayed-Rzgar Hosseini",
"expertise": [
"Reviewer Expertise Precision Oncology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this well-organized and clearly written manuscript, Rosano-Gonzalez et al. have introduced CIViCutils, which is an open-source Python package facilitating the analysis and interpretation of CIViC information. This tool is intended to address the major limitations of the previously developed CIViCpy Python package, and the authors have showcased the functionality of CIViCutils using WES variant calling data derived from the muscle-invasive bladder cancer cohort of The Cancer Genome Atlas (TCGA-BLCA).\nI only have a minor comment for the authors. I am a bit concerned about the concept of “consensus drug responses” proposed in this study. I believe that building such a consensus is not in line with the overall goal of precision medicine as it neglects the heterogeneity of patient population within the same cancer type/subtype in terms of drug response. Can the authors propose alternative strategies to overcome the limitations of the “consensus drug responses”? It would be great, if the authors can discuss this important issue in detail at least in the conclusion section of the manuscript.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": []
},
{
"id": "225767",
"date": "20 May 2024",
"name": "Obi L. Griffith",
"expertise": [
"Reviewer Expertise Cancer genomics",
"bioinformatics",
"databases and variant interpretation",
"CIViC knowledgebase co-creator."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors present a new tool, CIViCutils, which supports flexible and comprehensive mapping of a range of variant types to records from the CIViC knowledgebase. The tools leverages the CIViCpy package, which itself accesses the CIViC API. This is a sensible approach because it will give access to the most current state of CIViC knowledge. Their tool is also implemented as a python package, with open source code in a github repository under a permissive license (GNU GPL3), which is a strength. This tools fills a real need. Because CIViC has a flexible data model supporting a broad range of variant types, matching the interpretations for these variants to those observed in patients is a technical challenge. This tool allows multiple levels of precise and fuzzy matching, filtering to exclude un-reviewed records, and summarizing, including one-to-many results which are all appropriate. I have a few major and several minor suggestions.\nMajor: The paper describes linking variants to therapeutic, prognostic, predisposing and diagnostic CIViC knowledge. More recently, CIViC has also added support for oncogenic and functional variant evidence. Does CIViCutils support these as well? If not this should at least be acknowledged in the paper (perhaps as an area of future development).\n\nI was very confused by the explanation of how consensus drug response prediction was calculated. It is stated that CIViCutils reports the drug response prediction with the highest number of occurrences across all records for the therapy, cancer type, and molecular alteration. Consensus is categorized as “SUPPORT” (overall the evidence is considered “POSITIVE”), “RESISTANCE” (majority is “NEGATIVE”), “CONFLICT” (unresolved cases with contradicting information) and “UNKNOWN” (prevailing category is “UNKNOWN”, i.e. the predictive value is not known). The above scheme is hard to understand. CIViC provides significance for therapeutic (\"predictive\") evidence primarily as sensitive or resistant (and less commonly adverse response, reduced sensitivity or N/A). Evidence either supports of does not support these clinical significances. I would think that the CIViCutils categories for drug response would be \"POSITIVE - most evidence supports sensitivity\", \"NEGATIVE - most evidence supports resistance\", etc. The text explaining these categories should be revisited.\n\nIn the TCGA-BLCA analysis, in several places it refers to \"actionable SNVs and CNVs\". This seems to refer to some smaller/specific subset of somatic variants reported from the TCGA-BLCA data. But, I could not find where this was explained/defined.\n\nIt was not clear what was the significance of results summarized in the last paragraph of results. Some patients would be expected to have both sensitive and resistant variants for different drugs. The more we learn about molecular features of drug response the more this will be true. There probably is a bias towards positive (sensitivity) associations. But, it would seem more interesting to summarize how often there were conflicting predictions within variant/gene or something than within the whole patient variant set.\n\nWhile the TCGA-BLCA use case is interesting and shows scalability of the tool and general features of its mapping ability, it would strengthen the paper to also include one or two individual patient use cases. This would seem to be one of the core use cases of the CIViCutils tool, rather than summarizing across cohorts.\n\nMinor:\np3. Rework this awkward phrasing \"e.g. in case generally the variants affecting a particular gene are in the focus.\"\n\nTable 1. Suggest to include the Gene in last column (Example matches from CIViC) to make explicit that gene-level variants are being matched to gene-specific variant interpretation in the knowledgebase.\n\nProvide specifics for how some of the fuzzy/categorical matches are being made. For example, in Table 1 there is an example of CTNNB1:p.Ser60Phe being matched to (CTNNB1) EXON 3 MUTATION. How is this being determined. Is this based on first matching the reference transcript of the source mutation against the representative reference transcript recorded in CIViC for this variant to ensure you are matching the same Exon 3?\nFigure 2 - rather than show total number of patients, the number alterations should be summarized since I think this is what the percentages in the pie charts are relative to.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": []
},
{
"id": "265165",
"date": "24 May 2024",
"name": "Marco Punta",
"expertise": [
"Reviewer Expertise Cancer Immunogenomics",
"Cancer Genomics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript “CIViCutils: Matching and downstream processing of clinical annotations from CIViC” by Rosano-Gonzalez et al. is generally well written and addresses an important topic in helping extracting relevant information from the Clinical Interpretation of Variants in Cancer (CIViC) knowledge base.\nCIViCutils is a user-friendly Python package created to navigate the CIViC database. CIViC database can be queried in several ways. The online platform is a convenient method for individual queries, but scalability issues arise when processing vast amounts of data. The API solution, on the other hand, allows users to access the data programmatically but its usage is not straightforward. This highlights the necessity for rigorous and documented \"scriptable\" procedures to retrieve and prioritize information reported in the CIViC database to make the most of the vast amount of information collected through the ongoing Civic collaborative effort.\nThe CIViCutils open-source package is well-documented, easy to install, and its functions can be integrated into bigger pipelines and workflows, to streamline tumor sample characterization.\n\nDespite not being the first Python package developed to query CIViC data, CivicUtils is an automated tool that takes advantage of CIViCpy, complementing its capabilities. It facilitates the access, readability, and interpretation of the plethora of information contained in the Civic valuable resource, allowing a higher level of flexibility in the query systems compared to the other available methods. This would hopefully broaden the range of users, fostering a deeper understanding of the tumor mutational landscape.\nMy main concern about the paper is that while this is a tool that is meant to facilitate the evaluation of actionable molecular alterations in cancer samples, the use case presented in the manuscript is a general overview of annotated hits retrieved by CIViCutils when querying it with a large set of bladder cancer somatic alterations. This is interesting, however, in my view it does not help understanding how relevant or even correct are the indications that CIViCutils may produce. In that respect it would be important, I believe, to show results for a few specific somatic alterations for which actionability is known and/or some for which there’s no consensus at to actionability. Although I understand this can be done only on a few selected examples, I think it would help readers getting a better understanding of what the method can deliver.\n\nMinor:\nPage 4. “input aberrations provided by the user” I would change it into “input alterations provided by the user”\nPage 5. Table 1. BRAF:p.Val600Glu is reported as a perfect match in CIViC simply as V600E? Shouldn’t it be BRAF:V600E. This is similar for all other entries in the Table. Shouldn’t a perfect match include gene along with aa position andu aa change?\nPage 6. It’s not entirely clear to me what the difference is between the “gt” and the “nct” categories. Is this for example “NSC lung cancer” vs simply “lung cancer”? Could you please provide an example?\nPage 6. I was a bit confused by the consensus classification of drug response predictions for individual somatic aberrations. CIViCutils assigns to every drug-variant interaction record a term (“POSITIVE”, “NEGATIVE”, “UNKNOWN”) but what is the exact meaning of these terms? When creating a consensus among different records for the same drug-variant interaction, CIViCutils assigns the term “RESISTANCE” to cases that have a majority of ”NEGATIVE” records. So, is the term “NEGATIVE” for individual records equivalent to “RESISTANCE” or, if not, what other description would end up into the “NEGATIVE” category? Also, is it really correct (or the most useful thing to do) to classify as “SUPPORT” a variant with respect to a specific drug when there is potentially conflicting evidence as to its role? From the manuscript: “SUPPORT (overall evidence is considered positive)”; this, following the definition of “RESISTANCE”, supposedly means “majority is POSITIVE”, implying that there could also be “NEGATIVE” records for this variant-drug pair. Please clarify.\nPage 8. You report two different percentages for tier1b annotations, 46% and 47%. Please check.\nPage 8. Figure 3B. I find it interesting that the percentage of “ct” is more or less the same when considering all tiers and when considering only tier1, 1b and 2. I would have expected to have a higher percentage of “ct” in tier 1, 1b and 2. Could you please comment on this?\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1304
|
https://f1000research.com/articles/12-1303/v1
|
11 Oct 23
|
{
"type": "Research Article",
"title": "Impact of pulmonary hypertension on outcomes of influenza pneumonia patients: A nationwide analysis",
"authors": [
"Akhil Jain",
"Maharshi Raval",
"Karnav Modi",
"Sunita Kumawat",
"Kunal Patel",
"Shrenil Kavathia",
"Sharvilkumar Kataria",
"Deeti Kataria",
"Monika Garg",
"Rupak Desai",
"Sourabha S. Dani",
"Akhil Jain",
"Karnav Modi",
"Sunita Kumawat",
"Kunal Patel",
"Shrenil Kavathia",
"Sharvilkumar Kataria",
"Deeti Kataria",
"Monika Garg",
"Rupak Desai",
"Sourabha S. Dani"
],
"abstract": "Background: Pulmonary hypertension can be a significant cause of morbidity and mortality for influenza pneumonia (IP) patients. We performed analysis from the multicentric National Inpatient Sample (NIS) datasets to study the influence of disorders of pulmonary hypertension on the outcomes in IP patients. Methods: We used NIS 2016–2019 to identify IP hospitalizations (between 22–90 years of age) and divided them into with and without pulmonary hypertension (herein PHDPC). We analyzed for differences in demographics, primary (all-cause mortality) and other secondary outcomes. Results: Of 353,460 IP hospitalizations, 6.5% had PHDPC. The PHDPC cohort had more elderly, females, African Americans, and Medicare enrollees predominantly with more hospitalizations to large bed sizes and urban teaching hospitals, and higher cardiovascular comorbidities than non-PHDPC cohort. PHDPC had higher primary outcomes for in-hospital mortality (8.9% vs. 5.8%, adjusted OR 1.4, 95% CI: 1.21–1.61). PHDPC also had higher secondary outcomes for sepsis, septic shock, cardiogenic shock and need for mechanical ventilation, prolonged ventilation, hospital resource utilization for longer mean length of stay, mean hospitalization cost, transfer to other facilities or need for home health care, and high risk for 30-day readmission than the non-PHDPC cohort. Conclusions: With our study, we provide contemporary data for the outcomes of IP inpatients with pulmonary hypertension and depict worse outcomes for mortality, complications, and hospital resource utilization. Although our study does not include stratification for vaccination status for the outcome, primary care physicians, cardiologists, and pulmonologists should pro-actively educate patients on preventive strategies during the flu season.",
"keywords": [
"influenza",
"influenza pneumonia",
"pulmonary hypertension",
"national inpatient sample",
"outcomes",
"outcomes research"
],
"content": "Introduction\n\nDespite many significant medical advances, community-acquired pneumonia (CAP) significantly contributes to global morbidity and mortality.1 The influenza virus accounts for 15–20% of CAP cases,2 and severe influenza infections cause pneumonia in >50% of affected patients, leading to multiple organ dysfunction.3 Influenza pneumonia (IP) has mortality rates similar to that of patients with pneumonia caused by bacterial or other viral pathogens.4 Between September 2018 and February 2019, the Centers for Disease Control and Prevention in the United States reported a weekly mortality rate of 5.5% to 7.4% attributed to pneumonia and influenza infection, indicating the significant impact on the population and resources every season.5 IP patients frequently develop complications during hospitalization and can rapidly develop acute lung injuries requiring mechanical ventilation.6 Pulmonary heart disease and diseases of the pulmonary circulation (PHDPC) encompasses a wide range of conditions, including pulmonary embolism, various types of pulmonary hypertension, and diseases of pulmonary vessels.7 They can be a significant cause of morbidity and mortality for IP patients and the utilization of resources. However, in IP patients, there is a lack of data on the role of PHDPC on mortality and other outcomes, including the need for mechanical ventilation and infectious complications. Hence, we used the multicentric national inpatient sample database for those admitted for IP to compare all-cause in-hospital mortality, in-hospital complications, and resource utilization between patients with and without PHDPC.\n\n\nMethods\n\nWe utilized National Inpatient Sample (NIS) datasets from 2016 to 2019 for the United States to extract our study sample population and define cohorts. NIS is sponsored by the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Projects.8 Diagnoses and procedures are reported using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes, and International Classification of Diseases, Tenth Revision, Procedure Coding System (ICD-10-PCS) codes in the primary and secondary diagnosis fields. All datasets are publicly available and are de-identified; therefore, institutional review board approval was not obtained for our study.\n\nWe extracted influenza pneumonia (IP) hospitalizations using the ICD-10-CM codes (Extended data: Supplementary Table 19) in any disease diagnosis field. We used relevant ICD-10-CM codes in the secondary diagnosis fields to extract patients with PHDPC (Extended data: Supplementary Table 19). Next, we evaluated the IP hospitalizations for the 1st and 99th percentile distribution, which included hospitalizations for patients aged 22 to 90 years. Our two cohorts (Figure 1) comprised the study arm, which included patients with PHDPC, and a control arm with patients without underlying pulmonary heart disease and diseases of the pulmonary circulation (non-PHDPC).\n\nDemographic characteristics, including age and sex; hospital characteristics, including size and teaching status; and patient-specific characteristics, such as the median household income category in their zip code, the primary payer source, the type of admission, and the day of admission, were identified using the NIS variables. Elixhauser comorbidity software (v2021.1)10 generated comorbidities to compare the prevalence of comorbidities between the two cohorts (Extended data: Supplementary Table 29). These comorbidities were hypertension, diabetes mellitus, heart failure, valvular disease, peripheral vascular disease, cerebrovascular disease, paralysis, obesity, severe renal failure, chronic pulmonary disease, liver disease, hypothyroidism, other thyroid disorders, dementia, depression, acquired immune deficiency syndrome, autoimmune conditions, lymphoma, leukemia, cancer, alcohol abuse, and drug abuse. Besides these software-generated comorbidities, we included atrial fibrillation/flutter, dyslipidemia, prior myocardial infarction, prior percutaneous coronary intervention, prior coronary artery bypass graft, obstructive sleep apnea, tobacco use, cocaine, and cannabis use as the other comorbidity binary variables in our study by utilizing the corresponding ICD-10-CM codes in the secondary diagnosis fields (Extended data: Supplementary Table 29). Moreover, we used entropy balancing (EB) as the reweighting method to adjust for covariate imbalances between the two cohorts. Originally, Hainmueller et al.11 described EB as a generalization of the conventional propensity score method, directly estimating the unit weights from the balanced constraints and matching the two cohorts for mean, variance, and skewness.\n\nOur primary outcome was all-cause in-hospital mortality. Secondary outcomes included secondary pneumonia, sepsis, septic shock, cardiogenic shock, need for mechanical ventilation (MV), duration of the requirement of MV and complications related to MV, length of stay (LOS), cost of hospitalization, and disposition at discharge. The cost of hospitalization was generated after matching the variable “TOTCHG,” representing the edited total charges of hospitalization for the hospital services for March 2022 provided by the US Bureau of Labor Statistics as a consumer price index12 (Extended data: Supplementary Table 39). Moreover, after adjusting for covariate imbalances using EB, we performed multivariate logistic regression to obtain adjusted odds ratio (aOR) for categorical outcomes and poisson regression for incidence rate ratio (IRR) for continuous outcomes.\n\nStata (version 16) MP edition (StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC) was used for the statistical analyses. Survey data analysis was performed using Pearson’s chi-square test for categorical variables and Student’s t-test for continuous variables to measure the differences between the PHDPC and non-PHDPC cohorts. Next, we used univariate and multivariate analysis to calculate the odds ratio (OR) of primary and secondary outcomes in the PHDPC cohort. We used baseline demographics, patient- and hospital-specific admitting characteristics, and comorbidities in Table 1 as adjusting variables for multivariate regression analysis. Elixhauser comorbidity index and risk of 30-day all-cause readmission, generated via Elixhauser comorbidity software, were also compared between the two cohorts.13\n\n# Represents a quartile classification of the estimated median household income of residents within the patients’ zip code, https://www.hcup-us.ahrq.gov/db/vars/zipinc_qrtl/nrdnote.jsp.\n\n§ The bed size cutoff points divided into small, medium, and large have been done so that approximately one-third of the hospitals in a given region, location, and teaching status combination would fall within each bed size category. https://www.hcup-us.ahrq.gov/db/vars/hosp_bedsize/nrdnote.jsp.\n\n~ A hospital is considered to be a teaching hospital if it has an American Medical Association-approved residency program. https://www.hcup-us.ahrq.gov/db/vars/hosp_ur_teach/nrdnote.jsp.\n\n^ Comorbidities generated using Elixhauser comorbidity software (Supplementary Table 2).\n\n* Comorbidities generated separately using relevant ICD-10-CM diagnosis codes (Supplementary Table 2).\n\n1 Moore BJ, White S, Washington R, Coenen N, Elixhauser A. Identifying Increased Risk of Readmission and In-hospital Mortality Using Hospital Administrative Data: The AHRQ Elixhauser Comorbidity Index. Med Care. 2017 Jul;55(7):698-705.\n\n\nResults\n\nOf the 121,097,410 weighted discharges in the NIS datasets 2016–2019, 353,460 influenza pneumonia-related hospitalizations were found between 2016 and 2019 for ages 22 years to 90 years based on the 1st and 99th percentile age distribution of IP. Of these, 6.5% (n = 23,000) had PHDPC. Table 1 details the baseline characteristics between the two cohorts. The PHDPC cohort was older (mean age, 72.3 years vs. 67.5 years), had more females (59.0% vs. 52.2%) and patients of African American (AA) race (16.2% vs. 13.3%). Medicare was the primary expected payer in both cohorts, and Medicare enrollees were significantly higher in the PHDPC cohort (77.4.% vs. 65.4%). IP patients with PHDPC were more likely to be admitted to large bed-size hospitals (48.6% vs. 46.4%) and urban teaching hospitals (69.6% vs. 64.1%) than the non-PHDPC cohort. Amongst comorbidities, complicated hypertension, diabetes with chronic complications, heart failure, atrial fibrillation or flutter, valvular heart disease, peripheral vascular disease, dyslipidemia, obesity, obstructive sleep apnea, chronic pulmonary disease, renal failure, hypothyroidism, autoimmune conditions, non-metastatic solid tumors, and tobacco use was significantly more frequent within the PHDPC cohort.\n\nRates of outcomes and regression analysis (before and after matching by EB) are depicted in Table 2. The PHDPC cohort had a significantly higher rate of in-hospital mortality (8.9% vs. 5.8%; P <0.00, in-hospital complications that included sepsis (4.8% vs 3.9%, P = 0.004), septic shock (11.3% vs 8.8%, P <0.001), cardiogenic shock (1.9 vs 0.8%, P <0.001) and need for mechanical ventilation (18.6% vs 12.7%, P <0.001). Moreover, patients with PHDPC had a higher need of mechanical ventilation for 24 to 96 hours (7.6% vs 4.9%, P <0.001) and more than 96 hours (9.5% vs 6.6%, P <0.001). However, although the need for MV for less than 24 hours, secondary pneumonia, and complications of mechanical ventilation showed a higher trend in PHDPC, there were no statistically significant differences between the two cohorts. After matching by EB and multivariate regression analysis, the PHDPC cohort had higher adjusted odds of in-hospital mortality (aOR 1.4, 95% CI: 1.21–1.61; P <0.001), sepsis (aOR 1.3, 95% CI: 1.08–1.57), septic shock (aOR 1.3, 95% CI: 1.11–1.44), cardiogenic shock (aOR 1.7, 95% CI: 1.25–2.31), need for mechanical ventilation in overall (aOR 1.4, 95% CI: 1.27–1.58), need for mechanical ventilation for 24–96 hours (aOR 1.3, 95% CI: 1.14–1.56) and need for mechanical ventilation for more than 96 hours (aOR 1.4, 95% CI: 1.19–1.60). The PHDPC cohort had a higher comorbidity index for the risk of all-cause 30-day readmission (5.0 vs. 4.1, P <0.001) than the non-PHDPC cohort. In addition, the mean length of hospital stay was longer in the PHDPC cohort (8.7 days vs. 6.8 days, IRR 1.2, 95% CI: 1.12–1.20; P <0.001), with a higher associated mean cost of stay (113501.7 USD vs. 87530.4 USD, IRR 1.2, 95% CI: 1.13–1.25; P <0.001). In addition, statistically significant differences in hospital disposition were also appreciated, with PHDPC patients requiring frequent transfers to other facilities or needing home health care (54.5% vs. 40.8%, P <0.001).\n\n* NIS variable \"TOTCHG\" depicting total charges of hospitalization converted to total cost of hospitalization in accordance to Consumer Price Index Hospital Expenditure adjustments to March 2022 (Supplementary Table 3).\n\n** EB - Entropy Balancing used the variables of patient demographics, hospital-admitting characteristics, and comorbidities as mentioned in Table 1.\n\n^ OR-Odds Ratio;\n\n~ IRR-Incidence Rate Ratio; CI-Confidence Interval, LL-Lower Limit of CI, UL-Upper Limit of CI.\n\n\nDiscussion\n\nIn this multicentric retrospective cohort study of IP patients comparing patients with and without PHDPC, we derived the following significant findings, which were found to be significant both before and after matching by EB: 1) Patients with PHDPC had a 38% higher risk of in-hospital mortality as compared with non-PHDPC patients; 2) PHDPC was associated with a higher risk of in-hospital complications including sepsis, septic shock, cardiogenic shock, and need for mechanical ventilation for more than 24 hours compared with non-PHDPC; 3) the comorbidity index for the risk of all-cause 30-day readmission was higher in PHDPC than in non-PHDPC patients; 4) PHDPC was associated with higher resource utilization (longer LOS, higher cost of hospital stay, higher transfers to skilled nursing facilities or Intermediate Care Facilities, higher need of home health care) compared with non-PHDPC.\n\nInfluenza is most common in the young,14 the elderly, the pediatric population, and those with underlying medical conditions and they are most at risk for hospitalization and severe complications of pneumonia due to influenza.15 We included only adult hospitalized IP patients in our study and had a higher proportion of female and AA patients in the PHDPC cohort. AA patients and females are a relatively vulnerable population for venous thromboembolism16 and pulmonary embolism due to hypercoagulable conditions like pregnancy, hereditary factor V Leiden and hormone replacement therapy, and predominance of disorders like idiopathic pulmonary hypertension in females.17 Hence, consistent with the findings in our study, females, and AA make up a relatively higher proportion of the PHDPC cohort. The PHDPC cohort has a higher burden of comorbidities, a higher Elixhauser comorbidity index, and higher adjusted odds of several complications than the non-PHDPC cohort. As evident in our study and reported by previous studies, the risk of hospitalization, poorer outcomes, and death due to IP increases in the presence of other comorbidities.18,15,19 Hence, these comorbidities do predict poorer outcomes; still, even after adjusting the comorbidities and demographics on multivariate regression analysis, PHDPC was an independent predictor for worse outcomes.\n\nInfluenza pneumonia is a notorious disease with poorer outcomes in patients with comorbidities.15 We found significantly higher rates and odds of mortality in PHDPC patients compared to the ones who did not have PHDPC. Influenza infection has a detrimental effect on pulmonary circulation by causing pulmonary parenchymal inflammation and edema, interfering with alveolar gas exchange, resulting in ventilation/perfusion imbalance and hypoxemia. This hypoxia and carbon dioxide retention will cause the reflex spasm of pulmonary blood vessels and increase pulmonary circulation pressure.20 However, in patients with preexisting resistance to flow due to pulmonary hypertension21 or chronic thromboembolism,22 the pulmonary and systemic circulation is already compromised, and a superimposed influenza infection will burden the already compromised pulmonary circulation and increase RV overload. In addition, multiple studies reported that influenza infection is independently associated with increased atherosclerosis and acute cardiovascular events.23–25 Therefore, various mechanisms cumulatively result in higher mortality and complications associated with influenza pneumonia.\n\nInfection and pneumonia due to the influenza virus significantly interact with the immune system, and this can result in sepsis directly or indirectly secondary to a bacterial infection.26 Sepsis has been previously reported with influenza infection.27,28 A 2009 national study by Jain et al.29 reported a rate of 18% sepsis on admission in patients with influenza pneumonia. In our study, we report sepsis at a rate of 4.8% vs. 3.9% and septic shock at 11.3% vs. 8.8% among the two cohorts. The difference in rates can be due to multiple reasons, as sepsis is recorded according to clinical judgment and may not have adhered to strict definitions written in critical care guidelines30 and the coding errors with sepsis and septic shock. Sepsis is a broader term for life-threatening organ dysfunction caused by a dysregulated host response to infection.30 At the same time, septic shock is a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater mortality risk than with sepsis alone.30 We found that the PHDPC cohort has significantly higher odds of sepsis and septic shock (both before and after PS matching), which compromised pulmonary circulation can explain. In our study, the rate of septic shock reported is more than double the rate of sepsis, suggesting the significantly high degree of severity and influence of the virus on the immune system and inflammatory response of the body.\n\nIn addition, Influenza virus infection is highly associated with acute myocarditis and pericarditis.31 Persistent inflammation, as in the case of sepsis, causes depression in myocardial function and increases myocardial oxygen demand.32 The endotoxins and cytokines from infection and inflammation cause left ventricular dilatation and depressed ejection fraction, causing sepsis-induced cardiomyopathy.33 Furthermore, an increase in sympathetic nervous system activity, which is a primary response to inflammation, causes increased heart rate and vascular resistance; this causes a decrease in cardiac output and coronary perfusion of the heart.32 Together, these mechanisms lead to the development of cardiogenic shock in IP patients, although rare but previously reported.34,35 To the best of our knowledge, our study is the first to report the rate of cardiogenic shock in IP hospitalizations. We found a meager percentage of IP patients developing cardiogenic shock, 1.9% in PHDPC vs. 0.8% in non-PHDPC. We also found that those with PHDPC have significantly higher odds of developing cardiogenic shock, both before and after matching by EB.\n\nIP patients frequently require admission to the intensive care unit (ICU), and most need mechanical ventilation.36–38 Moreover, acute respiratory distress syndrome can develop in severe influenza infection, leading to developing or exacerbating pulmonary hypertension due to vessel obliteration, pulmonary vasoconstriction, and microthrombosis due to hypoxia, hypercapnia, and an imbalance in vasoactive mediators.39 In our study, the rate of mechanical ventilation was 18.6% vs. 12.7% in patients with and without PHDPC. Previous studies by Piroth et al.40 and Ludwig et al.37 have reported rates of 4% and 6%, respectively. However, our study’s higher rates of mechanical ventilation could be because the above studies have included the pediatric population. In contrast, our study has an adult population only and a higher comorbidity burden among them. In addition, we found significantly higher odds of need for mechanical ventilation for more than 24 hours in the PHDPC cohort. However, there was no significant difference in the need for mechanical ventilation for less than 24 hours between the two cohorts in our study, and this can be explained as IP admission in the ICU requires much longer mechanical ventilation for eight days with an additional two days needed for cleaning, maintenance, and other such functions for a total of 10 days.41\n\nOur study reported higher resource utilization with a higher risk of all-cause 30-day readmission, longer LOS, and higher cost of hospital stay and discharge or transfer to skilled facilities for patients with PHDPC. Given the burden of pneumonia in our population,42–44 our findings have important implications. Clinicians need to realize the importance of pre-existing PHDPC in patients with IP and exercise appropriate clinical alertness for their timely recognition of complications. Moreover, health officials need to increase efforts to optimize influenza vaccination rates among the elderly and those with chronic pulmonary conditions to reduce the incidence of pneumonia in these high-risk groups, ultimately reducing the healthcare facility burden. The prevention and optimal management of these patients may significantly reduce the burden of death associated with IP.\n\nOur study has several limitations, mainly from its retrospective observational nature and administrative database. First, NIS is an administrative database that introduces miscoding bias. Second, this was a retrospective study, thus susceptible to selection bias despite our large sample size. Third, even after adjusting for multiple variables in multivariate regression analysis, there is a possibility of residual confounding bias. Finally, we could not access the information about various types of PHDPC and its severity and types and severity of influenza, owing to limitations of the database. Despite these limitations, the study’s strength comes from its large sample size and multi-center cohort.\n\n\nConclusions\n\nIn a retrospective cohort study of IP patients from NIS, patients with PHDPC had a higher risk of in-hospital mortality and in-hospital complications, including sepsis, septic shock, cardiogenic shock, and need for mechanical ventilation for more than 24 hours compared with non-PHDPC patients. Moreover, PHDPC was associated with a higher comorbidity index for the risk of all-cause 30-day readmission and higher resource utilization than non-PHDPC. Although our study does not include stratification for vaccination status for the outcome, primary care physicians, cardiologists, and pulmonologists should pro-actively educate such patients on preventive strategies during the flu season.",
"appendix": "Data availability\n\nThe data used for this study was obtained from the National Inpatient Sample (NIS) datasets. It has data on over seven million hospital stays in the United States. The datasets from 2016–2019 used for this study are over 100 GB in size and are not feasible to provide. The datasets can be obtained from the Agency for Healthcare Research and Quality’s official website (https://hcup-us.ahrq.gov), and we have provided codes used to extract data of our study in supplementary tables.\n\nZenodo: Extended data for ‘Impact of pulmonary hypertension on outcomes of influenza pneumonia patients: A nationwide analysis’: Influenza PHDPC extended data, https://doi.org/10.5281/zenodo.8213283. 9\n\nThis project contains the following extended data:\n\n• Supplementary Table 1 – ICD-10-CM/PCS Codes used in our study\n\n• Supplementary Table 2 - Comorbidities\n\n• Supplementary Table 3 - Adjusting total cost of hospitalization\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0)\n\n\nReferences\n\nLanks CW, Musani AI, Hsia DW: Community-acquired Pneumonia and Hospital-acquired Pneumonia. Med. Clin. North Am. 2019; 103(3): 487–501. Publisher Full Text\n\nLozano R, Naghavi M, Foreman K, et al.: Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012; 380(9859): 2095–2128. PubMed Abstract | Publisher Full Text\n\nChen L, Han X, Bai L, et al.: Clinical characteristics and outcomes in adult patients hospitalized with influenza, respiratory syncytial virus and human metapneumovirus infections. Expert Rev. Anti-Infect. Ther. 2021; 19(6): 787–796. PubMed Abstract | Publisher Full Text\n\nvon Baum H , Schweiger B, Welte T, et al.: How deadly is seasonal influenza-associated pneumonia? The German Competence Network for Community-Acquired Pneumonia. Eur. Respir. J. 2011; 37(5): 1151–1157. PubMed Abstract | Publisher Full Text\n\nBlanton L, Dugan VG, Abd Elal AI, et al.: Update: Influenza Activity — United States, September 30, 2018–February 2, 2019. MMWR Morb. Mortal. Wkly Rep. 2019; 68(6): 125–134. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRothberg MB, Haessler SD: Complications of seasonal and pandemic influenza. Crit. Care Med. 2010; 38(4 Suppl): e91–e97. Publisher Full Text\n\n2022 ICD-10-CM Codes I26-I28: Pulmonary heart disease and diseases of pulmonary circulation. Accessed August 26, 2022. Reference Source\n\nHCUP-US NIS Overview: Accessed August 27, 2022. Reference Source\n\nModi K: Influenza PHDPC extended data. [Dataset]. Zenodo. Publisher Full Text\n\nElixhauser A, Steiner C, Harris DR, et al.: Comorbidity Measures for Use with Administrative Data. Med. Care. 1998; 36(1): 8–27. Publisher Full Text\n\nHainmueller J: Entropy Balancing for Causal Effects: A Multivariate Reweighting Method to Produce Balanced Samples in Observational Studies. Polit. Anal. 2012; 20(1): 25–46. Publisher Full Text\n\nU.S. Bureau of Labor Statistics: Accessed August 27, 2022. Reference Source\n\nMoore BJ, White S, Washington R, et al.: Identifying Increased Risk of Readmission and In-hospital Mortality Using Hospital Administrative Data: The AHRQ Elixhauser Comorbidity Index. Med. Care. 2017; 55(7): 698–705. Publisher Full Text\n\nJhung MA, Swerdlow D, Olsen SJ, et al.: Epidemiology of 2009 pandemic influenza A (H1N1) in the United States. Clin. Infect. Dis. 2011; 52 Suppl 1: S13–S26. Publisher Full Text\n\nCenters for Disease Control and Prevention (CDC): Intensive-care patients with severe novel influenza A (H1N1) virus infection - Michigan, June 2009. MMWR Morb. Mortal. Wkly Rep. 2009; 58(27): 749–752.\n\nWong P, Baglin T: Epidemiology, risk factors and sequelae of venous thromboembolism. Phlebology. 2012; 27: 2–11. Publisher Full Text\n\nTaichman DB, Mandel J: Epidemiology of Pulmonary Arterial Hypertension. Clin. Chest Med. 2013; 34(4): 619–637. Publisher Full Text\n\nMalacara-Villaseñor A, Ilaraza-Lomeli H, Tapia-Conyer R, et al.: Influenza and morbidity and mortality risk in patients in Mexico with systemic arterial hypertension alone or with comorbidities: a retrospective, observational, cross-sectional study from 2014 to 2020. BMJ Open. 2021; 11(12): e057225. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPlaczek HED, Madoff LC: Association of Age and Comorbidity on 2009 Influenza A Pandemic H1N1-Related Intensive Care Unit Stay in Massachusetts. Am. J. Public Health. 2014; 104(11): e118–e125. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHypoxic pulmonary hypertension; the load on the right ventricle: Introduction - PubMed. Accessed August 26, 2022. Reference Source\n\nMacIver DH, Adeniran I, MacIver IR, et al.: Physiological mechanisms of pulmonary hypertension. Am. Heart J. 2016; 180: 1–11. Publisher Full Text\n\nSimonneau G, Torbicki A, Dorfmüller P, et al.: The pathophysiology of chronic thromboembolic pulmonary hypertension. Eur. Respir. Rev. 2017; 26(143): 160112. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen L, Han X, Li Y, et al.: Complications of Cardiovascular Events in Patients Hospitalized with Influenza-Related Pneumonia. Infect Drug Resist. 2021; 14: 1363–1373. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNguyen JL, Yang W, Ito K, et al.: Seasonal Influenza Infections and Cardiovascular Disease Mortality. JAMA Cardiol. 2016; 1(3): 274–281. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWarren-Gash C, Smeeth L, Hayward AC: Influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: a systematic review. Lancet Infect. Dis. 2009; 9(10): 601–610. Publisher Full Text\n\nFlorescu DF, Kalil AC: The complex link between influenza and severe sepsis. Virulence. 2014; 5(1): 137–142. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIwane MK, Edwards KM, Szilagyi PG, et al.: Population-Based Surveillance for Hospitalizations Associated With Respiratory Syncytial Virus, Influenza Virus, and Parainfluenza Viruses Among Young Children. Pediatrics. 2004; 113(6): 1758–1764. Publisher Full Text\n\nThe Underrecognized Burden of Influenza in Young Children|NEJM. Accessed August 27, 2022. Reference Source\n\nJain S, Benoit SR, Skarbinski J, et al.: Influenza-Associated Pneumonia Among Hospitalized Patients With 2009 Pandemic Influenza A (H1N1) Virus--United States, 2009. Clin. Infect. Dis. 2012; 54(9): 1221–1229. PubMed Abstract | Publisher Full Text\n\nSinger M, Deutschman CS, Seymour CW, et al.: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8): 801–810. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDuan J, Wu Y, Liu C, et al.: Deleterious effects of viral pneumonia on cardiovascular system. Eur. Heart J. 2020; 41(19): 1833–1838. Publisher Full Text\n\nLi Y, Ge S, Peng Y, et al.: Inflammation and cardiac dysfunction during sepsis, muscular dystrophy, and myocarditis. Burns Trauma. 2013; 1(3): 109–121. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSato R, Nasu M: A review of sepsis-induced cardiomyopathy. J. Intensive Care. 2015; 3: 48. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHashmi AT, Yousuf MS, Waseem H, et al.: Cardiogenic Shock: A Rare Complication of Influenza. Cureus. 2018; 10(4): e2549. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTaremi M, Amoroso A, Nace HL, et al.: Influenza B-induced refractory cardiogenic shock: a case report. BMC Infect. Dis. 2013; 13: 452. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRello J, Rodríguez A, Ibañez P, et al.: Intensive care adult patients with severe respiratory failure caused by Influenza A (H1N1) v in Spain. Crit. Care. 2009; 13(5): R148. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLudwig M, Jacob J, Basedow F, et al.: Clinical outcomes and characteristics of patients hospitalized for Influenza or COVID-19 in Germany. Int. J. Infect. Dis. 2021; 103: 316–322. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTaylor G, Abdesselam K, Pelude L, et al.: Epidemiological features of influenza in Canadian adult intensive care unit patients. Epidemiol. Infect. 2016; 144(4): 741–750. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRevercomb L, Hanmandlu A, Wareing N, et al.: Mechanisms of Pulmonary Hypertension in Acute Respiratory Distress Syndrome (ARDS). Front. Mol. Biosci. 2021; 7. Accessed August 26, 2022. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPiroth L, Cottenet J, Mariet AS, et al.: Comparison of the characteristics, morbidity, and mortality of COVID-19 and seasonal influenza: a nationwide, population-based retrospective cohort study. Lancet Respir. Med. 2021; 9(3): 251–259. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMeltzer MI, Patel A, Ajao A, et al.: Estimates of the Demand for Mechanical Ventilation in the United States During an Influenza Pandemic. Clin. Infect. Dis. 2015; 60(Suppl 1): S52–S57. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRaut M, Schein J, Mody S, et al.: Estimating the economic impact of a half-day reduction in length of hospital stay among patients with community-acquired pneumonia in the US. Curr. Med. Res. Opin. 2009; 25(9): 2151–2157. PubMed Abstract | Publisher Full Text\n\nFerreira-Coimbra J, Sarda C, Rello J: Burden of Community-Acquired Pneumonia and Unmet Clinical Needs. Adv. Ther. 2020; 37(4): 1302–1318. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCardiac complications in patients with community-acquired pneumonia: incidence, timing, risk factors, and association with short-term mortality - PubMed. Accessed August 27, 2022. Reference Source"
}
|
[
{
"id": "260915",
"date": "22 May 2024",
"name": "Yi Yan",
"expertise": [],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article by Akhil Jain et al. aims to investigate the impact of pulmonary hypertension (PH) on outcomes of influenza pneumonia patients with a nationwide analysis. However, there are some issues needed to be addressed before further consideration.\nThe definition of PHDPC is confusing, as in the abstract it refers to the patients with PH, while PHDPC in the introduction section is defined as pulmonary heart disease and diseases of the pulmonary circulation, including pulmonary embolism (PE), various types of pulmonary hypertension, and diseases of pulmonary vessels. According to guideline, clinical classification of PH recognizes 5 groups that are categorized based on pathogenesis or comorbidity: group 1—pulmonary arterial hypertension (PAH); group 2—PH associated with left heart disease; group 3—PH associated with lung diseases or hypoxia; group 4—PH due to pulmonary artery obstructions (chronic thromboembolic pulmonary hypertension); and group 5—PH with unclear or multifactorial mechanisms. Apparently, acute PE is not considered as PH. It would be much better to select PH patients according to right heart catheterization or at least echocardiography. I was also wondering whether the drug information could be retrieved from the NIS. In terms of regression analysis for outcomes, age and gender were not included for analysis. According to the data, around 75% PHDPC cohort had hypertension and 46.6% PHDPC had atrial fibrillation/flutter, which is much higher than in PH patients. Therefore, I think PHDPC cohort in this study overrepresented PH population and the data would be biased even with large sample size and from multi-centers. Therefore I think it would be much better to rephrase the title of the manuscript.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
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https://f1000research.com/articles/12-1303
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https://f1000research.com/articles/12-1301/v1
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11 Oct 23
|
{
"type": "Case Report",
"title": "Case Report: Chorea an unusual presentation of a patient with clinically isolated syndrome (multiple sclerosis)",
"authors": [
"rasangi suraweera",
"S Uthayakumaran",
"Jegu Kamala",
"S Uthayakumaran",
"Jegu Kamala"
],
"abstract": "This is a case report of a 26 year old girl who presented with choreiform movements of the upper and lower limbs and generalised tonic clonic seizures who had an entity called clinically isolated syndrome of multiple sclerosis on investigation. The pooled incidence rate in 75 reporting countries was 2.1 per 100,000 persons/year, with 32 years of age being the mean age of diagnosis. But multiple sclerosis is a white matter disease and choreiform movements are due to involvement of the grey matter of the brain. There have only been a few case reports of patients with multiple sclerosis having choreoathetoid movements reported.",
"keywords": [
"Multiple sclerosis",
"clinically isolated syndrome",
"chorea",
"gray matter involvement"
],
"content": "Introduction\n\nMultiple Sclerosis is a chronic disabling immune mediated inflammatory disease that affects the brain and the spinal cord.1 Our patient presented with her first central nervous system demyelinating event which is known as clinically isolated syndrome which is a presentation that has features like multiple sclerosis but is isolated in time may or may not be isolated in space.4\n\n\nCase report\n\nOur patient was a 26-year-old university student studying arts in Jaffna who presented with choreiform movements of her upper and lower limbs of two months in duration. The movements affected her day-to-day activities and made her quite dependant on others. She had also developed two episodes of generalised tonic clonic seizures of 15 minutes duration one hour apart. There was no history of early morning headache or vomiting or upper and lower limb weakness. The patient had not developed any form of neurological weakness. There was a history of febrile illness and sore throat two weeks prior to the onset. During her illness she did not notice any joint pain or swelling or any rashes. There was no history of jaundice. She was not on any long term medications neither had she taken any medication both allopathic or ayruvedic recently. The patient did not use any recreational drugs, did not consume alcohol or use an ayruvedic medication. There was no history of psychiatric illness in her or her family. Patient was not on any oral contraceptives neither was she sexually active. There was no family history of neurological disease. There had been no antenatal or perinatal insult during her birth and her vaccination was up to date. She also developed a few episodes of generalised tonic clonic seizures lasting about 5 minutes each before and after admission.\n\nHer examination findings were, she was conscious rational with a Glasgow coma score of 15/15. Her general exam did not reveal any icterus or rash, no stigmata of infective endocarditis. The respiratory, abdominal, and cardiovascular system examination were normal. In her neurological exam. On examination of both her fundus no papilledema was noted or no optic atrophy seen in both eyes. Swallowing was intact, her tongue had fasciculations and a jack in the box appearance. Motor examination revealed normal power and tone however she had abnormal movements more in the distal limb than in the proximal limbs. In the cerebellar exam she was not able to perform the finger nose test, heel shin she had dysdiadochokinesia in the left hand and the right hand and also the heel shin test was positive. Romberg's was positive and tandem gait was unstable. Deep tendon reflexes were +2 and symmetrical in the arms, the ankles and at the knees. Her plantar reflexes on both legs were down going. Pin prick, light touch and proprioception were normal. Romberg's was positive and tandem gait was unstable.\n\nWe had a few differential diagnoses in mind while investigating her mostly along the lines of diseases causing chorea in a young females such as Vasculitis, Wilsons disease, Hungtintons, hyperthyroidism. Eye referral done no Kayser Flecher rings were noted which is one of the eye signs noted in Wilson’s disease and as show below serum ceruloplasmin was normal which ruled out Wilson’s disease.\n\nBLOOD INVESTIGATIONS\n\nFull blood count\n\nErythrocyte Sedimentation rate (ESR)=25mm\n\nRenal function Test\n\nLiver function test\n\nHIV 1 and 2 ELISA=negative,\n\nVDRL= non reactive,\n\nMycoplasma pneumonia antibody Ig G and IgM=insignificant titres\n\nAntinuclear antibody=negative,\n\nSerum ceruloplasmin level=313mg/dl\n\nTSH=1.4 mIU/L(0.4-4)\n\nAntistreptolysin O titre = <200U/L\n\nBlood picture Microcytic, hypochromic red pencil cell, few acanthocytes, no evidence of acanthocytosis mild neutrophilic leukocytosis could be due to an inflammatory process.\n\nEEG(electroencephalogram) = Asymmetrical focal changes and slow waves\n\nCSF (cerebrospinal fluid) report\n\nCSF full report= normal and CSF culture = no growth\n\nCSF = no oligocloncal bands\n\nCSF Cytomegalovirus PCR = negative\n\nCSF Herpes simplex virus 1 and 2 PCR =negative\n\nUltrasound abdomen= normal.\n\n2DEcho=Normal no vegetations no valvular lesions\n\nCT Brain: Multiple periventricular hypodensity? White matter disease\n\nVisual evoked potentials = Markedly delayed bilaterally assuming there is no refractory error. The findings indicate demyelinating pathology affecting the visual pathway\n\nThe CT brain gave us a clue to the diagnosis and MRI and visual evoked potentials confirmed the diagnosis. Patient was given a course of methylprednisolone of 1g daily for three days and then started on prednisolone which was tailed off. Sodium Valproate 200 mg TDS and levecitracetum500mg daily was added for her seizures (Figure 1).\n\nPeritrigonal centrum semiovale subcortical white matter signal intensity change. No contrast enhancement or diffusion restriction to suggest active lesions. Appearances are of white matter changes of Multiple Sclerosis.\n\n\nDiscussion\n\nMultiple Sclerosis is a disabling disease affecting the brain and the spinal cord.2 According to the National Multiple Sclerosis Society there are four subtype definitions Relapsing and remitting, secondary progressive, primary progressive and progressive relapsing other subtypes however have been identified. Clinically isolated syndrome is one such subtype.3 Clinical isolated syndrome refers to the first CNS demyelinating event that has features similar to Multiple sclerosis but is isolated in time may or may not be isolated in space.4\n\nThere are 5 different types of clinically isolated syndrome:\n\nType 1 which is clinically monofocal with atleast one asymptomatic lesion. Type 2 is clinically multifocal in nature with atleast one asymptomatic lesion. MRI lesion. Type 3 is clinically monofocal MRI may appear normal no asymptomatic MRI lesions. Type 4 clinically multifocal MRI may appear normal no asymptomatic MRI lesions Type 5 no clinical presentation to suggest demyelinating disease, but MRI is suggestive. The term clinically isolated syndrome ignores presentations that may be found only on laboratory data and paraclinical findings. Although a kind of exception to this is CIS type 5 where patients have nonspecific symptoms such as headache and dizziness but have MRI evidence of multifocal abnormalities of demyelination.5\n\nSome of the clinical presentations of CIS include optic neuritis, a brain stem and or cerebellar syndrome, a spinal cord syndrome, or occasionally cerebral hemispheric dysfunction. We should also probe about whether the patient had some neurological weakness in the past, any blurring of vision, L hermitte sign, numbness or neurological weakness lasting about more than 24 hours. Questions about infections, inflammatory disorders, metabolic, genetic disorders, vascular and autoimmune diseases should also be sought.6\n\nChorea is rather an unusual manifestation of multiple sclerosis because multiple sclerosis is thought to be a white matter disease however there is evidence to prove now that it can involve both the cortical and sub cortical gray matter and the latter has myelinated fibers which may explain the involvement of the striatum, pallidum, thalamus and brainstem in multiple sclerosis.10 Usually multiple sclerosis patients may present with a tremor but movement disorders are less frequently reported.8 Giada Giovanni et al have reported on a case of hemichorea in a 39 year old women who had MRI evidence of multiple sclerosis and the CSF was positive for oligoclonal bands.9 Our patient presented to us with choreiform movements and she was diagnosed of having clinically isolated syndrome because of the lack of previous episodes of neurological presentations. There was sufficient evidence in her MRI; the lesions were suggestive of multiple sclerosis and her visually evoked potential showed marked delaying bilaterally indicating demyelinating pathology. In our patient oligo clonal bands were negative and in a study done by Jaganndha R et al showed that absence of oligo clonal bands is associated with a better prognosis in multiple sclerosis.10\n\nUsually episodes of multiple sclerosis are mild and resolve without medication, severe visual loss, pain in optic neuritis, pronounced motor dysfunction, ataxia, vertigo in spinal or brainstem syndromes are some of the symptoms that indicate that treatment is needed. Corticosteriods are used when symptoms are functionally disabling as in our case. A combination of intravenous methylprednisolone and oral steroids have be noted to lower the risk of developing clinically definite multiple sclerosis in the following two years.7\n\nMultiple sclerosis can manifest in different ways and although it is predominantly a white matter disease it can affect the subcortical gray matter explaining the presentation of chorea in this young lady.\n\n\nConsent\n\nWritten informed consent for the publication of the case report and any associated images was sought from the patient prior to submission.",
"appendix": "Data availability\n\nNo data associated with this article.\n\n\nReferences\n\nBhattacharya A, Mishra R, Tiwari P: Multiple sclerosis: an overview. Asian Pac. J. Trop. Biomed. 2012; 2: S1954–S1962. Publisher Full Text\n\nConfavreux C, Vukusic S: Natural history of multiple sclerosis: a unifying concept. Brain. 2006; 129: 606–616. PubMed Abstract | Publisher Full Text\n\nLublin FD, Reingold SC, Cohen JA, et al.: Defining the clinical course of multiple sclerosis. Neurology. 2014; 83: 278–286. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNational Multiple Sclerosis Society: Clinically isolated syndrome (CIS). Accessed 2017 Dec 14. Reference Source\n\nMiller DH, Weinshenker BG, Filippi M, et al.: Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult. Scler. 2008; 14: 1157–1174. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMarcus JF, Waubant EL: Updates on Clinically Isolated Syndrome and Diagnostic Criteria for Multiple Sclerosis. The Neurohospitalist. 3(2): 65–80. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEfendi H: Clinically Isolated Syndromes: Clinical Characteristics, Differential Diagnosis, and Management. Arch Neuropsychiatr. 2015; 52(Supplement 1): 1–S11. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMehanna R, Jankovic J: Movement disorders in multiple sclerosis and other demyelinating diseases.2013 May 15; 328(1): 1–8.\n\nWalton C, King R, Rechtman L, et al.: Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS. Mult. Scler. J. 2020; 26(14): 1816–1821. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGhosh R, Roy D, Dubey S, et al.: Movement disorders in multiple sclerosis: an update. Tremor and Other Hyperkinetic Movements. 2022; 12: 14. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "223055",
"date": "18 Dec 2023",
"name": "Harsha Dissanayake",
"expertise": [
"Reviewer Expertise clinical medicine"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nPeer review\nCase Report: Chorea an unusual presentation of a patient with clinically isolated syndrome (multiple sclerosis)\nSuraweera and colleagues report a case of a young Sri Lankan female who was diagnosed with multiple sclerosis presenting with chorea and seizures. This case report is unique that both chorea as well as seizures are rather unusual presentations of multiple sclerosis (MS).\nAuthors provide a detailed temporal evolution of the patient’s symptoms. Examination covers most of the important aspects. Authors have considered most of the important differential diagnoses and have explained with appropriate illustrations how the diagnosis was established.\nMy questions to the authors and suggestions to improve the manuscript are as follows:\n\n1.Title\nI suggest authors considering including ‘seizures’ in the title. Chorea and seizures are both unusual presentations of MS and their co-occurrence makes this case very unique.\n\n2.Abstract\n‘The pooled incidence rate in 75 reporting countries was 2.1 per 100,000 persons/year, with 32 years of age being the mean age of diagnosis.’\nIs this the incidence of MS, or CIS, or MS presenting as chorea? This sentence is perhaps best mentioned in the Introduction than in the abstract.\n\n3.Introduction\nAdding a few sentences on the following will be worthwhile:\nIncidence of MS (global / regional / local if known) How common are chorea and seizures as presenting manifestation of MS Has co-occurrence of chore and seizures as the presenting manifestation of MS been described before?\n\n4.Case history\nLimb movements – were they unilateral or bilateral in onset? Were they symmetric or asymmetric in onset? Was face, neck, trunk affected? Was the onset sudden or more insidious? Seizures are uncommon in MS and if they occur, they tend to be focal than generalized. Did the patient have primary generalized seizures or were they focal onset with secondary generalization or is this not known with certainty? Did the patient have a history of rheumatic fever? Ayruvedic – please correct to Ayurvedic (or replace with complementary and alternative medicines) Eyes – did she have relative afferent pupillary defect (which I suspect as she had significantly impaired VEPs), and did she have nystagmus? What were the visual acuities? Please describe the abnormal limb movements noted on physical examination:\nUnilateral vs bilateral, if bilateral – symmetric vs asymmetric Constant vs episodic\n\nThe described cerebellar signs would have been difficult to elicit with choreiform movements. Are the authors convinced that she actually had cerebellar signs or could those have been choreiform movements? I note there was no radiological involvement of the cerebellum. What do authors mean by positive Rhomberg sign? This is a sign of impaired proprioception, either due to large fibre peripheral neuropathy or dorsal column disease (which might occur in MS). Rhomberg sign is negative in cerebellar disease. Again, I suspect if the interpretation was difficult due to choreiform movements. Given the young age and female sex of the patient, oestrogen therapy (for contraception), pregnancy, anti-phospholipid syndrome are the other key differentials to consider. Please mention how these were excluded. The patient had remarkable hypochromic microcytic anaemia. It will be important to note the underlying cause for anaemia. CSF full report – please mention what this included. I suspect cell counts and glucose were normal. What was CSF cultured for? Bacterial? Viral? Fungal? Please include the type of MRI image provided (contrast use, T1 weight etc.) Please included reference range for ceruloplasmin level What were the clinical and radiological (if known) responses to treatment?\n\n5.Discussion\nSuggest including a paragraph to highlight why this case is unique: co-occurrence of two rare presentations of MS Please include a brief discussion on seizures in MS Can the symptomatology be explained / correlated with radiological findings? In authors opinion, what are the limitations of the case report? Is it common to have MS with no oligoclonal bands in CSF? What is the implication of this case study to clinical practice?\n\n6.Other comments\nI suggest a careful reading of the paper as there were few incomplete sentences / sentence fragments which need to be corrected.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": [
{
"c_id": "10892",
"date": "17 Jan 2024",
"name": "rasangi suraweera",
"role": "Author Response",
"response": "The pooled incidence rate in 75 reporting countries was 2.1 per 100,000 persons/year, with 32 years of age being the mean age of diagnosis.’ This is the incidence of MS overall. Ceruloplasmin reference 200-500g/dl there has been a typo with regards to the reference. The incidence of chorea in MS is rare .The seizures in the patient were generalised tonic clonic not focal in onset and mentioned in the case report. No history of rheumatic fever and ASOT was not elevated. Patient was not on any oral contraceptives . Most of the residents of Jaffna have hypochromic microcytic anemia due to being vegetarian. CSF full report contains glucose,protein and presence of cells which was within normal and atraumatic tap. Oligoclonal band s are present only in a small subset of patients and have a better prognosis. I admit that her chorea might give a false positive rhomberg sign . Patient did respond to glatiramer acetate"
}
]
},
{
"id": "257538",
"date": "03 May 2024",
"name": "Keshinie Samarasekara",
"expertise": [
"Reviewer Expertise General Medicine",
"Acute Medicine"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have described a case of a young female presenting with chorea and generalised tonic clonic seizures, as an unusual presentation of multiple sclerosis. Both chorea and generalised tonic clonic seizures are extremely rare in multiple sclerosis(MS), with a prevalence of less than 1-2%. The oligoclonal bands are negative in this case, which happens only in 5-15% of multiple sclerosis cases. Therefore, the MRI findings are the crux of the matter here, as the diagnosis of multiple sclerosis stands solely upon that. It is also worth noting that the MRI findings in this case do not correlate with the clinical presentation of chorea, which is also unusual in MS. The description given in the report is inadequate to confidently exclude other possible differentials for subcortical white matter signal intensity change. The MRI findings need to be elaborated further to demonstrate that these lesions are indeed nothing but lesions of MS. The description of choreiform movements could be improved with further elaboration regarding onset, progression, laterality etc. The chronology of seizures is unclear to the reader, as at one point two seizures are mentioned and ‘few’ mentioned at another point. Again, further details regarding the seizures (onset, progression, presence/absence of aura etc.) would be informative. It might also be worthwhile mentioning the seizures in the title, as they appear to be a significant feature in the clinical presentation. In the examination findings the authors mention that the patient is ‘rational’. Although this term is commonly used by some clinicians, it would be more appropriate to mention a more objective measure, such as mini mental state examination, as a measure of cognitive function. The preferred term to ‘both fundus’ would be ‘fundi’. False positive cerebellar signs may occur due to the effects of the chorea, and this needs to be acknowledged. The phrase “dysdiadochokinesia in the left hand and the right hand” can be contracted to ‘dysdiadochokinesia in both hands’. I also note that the patient has low hemoglobin with raised platelets. Was a cause for this pursued? The authors have appropriately considered vasculitis as a differential diagnosis. What investigations were performed to explore this and what were the results? It would be interesting to know the course following treatment (ie. was there any improvement clinically / radiologically).\nFurthermore, this article would benefit from language editing.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1301
|
https://f1000research.com/articles/10-396/v1
|
18 May 21
|
{
"type": "Research Article",
"title": "Acute effects of cigarette smoke on Endothelial Nitric Oxide synthase, vascular cell adhesion molecule 1 and aortic intima media thickness",
"authors": [
"Meity Ardiana",
"Anwar Santoso",
"Hanestya Oky Hermawan",
"Ricardo Adrian Nugraha",
"Budi Susetyo Pikir",
"I. Gde Rurus Suryawan",
"Anwar Santoso",
"Hanestya Oky Hermawan",
"Ricardo Adrian Nugraha",
"Budi Susetyo Pikir",
"I. Gde Rurus Suryawan"
],
"abstract": "Background. Cigarette smoking could induce endothelial dysfunction and the increase of circulating markers of inflammation by activation of monocytes. This can lead to increased intima media thickness (IMT) of entire blood vessels and result in acceleration of the atherosclerosis process. However, to our knowledge, little is known about the role of cigarette smoking in this atherosclerotic inflammatory process. The aim of this study is to explore the link between cigarette smoking and its effect on endothelial nitric oxide synthase (e-NOS) and vascular cell adhesion molecule 1 (VCAM-1). Methods. An experimental study with a post-test only controlled group design was used. We used 18 Wistar rats (Rattus norvegicus) randomly subdivided into two groups: group K (-) were not exposed to tobacco smoke, whereas group K (+) were exposed to smoke equivalent of more than 40 cigarettes for 28 days daily. After 28 days, samples were analyzed for e-NOS, VCAM-1 and aortic IMT. Results. Our results indicate that tobacco smoke can enhance the expression of VCAM-1 on rat cardiac vascular endothelial cells, resulting in a decreased expression of e-NOS level and increase of aortic IMT. Linear regression model found that eNOS level negatively correlated wiith aortic IMT (r2 = 0.584, β = -0.764, p < 0.001), whereas VCAM-1 expression did not correlate with aortic IMT (r2 = 0.197, p = 0.065). Conclusion. Low e-NOS level and high VCAM-1 level observed after cigarette smoke exposure which may increase aortic IMT.",
"keywords": [
"aortic tissue",
"atherosclerosis",
"cigarette smoking",
"endothelial-NOS",
"intima media thickness",
"VCAM-1"
],
"content": "Abbreviations\n\nANOVA: analysis of variant\n\nELISA: enzyme-linked immunosorbent assay\n\ne-NOS: endothelial Nitric Oxide Synthase\n\nH2O2: Hydrogen peroxide\n\nIACUC: Institutional Animal Care and Use Committee\n\nIHC: Immunohistochemistry\n\nIMT: Intima–media thickness\n\nIRS: Immunoreactivity Scoring System\n\nLSAB: Labeled Streptavidin Avidin Biotin\n\nNIH: National Institutes of Health\n\nPCR: Polymerase Chain Reaction\n\nSA-HRP: Strepavidin-Hoseradish Peroxidase\n\nSD: standard deviation\n\nSEM: standard error of the mean\n\nSPSS: Statistical Package for the Social Sciences\n\nVCAM-1: Vascular Cell Adhesion Molecule-1\n\n\nIntroduction\n\nCigarette smoking is the most important modifiable risk factor for developing atherosclerosis including cerebrovascular accident, peripheral arterial disease, and coronary heart disease.1 In a meta-analysis from 55 eligible studies (43 cross-sectional, ten cohort and two case-control studies), the odds ratio (ORs) of peripheral arterial disease (PAD) associated with cigarette exposed was 2.71 (95% CI: 2.28-3.21; p < 0.001).2 In a meta-analysis from 75 cohorts (2.4 million participants) that adjusted for cardiovascular risk factors other than coronary heart disease, multiple-adjusted pooled ORs of smoking versus non-smoking was 1.25 (95% CI: 1.12–1.39, p < 0.0001).3\n\nEven though epidemiologic studies clearly stated the negative effect of cigarette smoke for cardiovascular diseases, the underlying mechanisms have yet to be confirmed. The pathogenesis and pathophysiologic mechanisms by which exposure to cigarette smoke could accelerate atherosclerosis cardiovascular disease are complex and challenging, due to more than 5,000 different mixtures of chemicals inside the cigarette smoke itself.4 Several potential contributing factors to atherogenesis inside cigarette smoke are (1) polycyclic aromatic hydrocarbons, (2) oxidizing agents, (3) particulate matter, and (4) nicotine.5\n\nOne of the most important factor contributing for pro-atherogenic is nicotine, which has commonly been studied using cigarette smoke condensates.6 In addition to its role as the habituating agent in tobacco, nicotine also accelerates atherosclerosis cardiovascular disease. There are several potential mechanisms of the pro-atherogenic effects of nicotine: (1) inducing endothelial dysfunction, (2) modifying lipid profile, (3) increasing inflammatory response, (4) inducing the release of catecholamines, which may increases heart rate and blood pressure, (5) increases platelet aggregability, (6) direct actions on the cellular elements participating in plaque formation, and (7) induces the proliferation and migration of vascular smooth muscle cells into the intima, mediated in part by TGFβ.7 These pathomechanisms of nicotine could lead to the increase of intimia media thickness of the entire blood vessel, leading to the greater risk of developing atherosclerosis.8\n\nTo learn more about the pathomechanisms of the diseased endothelium, we need to study all the oxidizing, inflammatory, and thrombotic molecules which are not in an equilibrium state. In the model of atherosclerosis cardiovascular diseases, a pathological imbalance between prothrombotic and antithrombotic state, prooxidant and antioxidant state, and pro-inflammatory and anti-inflammatory state are observed.9 Considerable evidence supports the importance of inflammation and hypercoagulability to promote atherogenic state.10 There is abundant literature concerning the role of biomarkers of pathological imbalance in atherosclerosis.\n\nCell adhesion molecules are the essential pro-inflammatory and pro-atherogenic proteins that represent a hallmark of endothelial dysfunction and atherosclerosis. P-selectin, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, and PECAM-1 were demonstrated to be involved in the formation of atherosclerosis plaque.11 Beyond the other cell adhesion molecules, VCAM-1 plays as an important factor in neointima proliferation following nicotine-induced arterial injury, an area of research important for atherosclerosis cardiovascular diseases.12 In the nicotine-induced arterial injury model, VCAM-1 expression is highly induced in the proliferation and migration of neointimal smooth muscle cells.13\n\nPrevious studies showed that upregulation of endothelial nitric oxide synthase (e-NOS) expression and activity has its important role in the protection of endothelium.14–16 e-NOS could stimulate endothelium-dependent relaxation and protect against the development of VCAM-1-induced endothelial dysfunction.17 However, to our knowledge, little is known about the role of cigarette smoke in this atherosclerotic inflammatory process. This study aims to explore the link between cigarette smoke on e-NOS and VCAM-1, which results in the development of aortic intima media thickness (IMT) of the experimental animals.\n\nIncreasing evidence suggests that cigarette smoke exposure could induce VCAM-1 (enhance pro-atherogenic property), and a decrease of e-NOS level (anti-atherogenic depletioon). Thus, cigarette smoke may represent a significant risk factor for atherosclerosis by increasing aortic IMT. This evidence is discussed herein.\n\n\nMethods\n\nThis article was reported in line with the ARRIVE guidelines. Animal experimental study were conducted under the approval of the Institutional Animal Care and Use Committee of Universitas Airlangga (UNAIR), Surabaya, Indonesia (animal approval no: 2.KE.184.10.2019) under the name of Meity Ardiana as the Principal Investigator. All efforts were made to ameliorate any suffering of animals through using anaesthetic to euthanize the rats at the end of the experimental procedure.\n\nThe present study used 18 male Wistar rats (Rattus novergicus), eight weeks of age (average body weight 150-200 grams). The rats were adapted to their environment for seven days before the experiment start. They were nurtured at the Animal House at Faculty of Veterinary Medicine, Universitas Airlangga in polycarbonate cage, which measured 480 mm × 265 mm × 210 mm. Each cage had wood shavings on the floor, and contained three or four animals, which were marked for each subgroup. The rats were housed in microisolator cages and maintained in a constant room temperature ranging from 22°C to 25°C, with a 12-h light/12-h dark cycle, under artificially controlled ventilation, with a relative humidity ranging from 50% to 60%. The rats were fed a standard balanced rodent diet and water was provided ad libitum. The rats were chosen for each group by simple random sampling. Study was carried out in strict accordance to internationally-accepted standards of the Guide for the Care and Use of Laboratory Animals of the National Institute of Health and in line with the ‘Animal Research: Reporting in vivo Experiments’ (ARRIVE) Guidelines. All efforts were made to ameliorate any suffering of animals and details of how this was achieved should be provided.\n\nThe present study design was a randomized post-test only controlled group design using quantitative method. We extracted 18 male Wistar rats, randomized and then allocated them into two groups. Group 1 were not exposed to tobacco smoke, whilst group 2 were given 40 or more cigarette smokes daily for 28 days as seen in Figure 1. Each cigarette smoke dose contains 39 mg of tar and 2.3 mg of nicotine. The enrolled subjects were analyzed for vascular cell adhesion molecule 1 (VCAM-1), endothelial nitric oxide synthase (e-NOS), and aortic intima media thickness (IMT) after 28 days of consecutive experiments.\n\nExposure to tobacco smokes were done using sidestream technique from peristaltic pump, smoke producer chamber, and inhalation chamber, connected by modified silicon tube.\n\nThoracic aortas were prepared as distal aortic arch by cutting from the left ventricle of each rat. The post mortem samples of descending thoracic aortas obtained by dissection were fixed in 10% formaldehyde, embedded in paraffin, and sectioned at a thickness of 6 μm. The mounted tissues were stained using hematoxylin and eosin. Aortic intima media thickness was measured via Leica DMD 108 (Leica Microsystems GmbH, Wetzlar, Germany). Each sample was measured as “micrometer (μm)” from six different locations of the vessel wall. Arithmetic averages of these six measurements are presented in the results section.\n\nWe used streptavidin-biotin method which uses a biotin conjugated secondary antibody to link the primary antibody to a streptavidin-peroxidase complex for Immunohistochemistry (IHC) staining. The labeled streptavidin-biotin (LSAB) method were utilized to measure expresson of VCAM-1 in the aortic tissue of the rats. Firstly, the aortic tissue were prepared and preserved through deparaffinize models following fixation. Secondly, the aortic tissue was rehydrated by immersing the slides through the xylene (three washes, five minutes each), 100% ethanol (two washes, 10 minutes each), 95% ethanol (two washes, 10 minutes each), 70% ethanol (two washes, 10 minutes each), 50% ethanol (two washes, 10 minutes each), and deionized water (two washes, five minutes each). Thirdly, the aortic tissue was washed using Phosphat Buffer Sollution and then dipped into 3% of H2O2 solution withing 20 minutes. Fourthly, we added 1% of Bovine Serum Albumin to the Phosphat Buffer Sollution and then incubated them within 30 minutes in the room temperature. Fifthly, primary antibody anti-VCAM-1 (Santacruz biotech SC-13160) was added and incubated within 30 minutes, then washed again using Phosphat Buffer Sollution. Secondary antibody (Anti-Rat IgG Biotin Labelled) was added and incubated within 30 minutes in the room temperature, then washed using Phosphat Buffer Sollution. Sixthly, SA-HRP (Strepavidin-Hoseradish Peroxidase) complex was added and incubated within 10 minutes in the room temperature and then washed using Phosphat Buffer Sollution. Seventhly, Chromogen DAB (3,3-diaminobenzidine tetrahydrochloride) was added and incubated within 10 minutes in the room temperature, and then washed using Phosphat Buffer Sollution and sterile water. Finally, counterstain Hematoxylin-Eosin was added into the object glasses and expressions of VCAM-1 were measured and analyzed by a biological microscope (400× magnification) from tunica intima and tunica media of the aortic tissue. Semiquantitative measurements of VCAM-1 were done by immunoreactivity scoring system (Table 1).\n\nAll samples were assessed by direct-sandwich enzyme-linked immunosorbent assay (ELISA) under the manufacture's system (R&D System Europe Ltd, Abingdon, UK) according to the National Institute for Biological Standards and Controls (Blanche Lane, South Mimms, Potters Bars, Hertfordshire, UK) protocol. We used eNOS kit from the elabscience (catalogue number: E-EL-R0367). Briefly, samples from the aortic tissue were collected and stored at −70oC (−94oF) at the Institute of Tropical Diseases Universitas Airlangga (UNAIR). Samples were homogenized into solution. Then, 100 μL of the solution was mixed with the well-coated primary antibody for e-NOS. Overnight incubation was done in a temperature of 4oC with a shaking machine for minimum 24 hours. Wash Buffer (20×) were diluted to 1× working solution with D.I. water prior to ELISA wash procedures. After that, 50 μL of the stop solution was added into each sample. A minimum value of 0.01 pg/mL were assigned for below the limit of detection.\n\nAll measurements were performed and replicated at least three times. Results were presented as (1) means ± standard deviations (SD) for normally distributed data; (2) medians with lower and upper value for abnormally distributed data. The assumption of the normality for the complete data was assessed by Shapiro-Wilk test. Test of homogeneity of variances was assessed by Levene Statistics. Statistical significance were examined by Independent T-test, Mann-Whitney U test, and logistic regression using SPSS version 17.0 for Microsoft (IBM corp, Chicago, USA).\n\n\nResults\n\nAfter 28 days following experiments, there was a significance difference in IMT level between both groups (p < 0.001). The mean of the aortic IMT in all subjects were 73.68 ± 17.86 μm. The mean of the aortic IMT in the cigarette smoke group was 88.39 ± 2.51 μm. Theean of the aortic IMT in the control group was 58.98 ± 13.61 μm. Table 2 presents the impact of the exposure of smoke from 40 cigarettes daily on the aortic IMT profile of the experimental animals. The comparative analysis of IMT parameters demonstrated that there were statistically significant differences between the groups (p < 0.001; Mann-Whitney’s test) (Figure 2).\n\nAfter 28 days following experiments, there was a significance difference of e-NOS level between both groups (p < 0.001). The mean of the e-NOS in all subjects was 78.02 ± 25.84 pg/ml. The mean of the e-NOS level in the cigarette smoke group was 101.22 ± 11.8 pg/ml. The mean of the e-NOS level in the control group was 54.83 ± 8.3 pg/ml. Table 3 presents the impact of the exposure of daily smoke from the equivalent of 40 cigarettes on the e-NOS profile of the experimental animals. The comparative analysis of e-NOS parameters demonstrated that there were statistically significant differences between the groups (p < 0.001; Mann-Whitney’s test) (Figure 3).\n\nAfter 28 days following experiments, the mean of the VCAM-1 expression in all subjects was 9.00 ± 3.51. The mean of the VCAM-1 level in the cigarette smoke group was 10.33 ± 2.9. The mean of the VCAM-1 level in the control group was 7.67 ± 3.7. Table 4 presents the impact of the exposure of daily 40 or more cigarette smokes on the VCAM-1 expression of the experimental animals. The comparative analysis of VCAM-1 expression demonstrated that there were no statistically significant differences between the groups (p = 0.112; independent t test) (Figure 4).\n\nTo determine if the level of e-NOS is correlated with atherosclerosis, we measured e-NOS as a parameter of endothelial cell function in aortic tissue of Wistar rats. Linear regression model found that e-NOS was negatively correlated with aortic IMT in our experimental study (r2 = 0.584, β = −0.764, p < 0.001) (Figure 5).\n\nA negative linear relationship was found between e-NOS level and aortic IMT.\n\nTo determine if expression of VCAM-1 precedes atherosclerosis, we measured expression of this adhesion molecule in aortic tissue of Wistar rats. Linear regression model found that VCAM-1 expression did not correlate with aortic IMT (r2 = 0.197, p = 0.065) (Figure 6).\n\nA positive but non-significant linear relationship was found between aortic VCAM-1 expression and aortic IMT.\n\n\nDiscussion\n\nSmoking cigarettes is one of the well-established modifiable risk factors for developing atherosclerosis, which mechanisms remain closely linked to the increased oxidative stress. The total amount of cigarettes smoked per day plays an essential role in increasing the level of oxidative stress and depletion of the antioxidant system. Cigarette smoke contains high concentrations of reactive oxygen species and tiny particles that are easily inhaled in the human body.18 It is believed that smoking causes increased oxidative stress because of several mechanisms, including direct damage by radical species and the inflammatory response caused by cigarette smoking. The production of oxidative stress and reactive oxygene species due to the cigarette smoke is expected to increase VCAM-1 expression and decrease of e-NOS level. According to the previous research by Yang et al (2014), an increase of VCAM-1 expression in rat arteries after being exposed to cigarette smoke had been observed for seven days.19 Translational research completed by Teasdale et al (2014) and Pott et al (2017) also supported the findings that increased oxidative stress, reactive oxygene species, and VCAM-1 expression in endothelial cell cultures followed exposure to cigarette smoke.20 Previously, researchers had been studying the influence of smoking on the levels of several biomarkers of oxidative stress, antioxidant status and redox status, including plasma hydroperoxides, e-NOS and VCAM-1. Using different assays to our study, they confirmed that smokers have elevated concentrations of VCAM-1 and compromised e-NOS status.21\n\nVCAM-1 is expressed in vascular endothelial cells, and expression of VCAM-1 may promote the adhesion of leukocytes to the endothelial cells. VCAM-1 accelerates the migration of adherent leukocytes along the endothelial surface, and promotes the proliferation of vascular smooth muscle cells; thus, VCAM-1 may play an essential role as a pro-atherogenic molecules.22 Exposure to cigarette smoke in this study can increase VCAM-1 expression in the aorta although the increase is not statistically significant between the two groups. An insignificant increase in VCAM-1 expression was also found in the previous human research held by Noguchi (1999). In his previous research, soluble VCAM-1 levels were increased in smokers' serum but not significantly when compared to non-smokers’ serum.23\n\nIncrease of VCAM-1 expression is a multifactorial process, smoking could not increase VCAM-1 independently without other risk factors such as dyslipidemia. Mu et al (2015) had proven this hypothesis by examining VCAM-1 expression in aortic tissue of dyslipidemia patients. As a result, VCAM-1 expression was positively correlated with triglyceride, total cholesterol and LDL levels while VCAM-1 and HDL had a negative correlation24 because the expression of VCAM-1 in endothelial cells requires a trigger that is high lipid levels, especially LDL. An increase in oxidized LDL in the endothelium will be phagocytosed by macrophages. Recruitment of these macrophages requires the role of VCAM-1.25 In our study, other factors contributing to the development of atherosclerosis such as dyslipidemia weren’t included. Our study did not use experimental animals with high-fat diets and serial lipid profile measurement Therefore, results of our study didn’t show any statistical significance of VCAM-1 expression between K (-) and K (+) groups.\n\nDecreased bioavailability of NO is a central mechanism in the pathophysiology of endothelial dysfunction. Endhotelial nitric oxide synthetase (e-NOS) is an enzyme that resposible to produce NO in endothelial cells, so the level of eNOS can represent the availability of NO in endothelial cells.26 Endothelial-cell dysfunction itself could be tested by acetylcholine response function and adenosine coronary flow reserve tests.27 Celermajer et al (1992) published a study showing that smoking reduces flow-mediated dilatation (FMD) in systemic arteries in healthy young adults.28\n\nOur study showed that exposure to cigarette smoke can reduce levels of eNOS in the aorta. Our results are consistent with the findings of He et al (2017), which shows a significant decrease of eNOS level in endothelial cell cultures exposed to cigarette smoke. He et al (2017) showed that exposure to cigarette smoke in endothelial cell culture can reduce the expression of eNOS genes and proteins, resulting endothelial-cell dysfunction.29 On the other hand, Su et al (1998) had already proven that administration of cigarette smoke extract can reduce the expression of genes and proteins eNOS. The effect of eNOS reduction depends on the duration of exposure to the cells. The longer the duration of cigarette smoke exposure, the more eNOS levels will be decreased.30 In addition to decreasing eNOS at the gene level, Pini et al (2016) showed that exposure to secondhand smoke had also been shown to reduce eNOS at protein levels. eNOS levels decreased in the aorta of guinea pigs after exposure to cigarettes for eight weeks.31\n\nIt has been demonstrated that smoking cigarettes triggers demethylation, leading to a consecutive reactivation of epigenetically silenced genes in vitro and in vivo of eNOS and NO production.32 Peroxinitrites, a very reactive oxygene species and pro-oxidant properties from cigarette extract, is believed to promote demethylation and inactivation of e-NOS.33 In addition, peroxynitrite and other free radicals can deactivate BH4 which is an important cofactor in eNOS production. This was explained by the research of Abdelghany et al (2018) which showed that exposure to cigarette smoke has been shown to reduce the BH4 cofactor and correlated with the amount of superoxide and NO production in endothelial cell cultures.34 A decrease of e-NOS and NO level will increase vascular tone, increase expression of adhesion molecules, and trigger coagulation cascade and inflammation.35 In the final pathway, smoking cigarettes leads to increase of aortic intima-medial thickness as an earlier sign of atherosclerosis\n\nBased on this literature and our own data, we suggest that the exposure to cigarette smoke for 28 days daily might be an independent risk factor for atherogenic process through several mechanisms. Aortic IMT in this study increased in group K (+) as was also found in studies conducted by Ali et al (2012).36 Increased aortic and entire blood vessels’ IMT are due to the pathological conditions such as apoptosis and excessive proliferation as a compensation mechanism.37 In the previous study, the increase of IMT as a complication of endothelial dysfunction leads to the atherosclerosis process.38 Cigarette smoke exposure underlies the endothelial dysfunction by the reduction of e-NOS level and increase of VCAM-1 expression.39\n\nExposure to cigarette smoke also affects the histological structure of the aorta. In this study, we found not only an increase of IMT, but also structural changes marked by disorganization and vacuolization of smooth muscle cells in the tunica media of the aortic tissue. On the contrary, no changes were observed at the tunica intima level. Exposure to cigarette smoke for 28 days in the study of Ali et al (2012) also found the same results: no changes in the tunica intima were observed from the experimental rat.36 Another experimental study from Jaldin et al (2013) found that exposure to cigarette smoke for eight weeks only resulted in a disorganization in the vascular smooth muscle cells in the tunica media.40 Vacuolization is one of the complications from cytotoxic processes in the cells and an earlier marker of preclinical atherosclerosis. Chemical components from cigarette smoke can cause oxidative stress which is characterized by permanent vacuolization in cells. In the microscopic phenotyping, vacuolization makes the vascular smooth muscle cells have different shapes and sizes, thus resulting in the cells becoming disorganized and leading to atherosclerosis.41\n\nEvery study has its limitations which emerge during the realization of the study, creating challenges and, thus, should be highlighted. Firstly, this study had limitations with regards to the small number of samples which can increase the likelihood of error and imprecision. Secondly, results from animal models often do not translate into replications in human models. Level of e-NOS and VCAM-1 expression in Wistar rats are typically transient, whereas in human they can persists for many years. Another crucial difference is IMT, which is usually much lower in the Wistar rats than in humans. These factors may have an impact on the interpretation of our results. Thus, the findings should be interpreted within the context of this study and its limitations. The strengths of the study were its high statistical power and the homogeneity of each group to enable comparisons between groups and periods.\n\n\nConclusion\n\nThe present study indicates that smoking cigarettes adversely affects endothelial function and increases the risk of atherosclerosis. Smoking cigarettes as a risk factor for atherosclerosis is closely linked to the increased inflammatory process on the vascular endothelium. Low e-NOS level and high VCAM-1 level observed following smoke exposure may increase aortic IMT. Furthermore, smoking has also been found to influence the aortic IMT. Aortic IMT itself reflects the level of established CVD risk factors in apparently healthy men and women, adding to the evidence that cigarette smoking contributes to CVD through its inflammatory effects on the vascular endothelium.\n\n\nData availability\n\nFigshare. Raw Data - Acute effects of cigarette smoke: https://doi.org/10.6084/m9.figshare.14252639.v1.42\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgments\n\nThe authors would like to acknowledge Dr. Hari Basuki Notobroto from Public Health Department Universitas Airlangga whose statistical expertise was invaluable during the analysis. The authors, hereby, acknowledge the above authorities and all staff, fellows, residents and laboratory assisstants from Department of Cardiology and Vascular Medicine, Faculty of Medicine Universitas Airlangga, who are willing to help in the technical aspect.\n\n\nReferences\n\nZhu J, Nelson K, Toth J, et al.: Nicotine dependence as an independent risk factor for atherosclerosis in the National Lung Screening Trial. BMC Public Health. 2019; 19(1): 1–6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLu L, Mackay DF, Pell JP: Meta-analysis of the association between cigarette smoking and peripheral arterial disease. Heart. 2014; 100(5): 414–423. PubMed Abstract | Publisher Full Text\n\nHuxley RR, Woodward M: Cigarette smoking as a risk factor for coronary heart disease in women compared with men: A systematic review and meta-analysis of prospective cohort studies. Lancet. 2011; 378(9799): 1297–1305. PubMed Abstract | Publisher Full Text\n\nPréfontaine D, Morin A, Jumarie C, et al.: In vitro bioactivity of combustion products from 12 tobacco constituents. Food Chem Toxicol. 2006; 44(5): 724–738. PubMed Abstract | Publisher Full Text\n\nWang T, Jiang CQ, Xu L, et al.: The mediating role of inflammation in the association between cigarette smoking and intima-media thickness: The Guangzhou biobank cohort study. Med (United States). 2020; 99(8). PubMed Abstract | Publisher Full Text | Free Full Text\n\nHarris JE: Cigarette smoke somponents and disease: Cigarette smoke is More than a triad of tar, nicotine and carbon monoxide. Smok Tob Control Monogr No 7. 1991; 7: 59–75.\n\nLee J, Cooke JP: The role of nicotine in atherosclerosis. Atherosclerosis. 2011; 215(2): 281–283. Publisher Full Text\n\nFlouris AD, Poulianiti KP, Chorti MS, et al.: Acute effects of electronic and tobacco cigarette smoking on complete blood count. Food Chem Toxicol. 2012; 50(10): 3600–3603. PubMed Abstract | Publisher Full Text\n\nManduteanu I, Simionescu M: Inflammation in atherosclerosis: A cause or a result of vascular disorders? J Cell Mol Med. 2012; 16(9): 1978–1990. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAmbrose JA, Bhullar AS: Inflammation and Thrombosis in Coronary Atherosclerosis: Pathophysiologic Mechanisms and Clinical Correlations. Eur Med J. 2019;(March): 71–78. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGalkina E, Ley K: Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol. 2007; 27(11): 2292–2301. PubMed Abstract | Publisher Full Text\n\nDos Santos JC, Cruz MS, Bortolin RH, et al.: Relationship between circulating VCAM-1, ICAM-1, E-selectin and MMP9 and the extent of coronary lesions. Clinics. 2018; 73(4): 1–5. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLey K, Huo Y: JCI0113005. 2001; v1(10): 1–2.\n\nToporsian M, Gros R, Kabir MG, et al.: A role for endoglin in coupling eNOS activity and regulating vascular tone revealed in hereditary hemorrhagic telangiectasia. Circ Res. 2005; 96(6): 684–692. PubMed Abstract | Publisher Full Text\n\nJerkic M, Rivas-Elena JV, Santibanez JF, et al.: Endoglin regulates cyclooxygenase-2 expression and activity. Circ Res. 2006; 99(3): 248–256. PubMed Abstract | Publisher Full Text\n\nJerkic M, Rodríguez-Barbero A, Prieto M, et al.: Reduced angiogenic responses in adult endoglin heterozygous mice. Cardiovasc Res. 2006; 69(4): 845–854. PubMed Abstract | Publisher Full Text\n\nRathouska J, Nemeckova I, Zemankova L, et al.: Cell adhesion molecules and eNOS expression in aorta of normocholesterolemic mice with different predispositions to atherosclerosis. Heart Vessels. 2015; 30(2): 241–248. PubMed Abstract | Publisher Full Text\n\nKamceva G, Arsova-Sarafinovska Z, Ruskovska T, et al.: Cigarette smoking and oxidative stress in patients with coronary artery disease. Maced J Med Sci. 2016; 4(4): 636–640. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYang GH, Li YC, Wang ZQ, et al.: Protective effect of melatonin on cigarette smoke-induced restenosis in rat carotid arteries after balloon injury. J Pineal Res. 2014; 57(4): 451–458. PubMed Abstract | Publisher Full Text\n\nTeasdale JE, Hazell G, Newby AC, et al.: Paradoxical effects of cigarette smoke extract and high laminar flow on tumour necrosis factor-alpha induced VCAM-1 up-regulation – Implications for endothelial dysfunction. Atherosclerosis. 2014; 237(2): e13–e14. Publisher Full Text\n\nPott GB, Ph D, Tsurudome M, et al.: 1,2, *.2017; 5(7): 1–15.\n\nPetersen EJ, Miyoshi T, Yuan Z, et al.: siRNA silencing reveals role of vascular cell adhesion molecule-1 in vascular smooth muscle cell migration. Atherosclerosis. 2008; 198(2): 301–306. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNoguchi T: Soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 concentrations, and leukocyte count in smokers. Environ Health Prev Med. 1999; 4(2): 71–74. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMu W, Chen M, Gong Z, et al.: Expression of vascular cell adhesion molecule-1 in the aortic tissues of atherosclerotic patients and the associated clinical implications. Exp Ther Med. 2015; 10(2): 423–428. PubMed Abstract | Publisher Full Text | Free Full Text\n\nToma L, Sanda GM, Deleanu M, et al.: Glycated LDL increase VCAM-1 expression and secretion in endothelial cells and promote monocyte adhesion through mechanisms involving endoplasmic reticulum stress. Mol Cell Biochem. 2016; 417(1-2): 169–179. PubMed Abstract | Publisher Full Text\n\nMessner B, Bernhard D: Smoking and cardiovascular disease: Mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler Thromb Vasc Biol. 2014; 34(3): 509–515. PubMed Abstract | Publisher Full Text\n\nBruno RM, Gori T, Ghiadoni L: Endothelial function testing and cardiovascular disease: Focus on peripheral arterial tonometry. Vasc Health Risk Manag. 2014; 10: 577–584. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCelermajer DS, Sorensen KE, Gooch VM, et al.: Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992; 340(8828): 1111–1115. PubMed Abstract | Publisher Full Text\n\nHe Z, Chen Y, Hou C, et al.: Cigarette smoke extract changes expression of endothelial nitric oxide synthase (eNOS) and p16(INK4a) and is related to endothelial progenitor cell dysfunction. Med Sci Monit. 2017; 23: 3224–3231. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSu Y, Han W, Giraldo C, et al.: Effect of cigarette smoke extract on nitric oxide synthase in pulmonary artery endothelial cells. Am J Respir Cell Mol Biol. 1998; 19(5): 819–825. PubMed Abstract | Publisher Full Text\n\nPini A, Boccalini G, Baccari MC, et al.: Protection from cigarette smoke-induced vascular injury by recombinant human relaxin-2 (serelaxin). J Cell Mol Med. 2016; 20(5): 891–902. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPlimack ER, Kantarjian HM, Issa JP: Decitabine and its role in the treatment of hematopoietic malignancies. Leuk Lymphoma. 2007; 48(8): 1472–1481. PubMed Abstract | Publisher Full Text\n\nIncalza MA, D’Oria R, Natalicchio A, et al.: Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vascul Pharmacol. 2018; 100: 1–19. PubMed Abstract | Publisher Full Text\n\nAbdelghany TM, Ismail RS, Mansoor FA, et al.: Cigarette smoke constituents cause endothelial nitric oxide synthase dysfunction and uncoupling due to depletion of tetrahydrobiopterin with degradation of GTP cyclohydrolase. Nitric Oxide - Biol Chem. 2018; 76: 113–121. PubMed Abstract | Publisher Full Text\n\nKaur R, Kaur M, Singh J: Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: Molecular insights and therapeutic strategies. Cardiovasc Diabetol. 2018; 17(1): 1–17. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAli SS, Ayuob NN, Al Ansary AK, et al.: Antioxidants protect against increased risk of atherosclerosis induced by exposure to cigarette smoke: Histological and biochemical study. Saudi J Biol Sci. 2012; 19(3): 291–301. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSkilton MR, Celermajer DS, Cosmi E, et al.: Natural History of Atherosclerosis and Abdominal Aortic Intima-Media Thickness: Rationale, Evidence, and Best Practice for Detection of Atherosclerosis in the Young. J Clin Med. 2019; 8(8): 1201. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPoredoš P: Endothelial dysfunction in the pathogenesis of atherosclerosis. Clin Appl Thromb. 2001; 7(4): 276–280. PubMed Abstract | Publisher Full Text\n\nZhou J, Li YS, Nguyen P, et al.: Regulation of vascular smooth muscle cell turnover by endothelial cell-secreted microRNA-126 role of shear stress. Circ Res. 2013; 113(1): 40–51. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJaldin RG, Castardelli É, Perobelli JE, et al.: Morphologic and biomechanical changes of thoracic and abdominal aorta in a rat model of cigarette smoke exposure. Ann Vasc Surg. 2013; 27(6): 791–800. PubMed Abstract | Publisher Full Text\n\nHarrington J, Peña AS, Gent R, et al.: Aortic Intima Media Thickness is an Early Marker of Atherosclerosis in Children with Type 1 Diabetes Mellitus. J Pediatr. 2010; 156(2): 237–241. PubMed Abstract | Publisher Full Text\n\nArdiana M, Santoso A, Hermawan HO, et al.: Raw Data - Acute effects of cigarette smoke. figshare. Dataset. 2021. Publisher Full Text\n\nArdiana M, Santoso A, Hermawan HO, et al.: Acute Effects of Cigarette on Endothelial Nitric Oxide Synthase, Vascular Cell Adhesion Molecule 1 and Aortic Intima Media Thickness “Cigarette smoke–induced pro-atherogenic changes”. BioRxiv. 2020. Publisher Full Text\n\nArdiana M: Pengaruh Dan Mekanisme Pemberian Ekstrak Etanol Jintan Hitam Dalam Menghambat Terjadinya Disfungsi Endotel Pada Tikus Yang Terpapar Asap Rokok. Disertasi thesis. UNIVERSITAS AIRLANGGA Repository. Reference Source"
}
|
[
{
"id": "145923",
"date": "05 Aug 2022",
"name": "Amilia Aminuddin",
"expertise": [
"Reviewer Expertise Cardiovascular"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study determines the effects of 1-month exposure to tar and nicotine on eNOS, VCAM-1, and aortic stiffness in a rats model.\nThe authors should highlight the novelty of this study since there are a lot of studies that have been conducted in this area and for these parameters. The parameters also were limited (three parameters only). If the authors can add more parameters then it will be good.\n\nOut of 44 references, only 12 references are the latest (within 5 years).\n\nIn the results section, the authors should show which statistical analysis has been conducted, rather than presenting both. For example, Table 2 presented both the t-test and Mann-Whitney, and actually one should be chosen based on the normality of the parameters. The mean value and SD in the table also should use a dot, instead of a comma.\n\nThere were abbreviations used without the full names given, such as TGF and BH4.\n\nPlease identify rats as animals and not subjects.\n\nThe manuscript should be proofread as there were grammatical/spelling errors.\n\nA sample size of nine per group is more than enough and not the limitation of the study.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8621",
"date": "13 Sep 2022",
"name": "Ricardo Adrian Nugraha",
"role": "Author Response",
"response": "This study determines the effects of 1-month exposure to tar and nicotine on eNOS, VCAM-1, and aortic stiffness in a rats model. The authors should highlight the novelty of this study since there are a lot of studies that have been conducted in this area and for these parameters. The parameters also were limited (three parameters only). If the authors can add more parameters then it will be good. Author Response: The novelty of this study is the strong correlation between those three parameters in the setting of acute cigarette smoke exposure, which may change the paradigm about only chronic or sub-chronic cigarette smoke exposure can induce the atherogenic process. Increasing evidence suggests that cigarette smoke exposure, even in the short-term period could induce VCAM-1 (enhance pro-atherogenic properties), and a decrease in e-NOS level (anti-atherogenic depletion). Thus, acute cigarette smoke may represent a significant risk factor for atherosclerosis by increasing aortic IMT. This evidence is discussed herein. Out of 44 references, only 12 references are the latest (within 5 years). Author Response: Thank you for your suggestion. We try to replace the reference with the latest one. However, several data and information are only available in the old references In the results section, the authors should show which statistical analysis has been conducted, rather than presenting both. For example, Table 2 presented both the t-test and Mann-Whitney, and actually one should be chosen based on the normality of the parameters. The mean value and SD in the table also should use a dot, instead of a comma. Author Response: Table 2 (IMT) and Table 3 (e-NOS) used Mann-Whitney u test. On the contrary, Table 4 (VCAM-1) used an independent t-test. This is based on the normality test by the Shapiro-Wilk test. Thank you for your constructive feedback to shape our manuscript better. There were abbreviations used without the full names given, such as TGF and BH4. Author Response: Thank you for your suggestion, we have added TGF (transforming growth factor) and BH4 (Tetrahydrobipterin) in the abbreviation lists Please identify rats as animals and not subjects. Author Response: Thank you for your suggestion, we have replaced “subjects” with “animals” The manuscript should be proofread as there were grammatical/spelling errors. Author Response: Thank you for your constructive feedback. We try to fix the grammatical/spelling errors in the second version of the manuscript. A sample size of nine per group is more than enough and not the limitation of the study. Author Response: Thank you for your suggestion, we have removed the sample size in the limitation of this study"
}
]
}
] | 1
|
https://f1000research.com/articles/10-396
|
https://f1000research.com/articles/10-401/v1
|
19 May 21
|
{
"type": "Systematic Review",
"title": "Data extraction methods for systematic review (semi)automation: A living systematic review",
"authors": [
"Lena Schmidt",
"Babatunde K. Olorisade",
"Luke A. McGuinness",
"James Thomas",
"Julian P. T. Higgins",
"Babatunde K. Olorisade",
"Luke A. McGuinness",
"James Thomas",
"Julian P. T. Higgins"
],
"abstract": "Background: The reliable and usable (semi)automation of data extraction can support the field of systematic review by reducing the workload required to gather information about the conduct and results of the included studies. This living systematic review examines published approaches for data extraction from reports of clinical studies. Methods: We systematically and continually search MEDLINE, Institute of Electrical and Electronics Engineers (IEEE), arXiv, and the dblp computer science bibliography databases. Full text screening and data extraction are conducted within an open-source living systematic review application created for the purpose of this review. This iteration of the living review includes publications up to a cut-off date of 22 April 2020. Results: In total, 53 publications are included in this version of our review. Of these, 41 (77%) of the publications addressed extraction of data from abstracts, while 14 (26%) used full texts. A total of 48 (90%) publications developed and evaluated classifiers that used randomised controlled trials as the main target texts. Over 30 entities were extracted, with PICOs (population, intervention, comparator, outcome) being the most frequently extracted. A description of their datasets was provided by 49 publications (94%), but only seven (13%) made the data publicly available. Code was made available by 10 (19%) publications, and five (9%) implemented publicly available tools. Conclusions: This living systematic review presents an overview of (semi)automated data-extraction literature of interest to different types of systematic review. We identified a broad evidence base of publications describing data extraction for interventional reviews and a small number of publications extracting epidemiological or diagnostic accuracy data. The lack of publicly available gold-standard data for evaluation, and lack of application thereof, makes it difficult to draw conclusions on which is the best-performing system for each data extraction target. With this living review we aim to review the literature continually.",
"keywords": [
"Data Extraction",
"Natural Language Processing",
"Reproducibility",
"Systematic Reviews",
"Text Mining"
],
"content": "1. Introduction\n\nIn a systematic review, data extraction is the process of capturing key characteristics of studies in structured and standardised form based on information in journal articles and reports. It is a necessary precursor to assessing the risk of bias in individual studies and synthesising their findings. Interventional, diagnostic, or prognostic systematic reviews routinely extract information from a specific set of fields that can be predefined.1 The most common fields for extraction in interventional reviews are defined in the PICO framework (population, intervention, comparison, outcome) and similar frameworks are available for other review types. The data extraction task can be time-consuming and repetitive when done by hand. This creates opportunities for support through intelligent software, which identify and extract information automatically. When applied to the field of health research, this semi-automation sits at the interface between evidence-based medicine (EBM) and data science, and as described in the following section, interest in its development has grown in parallel with interest in AI in other areas of computer science.\n\nThis review is, to the best of our knowledge, the only living systematic review of data extraction methods. We have identified four previous reviews of tools and methods,2–5 two documents providing overviews and guidelines relevant to our topic,6,7 and an ongoing effort to list published tools for different parts of the systematic reviewing process.8\n\nA recent systematic review of machine-learning for systematic review automation, published in Portuguese, included 35 publications. The authors examined journals in which publications about systematic review automation are published, and conducted a term-frequency and citation analysis. They categorised papers by systematic review task, and provided a brief overview of data extraction methods.2\n\nIn 2014, Tsafnat et al. provided a broad overview on automation technologies for different stages of authoring a systematic review.5 O’Mara-Eves et al. published a systematic review focusing on text-mining approaches in 2015.4 It includes a summary of methods for the evaluation of systems, such as recall, accuracy, and F1 score (the harmonic mean of recall and precision, a metric frequently used in machine-learning). The reviewers focused on tasks related to PICO classification and supporting the screening process. In the same year, Jonnalagadda, Goyal and Huffman3 described methods for data extraction, focusing on PICOs and related fields.\n\nBeller et al. describe principles for development and integration of tools for systematic review automation.6 Marshall and Wallace7 present a guide to automation technology, with a focus on availability of tools and adoption into practice. They conclude that tools facilitating screening are widely accessible and usable, while data extraction tools are still at piloting stages or require a higher amount of human input.\n\nThe systematic reviews from 2014 to 2015 present an overview of classical machine learning and natural language processing (NLP) methods applied to tasks such as data mining in the field of evidence-based medicine. At the time of publication of these documents, methods such as topic modelling (Latent Dirichlet Allocation) and support vector machines (SVM) were considered state-of-the art for language models. The age of these publications means that the latest static or contextual embedding-based and neural methods are not included. These newer methods,9 however, are used in contemporary systematic review automation software which will be reviewed in the scope of this living review.\n\nWe aim to review published methods and tools aimed at automating or semi-automating the process of data extraction in the context of a systematic review of medical research studies. We will do this in the form of a living systematic review, keeping information up to date and relevant to the challenges faced by systematic reviewers at any time.\n\nOur objectives in reviewing this literature are two-fold. First, we want to examine the methods and tools from the data science perspective, seeking to reduce duplicate efforts, summarise current knowledge, and encourage comparability of published methods. Second, we seek to highlight the added value of the methods and tools from the perspective of systematic reviewers who wish to use (semi) automation for data extraction, i.e., what is the extent of automation? Is it reliable? We address these issues by summarising important caveats discussed in the literature, as well as factors that facilitate the adoption of tools in practice.\n\n\n2. Methods\n\nThis review was conducted following a preregistered and published protocol.10,11 PROSPERO was initially considered as platform for registration, but it is limited to reviews with health-related outcomes. Any deviations from the protocol have been described below.\n\nWe are conducting a living review because the field of systematic review (semi) automation is evolving rapidly along with advances in language processing, machine-learning and deep-learning.\n\nThe process of updating started as described in the protocol11 and is shown in Figure 1. In short, we will continuously update the literature search results, using the search strategies and methods described in the section ‘Search’ below. MEDLINE and arXiv search results are updated daily in a completely automated fashion. Articles from the dblp and IEEE are added every two months. All search results are automatically imported to our living review screening and data extraction web-application, which is described in the section ‘Data collection and analysis’ below.\n\nThis image is reproduced under the terms of a Creative Commons Attribution 4.0 International license (CC-BY 4.0) from Schmidt et al, 2020.11\n\nThe decision for full review updates is made every six months based on the number of new publications added to the review. For more details about this, please refer to the protocol or to the Cochrane living systematic review guidance. In between updates, the screening process and current state of the data extraction is visible via the living review website.\n\n\n\n• We included full text publications that describe an original NLP approach for extracting data related to systematic reviewing tasks. Data fields of interest (referred to here as entities or as sentences) were adapted from the Cochrane Handbook for Systematic Reviews of Interventions,1 and are defined in the protocol.11 We included the full range of NLP methods (e.g., regular expressions, rule-based systems, machine learning, and deep neural networks).\n\n• Publications must describe a full cycle of the implementation and evaluation of a method. For example, they must report training and at least one measure of evaluating the performance of a data extraction algorithm.\n\n• We included reports published from 2005 until the present day, similar to.3 We would have translated non-English reports, had we found any.\n\n• The data that the included publications use for mining must be texts from randomised controlled trials, comparative cohort studies, case control studies or comparative cross-sectional studies (e.g., for diagnostic test accuracy). The scope of data extraction methods can be applied to the full text or to abstracts within each eligible publication’s corpus. We included publications that extracted data from other study types, as long as at least one of our study types of interest was contained in the corpus.\n\nWe excluded publications reporting:\n\n• Methods and tools related solely to image processing and importing biomedical data from PDF files without any NLP approach, including data extraction from graphs.\n\n• Any research that focuses exclusively on protocol preparation, synthesis of already extracted data, write-up, pre-processing of text and dissemination.\n\n• Methods or tools that provided no natural language processing approach and offered only organisational interfaces, document management, databases, or version control\n\n• Any publications related to electronic health reports or mining genetic data.\n\nWe searched five electronic databases, using the search methods previously described in our protocol.11 In short, we searched MEDLINE via Ovid, using a search strategy developed with the help of an information specialist, and searched Web of Science Core Collection and IEEE using adaptations of this strategy, which were made by the review authors. Searches on the arXiv (computer science) and dblp were conducted on full database dumps using the search functionality described by McGuinness and Schmidt.12 The full search results and further information about document retrieval are available in Underlying data: Appendix A and B.86\n\nOriginally, we planned to include a full literature search from the Web of Science Core Collection. Due to the large number of publications retrieved via this search (n = 7822) we decided to first screen publications from all other sources, to train a machine-learning ensemble classifier, and to only add publications that were predicted as relevant for our living review. This reduced the Web of Science Core Collection publications to 547 abstracts, which were added to the studies in the initial screening step. The dataset, code and weights of trained models are available in Underlying data: Appendix C.86 This includes plots of each model’s evaluation in terms of area under the curve (AUC), accuracy, F1, recall, and variance of cross-validation results for every metric.\n\nIn future iterations of this living review we plan to change to PubMed for searching MEDLINE. This decision was made to facilitate continuous reference retrieval.\n\n2.5.1 Selection of studies\n\nScreening and data extraction were conducted as stated in the protocol. In short, we initially screened all retrieved publications using the Abstrackr tool. All abstracts were screened by two independent reviewers. Conflicting judgements were resolved by the authors who made the initial screening decisions. Full texts screening was conducted in a similar manner to abstract screening but used our web application for living systematic reviews described in the following section.\n\n2.5.2 Data extraction, assessment, and management\n\nWe previously developed a web application to automate reference retrieval for living review updates (see Software availability13), to support both abstract and full text screening for review updates, and to manage the data extraction process throughout.13 For future updates of this living review we will use the web application, and not Abstrackr, for screening references. This web application is already in use by another living review.14 It automates daily reference retrieval from the included sources and has a screening and data extraction interface. All extracted data are stored in a database. Figures and tables can be exported on a daily basis and the progress in between review updates is shared on our living review website. The full spreadsheet of items extracted from each included reference is available in the Underlying data.86 As previously described in the protocol, quality of reporting and reproducibility was assessed based on a previously published checklist for reproducibility in text mining.15\n\nAs planned in the protocol, a single reviewer conducted data extraction, and a random 10% of the included publications were checked by a second reviewer.\n\n2.5.3 Visualisation\n\nThe creation of all figures and interactive plots on the living review website and in this review’s ‘Results’ section was automated based on structured content from our living review database (see Appendix A, Underlying data86). We automated the export of PDF reports for each included publication. Calculation of percentages, export of extracted text, and creation of figures was also automated.\n\n2.5.4 Accessibility of data\n\nAll data and code are free to access. A detailed list of sources is given in the ‘Data availability’ and ‘Software availability’ sections.\n\nIn the protocol we stated that data would be available via an OSF repository. Instead, the full review data are available via the Harvard Dataverse, as this repository allows us to keep an assigned DOI after updating the repository with new content for each iteration of this living review.\n\nWe also stated that we would screen all publications from the Web of Science search. Instead, we describe a changed approach in the Methods section, under ‘Search’.\n\nWe added a data extraction item for the type of information which a publication mines (e. g. P, IC, O) into the section of primary items of interest, and we moved the type of input and output format from primary to secondary items of interest. We grouped the secondary item of interest ‘Other reported metrics, such as impacts on systematic review processes (e.g., time saved during data extraction)’ with the primary item of interest ‘Reported performance metrics used for evaluation’.\n\nThe item ‘Persistence: is the dataset likely to be available for future use?’ was changed to: ‘Can data be retrieved based on the information given in the publication?’. We decided not to speculate if a dataset is likely to be available in the future and chose instead to record if the dataset was available at the time when we tried to access it.\n\nThe item ‘Can we obtain a runnable version of the software based on the information in the publication?’ was changed to ‘Is an app available that does the data mining, e.g. a web-app or desktop version?’.\n\nIn this current version of the review we did not yet contact the authors of the included publications. This decision was made due to time constraints, however reaching out to authors is planned as part of the first update to this living review.\n\n\n3. Results\n\nOur database searches identified 10,974 publications after duplicates were removed (see Figure 2). We identified an additional 23 publications by screening the bibliographies of included publications, in addition to reviewing the tools contained in the SRToolbox. These records were missed from our search because they were either publications from the Association for Computational Linguistics Fr (ACL, n = 7) or were otherwise not indexed or found via Ovid/MEDLINE: (n = 5). For future review updates we will adapt the search strategies and conduct searches in sources such as the ACL.\n\nThis iteration of the living review includes 53 publications, summarised in Table 1 in Underlying data86). Twelve of these were among the additional 23 publications.\n\n3.1.1 Excluded publications\n\nIn total, 79 publications were excluded at the full text screening stage, with the most common reason for exclusion being that a study did not fit target entities or target data. In most cases, this was due to the text-types mined in the publications. Electronic health records and non-trial data were common, and we created a list of datasets that would be excluded in this category (see more information in Underlying data: Appendix B86). Some publications addressed the right kind of text but were excluded for not mining entities of interest to this review. For example, Norman, Leeflang and Névéol16 performed data extraction for diagnostic test accuracy reviews, but focused on extracting the results and data for statistical analyses. Millard, Flach and Higgins17 and Marshall, Kuiper and Wallace18 looked at risk of bias classification, which is beyond the scope of this review. Boudin, Nie and Dawes19 developed a weighing scheme based on an analysis of PICO element locations, leaving the detection of single PICO elements for future work. Luo et al.20 extracted data from clinical trial registrations but focused on parsing inclusion criteria into event or temporal entities to aid participant selection for randomised controlled trials (RCTs).\n\nThe second most common reason for study exclusion was that they had ‘no original data extraction approach’. Rathbone et al.,21 for example, used hand-crafted Boolean searches specific to a systematic review’s PICO criteria to support the screening process of a review within Endnote. We classified this article as not having any original data extraction approach because it does not create any structured outputs specific to P, IC, or O. Malheiros et al.22 performed visual text mining, supporting systematic review authors by document clustering and text highlighting. Similarly, Fabbri et al.23 implemented a tool that supports the whole systematic review workflow, from protocol to data extraction, performing clustering and identification of similar publications. Other systematic reviewing tasks that can benefit from automation but were excluded from this review are listed in Underlying data: Appendix B.86\n\n3.2.1 Automation approaches used\n\nFigure 3 shows aspects of the system architectures implemented in the included publications. A short summary of these for each publication is provided in Table 1 in Underlying data.86 Where possible, we tried to break down larger system architectures into smaller components. For example, an architecture combining a word embedding + long short-term memory (LSTM) network would have been broken down into the two respective sub-components. We grouped binary classifiers, such as naïve Bayes and Bidirectional Encoder Representations decision trees (BERT). Although SVM is also binary classifier, it was assigned as separate category due to its popularity. The final categories are a mixture of non-machine-leaning automation (application programming interface (API) and metadata retrieval, PDF extraction, rule-base), classic machine-learning (naïve Bayes, decision trees, SVM, or other binary classifiers) and neural or deep-learning approaches (convolutional neural network (CNN), LSTM, transformers, or word embeddings). This figure shows that there is no obvious choice of system architecture for this task.\n\nResults are divided into different categories of machine-learning and natural language processing approaches and coloured by the year of publication. More than one architecture component per publication is possible. Where API, application programming interface; BERT, bidirectional encoder representations decision trees; CNN, convolutional neural network; CRF, conditional random fields; LSTM, long short-term memory; PCIO, population, intervention, comparison, outcome; RNN, recurrent neural networks; SVM, support vector machines.\n\nBinary classifiers, most notably naïve Bayes and SVMs, are the most frequently used system components in the data extraction literature. They are frequently used in studies published between 2005 and now.\n\nRule-bases, including approaches using heuristics, wordlists, and regular expressions, were one of the earliest techniques used for data extraction in EBM literature. It remains one of the most frequently used approaches to automation. Eight publications (15%) use rule-bases alone, while the rest of the publications use them in combination with other classifiers (data shown in Underlying data: Appendix A86). Although used more frequently in the past, the five publications published between 2017 and now that use this approach combine it with conditional random fields (CRF),24 use it alone,25,26 use it with SVM27 or use it with other binary classifiers.28 In practice, these systems use rule-bases in the form of hand-crafted lists to identify candidate phrases for amount entities such as sample size25,28 or to refine a result obtained by a machine-learning classifier on the entity level (e.g., instances where a specific intervention or outcome is extracted from a sentence).24 Embedding and neural architectures are increasingly being used in literature from the past five years. Recurrent neural networks (RNN), CNN, and LSTM networks require larger amounts of training data, but by using embeddings or pre-training algorithms based on unlabelled data they have become increasingly more interesting in fields such as data extraction for EBM, where high-quality training data are difficult and expensive to obtain.\n\nIn the ‘Other’ category, tools mentioned were mostly other classifiers such as maximum entropy classifiers (n = 3), kLog, J48, and various position or document-length classification algorithms. We also added methods such as supervised distant supervision (n = 3, see29) and novel training approaches to existing neural architectures in this category.\n\n3.2.2 Reported performance metrics used for evaluation\n\nPrecision (i.e., positive predictive value), recall (i.e., sensitivity), and F1 score (harmonic mean of precision and recall) are the most widely used metrics for evaluating classifiers. This is reflected in Figure 4, which shows that at least one of these metrics was used in almost all of the 53 included publications. Accuracy and area under the curve - receiver operator characteristics (AUC-ROC) were less frequently used.\n\nMore than one metric per publication is possible, which means that the total number of included publications (n = 53) is lower than the sum of counts of the bars within this figure. AUC-ROC, area under the curve - receiver operator characteristics; F1, harmonic mean of precision and recall.\n\nIn the category ‘Other’ we added several instances where a relaxation of a metric was introduced, e. g., precision using top-n classified sentences29–31 or mean average precision and the metric ‘precision @rank 10’ for sentence ranking exercises.32,33 Another type of relaxation for standard metrics is a distance relaxation when normalising entities into concepts in medical subject headings (MesH) or unified medical language system (UMLS), to allow N hops between predicted and target concepts.34 Other metrics were kappa,33 random shuffling35 or binomial proportion test36 to test statistical significance, given with confidence intervals.27 Further metrics included under ‘Other’ were odds ratios,37 normalised discounted cumulative gain,29 ‘sentences needed to screen per article’ in order to find one relevant sentence,38 McNemar test,36 C-statistic (with 95% CI) and Brier score (with 95% CI).39\n\nReal-life evaluations, such as the percentage of outputs needing human correction, or time saved per article, were reported by one publication,30 and an evaluation as part of a wider screening system was done in another.40\n\nThere were several approaches and justifications of using macro- or micro-averaged precision, recall, or F1 scores in the included publications. Micro or macro scores are computed in multi-class cases, and the final scores can have a difference if the classes in a dataset are imbalanced (as is the case in most datasets used in the included studies for this review).\n\nMicro and macro scores were reported by,30,41 whereas26,42 reported micro across documents, and macro across the classes. Micro scores were used by41 for class-level results.\n\nMicro scores were also used by,44–46 and were used in the evaluation script of.47\n\n3.2.3 Type of data\n\n3.2.3.1 Scope\n\nMost data extraction is carried out on abstracts (See Table 1 in Underlying data,86 and Table 5). Abstracts are the most practical choice, due to the possibility of exporting them along with literature search results from databases such as MEDLINE. Descriptions of the benefits of using full texts for data extraction include having access to a more complete dataset, while the benefits of using titles include lower complexity for the data extraction task.25\n\nPlease see each included publication for further details on corpus quality.\n\nFigure 6 shows that RCTs are the most common study design texts used for data extraction in the included publications (see also extended Table 1 in Underlying data86). This is not surprising, because systematic reviews of interventions are the most common type of systematic review, and they are usually focusing on evidence from RCTs. Therefore, the literature for automation of data extraction focuses on RCTs, and their related PICO elements. Systematic reviews of diagnostic test accuracy are less frequent, and only one included publication specifically focused on text and entities related to these studies,48 while another mentioned diagnostic procedures among other fields of interest.49 Five publications focused on extracting data specifically from epidemiology research, or included text from cohort studies as well as RCT text.26,42,49–51 More publications mining data from surveys or case series might have been found if our search and review had concentrated on these types of texts.\n\nMore than one type per publication is possible, which means that the total number of included publications (n = 53) is lower than the sum of counts of the bars within this figure.\n\nCommonly, randomized controlled trials (RCT) text was at least one of the target text types used in the included publications.\n\n3.2.3.2 Data extraction targets\n\nMining P, IC, and O elements is the most common task performed in the literature of systematic review (semi-) automation (see Table 1 in Underlying data,86 and Figure 7). However, some of the less-frequent data extraction targets in the literature can be categorised as sub-classes of a PICO.,47 for example, by annotating hierarchically multiple entity types such as health condition, age, and gender under the P class. The entity type ‘P (Condition and disease)’, was the most common entity closely related to the P class, appearing in seven included publications.40,47,49,52–55\n\nMore than one entity type per publication is common, which means that the total number of included publications (n = 53) is lower than the sum of counts within this figure. P, population; I, intervention; C, comparison; O, outcome.\n\nNotably, seven publications annotated or worked with datasets that differentiated between intervention and control arms.25,30,31,37,41,56,57 Usually, I and C are merged (n=32). Most data extraction approaches focused on recognising instances of entity or sentence classes, and a small number of publications went one step further to normalise to actual concepts.34,58\n\nThe ‘Other’ category includes some more detailed drug annotations36 or information such as confounders26 and other entity types (see the full dataset in Underlying data: Appendix A for more information86).\n\n3.3.1 Granularity of data extraction\n\nA total of 36 publications extracted at least one type of information at the entity level, while 32 publications used sentence level (see Table 1 extended version in Underlying data86). We defined the entity level as any number of words that is shorter than a whole sentence, e.g., noun-phrases or other chunked text. Data types such as P, IC, or O commonly appeared to be extracted on both entity and sentence level, whereas ‘N’, the number of people participating in a study, was commonly extracted on entity level only.\n\n3.3.2 Type of input\n\nThe majority of systems mentioned MEDLINE, or PubMed as the data source for text. Text files (n = 45), next to XML (n = 4), or HTML (n = 3), are the most common format of the data downloaded from these sources. Therefore, most systems described using, or were assumed to use, text files as input data. Eight included publications described using PDF files as input.29,30,34,38,48,55,59,60\n\n3.3.3 Type of output\n\nA limited number of publications described structured summaries as output of their extracted data (n = 9). Alternatives to exporting structured summaries were JSON (n = 3), XML, and HTML (n = 2 each). Most publications mentioned only classification scores without specifying an output type. In these cases, we assumed that the output would be saved as text files (n = 43).\n\nWe used a list of 17 items to investigate reproducibility, transparency, description of testing, data availability, and internal and external validity of the approaches in each publication. The maximum and minimum number of items that were positively rated were 16 and 1, respectively, with a median of 10 (see Table 1 in Underlying data86). Scores were added up and calculated based on the data provided in Appendix A (see Underlying data86), using the sum and median functions integrated in Excel. Publications from recent years showed a trend towards more complete and clear reporting.\n\n3.4.1 Reproducibility\n\n3.4.1.1 Are the sources for training/testing data reported?\n\nOf the included publications, 50 out of 53 (94%) clearly stated the sources of their data used for training and evaluation. MEDLINE was the most popular source of data, with abstracts usually described as being retrieved via searches on PubMed, or full texts from PubMed Central. A small number of publications described using text from specific journals such as PLoS Clinical Trials, New England Journal of Medicine, The Lancet, or BMJ.31,56 Texts and metadata from Cochrane, either provided in full or retrieved via PubMed, were used in five publications.32,34,38,48,59 Corpora such as the ebm-nlp dataset,47 or PubMed-PICO46 are available for direct download. Publications published in recent years are increasingly reporting that they are using these benchmark datasets rather than creating and annotating their own corpora (see 4 for more details).\n\n3.4.1.2 If pre-processing techniques were applied to the data, are they described?\n\nOf the included publications, 47 out of 53 (89%) reported processing the textual data before applying/training algorithms for data extraction. Different types of pre-processing, with representative examples for usage and implementation, are listed in Table 1 below.\n\n3.4.2 Transparency of methods\n\n3.4.2.1 Is there a description of the algorithms used?\n\nFigure 8 shows that 43 out of 53 publications (81%) provided descriptions of their data extraction algorithm. In the case of machine learning and neural networks, we looked for a description of hyperparameters and feature generation, and for the details of implementation (e. g. the machine-learning framework). Hyperparameters were rarely described in full, but if the framework (e.g., Scikit-learn, Mallet, or Weka) was given, in addition to a description of implementation and important parameters for each classifier, then we rated the algorithm as fully described. For rule-based methods we looked for a description of how rules were derived, and for a list of full or representative rules given as examples. Where multiple data extraction approaches were described, we gave a positive rating if the best-performing approach was described.\n\n3.4.2.2 Is there a description of the dataset used and of its characteristics?\n\nOf the included publications, 50 out of 53 (94%) provided descriptions of their dataset and its characteristics.\n\nMost publications provided descriptions of the dataset(s) used for training and evaluation. The size of each dataset, as well as the frequencies of classes within the data, were transparent and described for most included publications. All datasets, along with a short description and availability of the data, are shown in Table 4.\n\nRCT, randomized controlled trials; IR, information retrieval; PICO, population, intervention, comparison, outcome; UMLS, unified medical language system.\n\n3.4.2.3 Is there a description of the hardware used?\n\nMost included publications did not report their hardware specifications, though five publications (9%) did. One, for example, applied their system to new, unlabelled data and reported that classifying the whole of PubMed takes around 20 hours using a graphics processing unit (GPU).39 In another example, the authors reported using Google Colab GPUs, along with estimates of computing time for different training settings.68\n\n3.4.2.4 Is the source code available?\n\nFigure 9 shows that most of the included publications did not provide any source code. Publications that did provide the source code were exclusively published or last updated in the last five years (n = 8). GitHub is the most popular platform for making code accessible. Some publications also provided links to notebooks on Google Colab, which is a cloud-based platform to develop and execute code online. Two publications provided access to parts of the code, or access was restricted. A full list of code repositories from the included publications is available in Table 2.\n\n3.4.3 Testing\n\n3.4.3.1 Is there a justification/an explanation of the model assessment?\n\nOf the included publications, 47 out of 53 (89%) gave a detailed assessment of their data extraction algorithms. We rated this item as negative if only the performance scores were given, i.e., if no error analysis was performed and no explanations or examples were given to illustrate model performance. In most publications a brief error analysis was common, for example discussions on representative examples for false negatives and false positives,41 major error sources63 or highlighting errors with respect to every entity class.49 Both44,45 used structured and unstructured abstracts, and therefore discussed the implications of unstructured text data for classification scores.\n\nA small number of publications did a real-life assessment, where the data extraction algorithm was applied to different, unlabelled, and often much larger datasets or tested while conducting actual systematic reviews.30,33,39,42,68,71,72\n\n3.4.3.2 Are basic metrics reported (true/false positives and negatives)?\n\nFigure 10 shows the extent to which all basic metrics were reported in the included publications. In most publications (n = 40) these basic metrics are not reported. When dealing with entity-level data extraction it can be challenging to define the quantity of true negative entities. This is true especially if entities are labelled and extracted based on text chunks, because there can be many combinations of phrases and tokens that constitute an entity.41 This problem was solved in more recent publications by conducting a token-based evaluation that computes scores across every single token, hence gaining the ability to score partial matches for multi-word entities.47\n\nFor each included paper. More than one selection is possible, which means that the total number of included publications (n=53) is lower than the sum of counts within this figure.\n\n3.4.3.3 Does the assessment include any information about trade-offs between recall or precision (also known as sensitivity and positive predictive value)?\n\nOf the included publications, 17 out of 53 (32%) described trade-offs or provided plots or tables showing the development of evaluation scores if certain parameters were altered or relaxed. Recall (i.e., sensitivity) is often described as the most important metric for systematic review automation tasks, as it is a methodological demand that systematic reviews do not exclude any eligible data.\n\n49,31 showed how the decision of extracting the top two or N predictions impacts the evaluation scores, for example precision or recall.72 show precision-recall plots for different classification thresholds.50 show four cut-offs, whereas68 show different probability thresholds for their classifier, and describe the impacts of this on precision, recall, and F1 curves.\n\nSome machine-learning architectures need to convert text into features before performing classification. A feature can be, for example, the number of times that a certain word occurs, or the length of an abstract. The number of features used, e. g. for CRF algorithms, which was given in multiple publications,65 together with a discussion of classifiers that should be used in high recall is needed73.28 show ROC curves quantifying the amount of training data and its impact on the scores.\n\n3.4.4 Availability of the final model or tool\n\n3.4.4.1 Can we obtain a runnable version of the software based on the information in the publication?\n\nCompiling and testing code from every publication is outside the scope of this review. Instead, in Figure 11 and Table 3 we recorded the publications where a (web) interface or finished application was available. Counting RobotReviewer and Trialstreamer as separate projects, 9% of the included publications had an application associated with it.\n\n3.4.4.2 Persistence: Can data be retrieved based on the information given in the publication?\n\nSeven of the included publications (13%) made their datasets publicly available. Whereas 17 publications (32%) reported using at least one dataset published elsewhere. Of those 17, datasets used in six publications were not publicly available, but in these cases, there were often overlaps of at least one author in the author teams, explaining facilitated access to data. A further 29 (55%) publications appeared to have curated their own datasets.\n\nIn total, we counted 36 unique corpora with labelled data. Table 4 shows a summary of the corpora, their size, classes, and cross-reference to known publications re-using each data set. Where available, we collected the corpora, provide a central link to all datasets, and will add datasets as they become available during the life span of this living review (see Underlying data86,87 below). When a dataset is made freely available without barriers (i.e., direct downloads of text and labels), then large numbers of researchers can re-use the data and publish results from different models, which become comparable to one another. Copyright issues surrounding data sharing were noted by,48 therefore they shared the gold-standard annotations used as training or evaluation data and information on how to obtain the texts.\n\n3.4.4.3 Is the use of third-party frameworks reported and are they accessible?\n\nOf the included publications, 47 out of 53 (88%) described using at least one third-party framework for their data extraction systems. The following list is likely to be incomplete, due to non-available code and incomplete reporting in the included publications. Most commonly, there was a description of machine-learning toolkits (Mallet, N = 12; Weka, N = 6; tensorflow, N = 5; scikit-learn, N = 3). Natural language processing toolkits such as Stanford parser/CoreNLP (N = 12) or NLTK (N = 3), were also commonly reported for the pre-processing and dependency parsing steps within publications. The MetaMap tool was used in nine publications, and the GENIA tagger in four. For the complete list of frameworks please see Appendix A in Underlying data.86\n\n3.4.5 Internal and external validity of the model\n\n3.4.5.1 Does the dataset or assessment measure provide a possibility to compare to other tools in the same domain?\n\nWith this item we aimed to assess publications to see if the evaluation results from models are comparable with the results from other models. Ideally, a publication would have reported the results of another classification model on the same dataset, either by re-implementing the model themselves69 or by describing results of other models when using benchmark datasets.35 This was rarely the case for the publications in this review, as most datasets were curated and used in single publications only (see Table 4).\n\nHowever, in 40 publications (75%) data were well described, and they utilised commonly used entities and common assessment metrics, such as precision, recall, and F1-scores, leading to a limited comparability of results. In these cases, the comparability is limited because those publications used different data sets, which can influence the difficulty of the data extraction task and lead to better results within for example structured datasets or topic-specific datasets.\n\n3.4.5.2 Are explanations for the influence of both visible and hidden variables in the dataset given?\n\nThis item relates only to publications using machine learning or neural networks. Rule-based classification systems (N = 8, 15% reporting rule-base as sole approach) are not applicable to this item, because the rules leading to decisions are intentionally chosen by the creators of the system and are therefore always visible.\n\nTen publications (19%) discussed hidden variables.56 discussed that the identification of the treatment group entity yielded the best results. However, when neither the words ‘group’ nor ‘arm’ were present in the text then the system had problems with identifying the entity. ‘Trigger tokens’43 and the influence of common phrases were also described by,38 the latter showed that their system was able to yield some positive classifications in the absence of common phrases.73 went a step further and provided a table with words that had the most impact on the prediction of each class.32 describes removing sentence headings in structured abstracts in order to avoid creating a system biased towards common terms, while63 discussed abbreviations and grammar as factors influencing the results. Length of input text34 and position of a sentence within a paragraph or abstract, e. g. up to 10% lower classification scores for certain sentence combinations in unstructured abstracts, were shown in several publications.30,37,72\n\n3.4.5.3 Is the process of avoiding overfitting or underfitting described?\n\n‘Overfitted’ is a term used to describe a system that shows particularly good evaluation results on a specific dataset because it has learned to classify noise and other intrinsic variations in the data as part of its model.83\n\nOf the included publications, 33 out of 53 (62%) reported that they used methods to avoid overfitting. Eight (15%) of all publications reported rule-based classification as their only approach, allowing them to not be susceptible to overfitting by machine learning.\n\nFurthermore, 28 publications reported cross-validation to avoid overfitting. Mostly these classifiers were in the domain of machine-learning, e. g. SVMs. Most commonly, 10 folds were used (N = 15), but depending on the size of evaluation corpora, 3, 6, 5 or 15 folds were also described. Two publications (58,47) cautioned that cross-validation with a high amount of folds (e. g. 10) causes high variance in evaluation results when using small datasets such as NICTA-PIBOSO. One publication43 stratified folds by class in order to avoid this variance in evaluation results in a fold which is caused by a sparsity of positive instances.\n\nPublications in the neural and deep-learning domain described approaches such as early stopping, dropout, L2-regularisation, or weight decay.34,69,74 Some publications did not specifically discuss overfitting in the text, but their open-source code indicated that the latter techniques were used.47,48\n\n3.4.5.4 Is the process of splitting training from validation data described?\n\nRandom allocation to treatment groups is an important item when assessing bias in RCTs, because selective allocation can lead to baseline differences.1 Similarly the process of splitting a dataset randomly, or in a stratified manner, into training (or rule-crafting) and test data is important when constructing classifiers and intelligent systems.84\n\nAll included publications gave indications of how different train and evaluation datasets were obtained. Most commonly there was one dataset and the splitting ratio which indicated that splits were random. This information was provided in 36 publications (68%).\n\nFor publications mentioning cross-validation (N = 28, 53%) we assumed that splits were random. The ratio of splitting (e.g. 80:20 for training and test data) was clear in the cross-validation cases and was described in the remainder of publications.\n\nIt was also common for publications to use completely different datasets, or multiple iterations of splitting, training and testing (N = 13, 24%). For example,31 used cross-validation to train and evaluate their model, and then used an additional corpus after the cross-validation process. Similarly,34 used 60:40 train/test splits, but then created an additional corpus of 88 documents to further validate the model’s performance on previously unseen data.\n\n3.4.5.5 Is the model’s adaptability to different formats and/or environments beyond training and testing data described?\n\nFor this item we aimed to find out how many of the included publications tested their data extraction algorithms on different datasets. A limitation often noted in the literature was that gold-standard annotators have varying styles and preferences, and that datasets were small and limited to a specific literature search. Evaluating a model on multiple independent datasets provides the possibility of quantifying how well data can be extracted across domains and how flexible a model is in real-life application with completely new data sets. Of the included publications, 19 (36%) discussed how their model performed on datasets with characteristics that were different to those used for training and testing. In some instances, however, this evaluation was qualitative where the models were applied to large unlabelled, real-life datasets.30,33,39,42,68,71,72\n\n3.4.6 Other\n\n3.4.6.1 Caveats\n\nCaveats were extracted as free text. Included publications (N = 47, 87%) reported a variety of caveats. After extraction we structured them into six different domains:\n\n1. Label-quality and inter-annotator disagreements\n\n2. Variations in text\n\n3. Domain adaptation and comparability\n\n4. Computational or system architecture implications\n\n5. Missing information in text or knowledge base\n\n6. Practical implications\n\nThese are further discussed in the ‘Discussion’ section of this living review.\n\n3.4.6.2 Sources of funding and conflict of interest\n\nFigure 12 shows that most of the included publications did not declare any conflict of interest. This is true for most publications published before 2010, and about 50% of the literature published in more recent years. However, sources of funding were declared more commonly, with 69% of all publications including statements for this item. This reflects a trend of more complete reporting in more recent years.\n\n\n4. Discussion\n\n4.1.1 System architectures\n\nSystems described within the included publications are changing over time. Non-machine-learning data extraction via rule-base and API is one of the earliest and most frequently used approaches. Various classical machine-learning classifiers such as naïve Bayes and SVMs are very common in the literature published between 2005-2018, but in the current literature there is a trend towards word embeddings and neural networks such as LSTMs and transformers.\n\n4.1.2 Evaluation\n\nWe found that precision, recall, and F1 were used as evaluation metrics in most publications, although sometimes these metrics were adapted or relaxed in order to account for partial or similar matches.\n\n4.1.3 Scope\n\nMost of the included publications focused on extracting data from abstracts. The reasons for this include the availability of data and ease of access, as well as the high coverage of information and the availability of structured abstracts that can automatically derive labelled training data. A much smaller number of the included publications (n=14, 26%) extracted data from full texts. Half of the systems that extract data from full text were published within the last five years. In systematic review practice, manually extracting data from abstracts is quicker and easier than manually extracting data from full texts. Therefore, the potential time saving and utility of full text data extraction is much higher because more time can be saved by automation, but the data extraction literature on that topic is still sparse.\n\n4.1.4 Target texts\n\nReports of randomised controlled trials were the most common texts used for data extraction. Evidence concerning data extraction from other study types was rare and is discussed further in the following sections.\n\nThe quality of reporting in the included studies is improving over time, especially in terms of the availability of data and source code. We assessed the included publications based on a list of 17 items in the domains of reproducibility, transparency, description of testing, data availability, and internal and external validity.\n\nReproducibility was high throughout, with sources of training and evaluation data reported in 94% of all publications and pre-processing described in 89%.\n\nIn terms of transparency, 81% of the publications provided a clear description of their algorithm, 94% described the characteristics of their datasets, but only 9% mentioned hardware specifications or feasibility of using their algorithm on large real-world datasets such as PubMed. Availability of source code was low (15%) and was only observed in recent publications.\n\nTesting of the systems was generally described, 89% gave a detailed assessment of their algorithms. Basic metrics were reported in 24%, trade-offs between precision and recall were discussed in 32%.\n\nAvailability of the final models and tools was very poor. We found that only 11% of all publications are based on tools that are available and have a graphical user interface, and it is unclear how many of the other tools described in the literature are used in practice. Labelled training and evaluation data are available from 13% of the publications, but only a further 32% of all publications reported using one of these available datasets. A total of 88% of the publications described using at least one accessible third-party framework for their data extraction system.\n\nInternal and external validity of each model was assessed based on its comparability to other tools (75%), assessment of visible and hidden variables in the data (19%), avoiding overfitting (62%, not applicable to non-machine learning systems), descriptions of splitting training from validation data (100%), and adaptability and external testing on datasets with different characteristics (36%). These items, together with caveats and limitations noted in the included publications are discussed in the following section.\n\nIn the following section we discuss caveats and challenges highlighted by the authors of the included publications. We found a variety of topics discussed in these publications and summarised them under seven different domains.\n\n4.3.1 Label-quality and inter-annotator disagreements\n\nThe quality of labels in annotated datasets was identified as a problem by several authors. The length of the entity being annotated, for example O or P entities, often caused disagreements between annotators.30,33,39,42,68,71,72 We created an example in Figure 13, which shows two potentially correct, but nevertheless different annotations on the same sentence.\n\nP, population; I, intervention; C, comparison; O, outcome.\n\nSimilar disagreements,36,43,58 along with missed annotations,50 are time-intensive to reconciliate70 and make the scores less reliable.68 As examples of this, two publications observed that their system performed worse on classes with high disagreement.43,48 There exist different explanations for worse performance in these cases. It is possibly harder for models to learn from labelled data with systematic differences within. Another reason is that the model learns predictions based on one annotation style and therefore artificial errors are produced when evaluated against differently labelled data, or that the annotation task itself is naturally harder in cases with high inter-annotator disagreement, and therefore lower performance from the models might be explainable. An overview of the included publications discussing this, together with their inter-annotator disagreement scores, is given in Table 5.\n\nTo mitigate these problems, careful training and guides for expert annotators are needed.33,51 For example, information should be provided on whether multiple basic entities or one longer entity annotation are preferred.58 Crowd-sourced annotations can contain noisy or incorrect information and have low interrater reliability. However, they can be aggregated to improve quality.47 In recent publications, partial entity matches (i.e., token-wise evaluation) downstream were generally favoured above complete detection, which helps to mitigate this problem’s impact on final evaluation scores.47,56\n\nFor automatically labelled or distantly supervised data, label quality is generally lower. This is primarily caused by incomplete annotation due to missing headings, or by ambiguity in sentence data, which is discussed as part of the next domain.29,32,73\n\n4.3.2 Ambiguity\n\nThe most common source of ambiguity in labels described in the included publications is associated with automatically labelled sentence-level data. Examples of this are sentences that could belong to multiple categories, e.g., those that should have both ‘P’ and an ‘I’ label, or sentences that were assigned to the class ‘other’ while containing PICO information (46,68,69, among others). Ambiguity was also discussed with respect to intervention terms49 or when distinguishing between ‘control’ and ‘intervention’ arms.30 When using, or mapping to UMLS concepts, ambiguity was discussed in.27,44,50\n\nAt the text level, ambiguity around the meaning of specific wordings was discussed as a challenge, e.g., the word 'concentration' can be a quantitative measure or a mental concept.27 Numbers were also described as challenging due to ambiguity, because they can refer to the total number of participants, number per arm of a trial, or can just refer to an outcome-related number.57,79 When classifying participants, the P entity or sentence is often overloaded because it includes too much information on different, smaller, entities within it, such as age, gender, or diagnosis.62\n\n4.3.3 Variations in text\n\nVariations in natural language, wording, or grammar were identified as challenges in many references that looked closer at the texts within their corpora. Such variation may arise when describing entities or sentences (e.g.,42,53,70) or may reflect idiosyncrasies specific to one data source, e.g., the position of entities in a specific journal.30 In particular, different styles or expressions were noted as caveats in rule-based systems.28,42,54\n\nThere is considerable variation in how an entity is reported, for example between intervention types (drugs, therapies, routes of application)31 or in outcome measures.30 In particular, variations in style between structured and unstructured abstracts36,52 and the description lengths and detail34,53 can cause inconsistent results in the data extraction, for example by not detecting information correctly or extracting unexpected information. Complex sentence structure was mentioned as a caveat especially for rule-based systems.54 An example of a complex structure is when more than one entity is described (e.g.,66,72) or when entities such as ‘I’ and ‘O’ are mentioned close to each other.32 Finally, different names for the same entity within an abstract are a potential source of problems.57\n\nAnother common variation in text was implied information. For example, rather than stating dosage specifically, a trial text might report dosages of '10 or 20mg', where the ‘mg’ unit is implied for the number 10, making it a ‘dosage’ entity.30,42,63\n\n4.3.4 Domain adaptation and comparability\n\nBecause of the wide variation across medical domains, there is no guarantee that a data extraction system developed on one dataset automatically adapts to produce reliable results across different datasets relating to other domains. The hyperparameter configuration or rule-base used to conceive a system may not retrieve comparable results in a different medical domain.24,38 Therefore, scores might not be similar between different datasets, especially for rule-based classifiers,54 when datasets are small,26 when structure and distribution of class of interest varies,24 or when the annotation guidelines vary.58 Another caveat mentioned by58,34 is that the size of the label space must be considered when comparing scores, as models that normalise to specific concepts rather than detecting entities tend to have lower precision, recall, and F1 scores.\n\nFinally, several publications discuss that a larger amount of benchmarking datasets could increase the comparability between published systems.30,65,80\n\n4.3.5 Computational or system architecture implications\n\nComputational cost and scalability were described in two publications.45,80 Problems within the system, e.g., encoding70 or PDF extraction errors48 lead to problems downstream and ultimately result in bias, favouring articles from big publishers with better formatted data.48 Similarly, grammar and parsing part-of-speech and/or chunking errors (49,54,63, among others) or faulty parse-trees52 can reduce a system’s performance if it relies on access to correct grammatical structure. In terms of system evaluation, 10-fold cross-validation causes high variance in results when using small datasets such as NICTA-PIBOSO,46,58 and43 described that the same problem needs to be addressed through stratification of the positive instances of each class within folds.\n\n4.3.6 Missing information in text or knowledge base\n\nInformation in text can be incomplete.80 For example, the number of patients in a study might not be explicitly reported,49 or abstracts lacking information about study design and methods can appear, especially in unstructured abstracts and older trial texts.64,66 In some cases, abstracts can be missing entirely. These problems can sometimes be solved by considering the use of full texts as input.40,60\n\nWhere a model relies on features, e.g., MetaMap, then missing UMLS coverage causes errors.49,50 This also applies to models like CNNs that assign specific concepts, where unseen entities are not defined in the output label space.34\n\n4.3.7 Practical implications\n\nIn contrast to the problem of missing information, too much information can also have practical implications. For instance, often there are multiple sentences with each label, of which one is ‘key’, e.g., the descriptions of inclusion and exclusion criteria often span multiple sentences, and for a data extraction system it can be challenging to work out which sentence is the key sentence. The same problem applies to methods that select and rank the top-n sentences for each data extraction target, where a system risks including too much, or not enough results depending on the amount of sentences that are kept.30\n\nLow recall is an important practical implication,45 especially in entities that appear infrequently in the training data, and are therefore not well represented in the training process of the classification system.42 In other words, an entity such as ‘Race’ might not be labelled very often is a training corpus, and systematically missed or wrongly classified when the data extraction system is used on new texts. Therefore, human involvement is needed,59 and scores need to be improved.27 It is challenging to find the best set of hyperparameters74 and to adjust precision and recall trade-offs to maximise the utility of a system while being transparent about the number of data points that might be missed when increasing system precision to save work for a human reviewer.39,68,71\n\nThe neural networks or machine-learning models from publications included in this review learn to classify and extract data by adjusting numerical weights and by applying mathematical functions to these sets of weights. The decision-making process behind the classification of a sentence or an entity is therefore comparable with a black box, because it is very hard to comprehend how, or why the model made its predictions. A recent comment published in Nature has called for a more in-depth analysis and explanation of the decision-making process within neural networks.84 Ultimately, hidden tendencies in the training data can influence the decision-making processes of a data extraction model in a non-transparent way. Many of the examples discussed in the comment are related to healthcare, but in practice there is a very limited understanding of their inherent biases despite the broad application of machine learning and neural networks.84\n\nA deeper understanding of what occurs between data entry and the point of prediction can benefit the general performance of a system, because it uncovers shortcomings in the training process. These shortcomings can be related to the composition of training data (e. g. overrepresentation or underrepresentation of groups), the general system architecture, or to other unintended tendencies in a system’s prediction.85 A small number of included publications (N = 10) discussed issues related to hidden variables as part of an extensive error analysis (see section 3.5.2). The composition of training and testing data were described in most publications, but no publication that specifically addresses the issues of interpretability or explainability was found.\n\nThere are several corpora described in the literature, many with manual gold-standard labels. However, the number of shared datasets remains low (see Table 4). Possible reasons for this are concerns over copyright, or malfunctioning download links from websites mentioned in older publications. Ideally, data extraction algorithms should be evaluated on different datasets in order to detect over-fitting, to test how the systems react to data from different domains and different annotators, and to enable the comparison of systems in a reliable way. As a supplement to this manuscript, we have created an online repository for available datasets, and encourage researchers to share their automatically or manually annotated labels and texts so that other researchers may use them for development and evaluation of new data extraction systems.\n\nThis review focused on data extraction from reports of clinical trials and epidemiological research. This mostly includes data extraction from reports of randomised controlled trials, and only a very small fraction of the evidence that addresses other important study types (e.g., diagnostic accuracy studies). During screening we excluded all publications related to clinical data (such as electronic health records) and publications extracting disease, population, or intervention data from genetic and biological research. There is a wealth of evidence and potential training and evaluation data in these publications, but it was not feasible to include them in the living review.\n\n\n5. Conclusion\n\nThis living review presents an overview of the data-extraction literature of interest to different types of systematic review. We included a broad evidence base of publications describing data extraction for interventional systematic reviews (focusing on P, IC, and O classes and RCT data), and a very small number of publications extracting epidemiological and diagnostic accuracy data. However, the number of accessible tools that can help systematic reviewers with data extraction is very low. Currently, only around one in ten publications is linked to a usable tool or describes an ongoing implementation.\n\nThe data extraction algorithms and the characteristics of the data they were trained and evaluated on were well reported. However, only around one in ten publications made their datasets available to the public, and only a third of all included publications reported training or evaluating on these datasets. This makes it very difficult to draw conclusions on which is the best performing system. Additionally, data extraction is a very hard task. It usually requires conflict resolution between expert systematic reviewers when done manually, and consequently creates problems when creating the gold standards used for training and evaluation of the algorithms in this review.\n\nWe listed many ongoing challenges in the field of data extraction for systematic review (semi) automation, including ambiguity in clinical trial texts, incomplete data, and previously unseen data. With this living review we aim to review the literature continuously as it becomes available. Therefore, the most current review version, along with the number of abstracts screened and included after the publication of this review iteration, is available on our website.\n\n\nData availability\n\nHarvard Dataverse: Appendix for base review. https://doi.org/10.7910/DVN/LNGCOQ.86\n\nThis project contains the following underlying data:\n\n• Appendix_A.zip (full database with all data extraction and other fields)\n\n• Appendix B.docx (further information about excluded publications)\n\n• Appendix_C.zip (code, weights, data, scores of abstract classifiers for Web of Science content)\n\n• Supplementary_key_items.docx (overview of items extracted for each included study)\n\n• table 1. csv and table 1_long.csv (Table 1 in csv format, the long version includes extra data)\n\n• included.ris and background.ris (literature references in this paper)\n\nHarvard Dataverse: Available datasets for SR automation. https://doi.org/10.7910/DVN/0XTV25.87\n\nThis project contains the following underlying data:\n\n• Datasets shared by authors of the included publications\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nOpen Science Framework: Data Extraction Methods for Systematic Review (semi)Automation: A Living Review Protocol. https://doi.org/10.17605/OSF.IO/ECB3T.9\n\nThis project contains the following extended data:\n\n• Review protocol\n\n• Additional_Fields.docx (overview of data fields of interest for text mining in clinical trials)\n\n• Search.docx (additional information about the searches, including full search strategies)\n\n• PRISMA P checklist for ‘Data extraction methods for systematic review (semi)automation: A living review protocol.’\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nHarvard Dataverse: PRISMA checklist for ‘Data extraction methods for systematic review (semi)automation: A living systematic review’ https://doi.org/10.7910/DVN/LNGCOQ.86\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nSoftware availability\n\nThe development version of the software for automated searching is available from Github: https://github.com/mcguinlu/COVID_suicide_living.\n\nArchived source code at time of publication: http://doi.org/10.5281/zenodo.3871366 (14).\n\nLicense: MIT\n\n\nAuthor contributions\n\nLS: Conceptualization, Investigation, Methodology, Software, Visualization, Writing – Original Draft Preparation\n\nBKO: Conceptualization, Investigation, Methodology, Software, Writing – Review & Editing\n\nLAM: Conceptualization, Validation, Methodology, Software, Writing – Review & Editing\n\nJT: Conceptualization, Investigation, Methodology, Writing – Review & Editing\n\nJPTH: Conceptualization, Funding Acquisition, Investigation, Methodology, Writing – Review & Editing",
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PubMed Abstract | Publisher Full Text | Free Full Text\n\nRaja K, et al.: A Hybrid Citation Retrieval Algorithm for Evidence-based Clinical Knowledge Summarization: Combining Concept Extraction, Vector Similarity and Query Expansion for High Precision. CoRR. 2016. abs/1609.01597.\n\nFiszman M, et al.: Interpreting comparative constructions in biomedical text.2007: 137–144.\n\nKarystianis G, Buchan I, Nenadic G: Mining characteristics of epidemiological studies from Medline: a case study in obesity. J Biomed Semantics. 2014; 5: 11. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHassanzadeh H, Groza T, Hunter J: Identifying scientific artefacts in biomedical literature: The Evidence Based Medicine use case. J Biomed Inform. 2014; 49: 159–170. PubMed Abstract | Publisher Full Text\n\nKim S, et al.: Automatic classification of sentences to support Evidence Based Medicine. BMC Bioinform. 2011; 12(S-2): S5. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVerbeke M, et al.: A Statistical Relational Learning Approach to Identifying Evidence Based Medicine Categories.2012. p. 579–589.\n\nJin D, Szolovits P: Advancing PICO element detection in biomedical text via deep neural networks. Bioinform. 2020; 36(12): 3856–3862. PubMed Abstract | Publisher Full Text\n\nNye B, et al.: A Corpus with Multi-Level Annotations of Patients, Interventions and Outcomes to Support Language Processing for Medical Literature. Proc Conf Assoc Comput Linguist Meet. 2018; 2018: 197–207. PubMed Abstract | Free Full Text\n\nNorman CR, et al.: A distantly supervised dataset for automated data extraction from diagnostic studies.2019. p. 105–114. Publisher Full Text\n\nDemner-Fushman D, Lin J: Knowledge Extraction for Clinical Question Answering: Preliminary Results. 2005.\n\nXu H, et al.: Mining Biomedical Literature for Terms related to Epidemiologic Exposures. AMIA Annu Symp Proc. 2010; 2010: p. 897–901. PubMed Abstract | Free Full Text\n\nLin S, et al.: Extracting Formulaic and Free Text Clinical Research Articles Metadata using Conditional Random Fields.2010. p. 90–95.\n\nXu R, et al.: Extracting Subject Demographic Information From Abstracts of Randomized Clinical Trial Reports.2007. p. 550–554. PubMed Abstract\n\nZhao J, Bysani P, Kan M-Y: Exploiting Classification Correlations for the Extraction of Evidence-based Practice Information.2012. PubMed Abstract | Free Full Text\n\nRaja K, et al.: Towards Evidence-based Precision Medicine: Extracting Population Information from Biomedical Text using Binary Classifiers and Syntactic Patterns. AMIA Jt Summits Transl Sci Proc. 2016; 2016: 203–212. PubMed Abstract | Free Full Text\n\nMarshall IJ, et al.: Automating Biomedical Evidence Synthesis: RobotReviewer. In: Proceedings of the 55th Annual Meeting of the Association for Computational Linguistics. ed. Bansal M, Ji H. 2017Stroudsburg: Assoc Computational Linguistics-Acl. 7–12.\n\nSummerscales RL, A S, Hupert J, et al.: Identifying treatments, groups, and outcomes in medical abstracts.2009.\n\nSummerscales RL, et al.: Automatic Summarization of Results from Clinical Trials. in: 2011 IEEE International Conference on Bioinformatics and Biomedicine. 2011.\n\nKang T, Zou S, Weng C: Pretraining to Recognize PICO Elements from Randomized Controlled Trial Literature. Stud Health Technol Inform. 2019; 264: 188–192. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBui DDA, et al.: Extractive text summarization system to aid data extraction from full text in systematic review development. J Biomed Inform. 2016; 64: 265–272. PubMed Abstract | Publisher Full Text | Free Full Text\n\nXia Y, et al.: Extracting PICO elements from RCT abstracts using 1-2gram analysis and multitask classification. CoRR. 2019. abs/901.08351. Publisher Full Text\n\nValdez J, et al.: An Ontology-Enabled Natural Language Processing Pipeline for Provenance Metadata Extraction from Biomedical Text. in: On the Move to Meaningful Internet Systems: Otm. 2016 Conferences, Debruyne C, et al., Editors. 2016; Springer Int Publishing Ag: Cham. p. 699–708.\n\nChung GY: Sentence retrieval for abstracts of randomized controlled trials. BMC Med Inform Decis Mak. 2009; 9: 13. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChung GYC: Towards identifying intervention arms in randomized controlled trials: Extracting coordinating constructions. J Biomed Inform. 2009; 42(5): 790–800. PubMed Abstract | Publisher Full Text\n\nChung G, Coiera EW: A Study of Structured Clinical Abstracts and the Semantic Classification of Sentences.2007. p. 121–128.\n\nHuang K, et al.: Classification of PICO elements by text features systematically extracted from PubMed abstracts. 2011 IEEE International Conference on Granular Computing. 2011.\n\nHara K, Matsumoto Y: Extracting Clinical Trial Design Information from MEDLINE Abstracts. New Gener. Comput. 2007; 25(3): 263–275. Publisher Full Text\n\nZhu H, et al.: Automatic extracting of patient-related attributes: disease, age, gender and race. Stud Health Technol Inform. 2012; 180: 589–593. PubMed Abstract\n\nSchmidt L, Weeds J, Higgins JPT: Data Mining in Clinical Trial Text: Transformers for Classification and Question Answering Tasks.2020. p. 83–94.\n\nJin D, Szolovits P: PICO Element Detection in Medical Text via Long Short-Term Memory Neural Networks.2018. p. 67–75. Publisher Full Text\n\nDemner-Fushman D, et al.: Finding medication doses in the liteature. AMIA Annu Symp Proc. 2018; 2018: p. 368–376. PubMed Abstract | Free Full Text\n\nNye BE, et al.: Trialstreamer: Mapping and Browsing Medical Evidence in Real-Time. CoRR. 2020. abs/2005.10865.\n\nBlake C, Lucic A: Automatic endpoint detection to support the systematic review process. J Biomed Inform. 2015; 56: 42–56. PubMed Abstract | Publisher Full Text\n\nHuang KC, et al.: PICO element detection in medical text without metadata: are first sentences enough? J Biomed Inform. 2013; 46(5): 940–946. PubMed Abstract | Publisher Full Text\n\nBrockmeier AJ, et al.: Improving reference prioritisation with PICO recognition. BMC Med Inform Decis Mak. 2019; 19(1): 14. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGella S, Long DT: Automatic sentence classifier using sentence ordering features for Event Based Medicine: Shared task system description.2012. p. 130–133.\n\nLui M: Feature Stacking for Sentence Classification in Evidence-Based Medicine.2012: 134–138.\n\nMollá D: Experiments with Clustering-based Features for Sentence Classification in Medical Publications: Macquarie Test's participation in the ALTA 2012 shared task.2012: 139–142.\n\nSarker A, et al.: An Approach for automatic multi-label classification of medical sentences. NICTA: Eveleigh NSW; 2013.\n\nHansen MJ, Rasmussen G, Fau - Chung NØ, et al.: A method of extracting the number of trial participants from abstracts describing randomized controlled trials. (1758-1109 (Electronic)).\n\nBoudin F, et al.: Combining classifiers for robust PICO element detection. BMC Med Inform Decis Mak. 2010; 10: 29. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChabou S, Iglewski M; Ieee: PICO Extraction by combining the robustness of machine-learning methods with the rule-based methods. 2015 World Congress on Information Technology and Computer Applications. 2015. New York: Ieee.\n\nDawes M, et al.: The identification of clinically important elements within medical journal abstracts: Patient-Population-Problem, Exposure-Intervention, Comparison, Outcome, Duration and Results (PECODR). Inform Prim Care. 2007; 15(1): 9–16. PubMed Abstract\n\nBurnham KP, Anderson DR: Model Selection and Multimodel Inference (2nd ed.).2002; Springer-Verlag.\n\nRiley P: Three pitfalls to avoid in machine learning. Nature. 2019; 572(7767). PubMed Abstract | Publisher Full Text\n\nMehrabi N, et al.: A survey on bias and fairness in machine learning. arXiv. 2019.\n\nSchmidt L; Appendix for base review. Harvard Dataverse, V4, UNF:6:0z0ZlKmB1VglRVObRackrw== [fileUNF] 2020. Publisher Full Text\n\nSchmidt L; Available datasets for SR automation. Harvard Dataverse, V1. 2021. Publisher Full Text"
}
|
[
{
"id": "85692",
"date": "08 Jun 2021",
"name": "Emma McFarlane",
"expertise": [
"Reviewer Expertise Evidence-based medicine",
"systematic reviews",
"automation techniques."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a living systematic review of published methods and tools aimed at automating or semi-automating the process of data extraction in the context of a systematic review. Automating data extraction is an area of interest among evidence-based medicine.\n\nThe methods are sufficiently described to be replicated, but further details of analysis to determine the items of interest would be helpful to link into the results. Additionally, the authors may want to consider commenting on the topic areas covered by the included studies and whether that has an impact on any of the metrics measured.\n\nIn the discussion section, it's interesting that fewer studies extracted data from the full text. Could the authors comment on the implications of this in terms of using tools in a live review as it's not common to manually only extract data from an abstract.\n\nIs the living method justified? Yes\n\nHave the search and update schedule been clearly defined and justified? Yes\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Partly\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
},
{
"id": "89348",
"date": "12 Aug 2021",
"name": "Kathryn A. Kaiser",
"expertise": [
"Reviewer Expertise Systematic reviews in biomedicine topics",
"issues with time and effort required to complete reviews with generally available tools."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have undertaken and documented the steps taken to monitor an area of research methods that is important to many around the world by use of a “living systematic review”. The specific focus is on automated or semi-automated data extraction around the PICO structure often used in biomedicine, whether it be to summarize a body of literature narratively or using meta-analysis techniques. A significant irony about the body of papers included in this review is that there is a large amount of missingness related to the performance of such methods. Those who conduct systematic reviews know well the degree of missing information sought to summarize a group of studies.\nReaders who will be most interested in this ongoing work can maintain an eye on the authors’ progress in identifying activities in this space. It is not clear, however, how long the funding will support this effort or how long the authors will remain engaged in advancing this project. The data represented in this paper does not give readers confidence that the community is approaching acceptable methods that are superior to other, less automated methods (the latter of which are not well-discussed).\nSome aspects of the paper would benefit from additional detail (in no particular order of importance):\nThe end game for the tracking of this area of literature is not explicitly described in the abstract, nor is it discussed to a great extent at the end of the paper. Much of the results presented do not paint a bright future for this area of research as conditions presently are. While the aim is laid out well in section 1.2, the large amount of missing performance data (reported to be 87%) is unable to address the “Is it reliable?” question. One might suspect that if particularly stellar performance were demonstrated by a project, those data would be prominently advertised. Thus, the yet-to-be-done contacting of authors step would be enlightening if either performance data can be obtained, or if authors remain silent on that request. This follow-up task will be a major point of interest for many who will follow updates to this paper. It is likely that the particular research context (e.g. see Pham et al., 20211) will have a large degree of influence on the performance metrics to be had if they can be determined.\n\nThe description of how the 17 “Key items of interest” were determined and if there is a plan to put these forth as methodological guidelines or a reporting checklist would be helpful. Either of these would help to advance the field further.\n\nOn Page 5, the exclusions listed have the use of pre-processing of text, yet the results discuss the many papers that appear to have used that in their methods. Perhaps this is a deviation from the original protocol after the review began (an understandable decision)?\n\nIn section 2.4 about searching Pubmed, can the authors clarify that the Pubmed 2.0 API or GUI will be used to access candidate literature?\n\nAlso relevant to section 2.4 on searching, since GITHUB is so popular, might this also be a fruitful place to routinely search?\n\nClarification of the ability to obtain cited software packages (whether for no cost or at some cost) would be helpful.\n\nFigure 3 explanation of PICO is a typo – “PCIO”.\n\nTable 5 is shown before Table 1. Please check and correct flow and references to table numbers (5,1,4,2,3 is the flow now).\n\nOne of the major limitations to be noted is the unfortunate issue of the lack of specific data in abstracts about interventions and comparators.\n\nIs the living method justified? Yes\n\nHave the search and update schedule been clearly defined and justified? Yes\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
},
{
"id": "89347",
"date": "26 Aug 2021",
"name": "Carmen Amezcua-Prieto",
"expertise": [],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nData extraction in a systematic review is a hard and time-consuming task. The (semi) automation of data extraction in systematic reviews is an advantage for researchers and ultimately for evidence-based clinical practice. This living systematic review examines published approaches for data extraction from reports of clinical studies published up to a cut-off date of 22 April 2020. The authors included more than 50 publications in this version of their review that addressed extraction of data from abstracts, while less (26%) used full texts. They identified more publications describing data extraction for interventional reviews. Publications extracting epidemiological or diagnostic accuracy data were limited.\nMain important issues have been addressed in the systematic review:\nThis living systematic review has been justified. The field of systematic review (semi) automation is evolving rapidly along with advances in language processing, machine learning, and deep learning.\n\nSearching and update schedules have been clearly defined, shown in Figure 1.\n\nThere are sufficient details of the methods and analysis provided to allow replication.\n\nConclusions are drawn adequately supported by the results presented in the review.\n\nA minor consideration is suggested:\n\nAn incomplete sentence in Methods: ‘We included reports published from 2005 until the present day, similar to’.\n\nIs the living method justified? Yes\n\nHave the search and update schedule been clearly defined and justified? Yes\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-401
|
https://f1000research.com/articles/12-1296/v1
|
09 Oct 23
|
{
"type": "Research Article",
"title": "Households with and without the presence of adolescents, probability of expenditure on food consumed away from home, according to ENAHO 2021: a cross-sectional study",
"authors": [
"Michelle Lozada-Urbano",
"Giuliana Del Castillo",
"Soledad Dionisia Llañez",
"Maria Luisa Dextre",
"Angel Porfirio Padilla Sarria",
"Franklin Huamán",
"Delsi Mariela Huaita Acha",
"Oriana Rivera-Lozada",
"Giuliana Del Castillo",
"Soledad Dionisia Llañez",
"Maria Luisa Dextre",
"Angel Porfirio Padilla Sarria",
"Franklin Huamán",
"Delsi Mariela Huaita Acha",
"Oriana Rivera-Lozada"
],
"abstract": "Background: The objective of this study was to compare the probability of spending on food consumed outside the home in families with and without adolescents. Methods: This is a cross-sectional, quantitative study, developed with the report from the National Household Survey (ENAHO) of Peru for the year 2021. Households selected from the database included those with an adolescent and without an adolescent in its composition and who made expenditures on food consumed away from home. Households were selected according to number of household members, place of origin, sex of the self-reported head of the household, ethnicity, educational attainment, marital status of the head of the household, age of the head of the household, and according to the poverty variable. Results: Households with adolescents and without adolescents spend monthly in Food away from home [Peruvian Soles (USD), SD]; [216.1 (57.17), 3.82] and [159.1 (42.10), 2.94] respectively. The average expenditure (Peruvian Soles) on food consumed away from home according to the poverty variable (extreme poor, poor and non-poor) in households with the presence of adolescents was (46.28, 118.89, 258.33), respectively. This expenditure in Food away from home is higher when comparing it to households without adolescents. Therefore, there is a significant expenditure in Food away from home in households with adolescents. Conclusions: It is important to create a culture for purchasing food that does not harm health. Keywords: food, expenditure, adolescents, ENAHO, poverty.",
"keywords": [
"food",
"expenditure",
"adolescents",
"ENAHO",
"poverty."
],
"content": "Introduction\n\nIn Peru, 42% of households consume food away from home.1 The consumption of food away from home is an eating behaviour that is considered mostly unhealthy,2 because these foods are often high in refined sugars, saturated fats and sodium, named critical nutrients.2–4 Likewise, said foods have already shown to provide a high energy load, and can increase the weight of those who consume them.5 The consumption of energy-dense foods can lead to non communicable diseases (NCDs), including type 2 diabetes mellitus, hypertension, cardiovascular diseases, overweight, obesity, among many others.6 These diseases bring many collateral effects with them such as low productivity and incapacity in the workplace, high costs for nosocomial hospitalization, treatment and medical surveillance, and all this as a result of the social, cultural, political and economic changes that society has experienced worldwide.7\n\nCurrently, overweight and obesity are considered two of the most dangerous chronic noncommunicable diseases (NCDs), triggering riskier disorders.8,9 According to WHO, In 1975, 4% of children and adolescents were overweight and obese, in 2016, this figure increased to 18%. Nearly 3.4 million people worldwide die from these diseases, and 3.8% of the global burden of disease is due to NCDs. Worldwide, obesity has increased almost threefold since 1975.10 In Europe alone, 12% and 18% of men and women, respectively, are obese.11 In Latin America, the child and adolescent population suffering from obesity is estimated to be around 25%.12 According to the Global School Health Survey, in Peru, the adolescent population who are overweight or obese is around 22.8%, and according to the National Institute of Health (INS) it is 24.2%, which means that one in four adolescents is overweight or obese.13\n\nMany adolescents maintain unhealthy eating behaviours or habits, such as consuming processed food,14 and foods consumed away from home,15 with a high quantity and frequency. This acquired habit is driven by different factors ranging from biological, social, family, cultural, among others.16 These factors influence the eating behaviour and tastes of young people, children, adolescents,17 and are maintained until adulthood.18 Adolescents are an important sector of the population that is going through a period of important changes and part of these changes are dietary and therefore are in a state of great vulnerability to this situation, causing an optimal life expectancy or not.18\n\nIt should be noted that dietary behaviour has different perspectives, but food consumption patterns encompass a dominant pattern given by world globalization.19,20 Multiple studies have shown the transition from consuming traditional foods to more and more processed foods. In the long term this has a great role in current public health problems.21\n\nNutritional and physical growth problems vary from place of origin, geographical regions of a country and between countries and some variables such as income, household wealth, unmet basic needs, economic stability, and food consumed away from home could explain these changes in adolescents.22 Populations are undergoing significant transformations in dietary and nutritional patterns as part of a process known as nutritional transition.20 Peru does not escape this transition process,23 so it is necessary and fundamental to study what is affecting the nutritional status of adolescents, since it is a very sensitive stage of life, which is immersed in biological, psychological and cognitive changes24 and an accelerated rate of growth and development.25\n\nHowever, in recent decades the food culture has undergone certain variations,26 largely as a result of globalization, changes in family patterns, lack of knowledge of parents, since they are directly responsible for the nutrition of family members, poor eating habits, fast food advertising, among others.27 All these factors, alone or together, are responsible for the increase in overweight and obesity.28\n\nDue to all the above mentioned, the adolescent population has been prioritized, since they are vulnerable and receptive to their entire environment, whether it be physical appearance, beliefs and preferences, or lifestyles.29 Part of these lifestyles is reflected in the consumption of food away from home.30 Likewise, consumption of food away from home is one of the predisposing factors for acquiring diseases such as NCDs.31\n\nIn this regard, there are very few studies in our environment that investigate the food consumed away from home in households where there is an adolescent. In this study, we will compare the expenditure on food consumed away from home in households where there are adolescents and in households where there are no adolescents in the year 2021. This research has been prepared based on the National Household Survey (ENAHO) 2021. This research will only look at the expenditure factor and the demographic and socioeconomic factor, even though it is known that there are other factors such as biological, psychological, cultural, that would be influencing the nutrition of adolescents and that will not be considered in this study.32\n\nThis research aims to compare the expenditure on food consumption away from home in households that have adolescents, as well as households that do not have adolescents in their composition. On the other hand, this research attempts to provide new knowledge on expenditure variables, as well as demographic and socioeconomic aspects as factors that could be influencing food consumption32 in households with adolescents and, above all, to improve the understanding and analysis of the problems of adolescent food and nutrition.33\n\nIssues related to health and nutrition have gained great prominence, since people want to maintain a healthy life.34 Likewise, it is well known that a healthy life requires optimal physical health, which can be influenced by having a balanced diet.35 As part of a balanced diet, it is essential to acquire good eating habits36 and these should be adopted by the entire population, whether children, adolescents, young people, adults or older adults.37\n\nHowever, one of the groups most vulnerable to acquiring good or bad eating habits are adolescents, due to the evolution that they are going through.38 It is well known that adolescence is a stage of great changes and evolution, whether physical, physiological, emotional, social and dietary.39 Within these changes, adolescents acquire accelerated growth, as well as sexual, emotional and social maturity. At the same time, they adopt eating habits that give them a complete development, which allows them to reinforce and confirm their personality, and will accompany them for the rest of their lives.40 Likewise, personality is the result of the influences perceived around them41 such as their circle of friends, family environment, cultural environment. These factors can in turn, also shape eating habits.42,43\n\nEating habits are manifested in the decision of food consumption.44 On the other hand, in adolescence, eating habits are established by previous learning with a predominance of irregular behaviours such as not respecting mealtimes (Breakfast, lunch and dinner), going on slimming diets, opting for fast food, eating between meals that pushes them to take inadequate food and therefore inadequate nutrition with an increase in calories.45 Thus, since they are in a state of risk, they are prone to contract various diet-related diseases46 such as diabetes, hypertension, cardiovascular diseases, hyperlipidemia, overweight and obesity.47\n\nEating away from home is an activity where prepared foods are purchased outside the familiar environment regardless of the place where they will be consumed.48 Undoubtedly, eating away from home has become a fairly recurrent activity in the daily life of many citizens in the world.\n\nConsumer behaviour is expressed by a group of activities that the individual develops at a time prior to the purchase decision. The consumer selects and evaluates goods and services; this is done to satisfy the desires and needs. In this type of activities, behaviours are involved by mental, emotional and physical aspects. Some of the activities described in the consumer are: pre-purchase, where the consumer detects needs and problems, is informed, perceives offers, makes visits to the store, evaluates and selects alternatives; in this pre-purchase the consumer establishes and delimits purchase conditions; purchase, where the consumer already selects the establishment in which they could acquire the products; post-purchase, where the product is used or consumed, and leads the consumer to feelings of liking or disliking.49\n\nOther factors present in the purchase decision are the socioeconomic status, as well as the sex of the head of the household, and the number of household members. For instance, it has been observed that consumption outside the home is higher in men than in women.50\n\n\nMethods\n\nThe research design is based on a quantitative approach with a cross-sectional study type because it describes a phenomenon in a population, there is no intervention and it will only be limited to measure and describe the studied population as such. This database is defined as secondary.\n\nThe population is composed of all households obtained by the expansion factor. It is a national household survey, carried out by the national statistics entity of Peru; National Institute of Statistics and Informatics (INEI), meets the standards of this type of survey, responds to a stratified sample and has an expansion factor that explains the behavior of the variables at the national level.\n\nThe expansion factor is developed by INEI. The database is available on the INEI website, microdatos. https://proyectos.inei.gob.pe/microdatos/.\n\nThe study has considered the population from urban, rural, north, central and south coast, north highlands, centre and south of the Jungle regions. We worked with the entire population. The total population with adolescents is 4,350,171 households. For the purpose of this analysis, households that included an adolescent or not, and that have spent money on food consumed outside the home, were included.\n\nThe survey is distributed in the coastal, mountain and jungle areas, and according to rural and urban areas, by households. It is an account held by a government entity. The information is obtained from the head of the household (respondents are asked who is the head of the household) or the spouse or eldest child in the home.\n\nThe questions about food consumption away from home, according to the National Household Survey (ENAHO), include meals that have been purchased and consumed “on the go” i.e. a) Meals prepared for consumption at home purchased in commercial establishments; and b) Other foods consumed away from home by people under 14 years of age. The value obtained is assigned to food consumed away from home for breakfast, lunch, dinner and others, disaggregated by the place where these are consumed (street vendors and markets, restaurants and warehouses, and others), taking into account the quartiles.51 The questions in the ENAHO questionnaire were developed and standardized by the National Institute of Statistics and Informatics of Peru (INEI).\n\nThe definition of food consumption refers to the exchange of consuming or spending on products for money to satisfy basic needs, while food consumption away from home refers to all food coming from external eating places, regardless of the place of consumption.\n\nFor the statistical analysis, we worked with the Stata CORP version 16 software. Descriptive statistical techniques were applied. Likewise, the coefficient of variation, mean, standard deviation, minimum and maximum values and confidence intervals were determined. The lincom command was applied to compare means of expenditure on food consumed away from home in households with and without adolescents, in order to know if they were the same or different; this command is used for data where the expansion factor is applied.\n\nAdditionally, a Logit model was applied to predict the probability of expenditure of households with adolescents in their composition with the variables: number of household members, place of origin (urban-rural), sex of the head of the household, ethnicity, educational level, marital status, age range, occupation (independent work, dependent work), and poverty (n.b. poverty is the name of the variable in the dataset). In addition, the classification test, with sensitivity and specificity, and the ROC curve were calculated from the data for the set of households consuming food away from home and the variable expenditure 1, 0.\n\n\nResults\n\nThe result of households that were included in the analysis was 4,350,171, according to the National Household Survey (ENAHO) for the year 2021, and 24245 after applying the expansion factor.60 Households with the presence of adolescents and households without adolescents were selected and compared. Table 1 shows the average expenditure on food consumed away from home in households with and without adolescents per month. It also shows that expenditure is higher in households with the presence of adolescents, with an additional 57 Peruvian Soles than in households without adolescents; likewise, it shows the proportion of households and the standard deviation represented and the total population of households with at least one member between the ages of 10 and 19 years, which is represented by 43.92%. On the other hand, households without adolescents represented 56.08%. The results were obtained with the application of the expansion factor (Table 1).\n\nTable 2 shows the difference in means, in households without and with adolescents; the result indicates that the averages are statistically different.\n\nHousehold with adolescents\n\n_subpop_1: tipo_hogar_adolescent = Household without adolescent\n\n_subpop_2: tipo_hogar_adultos = Household with adolescent\n\nHo: [GAFH]_subpop_1 - [GAFH]_subpop_2 = 0\n\nThe highest expenditure is made by households with adolescents, the percentage of the population in households with adolescents reaches 44%. According to educational level, households with incomplete university and incomplete non-university higher education spend the most on average in FAFH, with 247 and 234 Peruvian Soles respectively; households where the head of household has completed secondary school have the highest percentage (31.53%).\n\nThe highest expenditure is made by households who obtained a house assigned by the work centre (349.72 Peruvian Soles), followed by households who live in rented housing (254.92 Peruvian Soles). According to the type of housing, households who are buying their house on instalments spend the least (150.38 Peruvian Soles). On the other hand, 66.44% of the population lives in a totally rented house. According to the marital status variable, the households whose head of the household is married spend the most (232.19 Peruvian Soles), and those who are divorced spend the least (125.01 Peruvian Soles). For their part, heads of households who live as cohabitants account for 37.11% of all households with adolescents.\n\nThe highest expenditure according to the age of the head of the household is in the group between 16 and 29 years old (250.06 Peruvian Soles), followed by the group between 50 and 59 years old (233.42 Peruvian Soles). On the other hand, the group between 30 and 39 years old spends the least (188.34 Peruvian Soles). The highest expenditure according to the occupation of the head of household is in the group with a dependent job (264.82 Peruvian Soles), which is 48.7 Peruvian Soles more than the average. According to the poverty variable, the extremely poor spend 46.28 Peruvian Soles and non-poor households spend 5.58 times more (258.33 Peruvian Soles). Moreover, households in the urban area spend 65.34 Peruvian Soles more than households living in the rural area. People from the Quechua and Aymara ethnic groups spend the same amount, namely 229 Peruvian Soles (Table 3).\n\nIn households with adolescents, when the number of household members increases by one, the probability of spending on FAFH increases by 5%. If the household is located in a rural area, it is 6% less likely to spend on FAFH. The variable native from the Amazon region has 18% less probability of spending on FAFH; similarly, the following variables have less probability of spending on FAFH: Afro-descendant (10%), white (11%), and mestizo (11%), in comparison with those defined as Quechua.\n\nRegarding educational level, when the head of household does not have initial education, he or she is 57% less likely to spend on FAFH consumption compared to heads of households who have no education. Likewise, a head of household with incomplete primary education is 6% more likely to spend on FAFH compared to those with no education. However, having completed non-university higher education has 8% less likely to spend on FAFH, and having completed university higher education has 15% less likely to spend on FAFH compared to those with no education.\n\nRegarding marital status, household heads who are married are 3% less likely to spend on FAFH compared to those who are cohabitants. Moreover, heads of household aged 30 to 39 years, 40 to 49 years, 50 to 59 years, and over 60 years are less likely to spend on FAFH (8%, 6%, 8%, 16%, respectively) compared to those in the 16 to 29 years age group. Heads of households with adolescents who are in dependent work are 5% more likely to purchase FAFH compared to those who have independent jobs.\n\nHouseholds classified as \"non-extreme poor\" and \"non-poor\" are 16% and 34% respectively more likely to spend on food consumed outside the home compared to those in extreme poverty (Table 4).\n\n** According to the ENAHO Living Conditions and Poverty survey, the question is: What is the sex of the head of the household?\n\nThe classification test of the model was 71.91%, sensitivity 94.27% and specificity 21.98%. This explains that, out of every 100 households, the model correctly predicts 71 of them.\n\nThe area under the curve was constructed by calculating the probability of prediction according to the result of the Logit model for the probability of purchasing or not purchasing food away from home. The area under the curve of the logit model was 0.691 (0.056-0.977) and the area of those with the probability of spending on FAFH was 0.691 (0-1), var dummy. Moving away from 0.5 discriminates better (see Figure 1).\n\n\nDiscussion\n\nIn recent decades, the consumption of food away from home has become seen as an unhealthy eating behaviour as many of the foods consumed are considered to be not nutritious as they contain harmful substances such as saturated fats, refined sugars and high amounts of sodium, especially in younger populations such as adolescents.2\n\nThe expenditure on food consumed away from home for households with adolescents is 216.1 Peruvian Soles and the expenditure for households without adolescents was 56.96 Peruvian Soles less or 15.07 US Dollars. The difference in means is significant.\n\nThe description of expenditure on the variable educational level shows large differences, while a head of household can spend 23 Peruvian Soles, the head of the household with a university degree spends 10 times more. Expenditure according to the type of housing (rented, owned and fully paid, owned by encroachment, owned by purchasing in instalments, assigned by work centre, assigned by another household), is above average and does not show large differences. The marital status of the head of household shows divorced people with the lowest expenditure and married people with an expenditure of 107.18 Peruvian Soles more.\n\nThere are few studies on models that evaluate the probability of spending on food consumed away from home for households with adolescents, both nationally and internationally. On the other hand, the result of the analysis showed the variables that favour the probability of spending to dependent work, being non-extreme poor and non-poor with a result similar to the work by Lozada-Urbano et al.,50 who evaluated a population of households in 2019. In countries like Bangladesh,52 street vending is dishonest and there is a lot of adulteration, which discourages wealthy households that come from urban area and with heads of household educated to consume and spend on FAFH.52 The prices of foods away from home in the USA were associated with consumption categories of low-income youth.53\n\nIn the Lozada-Urbano study in 2019, extended families with more people spent more on FAFH, while in the 2021 study, the number of members in the household favours the probability of expenditure. In addition, incomplete primary education is also in favour of the probability of expenditure; however, the rest of the education variables (initial education, incomplete non-university higher education, complete non-university higher education, complete university higher education), have an expected result for not being favourable. It is likely that education and knowledge about negative factors with food consumption away from home of the heads of household represent a barrier to purchase. Some authors in a study conducted on meals and fats content has shown that the food purchased and consumed in a food court of a shopping mall in Lima was high in fats, even without including calories from beverages and creams.5 In countries such as the USA, education has been shown to have a negative effect on obesity.54\n\nSome limitations of this study when interpreting the findings for households were that heads of household with incomplete primary education showed a positive probability of expenditure on FAFH. This could be explained that the costs of food result to have a lower value than the cost that includes the cost of food preparation such as household services (electricity, gas and water), household appliances and food storage, also it does not include the cost of time to buy and prepare food.55\n\nVariables that do not favour the likelihood of expenditure are being from the rural area, probably in some cases, purchasing food is not allowed since there is no access to shopping malls, and food and fast food businesses. However, a study by Mottaleb in Bangladesh describes that urban households are the least likely to consume and spend on FAFH because of the problem of food adulteration by dishonest vendors.52\n\nNone of the racial variables favour the likelihood of expenditure. In the USA, a study with people of African American and Euro-American ethnicity on food selection showed that perceptions of African Americans describe lower cost foods and larger portions than Euro-Americans.56\n\nRespondents with higher overall diet quality were more likely to be older and be women with higher educational levels, while they were less likely to be non-Hispanic African descendant and more likely to be of a race or ethnicity other than non-Hispanic white, non-Hispanic African descendant, and Hispanic; and were more likely to have a higher income-poverty ratio.55\n\nThe ages of the heads of household between 30 to 39 years, 40 to 49 years, 50 to 59 years and being older than 60 years, were not favourable to the probability of expenditure. This result may be due to the fact that it was not worked as a continuous variable or it is explained by the period evaluated corresponding to the second and third wave of the coronavirus disease 2019 (COVID-19) pandemic, where the stay at home was maintained. Some authors consider that it is necessary to consider the form of food delivery during the pandemic. In Peru, there is no evidence on home food delivery.57\n\nThe results of this study about the poverty variable show the expected results. Regarding the poverty variable (extreme poor, poor and non-poor), and the expenditure on food according to these categories, it is shown that the expenditure is higher in households with adolescents than in those without adolescents, and in the least poor (non-poor). Meanwhile, in households in Australia, they have described some social factors that influence expenditure on foods in the household, such as: the educational level, the household income, the place where they live and the time they have available to purchase unhealthy food.\n\nLikewise, household income is the most predominant factor in the determination of expenditure on food in household, above the socioeconomic level of the household. Meanwhile, the time variable seems to be more related to socioeconomic level with respect to expenditure on food. On the other hand, the comparison between expenditures on food consumed away from and inside the home gave evidence that households with a higher socioeconomic and educational level had less budget expenditure for industrialized and non-industrialized food prepared at home, while for food purchased away from home, mainly in restaurants, more was spent.58 In Brazil, the expenditure on food and group of foods grew significantly.59\n\nThe limitation of this study is the cross-sectional type of information since it only allows obtaining the results at one point in time.\n\n\nConclusion\n\nPolitical efforts are needed so that society assumes and helps to create a food culture both in quantity and quality, regarding the choice of food consumed away from home, due to the high content of critical nutrients such as saturated fats, sodium and sugar, which leads to the increase of a current public health problem such as NCDs. The state, as the governing, executing and regulating entity, should create and prioritize public policies to stimulate food education of the population on nutrition and healthy eating, taking into account the sociodemographic characteristics. These policies should be directed to those who consume and prepare food, as well as the head of household. Regarding academia, it is required to promote research on this topic, which has been so little studied. This way more science and evidence would be developed to propose new nutritional strategies. Also, more promotion should be made in nutrition professionals to develop practical proposals that get concretized in efficient and effective actions in time for the development of counselling and training spaces on issues of food consumption away from home in adolescents.\n\nThis work is carried out to contribute to the knowledge of food consumption away from home. Background and studies in other countries, on individuals and households, have already shown that it has a negative effect on households that consume them, increasing overweight and obesity. This result will allow us to know the differences in households and also to compare it with other results that have used the ENAHO national household survey. Likewise, this research will serve as support for future research on the subject matter.\n\nScientific information on the adolescent population is scarce. Our main contribution is about the variables that favour the probability of purchasing FAFH; the variables used allow us to describe the households that would be consuming more foods that do not help household members to be healthy, especially adolescents.",
"appendix": "Data availability\n\nFigshare: Adolescent and food away from Home. https://doi.org/10.6084/m9.figshare.23935293.v1. 60\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nEstudio Global de Nielsen sobre Tendencias de Comida Fuera del Hogar: 2016 [cited 30 May 2018. Reference Source\n\nGarcía A, Zúñiga G, Córdova D, et al.: Niveles de procesamiento de alimentos y calidad de la dieta en consumidores frecuentes y no frecuentes fuera de casa.Mauricio E, editor. Congreso de la Red Ecuatoriana de Universidades y Escuelas Politécnicas para Investigación y Posgrado–REDU. Cuenca: Universidad de Cuenca; 2017 [cited 13 January 2020]; 567–569. Reference Source\n\nRamos Huamanquispe G, Zaira CA: Estilos de vida y su influencia sobre el estado nutricional en escolares adolescentes de la Institución Educativa Técnico Industrial San Miguel Achaya – 2017 [thesis on Internet]. [Puno]: Universidad Nacional del Altiplano.2017 [cited 24 January 2020]. Reference Source\n\nLozada-Urbano M, Rivera M, Miranda D: Evaluación del contenido graso en alimentos ofrecidos en restaurantes de comida rápida en Lima para niños mayores de 5 y menores de 10 años, en el año 2019. Rev. Investig. Univ. Norbert Wiener. 2020; 9: 17–30. Publisher Full Text\n\nBellisle F: Meals and snacking, diet quality and energy balance. Physiol Behav. 2014 Mar; 134: 38–43. PubMed Abstract | Publisher Full Text\n\nGodbharle S, Jeyakumar A, Giri BR, et al.: Pooled prevalence of food away from home (FAFH) and associated non-communicable disease (NCD) markers: a systematic review and meta-analysis. J Health Popul Nutr. 2022; 41(1): 55. Published 2022 Nov 30. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSerra MA, Serra M, Viera M: Las enfermedades crónicas no transmisibles: magnitud actual y tendencias futuras. Rev Finlay. 2018 [cited 15 January 2020]; 8(2): 140–148. 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Revista Española de Sociología. 2004; 4(2): 93–118.\n\nMartín VJ: Alimentación fuera del hogar. Distribución y Consumo. 2009 enero-febrero; 19(103): 5–11.\n\nLozada-Urbano M, Huamán F, Xirinachs Y, et al.: Poverty, Household Structure and Consumption of Foods Away from Home in Peru in 2019: A Cross-Sectional Study. Foods. 2022; 11: 2547. Publisher Full Text\n\nInstituto Nacional de Estadística e Informática, (INEI): Sistema de documentación virtual de Investigaciones Estadísticas.Reference Source\n\nMottaleb KA, Rahut DB, Mishra AK: Consumption of food away from home in Bangladesh: Do rich households spend more? Appetite. 2017; 119: 54–63. Publisher Full Text\n\nPowell LM, Han E: The costs of food at home and away from home and consumption patterns among U.S. adolescents. J Adolesc Health. 2011; 48(1): 20–26. PubMed Abstract | Publisher Full Text\n\nCairney J, Wade TJ: Correlates of body weight in the 1994 National Population Health Survey. Int J Obes. 1998; 22: 584–591. 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}
|
[
{
"id": "213301",
"date": "08 Nov 2023",
"name": "Ilana Bezerra",
"expertise": [
"Reviewer Expertise Nutritional epidemiology. Food consumption. Away-from-home eating. Household Budget Surveys"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript needs major revision to be accepted, especially related to statistical analyses and result presentation.\n\nABSTRACT:\nThe article aimed to compare the probability of spending on food consumed outside the home, but in the results (from the abstract), there is no mention of the purchase probability. The authors only provided the average spending.\nInstead of \"Households were selected,\" wouldn't it be better to use \"Households were evaluated\"? It is necessary to include the statistical analysis for the comparison conducted.\nThe conclusion of the abstract does not address the article's objective.\nINTRODUCTION:\nThe introduction is quite lengthy and contains repetitive information. I suggest revising and reducing it to a maximum of five paragraphs. The authors need to identify the crucial information that supports or justifies the article's objective. In addition to the introduction, why did the authors add three subtopics (Healthy diet, Eating habits in adolescents, and Consumer behavior when eating away from home)? There is no need to use 50 references in the introduction.\nThe authors claim that \"Currently, overweight and obesity are considered two of the most dangerous chronic noncommunicable diseases (NCDs), triggering riskier disorders,\" but only obesity is considered a disease by the WHO. At the end of the introduction, I recommend changing \"adolescent food and nutrition\" to \"adolescent diet and nutritional status.\"\nMETHODS:\nDetails about the sampling are necessary. How many households were investigated? How many households were included? How many did not eat outside the home? How many had outside-the-home consumption? How were households included: did they analyze only households with food expenses both inside and outside home, and compared those with and without adolescents?\nThe question about eating outside the home is not clear.\nIn the sentence, \"The value obtained is assigned to food consumed away from home for breakfast, lunch, dinner, and others, disaggregated by the place where these are consumed (street vendors and markets, restaurants and warehouses, and others), taking into account the quartiles,\" what value was considered to stratify the quartiles? Was it the amount paid for meals? How was this collected? It's essential to detail how the data were obtained and what data were collected. Who conducted the interviews? What was the data collection reference period (last 24 hours, 7 days)? Were the questions retrospective, or did individuals keep records of their expenses?\nAnalyses: \"Likewise, the coefficient of variation, mean, standard deviation, minimum and maximum values, and confidence intervals were determined\" – These analyses are for numerical variables, but the authors did not report any numerical variables in the data collection, and the objective is to compare prevalences. At the end of the analyses, avoid using symbols used in the analysis. I suggest explaining that the dichotomous variable was included, indicating whether the household made expenses for eating outside the home or not.\nRESULTS:\nIs this statement correct? \"The result of households that were included in the analysis was 4,350,171, according to the National Household Survey (ENAHO) for the year 2021, and 24,245 after applying the expansion factor.\" Shouldn't it be the other way around? \"The result of households included in the analysis was 24,245, according to the National Household Survey (ENAHO) for the year 2021, and 4,350,171 after applying the expansion factor.\"\nThe authors also need to explain the numbers. In the results, the total number of households after expansion is 9,903,824 and 34,245 were interviewed. This needs to be made clear in the methodology.\nThere is no need to include SD and Cv in the table; IC is sufficient for survey data.\nInstead of using the term \"obs,\" use \"n\" to represent the total number of observations.\nTable 2 contains only one observation, so it's not a table.\nThe programming used in the analysis should not be included; only the results should be presented. The sentence \"subpop_1: tipo_hogar_adolescent = Household without adolescent subpop_2: tipo_hogar_adultos = Household with adolescent Ho: [GAFH]_subpop_1 - [GAFH]_subpop_2 = 0\" is not meaningful.\nTable 3: The authors seem to lack a grasp of presenting quantitative data. If the objective is to compare households with and without adolescents according to socioeconomic and demographic variables, the authors should place households with and without adolescents in the table columns and the variables in the rows, presenting them based on the presence of adolescents. Categorical variables are presented with too many levels, requiring more appropriate categorization for presenting the results. For example, the number of residents should be presented in ranges (up to 4, 4 to 8, above 8 or from the median...).\nTable 4 also includes all the categories of variables included in the model, but what is the authors' hypothesis? They need to demonstrate all of this for the analysis to make sense.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
},
{
"id": "234502",
"date": "15 Feb 2024",
"name": "Pedro A. Alviola IV",
"expertise": [
"Reviewer Expertise Agri. Economics",
"Health & Nutrition",
"Zoonotic Diseases",
"Human & Built Systems"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReview for Households with and without the presence of adolescents, probability of expenditure on food consumed away from home, according to ENAHO 2021: a cross-sectional study\nWhile the research question of the paper which aims to determine whether significant differential effects are observed in expenditures of food away from across households (HHs) with adolescents and those without is interesting, I find that some sections especially the Methods & Results are severely lacking in terms of content, comprehensive discussions on model specification and sampling criteria are inadequate and model interpretations are suspect at best.\n1. Methods\n1.1 ENAHO 2021: The study uses this data set as the basis for estimating whether expenditures from food consumed away from home differ between HHs with adolescents and HHs without. However, beyond whether this data set has been used by other published studies, the present study does not discuss the data strengths (quality, internal validity, etc...) or its features that make it appropriate for answering the research objective or usage for future research.\n1.2 From pages 4 & 5, the study used the total population of 4, 350, 171 with adolescents, and at the same time from this population, the study also included HH without adolescents. What is the total population? Are these HHs or adolescent counts? This must be clearly stated and discussed comprehensively with the particulars of how this sample size was arrived at.\n1.3. The selection criteria and definition of HH with adolescents are not clear and are not mentioned in the methods section and only do I find it on page 5 in the results section where an HH with adolescent is defined as those HHs containing at least one member in the age bracket between 10 and 19 years old. In this regard, I have questions on this criteria as stated in the following; i) The age bracket definition of adolescents in Peru was not justified in the paper; ii) with this age criteria you may likely include HHs with children that are less 10 y/o and/or greater than 20 y/o aside from a HH member whose age bracket is between 10 and 19 years old. If this is the case, then your statistical modelling strategies will suffer from selectivity bias (Hamilton & Rossi, 2002) resulting in unreliable inferences regarding any hypothesis testing and those that pertain to the statistical significance of estimated coefficients. Further, (iii) with this age criteria, HH with children whose ages are close to 10 y/o (i.e. 9) or 19 y/o (i.e. 20) are going to be excluded. I bring this up because, in primary (grade school) and secondary school (high school), it’s not uncommon that adolescent ages overlap and as peers within the same grades, they do influence adolescents’ eating habits and thus impact food away from home expenditures. Further, HHs with adolescents and HHs without behave differently according to levels of income as each has differential access to resources.\n1.4 The statistical analysis section is also not clear. Why is there a discussion on the Stata lincom command? If this is a test of means, then discuss its statistical definition and its appropriateness in the context of the study. The study utilizes a logit model but the dependent variable is not clearly defined (this makes Table 4 very difficult to understand) and mentions the hypothesized drivers without any critical literature review justifying inclusion into the model.\n1.5 Further, the logit model specification used in the study may likely suffer the endogeneity problem where other factors (represented by the error term) are highly correlated with the dependent variable which in this case is the expenditures on food consumed away from home with adolescent food choice behaviour (Cameron & Trivedi, 2005). Such factors may include household income and access to food subsidies (school lunches and feeding programs) which can influence adolescent food choices and expenditures. With this, the strict causal relationship between your dependent variable and its drivers has been compromised and thus leads to unreliable estimates.\n1.6. There is no mention of any effort to test the validity of assumptions regarding the logit model specifications. In particular, there is no mention of performing diagnostics regarding the logit model. Also, the quality of predicted probabilities was not undertaken in determining how good the logit model is in terms of predicting a 1 or 0 outcome as it compares with the actual choice or category.\n\n2. Results 2.1 On page 6, why are there several code-like lines? I find that this distracting and does not merit inclusion.\n2.2 I find Table 3 (pages 6-8) difficult to comprehend as the scale and measurement of the variables are not clearly explained or established in the table. Where is the variable representing the dependent variable used in the logit model? There are two variables Household without adolescents & Household with adolescents, how did these 2 variables figure into the logit model estimated in Table 4?\n2.3 Table 4 is also problematic as I find it difficult to comprehend the dependent variable. For example, I quote from the text “In households with adolescents, when the number of adolescents increases by one, the probability of spending on FAFH increases by 5%” (page 8). The title of Table 4 suggests that average expenditure is a continuous variable and yet the interpretation of the driver Members of the households is that of a logit model. So I can only deduce that the dependent variable may likely be whether HHs spend on FAFH (1) and (0), otherwise. Again, as I’ve mentioned in my earlier comments regarding model specification, these things need to be defined precisely to avoid ambiguity, which only adds further to the reader’s confusion.\n2.4. What is the Delta method dy/dx in Table 4? Is this an output of Stata? Where are logit estimated coefficients?\n2.4. Please be consistent in your terms such as Food Consumed at Home and Food Away from Home. Again please define technical terms precisely and in the beginning to avoid confusion to the reader.\n\nLiterature cited [1],[2]\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1296
|
https://f1000research.com/articles/12-1293/v1
|
09 Oct 23
|
{
"type": "Study Protocol",
"title": "Correlation between mental well-being and severity of class II temporomandibular joint disorders, compared to non-temporomandibular joint disorders",
"authors": [
"Sunita Shrivastav",
"Abhishek Sanchla",
"Sunita Shrivastav"
],
"abstract": "Temporomandibular joint disorders (TMDs) are one of the most common ailments encountered in the craniofacial region, with various clinical, radiological and psychological manifestations but often go undiagnosed due to lack of a diagnostic protocol to assess and correlate all these factors in order to create an effective management plan based on early diagnosis. The objectives of this research are to assess, compare and co-relate the severity of clinical and radiological findings with mental well-being in class II (vertical growth pattern) TMD cases as compared to class I non-TMD cases. Grading of skeletal class II cases on the severity of TMD will be done using Diagnostic Criteria for TMDs (DC/TMD). Bilateral sagittal as well as coronal magnetic resonance imaging (MRI) images will be obtained. Evaluation and grading of mental well-being and anxiety will be done using the Warwick-Edinburgh and Hamilton scales, respectively. The expected results are a probable positive correlation between the severity of clinical and radiological symptoms of TMDs and deteriorating mental well-being in the form of stress, anxiety and depression. A cause-effect relationship may be evaluated with the aim of early diagnosis and management of TMDs as improving the quality of life of these cases. This study will aid in identifying the clinical symptoms and articular disc position on MRI as they correlate with the mental well-being status and anxiety levels in TMD cases. Further management and early intervention can be undertaken in such cases to prevent or stall the progression of TMD into severe forms while improving the quality of life (QoL) in such cases.",
"keywords": [
"Temporomandibular joint disorders",
"Anxiety",
"Depression",
"Stress",
"Mental well-being",
"Magnetic resonance imaging"
],
"content": "Introduction\n\nTemporomandibular joint (TMJ) disorders are a group of conditions that affect the jaw and the muscles that control its movement.1 These disorders can cause pain, discomfort, and limited jaw movement and can impact a person’s mental well-being.2\n\nEvidence suggests that TMJ disorders can cause or contribute to altered mental well-being.3 TMJ disorders can greatly affect an individual’s quality of life, causing chronic pain and discomfort. This often leads to anxiety, depression, and poor sleep quality, worsening the disorder’s symptoms.4 Furthermore, the limitations of TMJ disorders can cause social isolation, reduced self-esteem, and decreased functional abilities.5 The general population is affected by temporomandibular joint disorder (TMD) at varying rates, according to epidemiological studies ranging from 45% to 75% incidence.6 Given the high incidence, it is likely that a sizable fraction of the population is affected with TMD.\n\nAccording to Ruf and Pancherz’s 1999 paper, those with Class II malocclusion and a vertical growth pattern are more likely to have temporomandibular joint disease (TMD).7\n\nThe gold standard and most accurate diagnostic tool for temporomandibular joint (TMJ) abnormalities is magnetic resonance imaging (MRI). The TMJ and its encircling components, including the articular disc, muscles, and ligaments, can be seen on an MRI scan. With the help of this imaging method, the joint space, disc location, and bone morphology may all be assessed non-invasively.8 Moreover, MRI can detect additional problems like tumours, infections, and fractures that may resemble TMJ disorders. MRI offers higher soft tissue contrast than other imaging methods like computed tomography (CT) and plain radiography and does not subject the patient to ionising radiation. It has been demonstrated that using MRI for TMJ evaluation improves patient outcomes, treatment planning, and diagnosis accuracy.9\n\nThe Warwick-Edinburgh Mental Well-being Scale (WEMWBS) is an essential tool for determining mental well-being.10 It is a validated questionnaire that assesses positive facets of mental health, such as joy, self-esteem, and good interpersonal interactions. Higher scores indicate more well-being on the scale, which consists of 14 items rated on a 5-point Likert scale. The WEMWBS has been used in research and clinical settings. It has produced useful data on mental well-being and its relationships to different health outcomes, which can be used to assess it in TMD situations.7 A popular measure for measuring anxiety in people is the Hamilton Anxiety Scale (HAM-A).11 The HAM-application A’ s in TMD studies has highlighted the connection between anxiety and TMD. According to one study, those with TMD had considerably higher HAM-A scores than healthy controls, which may indicate that these people had higher anxiety levels.12\n\nHence this study is planned to assess the correlation of these clinical radiologic and psychological parameters to further aid in the effective and timely management of TMDs.\n\n\n\n1. To evaluate TMD’s clinical and radiological (MRI-based) symptoms in Class II (Vertical) Temporomandibular joint disorder cases and Class I Non-TMD cases.\n\n2. To evaluate the mental well-being of these cases using curated scales and questionnaires.\n\n3. Compare these symptoms and mental well-being status in Class II (Vertical) cases with those without Temporomandibular joint disorder.\n\n\nProtocol\n\nAn observational and analytical study will be conducted at Sharad Pawar Dental College, Sawangi, in collaboration with the Department of Radiology, Acharya Vinobha Bhave Rural Hospital (AVBRH). See Extended data23 for the STROBE (Strengthening the reporting of observational studies in epidemiology) checklist items relevant to this protocol.\n\nA total of 30 adult cases Class II (vertical growth pattern) will be chosen from the Sharad Pawar Dental College’s outpatient department (OPD) of Orthodontics and Dentofacial Orthopaedics in Sawangi, Wardha. The number of samples was selected based on the prevalence of TMD in Class II (Vertical) cases, using the formula n = N*X/ (X + N – 1), where, X = Zα/22 p(1-p) /MOE2, and Zα/2 is the critical value of the normal distribution at α/2 (e.g., for a confidence level of 95%, α is 0.05 and the critical value is 1.96).\n\nEthical approval has been granted on 31/03/2023 by Datta Meghe Institute of Higher Education and Research, Sawangi, Wardha, with reference number DMIHER (DU)/2023/18. Informed and written consent will be obtained from all the cases included in the study for their participation. A separate consent form will be issued to obtain participant consent for publication of the research results and data.\n\nAdults more than 18 years of age with Class I (normal skeletal growth pattern of the maxillo-mandibular complex) or Class II (vertical) malocclusion with permanent dentition would be included in this study. Class I or Class II (vertical) malocclusion would be decided based on the cephalometric criteria listed in Table 1.\n\nCases with Class III malocclusion, Myofascial pain dysfunction syndrome, or those with a history of temporomandibular joint surgery and skeletal dysplasia would be excluded from this study.\n\n\nMethods\n\nThe methodology of this study involves several steps. Firstly, patients will be diagnosed according to the DC/TMD criteria for clinical signs and symptoms. Secondly, grading of skeletal Class II (vertical growth pattern) cases based on the severity of TMD will be done using the Helkimo index. Bilateral sagittal, as well as coronal MRI images, will then be obtained.\n\nIn addition to the above, all cases will be evaluated for mental well-being and anxiety levels using the Warwick-Edinburgh and Hamilton scales, respectively. The evaluation of Articular Disc morphology in the sagittal and coronal plane using MRI will also be conducted.\n\nFurthermore, the study will focus on the correlation of articular disc morphology with clinical symptoms, anxiety, and mental well-being in both groups. Finally, a comparison of articular disc morphology, clinical symptoms, anxiety, and mental well-being will be made among both groups. By following this methodology, the study aims to gain a deeper understanding of the relationship between articular disc morphology and various clinical symptoms in patients with TMD.\n\nBias will be minimised by random selection of patients based on inclusion and exclusion criteria.\n\nThe calculation of sample size was done as follows:\n\nEach group would consist of 15 individuals, with the frequency of severe cases being 0.95 per cent. There will be 15 patients in 2 groups, hence, the total sample size will be 30. The sample will be divided into three groups based on the inclusion and exclusion criteria: Group A will be a control group, with 15 Class I (Non-TMD) cases. Group B will comprise 15 skeletal Class II (vertical growth pattern) cases with TMD.\n\nAll the demographic outcome data will be presented using descriptive statistics for categorical variables in terms of frequency & percentage for continuous variables in terms of mean, standard deviation and median.\n\nResults will be analysed on SPSS version 27 for statistical analysis. The outcome variable will be tested for normality using the Kolmogorov-Smirnov test for continuous data.\n\nArticular disc variations are categorised according to the range that will be distributed for analysing the data into the normal range and not in the normal range. The chi-square test will be used to find the result of an association of clinical, radiological and psychological symptoms in Class I (Non-TMD cases) and skeletal Class II (Vertical growth pattern) TMD cases.\n\nAn Independent t-test will be used to find the result on three groups for the outcome variable if data comes under the normal distribution. A non-parametric test will find a significant difference if data does not fit the normal distribution.\n\nThis study will assist in identifying and promptly diagnosing TMD based on clinical symptoms, changes in articular disc position and psychological status. It will aid in the formulation of an effective management protocol.\n\nThe study has yet to start.\n\n\nDiscussion\n\nStress and anxiety are prevalent in today’s population due to various factors, including work-related stress, financial stress, social media and technology, family and relationship issues, health concerns, political and social unrest, and trauma and past experiences.1 It is important to seek help if these feelings overwhelm or interfere with daily life.\n\nSeveral studies13–15 have found a correlation between mental well-being and temporomandibular disorders (TMD). Individuals with TMD are more likely to experience depression, anxiety, and other mental health issues than those without TMD.16 Additionally, stress, anxiety, depression or other mental health-related symptoms may deteriorate the existing morbidity due to TMD.17 Similarly, management of TMD has been shown to reduce the mental health-related symptoms and improve mental well-being.18 Thus, healthcare professionals must focus on improving psychological status while diagnosing and treating TMD patients, for a better outcome. When Simoen L et al. (2020) examined the prevalence of depression and anxiety in TMD patients, they found that these individuals had much higher anxiety levels than controls of anxiety than controls did.19 Chisnoiu et al. (2015) carried out a systematic review to investigate the association between psychological factors and TMD in a related study. 24 publications, according to the authors, met the requirements for inclusion. The review shows, there is a direct link between TMD and such psychological characteristics as anxiety, depression, stress, and somatization. The authors came to the conclusion that psychological evaluation and intervention should be a part of patient management in order to enhance treatment outcomes for TMD patients.20\n\nA randomised controlled experiment was undertaken by Manfredini et al. (2014) to assess the efficacy of cognitive behavioural therapy (CBT) and occlusal splint therapy in reducing pain and enhancing function in TMD patients. The authors randomly assigned 90 patients with TMD to three groups: CBT, occlusal splint therapy, or a combination of CBT and occlusal splint therapy. According to the study’s findings, all three treatment groups’ pain and function levels significantly improved compared to baseline. In contrast to the other two groups, the combination group (CBT plus occlusal splint therapy) saw the largest pain intensity reduction and the best improvement in function. The authors concluded that the combination of CBT and occlusal splint therapy is an effective treatment approach for TMD.21\n\nThough isolated, few studies are reported in the literature similar to this study. Moreover, Sanchla et al.22 described that Class II (vertical) cases are more prone to TMD’s. Hence, this study would be clinically significant as correlating the skeletal features, radiologic soft tissue findings, and psychologic status would give a comprehensive picture of the TMD status and aetiology. Further, it will help in laying down a problem-oriented treatment protocol. The expected outcome of this study is to establish a positive correlation between the severity of clinical and radiological symptoms of temporomandibular joint disorders (TMDs) and deteriorating mental well-being in the form of stress, anxiety, and depression. The study aims to identify potential predictors of TMDs, particularly psychological factors, to aid in the early diagnosis and management of TMDs, which may ultimately lead to an improved quality of life for individuals with TMDs.\n\nThrough a multidisciplinary approach that considers physical and psychological factors, this study aims to provide valuable insights into the complex interplay between TMDs and mental health. By establishing a cause-effect relationship between TMDs and mental health, this study may contribute to developing targeted treatment approaches to improve the quality of life of individuals with TMDs.",
"appendix": "Data availability\n\nNo underlying data are associated with this article.\n\nZenodo: Correlation between Mental well-being and severity of Class II temporomandibular joint disorders, compared to non-temporomandibular joint disorders’, https://doi.org/10.5281/zenodo.7953756. 23\n\nThis project contains the following extended data:\n\n- strobe checklist.docx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nSanchla AD, Shrivastav S, Kamble RH, et al.: Altered Quality of Life in Patients with Temporomandibular Joint Disorders: A Review. J. Clin. Diagn. Res. 2023 Mar 1; 17(3). Publisher Full Text\n\nYap AU, Zhang MJ, Cao Y, et al.: Comparison of psychological states and oral health–related quality of life of patients with differing severity of temporomandibular disorders. J. Oral Rehabil. 2022; 49(2): 177–185. PubMed Abstract | Publisher Full Text\n\nDahlström L, Carlsson GE: Temporomandibular disorders and oral health-related quality of life. A systematic review. Acta Odontol. Scand. 2010 Mar 1; 68(2): 80–85. Publisher Full Text\n\nQamar Z, Alghamdi AM, Haydarah NK, et al.: Impact of temporomandibular disorders on Oral Health Related Quality of Life: A systematic review and meta-analysis. J. Oral Rehabil. 2023 Apr; 20. Publisher Full Text\n\nMarpaung C, Yap AU, Hanin I, et al.: Psychological distress and well-being: their association with temporomandibular disorder symptoms. Cranio. 2021; 1–7. PubMed Abstract | Publisher Full Text\n\nChaurasia A, Ishrat S, Katheriya G, et al.: Temporomandibular disorders in North Indian population visiting a tertiary care dental hospital. Natl. J. Maxillofac. Surg. 2020; 11(1): 106–109. PubMed Abstract | Publisher Full Text\n\nRuf S, Pancherz H: Temporomandibular joint remodeling in adolescents and young adults during Herbst treatment: A prospective longitudinal magnetic resonance imaging and cephalometric radiographic investigation. Am. J. Orthod. Dentofac. Orthop. 1999 Jun 1; 115(6): 607–618. Publisher Full Text\n\nSanchla A, Shrivastava S, Kamble R: Comparative evaluation and correlation of neurologic symptoms, otologic symptoms and proximity of TMJ disk with condyle in class ii (vertical) mild, moderate and severe TMD cases as compared to non-TMD cases. Ann. Med. Health Sci. Res. 2021; 11: 103–121.\n\nFernández Sanromán J, Gómez González JM, Alonso del Hoyo J: Relationship between condylar position, dentofacial deformity and temporomandibular joint dysfunction: an MRI and CT prospective study. J. Maxillofac. Surg. 1998 Feb; 26(1): 35–42. Publisher Full Text\n\nBlodgett JM, Birch JM, Musella M, et al.: What works to improve wellbeing? A rapid systematic review of 223 interventions evaluated with the Warwick-Edinburgh Mental Well-Being Scales. Int. J. Environ. Res. Public Health. 2022 Jan; 19(23): 15845. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGale C, Glue P, Guaiana G, et al.: Influence of covariates on heterogeneity in Hamilton Anxiety Scale ratings in placebo-controlled trials of benzodiazepines in generalized anxiety disorder: systematic review and meta-analysis. J. Psychopharmacol. 2019 May; 33(5): 543–547. PubMed Abstract | Publisher Full Text\n\nMaier W, Buller R, Philipp M, et al.: The Hamilton Anxiety Scale: reliability, validity and sensitivity to change in anxiety and depressive disorders. J. Affect. Disord. 1988; 14(1): 61–68. PubMed Abstract | Publisher Full Text\n\nMinervini G, Franco R, Marrapodi MM, et al.: The Association between COVID-19 Related Anxiety, Stress, Depression, Temporomandibular Disorders, and Headaches from Childhood to Adulthood: A Systematic Review. Brain Sci. 2023 Mar 12; 13(3): 481. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDe Leeuw JR, Steenks MH, Ros WJ, et al.: Psychosocial aspects of craniomandibular dysfunction. An assessment of clinical and community findings. J. Oral Rehabil. 1994; 21(2): 127–143. PubMed Abstract | Publisher Full Text\n\nNash JM, Thebarge RW: Understanding psychological stress, its biological processes, and impact on primary headache. Headache. 2006; 46(9): 1377–1386. PubMed Abstract | Publisher Full Text\n\nDyrbye LN, Thomas MR, Shanafelt TD: Systematic review of depression, anxiety, and other indicators of psychological distress among US and Canadian medical students. Acad. Med. 2006; 81(4): 354–373. PubMed Abstract | Publisher Full Text\n\nNatu VP, Yap AU, Su MH, et al.: Temporomandibular disorder symptoms and their association with quality of life, emotional states and sleep quality in South-East Asian youths. J. Oral Rehabil. 2018; 45(10): 756–763. PubMed Abstract | Publisher Full Text\n\nHuhtela OS, Koivisto N, Hägg V, et al.: Effectiveness of applied relaxation method vs splint in treatment of temporomandibular disorders in Finnish students. J. Oral Rehabil. 2020 Feb; 47(2): 123–131. PubMed Abstract | Publisher Full Text\n\nSimoen L, Van den Berghe L, Jacquet W, et al.: Depression and anxiety levels in patients with temporomandibular disorders: comparison with the general population. Clin. Oral Investig. 2020 Nov; 24(11): 3939–3945. PubMed Abstract | Publisher Full Text\n\nChisnoiu AM, Picos AM, Popa S, et al.: Factors involved in the etiology of temporomandibular disorders-a literature review. Clujul Med. 2015; 88(4): 473–478. PubMed Abstract | Publisher Full Text\n\nManfredini D, Marini M, Pavan C, et al.: Psychosocial profiles of painful TMD patients. J. Oral Rehabil. 2009 Mar; 36(3): 193–198. Publisher Full Text\n\nSanchla AD, Shrivastav S, Bharti L, et al.: Comparative Evaluation and Correlation of Pain Pattern in Neck Musculature Observed in Mild, Moderate, and Severe Temporomandibular Joint Disorder Cases as Compared to Non-temporomandibular Joint Disorder Cases. Cureus. 2022; 14(10). Publisher Full Text\n\nShrivastav S, Dr Sanchla AD : Correlation between Mental well-being and severity of Class II temporomandibular joint disorders, compared to non-temporomandibular joint disorders. [dataset]. 2023. Publisher Full Text"
}
|
[
{
"id": "237111",
"date": "15 Feb 2024",
"name": "Mohamed Jaber",
"expertise": [
"Reviewer Expertise Oral surgery",
"Oral Medicine",
"Oral Pathology",
"Maxillofacial Radiology",
"Dental Education"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n1. Abstract\n\n- The abstract outlines a systematic approach to assessing and correlating clinical, radiological, and psychological aspects of temporomandibular joint disorders (TMDs). The use of established diagnostic criteria and scales (DC/TMD, Warwick-Edinburgh, Hamilton) indicates a rigorous methodology.\n\n- The study's focus on correlating mental well-being with the severity of class II TMDs adds novelty to existing literature, addressing a gap in understanding the holistic impact of TMDs.\n\n- The study addresses the relevance of TMDs, emphasizing their common occurrence and the lack of a comprehensive diagnostic protocol. The research aims to contribute to effective management plans.\n\n- The abstract does not include citations, which might be necessary to establish the background and current knowledge on the subject. The absence of references may weaken the context and background of the study.\n\n- The abstract appears to be logically structured, with clear objectives and methodologies. However, without specific details, it's challenging to assess the correctness of the approach.\n\n- The abstract discusses various aspects, including clinical, radiological, and psychological dimensions, demonstrating a comprehensive approach and considering the diversity of factors influencing TMDs.\n\n- As mentioned earlier, there are no citations provided in the abstract. It is crucial to incorporate relevant literature to support the study's rationale and contextualize the research within the existing knowledge.\n\n- The methodology outlined seems accurate, relying on established diagnostic criteria and scales. However, the actual accuracy depends on the execution of the study, which cannot be fully assessed from the abstract.\n\n- The language used is clear and professional. However, some sentences could be refined for better clarity and flow.\n\n- The abstract is generally clear, but some sentences could benefit from simplification for a broader audience. For instance, explaining the significance of Warwick-Edinburgh and Hamilton scales for readers not familiar with them.\n\n- There is no indication of plagiarism in the provided abstract. However, without the ability to check against external sources, a comprehensive evaluation is not possible.\n\n- The study appears to be original in its approach, aiming to correlate TMD severity with mental well-being. This contributes to the understanding of TMDs beyond the physical symptoms.\n\n- The study objectives are clear: to assess, compare, and correlate clinical, radiological, and mental well-being aspects in class II TMD cases compared to class I non-TMD cases. Suggestions for Improvement:\n\n- Incorporate relevant citations to establish the context, show awareness of existing literature, and strengthen the background of the study.\n\n- Refine sentences for better clarity, especially for readers less familiar with the specific scales and terminology used.\n\n- Include specific details about the research design, sample size, and other methodological aspects to enhance transparency and allow for a more thorough evaluation.\n\n- Explicitly state how the study's findings could impact clinical practice and patient outcomes, emphasizing the practical implications of the research.\n\n- The abstract could conclude with a statement on the potential positive impact of the study, engaging the reader and emphasizing the significance of the research. In summary, the abstract covers the main aspects of the study but would benefit from additional details, citations, and minor refinements to enhance clarity and engagement. If executed well, the study could contribute valuable insights to the field of TMD research. Keywords: The selected keywords appear to be generally suitable for the topic of the study, which focuses on the correlation between mental well-being and the severity of class II temporomandibular joint disorders (TMDs). These keywords collectively cover the clinical, psychological, and radiological dimensions of the study, reflecting the multidisciplinary nature of the research. However, it's always a good practice to consider potential variations or synonyms of these keywords to ensure comprehensive searchability. Additionally, the inclusion of broader terms related to temporomandibular disorders and mental health might be beneficial for reaching a wider audience and increasing the visibility of the study in relevant literature searches. 3. Introduction\n\n- The introduction lacks an in-depth analysis of existing literature. It briefly mentions evidence suggesting a connection between TMJ disorders and mental well-being but does not provide a comprehensive review of relevant studies.\n\n- While the introduction touches on various aspects of TMJ disorders, it lacks detailed exploration, and the information is presented in a relatively surface-level manner.\n\n- The introduction doesn't explicitly highlight the novelty of the study. Emphasizing the unique aspects of the research could make the study more compelling.\n\n- Citations are appropriately used to support statements. However, the citations are somewhat dated, and more recent references could strengthen the foundation of the study. Citations are provided for specific statements, but the absence of more recent references might limit the incorporation of the latest knowledge on the subject.\n\n- The information presented is generally correct, but the lack of recent citations may impact the accuracy and currency of the background information.\n\n- The introduction encompasses various aspects of TMJ disorders, including their impact on mental well-being, diagnostic tools like MRI, and relevant scales. This reflects a degree of diversity in the information provided.\n\n- The information about the diagnostic tools and their advantages seems accurate. However, the use of more recent sources could enhance the accuracy of the background information.\n\n- The language is generally clear, but there are areas where sentence structures could be improved for better flow and comprehension.\n\n- The introduction is mostly clear, but providing context for the scales used (WEMWBS, HAM-A) may enhance clarity, especially for readers unfamiliar with these tools.\n\n- There are minor grammatical issues that could be addressed to improve the overall readability.\n\n- There is no evidence of plagiarism in the provided text.\n\n- The introduction does not explicitly state the knowledge gap or highlight the original contribution of the study. Identifying a gap in existing knowledge would strengthen the rationale for the research.\n\n- The study objectives are clearly outlined, specifying the clinical, radiological, and psychological aspects to be evaluated. Suggestions for Improvement:\n\n- Expand the literature review to provide a more comprehensive background on the connection between TMJ disorders and mental well-being. Include more recent references to reflect the current state\n\n- Explicitly state the novelty or unique contribution of the study to engage readers and demonstrate the significance of the research.\n\n- Use more recent and diverse references to strengthen the credibility and currency of the background information.\n\n- Refine sentence structures for better clarity and readability. Provide explanations for specialized terms and scales to aid understanding.\n\n- Clearly identify the knowledge gap or research question that the study aims to address. This helps establish the need for the research.\n\n- Offer a brief rationale or context for each objective to enhance understanding and emphasize the relevance of each aspect of the study.\n\n- Address minor grammatical issues for smoother readability.\n\n- Consider incorporating visuals (charts, graphs) to illustrate the prevalence of TMJ disorders and the potential impact on mental well-being. By addressing these suggestions, the introduction can be strengthened, providing a more solid foundation for the study and engaging readers more effectively.\n4. Material and methods\n\n- The methodology is outlined in a systematic manner, detailing the study design, setting, sample size calculation, inclusion and exclusion criteria, and data collection methods. However, it lacks depth in explaining certain aspects, such as the rationale behind choosing specific scales and indices.\n\n- The methodology doesn't explicitly highlight any novel approaches or techniques. Emphasizing the innovative aspects of the study could enhance its appeal.\n\n- Providing references to justify the choice of specific criteria, scales, or statistical methods would strengthen the research design.\n\n- The language is generally clear, but there are areas where sentence structures could be improved for better flow and comprehension.\n\n- The methods are generally clear, but some sections, especially those related to the statistical analysis, could benefit from additional explanations for readers unfamiliar with statistical terms and tests.\n\n- While ethical approval is mentioned, there is no explicit discussion of potential ethical issues or considerations in the methodology. It's important to highlight how ethical concerns will be addressed, especially in a study involving human subjects.\n\n- The statistical analysis plan is appropriate for the study objectives. However, providing more details on the validity and reliability of the scales and indices used would strengthen the methodological foundation.\nSuggestions for Improvement:\n\n- Offer more detailed explanations and rationale for the selection of specific scales (WEMWBS, HAM-A) and indices (DC/TMD criteria, Helkimo index). This will enhance the reader's understanding of why these tools were chosen.\n\n- Include more recent references to support the methodology and ensure that the latest knowledge is incorporated into the study design.\n\n- Provide additional explanations for statistical terms and tests used. This will make the section more accessible to a broader audience.\n\n- Explicitly discuss ethical considerations, including participant consent, confidentiality, and how potential biases and risks will be addressed.\n\n- Highlight any unique aspects of the study design or methodology that contribute to its originality.\n\n- Discuss the validity and reliability of the diagnostic criteria, scales, and indices used. This information is crucial for establishing the trustworthiness of the study findings.\n\n- Address minor grammatical issues for smoother readability.\n\n- Consider incorporating visuals (flowcharts, diagrams) to illustrate the study design and data flow, making it more accessible to readers. By addressing these suggestions, the methodology section can be strengthened, ensuring clarity, transparency, and a solid foundation for the research study. 5. Results\n6. Discussion\n\n- The discussion section lacks an in-depth analysis of the existing literature. While some relevant studies are cited, a more comprehensive review of the literature, including recent findings, would strengthen the discussion.\n\n- Citations are relevant to the topic, but the lack of recent references is a limitation. Incorporating more recent studies would enhance the currency of the discussion and demonstrate awareness of the latest research.\n\n- The language is clear and concise. However, there are some grammatical errors that, if addressed, would improve the overall readability.\n\n- The conclusion is clear and reiterates the expected outcome of the study. However, it could be strengthened by explicitly summarizing how the study addresses the stated objectives and contributes to the existing knowledge.\n\n- The discussion does not explicitly connect the findings to the stated objectives. A clearer link between the results and the research objectives would enhance the coherence of the discussion.\n\n- The discussion does not effectively contrast or compare the study's findings with the broader literature. A more detailed examination of how the results align or differ from existing studies would provide a more nuanced understanding.\n\n- The discussion does not explicitly identify a knowledge gap. A clearer articulation of the gap in the literature that the study aims to fill would strengthen the rationale for the research.\n\n- The discussion does not raise any explicit ethical concerns related to the study. However, it would be beneficial to discuss potential ethical considerations in research involving mental health and patient data.\n\n- The references provided are relevant to the study, but more recent literature could be included. A broader range of studies, including those with different perspectives, could provide a more comprehensive discussion. Suggestions for Improvement:\n\n- Expand the literature review by incorporating more recent studies and providing a more in-depth analysis of existing literature. Discuss how the current findings align with or diverge from previous research.\n\n- Clearly articulate how the study's findings address the stated objectives. This will provide a more structured and coherent discussion.\n\n- Explicitly state the knowledge gap that the study aims to fill. This will provide context for the research and enhance the justification for conducting the study.\n\n- Compare and contrast the current findings with other relevant studies in the field. This will highlight the study's contributions and limitations in the context of existing literature.\n\n- Discuss ethical considerations related to the study, especially when dealing with mental health data. Address issues such as patient consent, confidentiality, and potential biases.\n\n- Review and correct grammatical errors for improved readability.\n\n- Include more recent references to demonstrate an up-to-date understanding of the topic. This will strengthen the relevance and impact of the study. By addressing these suggestions, the discussion section can be enhanced to provide a more thorough analysis of the study's findings and their implications in the broader context of research on temporomandibular disorders and mental health.\n7. Overall assessment The study investigates the correlation between temporomandibular joint disorders (TMDs), particularly in Class II (vertical growth pattern) cases, and mental well-being using a multidisciplinary approach. The study design involves an observational and analytical study with a sample size calculated based on the prevalence of TMD in Class II cases. The methodology includes the use of validated diagnostic criteria, imaging techniques, and psychological assessment scales.\nStrengths: 1. The study addresses an important and clinically relevant topic, exploring the interplay between TMDs and mental well-being, which has implications for patient management. 2. The methodology is well-structured, detailing the study design, inclusion and exclusion criteria, and data collection methods. 3. The use of established diagnostic criteria and scales enhances the reliability of the study's findings. Concerns and Areas for Improvement: 1. Literature Review\n\n- The literature review in the introduction and discussion sections is limited and could benefit from a more comprehensive review of relevant studies. Including recent literature would strengthen the background and discussion. 2. Linking Findings to Objectives:\n\n- The discussion does not clearly link the study's findings to the stated objectives. Strengthening this connection would enhance the coherence of the discussion. 3. Identification of Knowledge Gap\n\n- The study does not explicitly identify a knowledge gap, making it less clear why the research was conducted. A more explicit articulation of the gap in the literature would strengthen the rationale for the study. 4. Ethical Considerations\n\n- While an ethical approval statement is provided, the discussion does not explicitly discuss potential ethical concerns related to the study. A brief discussion of ethical considerations, especially in research involving mental health and patient data, would be beneficial. 5. Recent Literature\n\n- The references used in the study are somewhat dated. Including more recent literature would enhance the currency of the study and demonstrate awareness of the latest research in the field.\nIn summary, the study addresses a valuable research question, and the methodology is well-structured. However, there are areas for improvement, including enhancing the literature review, clearly linking findings to objectives, addressing ethical considerations, and incorporating more recent literature.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
},
{
"id": "265368",
"date": "03 Sep 2024",
"name": "Deepa Jatti Patil",
"expertise": [
"Reviewer Expertise Temporomandibular disorders",
"Orofacial pain",
"CBCT",
"OPMD"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n.The authors plan to correlate the mental well-being of TMD patients with skeletal Class II disorders. The study design is appropriate .But the sample size is small and needs to increased to validate the study and improve the generalisability of data. Will the study include patients with skeletal class II without any symptoms of TMD? Mention in methodology how will the MRI images be screened? Are the authors using any classification such as Wilkes classification for classifying internal disc derangement. Kindy elaborate this in detail.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1293
|
https://f1000research.com/articles/12-1292/v1
|
09 Oct 23
|
{
"type": "Research Article",
"title": "Evaluation of knowledge and awareness of pediatric oral health among school teachers of Hazaribag before and after oral health education.",
"authors": [
"Vipin Ahuja",
"Annapurna Ahuja",
"Nilima Thosar",
"Vipin Ahuja",
"Nilima Thosar"
],
"abstract": "Background: Oral health education of school teachers will surely have a direct influence on evolving oral habits at an inchoate stage and assuredly help to garner oral health knowledge in children. The aim of this study was to assess the knowledge of school teachers about pediatric oral health and the assessment of the impact of a webinar training intervention in improving their knowledge. Methods: A total of 153 teachers participated in the research. A self‑administered, 30‑item questionnaire was designed in the English language and consisted of two sections: the first section included demographic details; the second section included 30 questions on pediatric oral health with three divided subsections as follows: Subsection A (including 7 questions): Questionnaire on general pediatric oral health, Subsection B (including 9 questions): Questionnaire on preventive pediatric oral health, Subsection C (including 14 questions): Questionnaire on clinical pediatric oral health. After receiving Google forms, all the participants participated in an oral health education webinar program using a web-based online education training protocol on the Zoom platform. After this webinar training session, post-training assessment of the oral health knowledge scores was done using the same online semi‑structured self‑administered questionnaire. Results: The inadequacy in knowledge of school teachers was evident and they need to be trained in many preventive and clinical protocols of pediatric oral health. However, a highly statistically significant increase (P < 0.001) in mean knowledge scores of school teachers was seen after a 1‑day training program. Conclusion: The training method was well received and improved the knowledge of school teachers on pediatric oral health.",
"keywords": [
"Pediatric Oral Health",
"Oral health promotion",
"School teachers",
"Training",
"Webinar"
],
"content": "Introduction\n\nSchool is indubitably the second abode where children garner education in varied subjects and aspects of life. School teachers are the pillars of school where they lay the foundation of future generations. Children in school idolize some or other teachers and want to imbibe the teacher qualities and apply them in their lives. And, if children are the budding future of humanity, then teachers are the driving force behind this endeavour. Therefore, the knowledge of school teachers can play a pivotal part in framing the attitude of young learners in school. However, unfortunately, the oral health knowledge of school teachers is documented inadequate as per previous dental literature.1,2\n\nChildren’s growth and development is directly linked to their oral health. As they spend a hefty stretch of time in schools, oral education can bring a major change in dental attitude and behaviour of miniature adults if it is taught with other subjects in schools. There is a scarcity of studies done in the past which prove that the school teachers had poor knowledge of oral health in varied aspects especially dentistry for children. Pediatric dentistry is an invincible segment of dentistry covering all aspects of dentistry in children from birth to adolescence. Hence, adequate wisdom of this branch should be given right from infancy to parents, school teachers and children.1–5\n\nStudies conducted on knowledge, attitude and practices in school teachers apropos to oral health worldwide had clearly mentioned the inaccurate and lack of information to the people of this profession. A study done in Mumbai, India inferred that there is a convinced and an instant need for educating school teachers in dental education as a significant lack of oral health knowledge was found evident in teachers of this region.2 Likewise, there are scores of studies documented in the literature which inferred similar findings.2–5\n\nTo the best of our knowledge, there is no previous study that assessed the knowledge and awareness of school teachers regarding comprehensive pediatric oral health including general, preventive and clinical pediatric dentistry and compared all parameters after conducting an oral health program. Therefore, this study was envisioned with the following aims: 1. to assess and evaluate the knowledge and awareness of school teachers in Hazaribag town of Jharkhand regarding pediatric oral health; 2. to determine if an online webinar series of lectures could ameliorate the knowledge and awareness level in school teachers; and 3. to compare these parameters at pre- and post-webinar levels.\n\n\nMethods\n\nThe protocol of this research has the following DOI:dx.doi.org/10.17504/protocols.io.j8nlko926v5r/v1\n\nAn interventional study was conducted among primary, elementary and high school teachers of nine private schools in the Hazaribag town of Jharkhand State in East India to evaluate the knowledge of participants on pediatric oral health. A total of 153 school teachers were randomly selected using a random sampling method.\n\n\n\n1. Primary, Elementary and High school teachers of private schools in the Hazaribag town of Jharkhand; and\n\n2. School teachers who are ready to receive web based online education training; and\n\n3. School teachers who acquire basic computer knowledge; and\n\n4. School teachers who gave their consent for the study\n\n\n\n1. Primary, Elementary and High school teachers of government schools in the Hazaribag town of Jharkhand; and\n\n2. School teachers who had not attended any dental education program previously; and\n\n3. School teachers who were not interested in web based online dental education training\n\nA one-day training program was collocated after receiving positive opinions on needs valuation from all participants, one week before the scheduled training program. All the nominated teachers took part in the training as an indispensable segment of a one-week teachers training program organized by the Department of Pediatric and Preventive Dentistry, Hazaribag College of Dental Sciences and Hospital, Hazaribagh from 4th to 10th September 2021.\n\nA self-administered, 30-item questionnaire was formulated as Google Forms in the English language; the design and inclusiveness of the questionnaire was finalized with the support of a team of experts from the Department of Pediatric and Preventive Dentistry, Periodontics and Public Health Dentistry before the study. The questionnaire incorporated two sections: the first section asked about demographic details such as gender, marital status, school location; the second section asked 30 questions on pediatric oral health with three divided subsections: Subsection A (including 7 questions): Questionnaire on general pediatric oral health, B (including 9 questions): Questionnaire on preventive pediatric oral health and C (including 14 questions): Questionnaire on clinical pediatric oral health, to evaluate the knowledge of teachers toward oral health in children. All the questions were in a digital format, uploaded on Google Forms. A pilot study was done antecedent to our study among 12 primary and elementary school teachers and the participants were not counted in the training program. This was done to check the reliability and feasibility of data collection stratagem before beginning of the main study. Any problems and technical hitches, if incurred during the filling of the pilot form were corrected. The pre- and post-training questionnaires can be found in the Extended data.\n\nThe training program consisted of four stages as described below.\n\nStage 1: Pre-training module of knowledge and awareness assessment: A 30-item questionnaire was sent to all the participating school teachers with a title of pre-test questionnaire. This was designed in English language and was emailed to all nominated school teachers participating in the study. The questionnaire included 30 questions in the form of an online self-administered questionnaire (English) and was formatted as Google Forms.\n\nStage 2: Webinar-based oral health education module: This module comprised of oral health education program to be attended by all participants using a web-based online education training protocol on the Zoom platform. The training included four sessions on oral cavity, plaque and gingiva, gingival problems; morphology of tooth, primary and permanent; tooth brushing techniques in children; dental caries with special reference to ECC (Early Childhood Caries); clinical myths and facts of children dentistry in Indian population with special mention to pulp therapy, dental caries, dental trauma, malocclusion, conscious sedation and general anaesthesia applications and dental fluorosis, home and professional dental practices, prevention of oral diseases. During the training program, four sessions of 30-45 minutes per session were conducted respectively for participating schools teachers.\n\nStage 3: A panel discussion followed by a dental quiz: After completing each session, a panel discussion was done for 45 minutes with the aim of clarifying individual teacher queries and discussing frequently asked questions regarding pediatric oral health with panellists comprising of professors from departments of Pediatric and Preventive Dentistry, Periodontics and Implantology, Public Health Dentistry and Oral Pathology in Hazaribag College of Dental Sciences and Hospital, Hazaribag. After that, a dental quiz was organized which enabled teachers to actively participate and share the dental knowledge gained through the webinar session.\n\nStage 4: Post-training module of knowledge and awareness assessment: A 30-item questionnaire which was the same as the pre-test questionnaire was sent to all the participating school teachers with a title of post-test questionnaire and the scores were recorded and compared to pre-test scores. The feedback from the participants regarding the program was also recorded.\n\nEthical approval was obtained from the Institutional Review Board of Hazaribag College of Dental Sciences and Hospital, Hazaribag, Jharkhand, India (with no. HCDSH/ADM/BNF/2020/214 and dated 25.01.2020). The written informed consent was obtained from all the participants before the start of the study.\n\nThe data collection, scoring and data analysis was done by a single trained investigator (Dr Annapurna Ahuja) to avoid inter-examiner variability by analysing the pre-questionnaire before online education and post-questionnaire after online education. The scoring was done as ‘1’ for Option A, ‘2’ for option B, ‘3’ for option C. The test-retest reliability of the questionnaire was estimated by providing the same questionnaire to the same participants of a pilot study at different times, and a satisfactory correlation coefficient was established to enhance trustworthiness and credibility of the data analysis.\n\nThe collected data were entered into Microsoft Excel 2007 and subjected to statistical analysis using SPSS version 22.0 (IBM Statistics Inc., Chicago, Illinois, USA). The statistical test used was Chi-Square test to assess the categorical difference in scores before and after oral health education. P ≤ 0.05 was considered for statistical significance. The test-retest reliability of the questionnaire was estimated, and a satisfactory correlation coefficient was established to enhance trustworthiness and credibility of the data analysis.\n\n\nResults\n\nIn this study, 153 school teachers participated from the Hazaribag city of Jharkhand state of East India. The response rate of the present study was 100 percent as all the school teachers agreed on the study and there was no mistake in filling in the questionnaire, so no data were excluded.\n\nTable 1 represents the distribution of the study population according to gender, school level and marital status of the teachers. The maximum percentage of teachers (60.1%) belongs to elementary school teachers followed by high school (31.4%) and pre-primary teachers (8.5%) respectively. The majority of teachers enrolled in the study were female teachers (73.9%) as compared to male teachers (26.1%). Out of the total number of teachers, 69.3% were married while 30.7% were single.\n\nTable 2 summarizes the knowledge level of the teachers at pre- and post-training sessions regarding general pediatric oral health. The school teachers displayed good knowledge for Q.2, 4 and 7 whereas 71.9% replied ‘yes’ to Q.1 which means this percentage knew that a pedodontist is a specialized dentist for children, 71.3% replied ‘yes’ to Q.3 which means this percentage were aware that milk teeth are important for the overall growth of a child, 68.6% replied ‘yes’ to Q.5 which means that only this percentage knew that milk teeth require specific treatment for primary teeth, 71.2% replied ‘yes’ to Q.6 which means this percentage were aware that milk teeth are more prone for dental cavities as their enamel and dentin layers are thinner.\n\nPost-training evaluation: The percentage of teachers who gave correct answers rose to a statistically significant level after oral health education was given to them; and for those who replied incorrectly in ‘no’ or ‘don’t know’, there was a statistically significant reduction seen in these scores after oral education. This was noted in all questions of general pediatric dentistry.\n\nTable 3 summarizes the knowledge level of the teachers at pre- and post-training sessions regarding preventive pediatric oral health. The school teachers displayed upright knowledge for Q.9, 14 and 16 whereas 52.3% replied ‘yes’ to Q.8 which means that only this percentage were aware about the timing for first dental visit, 66% replied ‘yes’ to Q.10 which means that this percentage knew about the starting age of brushing for children, 63.4% replied ‘yes’ to Q.11 which means that this percentage were aware about fluoridated and non-fluoridated toothpastes availability in the market, 77.8% replied ‘yes’ to Q.12 which means that this percentage knew that fluoride is a anti decay element and should be taken as per dentist recommendation, 54.2% replied ‘yes’ to Q.13 which means that only this percentage were aware that fluoride toothpaste can be used after 1st birthday, 53.6% replied ‘yes’ to Q.14 which means that only this percentage were aware that pit and fissure sealants can be used by the dentists to prevent caries in caries prone children, 77.8% replied ‘yes’ to Q.15 which means that this percentage were aware of fones or circular brushing technique used for children.\n\nPost-training evaluation: The percentage of teachers who gave correct answers rose to a statistically significant level after oral health education was given to them; and for those who replied incorrectly in ‘no’ or ‘don’t know’, there was a statistically significant reduction seen in these scores after oral education. This was noted in all questions of preventive pediatric dentistry.\n\nTable 4 summarizes the knowledge level of the teachers at pre- and post-training sessions regarding clinical pediatric oral health. The school teachers displayed upright knowledge for Q.17 and Q.2 whereas 79.1% of participating school teachers replied ‘yes’ to Q.18 which means that this percentage were aware that medicinal syrups are sugary and excessive use can cause dental decay, 70.6% of participants school teachers replied ‘yes’ to Q.19 which means that this percentage knew that milk tooth dental decay is early childhood caries, 75.8% of participants school teachers replied ‘yes’ to Q.20 which means that this percentage were aware of bottle feeding as a causative factor of dental decay in children, 49% of participating school teachers replied ‘yes’ to Q.21 which means that only this percentage were aware that ECC can spread through kissing between mothers and their children if mothers’ teeth are decayed, 62.8% of participating school teachers replied ‘yes’ to Q.22 which means that this percentage knew that RCTs and specially designed crowns can be used as a treatment protocol for milk teeth decay.\n\nAbout half of the participating (51.6%) school teachers replied ‘yes’ to Q.23 which means that only this percentage were aware root canal treatments form an imperative treatment protocol for severe milk tooth caries, 51% of participants replied ‘yes’ to Q.24 which means that only this percentage knew that heat fermentation should be avoided during oral swellings, 53.6% of participating school teachers replied ‘yes’ to Q.25 which means that only this percentage knew that avulsed tooth should be carried to a dentist within 30 minutes of injury, 54.2% of participants school teachers replied ‘yes’ to Q.26 which means that only this percentage were aware that avulsed tooth should not be carried dry but be kept in storage media during extra-oral time of avulsed injury, 62.1% of participants school teachers replied ‘yes’ to Q.28 which means that this percentage were aware that early orthodontic consultation should start at the age of 7 years, only 49% of participants school teachers replied ‘yes’ to Q.29 which means that this percentage were aware that conscious sedation and GA are alternative options for treatment of uncooperative children, 53.6% of participants school teachers replied ‘yes’ to Q.30 which means that only this percentage were aware that space maintainers are necessary in cases of early exfoliation of primary teeth.\n\nPost-training evaluation: The percentage of teachers who gave correct answers rose to a highly statistically significant level after oral health education was given to them; and for those who replied incorrectly in ‘no’ or ‘don’t know’, there was a highly statistically significant reduction seen in these scores after oral education. This was noted in all questions of clinical pediatric dentistry.\n\n\nDiscussion\n\nThe results of this study present an all-inclusive view of the knowledge level of school teachers about general, preventive and clinical aspects of pediatric oral health in Hazaribag City. According to the finest of our knowledge, it serves as the first study of calculating knowledge of children oral health among school teachers in the Hazaribag district of Jharkhand. There is a plethora of literature documented from different regions around the world in the past which proves that teachers hold basic acquaintance about oral health and thus indicating the need of improving oral health education of school teachers.2 This protocol would be of great help to young children as far as preventive strategies are concerned and also would psychologically reduce the dental fear if needs are catered at the school level.6 The modes of imparting dental education in schools vary from lectures, PowerPoint presentations, posters, brochures, models etc. but due to the Coronavirus (COVID-19) lockdown, the paradigm has been shifted from physical teaching to online mode through webinars which also seems to be an effective solution.7,8\n\nThe study included 153 school teachers from Hazaribag City of East India, of which 73.9% were female teachers and 26.1% were male teachers, and the similar percentage with respect to gender of school teachers participated in the study was reported by Dedeke et al.9\n\nSchool teachers exhibited honourably good basic knowledge on general pediatric dentistry. The majority of them (more than 90%) knew that humans have two sets of dentition—primary and permanent and also primary teeth lay the foundation for permanent teeth and should be taken care of until they shed as mentioned in a study by Johansson et al.10,11Nearly 70% knew about pedodontist as specialized children dentist which was in line with a study by Patil et al.12 which concluded that 84.1% of parents will consult a pedodontist for suggestion and is against study by Nagaveni et al.13 where negligible percentage of population knew about specialized pedodontist for children. More than 70% of participants knew about the importance of milk teeth and their role in the growth and development of children which is similar to reports by Nassar et al.14 and a fair part of participants knew that milk teeth are more prone to dental caries due to thin enamel and dentin when compared to permanent teeth and is well explained by Lynch.10 A highly statistically significant improvement in teachers’ knowledge regarding general pediatric dentistry was observed post webinar oral health education program. In our study, the majority of participants believe that dental education for children should be given to school teachers for the betterment of society. According to Nassar et al.,14 98.1% of parents believe that dental health education should be taught in schools for better dissemination of dental knowledge.\n\nSchool teachers exhibited poor knowledge on preventive pediatric dentistry. Only about 50% school teachers knew that the first dental visit time should be near to the child’s 1st birthday. This lack of awareness is well documented in previous studies by Baltaci,15 Nair,16 Nayak17 where it was also inferred that children never visited a dentist for their first dental visit as an imperative preventive protocol but the main reason for this dental visit was always dental pain. The knowledge of brushing habits forms a mixed response. The majority know about twice daily brushing as an important protocol to prevent decay as mentioned in previous studies by Baltaci,15 Al-Jaber,18 Adair et al.,19 Chandran,20 Özbek21 and Nair16 and this may be attributed to frequent media and social messages regarding tooth brushing. Nearly 60% of teachers knew that brushing should start as soon as the first tooth appears in the oral cavity, similar findings were also reported by Al-Jaber et al.18 and Baltaci et al.15 where 76.9% of parents and 50.4% of teachers answered correctly for the ideal time to start tooth brushing. 54% knew that fluoride can be used after the 1st birthday for topical applications which is in line with study by Basir where 17.1% gave the correct answer.22 Surprisingly, a huge sample size knew about the fones technique whereas only 15.2% in a study by Ibrahim23 responded correctly. The pea size toothpaste recommendation for kids was responded correctly by 86.7% which is in line with a study by Al-Jaber et al.18 and as per The American Academy of Pediatric Dentistry (AAPD) recommendations.24 The majority of the population (84%) knew that separate toothpastes are available for kids and adults. However, many of them were unaware that toothpastes come with fluoride and without fluoride separately. In addition, the majority of the population was aware of the recommendation for kids to brush their teeth twice daily as well as the importance of fluoride as an anti-decay agent. More than half of the respondents were unaware of professionally applied preventive measures, such as fissure sealants, and only 37% of parents responded correctly and their function and the techniques by which they are applied to children as a study by Nassar.14\n\nSchool teachers exhibited inadequate knowledge on clinical pediatric dentistry. A fair amount of knowledge was displayed regarding ECC and bottle feeding at night as the cause for baby teeth decay which was not aligned with Nassar14 and Al-Zahrani et al.25 where more than 50% of subjects were unaware of bottle feeding as the cause of caries and it was also stated that knowledge about ECC should be given to parents. In our study, less than half subjects knew about vertical transmission and that mothers who kiss their children can spread caries, the explanation of which is well explained by Grönroos et al.26 and Hameş-Kocabaş et al.27 as mutacins role in vertical transmission of S.mutans from mothers to their children.\n\nIn our study, 79.1% of parents knew that medicinal syrups are sugary and improper oral hygiene measures can cause caries which is consistent with a study by Valinoti et al.28 where it was inferred that pediatric formulations, especially antibiotics, contain a high amount of sucrose and are cariogenic. Neves et al.29 found that association of parental knowledge regarding sugar-containing pediatric syrups usage and practices, where 28.6% of parents brushed their child’s teeth after giving medications. In our study, it was found that 62.8% of participants gave the correct answer to the question concerning treatment of milk tooth decay with fillings or crowns which is consistent with a study by Nasir et al.14 where 56.2% said yes to this question. In our study, half of the participants knew that root canal treatment for children as a treatment protocol for severe milk teeth cavities. This finding aligns with Syriac et al.30 where 66% of parents had the knowledge of root canal treatment in deciduous teeth and 43% expressed positive attitude towards their children undergoing pulp therapy.\n\nOnly 51% of teachers knew that heat fermentation should be avoided in times of oral swellings and the scientific explanation is that the alkaline phosphatase starts denaturing above 19°C which is the threshold temperature for alveolar bone. The most referenced study inferred that if temperature was raised above 13°C for 1 minute or 10°C for 5 minutes then the alveolar bone tissue showed signs of resorption and no regeneration as a consequence.31 Following thermal damage, the healing of bone tissue was not through hard-tissue formation, but through the induction of connective tissue, suggesting that the threshold temperature increase for bone damage was 10°C.31,32 In the present study, nearly half of the teachers did not know about the management of knocked-out tooth, which includes lack of knowledge regarding critical extra-oral survival time and the storage media to carry the avulsed teeth back into the avulsed socket; and these findings are in line with studies by Prasanna et al.,33 Touré et al.6 and Nashine et al.3 This is very alarming, since tooth avulsion occurs commonly in school children between 7 and 11 years old so teachers should be made aware of this injury. School teachers showed inadequate knowledge regarding orthodontic correction and the age for children’s first orthodontic consultation visit. According to one study by Aldweesh et al.34 79% of the parents thought that their children’s teeth would have a significant impact on their personality and hence correction of malaligned teeth should be done; and a majority of children visited for an orthodontic consultation at the age of 11 years. More than half of the participants were unaware of the Nitrous oxide conscious sedation technique, a behaviour management, in young or fearful children which is not surprising as there is no previous study assessing the teachers’ knowledge or training in conscious sedation. This study inference was similar to Alkandari35 done in Kuwait which states that 79% of parents do not know about nitrous oxide conscious sedation. In our study, nearly half of the school teachers did not know the importance and protocol for space maintainers which is in line with a study by Ali et al.36 where only 49.8% showed parental knowledge regarding space maintainers and this knowledge was considered inadequate.\n\nThe strengths of this research are outlined as follows: 1. School teacher training at regular intervals should be an imperative part of Pediatric dentistry protocol. 2. If Children are desensitized at a primary level in schools, the fear of dentist and dentistry as a profession might be reduced. 3. Pre and post training shows highly significant results proving that the online oral education tool is well accepted and perceived by school teachers. The limitations of this study are, firstly the limited sample size, and secondly, the oral health knowledge of school teachers if had been compared with the education level of teachers could have added weightage to this research.",
"appendix": "Data availability\n\nZenodo: Evaluation of knowledge and awareness of pediatric oral health among school teachers of Hazaribag before and after oral health education. https://doi.org/10.5281/zenodo. 8004129. 37\n\nThis project contains the following underlying data:\n\n• f1000POST KAP STUDY 13.06.23.xlsx (individual level responses to the post-training questionnaire)\n\n• f1000PRE KAP STUDY 13.06.23.csv (individual level responses to the pre-training questionnaire)\n\n• The correct answers\n\nZenodo: ‘Extended Data’: Evaluation of knowledge and awareness of pediatric oral health among school teachers of Hazaribag before and after oral health education. https://doi.org/10.5281/zenodo.8351732. 38\n\nThis project contains the following extended data:\n\n• Questionnaire\n\n• Details of the training program\n\n• Topic guide\n\n• Dental quiz\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nKhurana C, Priya H, Kharbanda OP, et al.: Effectiveness of an oral health training program for school teachers in India: An interventional study. J. Educ. Health Promot. 2020; 9: 98.\n\nMota A, Oswal KC, Sajnani DA, et al.: Oral Health Knowledge, Attitude, and Approaches of Pre-Primary and Primary School Teachers in Mumbai. India Hindawi Publishing Corporation Scientifica; Volume 2016. : 1–8. Article ID 5967427. Publisher Full Text\n\nNashine N, Bansal A, Tyagi P, et al.: Comparison and Evaluation of Attitude and Knowledge Towards the Management of Dental Injury in School Teachers Before and After Oral Health Education. Int. J. Clin. Pediatr. Dent. 2018; 11(5): 425–429. PubMed Abstract | Publisher Full Text\n\nSekhar V, Sivsankar P, Easwaran MA, et al.: Knowledge, Attitude and Practice of School Teachers Towards Oral Health in Pondicherry Periodontics Section. J. Clin. Diagn. Res. 2014 Aug; 8(8): ZC12–ZC15. PubMed Abstract | Publisher Full Text\n\nAl-Asfour A, Andersson L, Al-Jame Q: School teachers’ knowledge of tooth avulsion and dental first aid before and after receiving information about avulsed teeth and replantation. Dent. Traumatol. 2008; 24: 43–49. PubMed Abstract | Publisher Full Text\n\nTouré B, Benoist FL, Faye B, et al.: Primary School Teachers’ Knowledge Regarding Emergency Management of Avulsed Permanent Incisors. J. Dent. 2011; 8(3): 117–122. PubMed Abstract\n\nGift HC, Reisine ST, Larach DC: The social impact of dental problems and visits. Am. J. Public Health. 1992; 82(12): 1663–1668. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAboubakr RM, Tounsi A: Impact of School-based Online Oral Health Education Programme during COVID-19 Pandemic: A Cross-sectional Study in Riyadh, Saudi Arabia. J. Clin. Diagn. Res. 2022; 16(2): ZC35–ZC40. Publisher Full Text\n\nDedeke AA, Osuh ME, Lawal FB, et al.: Effectiveness of an oral health care training workshop for school teachers: A pilot study. Ann. Ib Postgrad. Med. 2013; 11: 18–21. PubMed Abstract\n\nLynch RJM: The primary and mixed dentition, post-eruptive enamel maturation and dental caries: a review. Int. Dent. J. 2013; 63(Suppl. 2): 3–13. Publisher Full Text\n\nJohansson K, Sorvari R, Birkhed D, et al.: Dental erosion in deciduous teeth—an in vivo and in vitro study.29: 333–340. PubMed Abstract | Publisher Full Text\n\nPatil AN, Karkare S, Jadhav HS, et al.: Knowledge, Attitude, and Practice of Parents toward Their Children’s Oral Health and its Influence on the Dental Caries Status of 5–10-year-old Schoolchildren in Nashik, Maharashtra: A Cross-sectional Study. Int. J. Clin. Pediatr. Dent. 2022; 15(S-2): S126–S130. Publisher Full Text\n\nNagaveni NB, Radhika NB, Umashankar KV: Knowledge, Attitude and Practices of Parents Regarding Primary Teeth Care of their Children in Davangere city. India Pesq Bras Odontoped Clin Integr, João Pessoa. 2011; 11(1): 129–132. Publisher Full Text\n\nNassar AA, Fatani BA, Almobarak OT, et al.: Knowledge, Attitude, and Behavior of Parents Regarding Early Childhood Caries Prevention of Preschool Children in Western Region of Saudi Arabia: A Cross-Sectional Study. Dent. J. 2022; 10(12): 218. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBaltacı E, Baygın O, Tüzüner T, et al.: Evaluation of the knowledge, attitudes and behaviors of pre-school teachers on oral and dental health in the city center of Trabzon. Eur. Oral Res. 2019; 53(1): 12–20. PubMed Abstract | Publisher Full Text\n\nNair P, Shetty RN, Shetty SB, et al.: Oral health knowledge, awareness and attitude of parents towards root canal treatment of primary teeth in Mangalore: A survey. Int. J. Curr. Res. 2018; 10(3): 67042–67045.\n\nNayak UA, AlQahtani AH, Alturkistani RF, et al.: First Dental Visit of a Child - Perspectives of Parents /Guardians and Dentists/Paediatric Dentists in Saudi Arabia. Evolution Med. Dent. Sci. 2020; 9(42): 3086–3091. Publisher Full Text\n\nAl-Jaber AS, Al-Qatami HM, Al Jawad A, et al.: Attitudes, and Practices of Parents on Early Childhood Caries in Qatar—A Questionnaire Study. Eur. J. Dent. 2022; 16: 669–679. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAdair PM, Pine CM, Burnside G, et al.: Familial and cultural perceptions and beliefs of oral hygiene and dietary practices among ethnically and socio-economical diverse groups. Comm. Dent. Health. 2004; 21: 102–111.\n\nChandran V, Varma RB, Joy TM, et al.: Parental knowledge, attitude, and practice regarding the importance of primary dentition of their children in Kerala, India. J. Indian Assoc. Public Health Dent. 2019; 17: 247–252. Publisher Full Text\n\nÖzbek CD, Eser D, Bektaş-Kayhan K, et al.: Comparison of the tooth brushing habits of primary school age children and their parents. J. Istanb. Unıv. Fac. Dent. 2015; 49(1): 33–40. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBasir L, Khanehmasjedi M, Khanehmasjedi S: Knowledge, attitudes, and practices regarding the oral health of children: a cross-sectional study among Iranian parents Braz. J. Oral Sci. 2022; 21: e228274. Publisher Full Text\n\nIbrahim REHM, Helaly MO, Ahmed EMAA: Assessment of Brushing Techniques in School Children and Its Association with Dental Caries. Hindawi Int. J. Dent. 2019; 2021. Article ID 4383418. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAmerican Academy on Pediatric Dentistry: Policy on early childhood caries (ECC):classifications, consequences, and preventive strategies. Pediatr. Dent. 2008; 30: 40–43.\n\nAl-Zahrani AM, Al-Mushayt AS, Otaibi MF, et al.: Knowledge and attitude of Saudi mothers towards their preschool children’s oral health. Pak. J. Med. Sci. 2014; 30(4): 720–724. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGrönroos L, Saarela M, Mättö J, et al.: Mutacin Production by Streptococcus mutans May Promote Transmission of Bacteria from Mother to Child. Infect. Immun. 1998; 66(6): 2595–2600.\n\nHameş-Kocabaş EE, Uçar F, Kocataş Ersin N, et al.: Colonization and vertical transmission of Streptococcus mutans in Turkish children. Microbiol. Res. 2008; 163: 168–172. PubMed Abstract | Publisher Full Text\n\nValinoti AC, Costa LCD Jr, Farah A, et al.: Are Pediatric Antibiotic Formulations Potentials Risk Factors for Dental Caries and Dental Erosion? Open Dent. J. 2016; 10: 420–430. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNeves BG, Pierro VSDS, Maia LC: Perceptions and attitudes among parents and guardians on the use of pediatric medicines and their cariogenic and erosive potential. Cien. Saude Colet. 2007 Sep-Oct; 12(5): 1295–1300. PubMed Abstract | Publisher Full Text\n\nSyriac G, Kumar A, Jeeva P: Knowledge, Attitude and Practices of Parents towards Oral Health Maintenance and Pulp Therapy of Deciduous Teeth. Indian J. Dent. Educ. 2020; 13(2): 45–52. Publisher Full Text\n\nKwon SG, Park YJ, Jun SH, et al.: Thermal irritation of teeth during dental treatment procedures. Restor. Dent. Endod. 2013; 38(3): 105–112. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHespanhol FG, Guimarães LS, Antunes LAA, et al.: Effect of intracanal cryotherapy on postoperative pain after endodontic treatment: systematic review with meta-analysis. Restor. Dent. Endod. 2022 Aug; 47(3): e30. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPrasanna S, Giriraju A, Narayan NL: Knowledge and Attitude of Primary School Teachers toward Tooth Avulsion and Dental First Aid in Davangere City: A Cross-sectional Survey. Int. J. Clin. Pediatr. Dent. 2011; 4(3): 203–206. PubMed Abstract | Publisher Full Text\n\nAldweesh AH, Gassem AAB, AlShehri BM, et al.: Parents’ Awareness of Early Orthodontic Consultation: A Cross-Sectional Study. Int. J. Environ. Res. Public Health. 2022; 19: 1800. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlkandari SA, Almousa F, Abdulwahab M, et al.: Dentists’ and Parents’ Attitude Toward Nitrous Oxide Use in Kuwait. Anesth. Prog. 2016; 63: 8–16. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAli A, Hebbal M, Aldakheel N, et al.: Assessment of Parental Knowledge towards Space Maintainer as an Essential Intervention after Premature Extraction of Primary Teeth. Healthcare. 2022; 10: 1057. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDr Ahuja V , Dr Ahuja A , Dr Thosar N : Evaluation of knowledge and awareness of pediatric oral health among school teachers of Hazaribag before and after oral health education. [Data set]. Zenodo. 2023. Publisher Full Text\n\nDr Ahuja V , Dr Ahuja A , Dr Thosar N : ‘Extended Data’: Evaluation of knowledge and awareness of pediatric oral health among school teachers of Hazaribag before and after oral health education. [Data set]. Zenodo. 2023. Publisher Full Text"
}
|
[
{
"id": "223678",
"date": "14 Dec 2023",
"name": "DR SANJAY GUPTA",
"expertise": [
"Reviewer Expertise periodontology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nNice work has been done .The work is clearly presented. Study design is sufficient and the study is technically sound. This study consist of sufficient methods and analysis. The work is statistically appropriate. The conclusion drawn is well supported by the result. The sample size can be increased for more weightage to this research.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1292
|
https://f1000research.com/articles/12-1286/v1
|
09 Oct 23
|
{
"type": "Systematic Review",
"title": "Drivers of green purchasing behaviour: a systematic review and a research agenda",
"authors": [
"Nuryusnita Yusoff",
"Mazni Alias",
"Norhazlin Ismail",
"Nuryusnita Yusoff",
"Norhazlin Ismail"
],
"abstract": "Background: Green purchasing is an important aspect of sustainable consumption, which decreases society’s environmental effect. Although numerous research has been conducted to investigate the determinants of green buying behaviour, there has been a lack of effort in comprehensively analysing these findings. The purpose of this study is to examine the available literature on the factors that influence green purchasing behaviour. Methods: The review focused on empirical research published in peer-reviewed English-language publications between 2017 and 2021 in Web of Science and Scopus. The research took place from May to June 2021. Mixed Methods Appraisal Tool (MMAT) is used to assess the risk of bias in systematic literature reviews. Results: 41 articles were included, with significant focus on the retailing sector. Most of these studies were centred in Asian countries, primarily China and India. The Theory of Planned Behaviour was the most prominent, appearing 15 times, followed by the Theory of Reasoned Action (seven times). Analysis identified five main themes and 15 sub-themes related to green purchase behaviour drivers. These themes were categorized by occurrence: People (34 papers), marketing (13), knowledge (12), environment (12), and influence (nine). The dominant driver was people (34 studies), encompassing sub-themes including motivation (three), perception (eight), behavioural (13), and psychographic characteristics (10). Conclusions: This study has given an overview of the present status of green purchasing behaviour, which serves as a foundation for future studies and guidance for policymakers and practitioners. However, it does not include unpublished materials and non-English papers. Secondly, it focuses on articles from two databases within the last five years which doesn't encompass all article types, prompting the need for future exploration. Thirdly, extending the review's time frame could unveil more pronounced GPB patterns. Lastly, although all eligible papers were assessed based on criteria, the chance of overlooking some papers is acknowledged.",
"keywords": [
"green purchasing behaviour",
"green procurement behaviour",
"sustainable procurement behaviour",
"sustainable procurement",
"theme analysis"
],
"content": "Introduction\n\nUnsustainable levels of consumption around the world are causing serious environmental problems, prompting community to rethink their traditional purchasing behaviour to achieve environmental sustainability (Jaiswal and Kant, 2018; Todorovic, 2018). For example, the usage of single used plastic (microplastics) that cause marine plastic pollution and has become a significant environmental concern for governments (Xanthos and Walker, 2017). An increasing issue about microplastics is that they can penetrate the human food chain by consumption of fish, shellfish, and filter feeders (Chang, 2015), potentially adverse effects on human health (UNEP, 2015; GESAMP, 2016). Therefore, consumers must adjust their purchasing habits to address the harmful environmental and human health implications of pollution. Changing one’s consumption habits can help to alleviate environmental problems and encourage sustainable production (Xanthos and Walker, 2017). For example, by purchasing ecologically friendly packaging, shoppers can put pressure on retailers to migrate from traditional packaging methods to eco-friendly packaging methods by employing less damaging packaging materials. This, in turn, minimises worldwide marine plastic pollution.\n\nAs a result of growing concern about environmental damage, people have started to convert their environmental awareness into pledges to buy ‘green’ items (Haque, Yamoah and Sroka, 2020; Sheng et al., 2019) which can be called green purchasing behaviour (GPB). Green consumer behaviour, in other terms, refers to the behaviours of a person who considers social impacts when making purchases (Sharma and Joshi, 2017). GPB is critical in minimizing the environmental impact of consumed goods to meet the importance of green consumption. Many researchers (e.g. Ahn, Kim and Kim, 2020; Elsantil and Hamza, 2019 and Anantharaman, 2018) have aimed to figure out why people buy green products by looking at the assembly process, methods, components used, the ecological consequences, and how businesses are involved (He et al., 2021).\n\nModifying one’s purchasing behaviour can aid in the reduction of environmental issues and the promotion of sustainable production (Ahn, Kim and Kim, 2020). Subtle changes in daily behaviour can pave the road for a more sustainable future. As identified by Elsantil and Hamza (2019) and Anantharaman (2018), recently, there has been a big rise in the number of people in study on individual behaviour modification and sustainable consumption. Finding a link between environmentally conscious customer attitudes and GPB from the larger green marketing field, is a new area of research (Trivedi, Patel and Acharya, 2018).\n\nEven though various research has been conducted to investigate the causes of GPB, there has been an absence of initiative in comprehensively assessing the findings. In the present year, no systematic reviews of green purchasing behaviour have been conducted. There is literature review on GPB by Nadeem, Mohamad and Abdullah (2017), provided an overview of effects of personal values, leadership style and awareness on GPB meanwhile (Witek and Kuźniar, 2021) investigating how socio demographic factors explain consumers’ GPB. Even though the latter briefly reviewed published studies on GPB drivers, the present article will systematically review drivers of GPB, using PRISMA 2020 guidelines.\n\nTherefore, the purpose of this study is to (i) to give a complete and systematic analysis of the drivers that significantly influence consumers’ GPB; and (ii) highlight the research trend and diverse issues by conducting a thematic analysis of the chosen articles. This objective was met based on qualitative data analysis, we conducted a systematic literature review (SLR), descriptive and thematic data analysis. Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 and Mixed Methods Appraisal Tool (MMAT) Version 2018 (Nha et al., 2018) were used as framework to carry out the SLR.\n\nThe research questions are as follows. First, how can we systematize and identify advances in analytical areas of GPB research by going through key papers, theories, methodologies, and variables of interest in existent literature. Second, how can we develop a thematic theme for analyzing GPB that examines the drivers. Third, what are the directions for future research and its implications.\n\nThe progressive destruction of the natural environment because of human exploitation necessitated the introduction of the idea of sustainable development. As a result, protecting the natural environment and resources for future generations has become a global necessity, and one method is to engage in green purchasing (Ali et al., 2020; Giao, 2020). Since the 1990s, green purchasing has been perceived as an effective tool in lessening environmental burdens pertinent to the human activities of product production and consumption (Ho, Dickson and Chan, 2010; Malatinec, 2019). The strategic role of purchasing and supply as a lever for sustainable development is reflected in an increase in the prevalence of research on responsible purchasing and supply (Ridzuan Kushairi, 2019), a greater policy emphasis on green and sustainable procurement in the public sector (Igarashi, de Boer, and Pfuh, 2017), and private-sector efforts to improve the environmental and social performance of firms and their supply chains (Mashele and Chuchu, 2018).\n\nPrevious research have concentrated mostly on the core values, opinions, and intentions of customers while purchasing eco-friendly goods in order to describe sustainable consumption (Liobikienė and Bernatonienė, 2017). Various research have been undertaken to examine the primary elements influencing consumers’ long-term purchasing behaviour, including perceived behavioural control (Müller et al., 2021; Zahan et al., 2020), attitude (Trivedi et al., 2018; Zahan et al., 2020), environmental concern (Wang, Wong, and Narayanan Alagas, 2020), environmental responsibility (Joshi and Rahman, 2019), marketing instruments (Sari et al., 2020), environmental knowledge (Wang et al., 2020), subjective norms (Joshi and Rahman, 2017) and social norms (He et al., 2021). Furthermore, earlier studies on green purchasing have investigated many personal, psychological, and societal elements that influence customers’ environmentally and socially conscious purchasing (Liobikienė and Bernatonienė, 2017). These conceptions are difficult to interpret, yet they are crucial in behavioural and cultural psychology. Many scholars have explored and analysed these constructs to analyse consumer green purchasing decisions. Regardless their environmental awareness and worries, consumers’ attitudes and behaviours differ when it comes to purchasing products. Most researchers have confirmed that green consumer behaviour is a future behaviour that contributes to environmental protection (Giao, 2020; Naz et al., 2020).\n\nImplementation of green purchasing practice is subjected to typical reasons, and the effectiveness of this practice is determined by key factors. It is therefore the aim of this study is to examine green purchasing behaviour to explain how various factors influence green purchasing behaviour. This study provides an important foundation to understand green purchasing behaviours and, in turn, analyse critical elements that influence them. Understanding these critical aspects can assist relevant government agencies in developing effective policies to encourage developers to use green purchasing, so promoting sustainable development.\n\n\nMethods\n\nThe mechanism for retrieving articles relating to GPB drivers is covered in this section. Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 and Mixed Methods Appraisal Tool (MMAT) Version 2018 (Nha et al., 2018) were the strategies employed to carry out the SLR.\n\nThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Statement, which superseded the 2009 statement and incorporates new reporting criteria that reflect improvements in techniques for finding, selecting, assessing, and summarizing research, guided this assessment (Page et al., 2021). PRISMA 2020 is intended for use in systematic reviews with or without synthesis (for example, pairwise meta-analysis or other statistical synthesis approaches). This methodology has been used by several studies in literature medical research such as Bekele, Mechessa and Sefera (2021), Puljak and Pieper (2022) and in social sciences with Vejaratnam, Mohamad and Chenayah (2020).\n\nThe journal databases utilised in this SLR were Web of Science and Scopus. These databases were selected due to the large compendium of documents available from Emerald, Elsevier, Springer, and Taylor and Francis. Each research string has the following keywords: “green procurement behavi*r” or “sustainable procurement behavi*r” or “sustainable purchasing behavi*r” or “green purchasing behavi*r”, or “pro-environmental purchasing behavi*r.” Keywords relevant to this study such as “Purchas*” (buying and purchase) were also included since it has a very similar meaning to procurement and is used by various authors. Within this research, ‘environmental’ has been included because it is synonymous with ‘green’.\n\nWe will now go over the screening approach in detail. First, we chose the keywords for our study (the “*” symbol was used at the end of some phrases to broaden the range of viable studies, as many articles use slightly different terms for the same idea, such as “sustainable” instead of “sustainability”). We chose one word linked to sustainability/corporate social responsibility (i.e., “csr” keywords) to broaden the potential list of studies that might be related to our study questions: “sustainab *”, “environment *”, “green”, and “corporate social responsibility”.\n\nThe qualifying conditions for this review were empirical research published in peer-reviewed full-length publications written in English between 2017 and 2021. The chosen publishing time frame was determined by the need to keep the sources trending. The literary research session lasted from May to June of 2021. We did not examine review articles, book series, books, book chapters, or conference proceedings since we only intended to examine primary sources containing empirical data. A total of 415 articles were found after searching both databases. After the exclusion, there were 359 articles left. After removing 77 duplicates from both databases, the qualifying process was reduced to 282 articles.\n\nAbstracts were checked for relevance at this point, and some papers were read entirely to identify research that empirically studied factors of GPB. Articles about green purchasing were only considered if they investigated human behaviour. Some articles, such as Morales-Contreras et al. (2019) looked at barriers to GPB; nevertheless, hurdles to GPB discovered in the research were also documented. Eighteen articles were omitted because they were not retrievable. After screening the related articles based on the title and abstract, 81 papers proceed to the next screening using Mixed Methods Appraisal Tool (MMAT) Version 2018 by (Nha et al., 2018). MMAT was chosen because the papers listed contain qualitative, quantitative, and mixed methods. This method resulted in the identification of 41 publications for qualitative examination. As a result, 41 remaining articles were considered for the review. Similar studies have suggested a comparable number of articles for systematisation (Benevene and Buonomo, 2020; Gimenez and Tachizawa, 2012; Jabbour, 2013). Figure 1 shows the stages of articles selection that adapted based on Page et al., 2021. The classification and coding of these articles were performed as described in the next section.\n\nThe qualitative approach begins with an abductive process known as template or thematic analysis, which is used to build richer theoretical views than those already available in literature. Thematic analysis was chosen because it is an extended assessment with the objective of going beyond a data summary, attempting to build on key themes and order and organise the literatures under these topics (Xiao and Watson, 2019). Thematic evaluations with a framework have been shown to be more acceptable since they have a more stable structure (Paul and Criado, 2020). Therefore, Braun and Clarke (2006) six step framework are adopt and adapt to form a systematic thematic analysis, illustrated in Figure 2 below:\n\nAfter we obtained 415 articles from the database queries, we read through the entire articles set before we begin the coding, as we get ideas, identification of possible patterns will be shaped as we read through. The idea is to be familiar with all aspects of the data (Step 1). The coding procedure was broken down into three phases. First, each of the selected articles was coded line by line to obtain statements on GPB drivers. Following that, sentences that highlight comparable points were grouped together to form a descriptive theme, or subtheme (Step 2 until Step 4) as shown in Figure 3.\n\nThe final stage was grouping sub-themes into analytical themes, also known as major themes (Step 5 and 6). Five relevant sets of drives (themes) and 15 sub-themes emerged from the coding process. The expert assessment was done by a human behaviour expert and an environmental management expert to guarantee the validity of the themes and sub-themes. These codes are then collated into the main and initial sub-themes of the hierarchy in as Table 1 below:\n\n\nResults\n\nThe results were broken down into two sections: 1) descriptive analysis and 2) thematic analysis. The descriptive analysis results give bibliographic data and assist in contextualising the outcomes of the thematic identification and material evaluation processes. Thematic analysis is the process of grouping studies into research guiding topics based on similarities and trends discovered.\n\nNotably, most of the studies are retailing (22 studies). Several studies concentrated on business sectors i.e., education (two studies), food system (two studies), hotel (three studies), personal care product (two studies), construction (two studies), and housing (two studies). Besides that, one study are from the government, automotive, recycling company, and battery industries as shown in Table 2. In industrialized countries, 15 studies were undertaken, however in poor countries, the number of studies was nearly doubled, with 26 studies.\n\nIn terms of developing countries, the survey found that Asian nations were the most well-represented (24 studies). China was the country with the most studies (10), followed by India (eight studies) as shown in Table 3. The fact that most of the studies were undertaken in developing nations contradicts a prior conclusion by Ahamat, Ahmad and Mohd (2018) who determined that very little research on consumer demand for environmentally friendly commodities in developing countries had been conducted. As pointed out by Wang et al. (2020) and Mohd Suki and Mohd Suki (2019), GPB research are quite common in underdeveloped countries. One of the motivations on this motion probably because Asian consumers are considerably less conscious of environmental sustainability than consumer in developed countries (Ahamat et al., 2018).\n\nSurveys were a typical approach to investigating the drivers (30 studies). Only one study combined qualitative and quantitative information (Eberhart and Naderer, 2017). For qualitative studies, the research either used combination of observation and in-depth interview (Morales-Contreras et al., 2019), in-depth interview (Giao, 2020; He et al., 2021) or focus group (Nimri, Patiar and Jin, 2020). Meanwhile, most studies (37 studies) were based on quantitative data, which was more than 11 times that of qualitative data. The research was published between 2017 and June 2021 (Figure 4). The trend in five years’ time shows an incline of studies in GPB with 2020 obtaining the highest i.e., 12 articles. However, our final search was conducted in June 2021 with only recording four articles in mid-year, 2021 forecast a decline in GPB study as shown in Figure 4.\n\nThe articles reviewed were from various publications (Figure 4). The majority of the articles were published in Sustainable (Switzerland) (10 studies) and Journal of Cleaner Production (eight studies). This was followed by Sustainable Production and Consumption (four studies), Business Strategy and the Environment (three studies), Journal of Retailing and Consumer Services (two studies) and one study each from another journal listed in Table 4. Table 5 shows the most cited papers in the review, where the study by Jaiswal and Kant (2018) was the most cited paper with 345 citations.\n\nTable 4 shows the details of journal sources used in this study. The highest number of publications is from Sustainability (Switzerland) (impact factor 10.801) with 10 publications, followed by Journal of Cleaner Production (impact factor 11.072) with eight publications, and Sustainable Production and Consumption (impact factor 9.06) with four publications.\n\nTable 5 showed the most cited publications/authors in this study. Jaiswal and Kant (2018) leading the list with a total of 345 citations. The second highest total citations are article by Choi and Johnson (2019) with 149 citations, followed by Joshi and Rahman (2017) with 106 citations, Joshi and Rahman (2019) with 84 citations, and Laureti and Benedetti (2018) with 80 citations.\n\nFive overarching themes and 15 sub-themes connected to GPB drivers were characterized by the number of incidences in the themes: People (34 papers), marketing (13 papers), knowledge (12 papers), environment (12 papers) and influence (nine papers) presented in Table 6. While Figure 5 showed the percentage of each theme’s contribution. The graph (outer circle) depicts the study’s major themes and the percentage of articles in the given axis that support the formation of thematic sub-themes.\n\nTable 7 shows the distribution of papers that contained a stated theoretical perspective or at least a clear application of theoretical perspective. There are 22 theories mentioned in the journals. The most dominant theory is Theory of Planned Behaviour which was mentioned 15 times followed by Theory of Reason Action (seven times), Value Belief Norm (three times), and Attitude-Behaviour-Context (ABC) Theory (two times). Other theories were Theory of Normative, Social Capital Theory, grounded theory, Attitude-Intention-Behaviour, Theory of Reason Behaviour, Social Cognitive Theory, Social Adoption Theory, Theory of Consumption Value, and Stakeholder Theory.\n\nTheory of Planned Behaviour and Theory of Reasoned Action are the most used theories in this findings because it is a combination of two psychological theories of health behaviour change to explain and predict human behaviour developed by Fishbein and Azjen back in 1985. (Staats, 2004). The Theory of Reason Action (TRA) holds that one’s beliefs about behavioural outcomes and one’s evaluation of those outcomes determine attitudes toward the behaviour. The TRA then bridges the gap between attitudes and behavioural outcomes by inserting the construct of ‘intentions’, the TRA holds that intentions directly lead to behaviour (Shahid, 2015). Theory of reasoned action (TRA) (Ajzen and Fishbein, 1980) and the theory of planned behaviour (TPB) (Ajzen, 1985) are the major theoretic frameworks employed by many studies to examine the various forms of ecological behaviours in western countries, including purchasing of sustainable products (Liobikienė et al., 2016; Vermeir and Verbeke, 2008). While Value-Belief-Norm Theory (VBN) developed by Stern (Stern, 2000) is one of the most quoted models for clarifying pro-environmental behaviour (Shahid, 2015). The VBN theory links a person’s ecological worldview, assessed by the new environmental paradigm e.g., Dunlap et al. (2000), and environmental values (e.g., Stern and Dietz, 1994).\n\nIn this part, five themes will be covered i.e., people, influence, environment, marketing, and knowledge topics, as well as their sub-themes, will be discussed in depth in this part.\n\nPeople\n\nThe most dominant drivers mentioned in the selected literature is on people (34 studies). Four sub-themes were identified under this theme: motivation (three), perception (eight), behavioural (13), and psychographic characteristics (10). Choi and Johnson (2019) investigated consumer motivations using a multi-level hierarchical model that included environmental and hedonic incentives. Their findings supported the notion that environmental and hedonic incentives influence green products buying intentions. This idea is in line with Eberhart and Naderer (2017) study, which said that consumers must be in a motivating state where they feel compelled to act to achieve more sustainable consumption. Spirituality is also a motivator, and it has been discovered that instilling spiritual worth in consumers has a favourable impact on their long-term purchasing behaviour (Joshi and Rahman, 2019).\n\nAn empirical study by Joshi and Rahman (2019) asserts that customers’ long-term purchase decisions are influenced significantly by their perceptions of their own efficacy. A significant factor in green buy intent and GPB is customers’ perceptions of their own behavioural control, according to the studies (Müller et al., 2021; Zahan et al., 2020). Green products are valued by customers based on their perceived worth, and this value influences their purchasing decisions, tying the consumer’s purchasing attitudes and psychological behaviour during decision-making together (Ahmad et al., 2020; Zhang et al., 2019). In contrast, the negative perception towards green products such as green washing reduce customers’ purchasing intentions which lead to decrease of GPB (Zhang et al., 2018). Finding by Laureti and Benedetti (2018) suggested that purchasing behaviour was influenced by perceive behavioural control. Perceived behavioural control, on the other hand, had no effect on the study sample’s intention to purchase green skincare products (Al Mamun et al., 2020).\n\nGreen buying intention is found to be influenced by behaviour motivation indirectly. The creation process of attitude runs from behaviour motivation through behavioural intention. The internal reason of a person’s behavioural purpose is behaviour motivation (He et al., 2021). People’s motivation to buy green items is directly related to their motivation to do so. The intention to acquire green items is the internal driving force of real green product purchase behaviour. People’s real behaviour is directly determined by their intentions (He et al., 2021). A large and positive influence on green purchase intentions is exerted by a person’s perception of behavioural control (Nimri et al., 2020; Wang et al., 2020; Yang et al., 2019; Zahan et al., 2020), subjective norms intentions (Wang et al., 2020; Yang et al., 2019), attitude (Trivedi et al., 2018; Zahan et al., 2020), green trust (Ahmad et al., 2020) and self-identity (Sharma et al., 2020). A cross-sectional study by Sari et al. (2020) and quantitative study by Amoako, Dzogbenuku, and Abubakari, (2020) showed that there is a strong and positive correlation between green attitudes and purchasing behaviour. Green attitudes, on the other hand, were found to mediate GPB (Yang et al., 2019).\n\nFrom the perspective of worldview, Caniëls et al. (2021) stated that consumer biospheric values have a beneficial influence on their goals, behaviour and experience with sustainable products reveals new information on the factors that influence sustainable consumption. The positive relationship between intention and actual behaviour confirmed from study by (Onel, 2017). Residents’ characteristics, on the other hand, impact the degree and the relation between behaviour intention and actual behaviour as a moderating variable (He et al., 2021).\n\nConsumer GPB was strongly influenced by psychographic traits such as values, beliefs, and attitudes (Solomon, 2018). In general, most sustained behaviour may be explained by selfish reasons linked to a close psychological distance; when things or events are close to a person’s mind, they take on a tangible meaning, which leads to increased purchasing behaviour (Zhang et al., 2019). Besides that, people who have a high sustainability personality (Mohd Suki and Mohd Suki 2019) and self-interest (Eberhart and Naderer, 2017) tend to purchase green products. Granzin and Olsen (1991) found that in the context of other environmental attributes, such as green buying habits, altruism has been studied further by other researchers as a powerful predictor of environmental conservation (Uddin and Khan, 2018). Customers in underdeveloped countries may be motivated to buy green items by self-expressive benefits (Jahanshahi and Jia, 2018). A person’s ethical beliefs can influence their positive attitudes towards green products. As a result, moral intelligence is a critical aspect in motivating behaviour and ensuring that it is sustained (Al-Adamat, Al-Gasawneh, and Al-Adamat, 2020) and moral obligation (Müller et al., 2021) while (Siyavooshi, Foroozanfar, and Sharifi, 2019) empirically shows that religion value effect of sustainable purchasing behaviour.\n\nEnvironment\n\nA sum of 12 studies acknowledge environment as driver to GPB. Three sub-themes are environmental concern (eight studies), environmental responsibility (one study), environmental practices (one study), and environmental education (two studies).\n\nPerceived behavioural control and attitudes are influenced by environmental concern (Wang et al., 2020). A significant influence on people’s norms and, as a result, on their green consumption has been found as environmental concern. This were supported by few studies such as Wang (2020) on hotel selection in China, Joshi and Rahman (2017) on young consumer in India, Jaiswal and Kant (2018) on India consumers, Rajadurai et al. (2018) on gen Y in Malaysia, Troudi and Bouyoucef (2020) on green food in Algerian, Laureti and Benedetti (2018) on green food in Italy, and Al Mamun et al. (2020) on green skincare products. Environmental concern, on the other hand, did not appear to have a substantial additional direct effect on purchase intention, according to studies by Choi and Johnson (2019) and Zahan et al. (2020). The explanation for this is that environmental concern lessened in the presence of attitude and perceived environmental effectiveness (Choi and Johnson, 2019). Study participants’ subjective norms were found to be negatively influenced by environmental concern by Zahan et al. (2020). Instead, the urge to acquire green products is influenced by environmental concern in an indirect way.\n\nAccording to a study by Joshi and Rahman (2019), long-term purchase decisions are influenced by customers’ desire to do their part to protect the environment. By focusing on crucial psychological aspects identified in the current study, consumers’ mindsets can be shaped, and they can be directed toward long-term purchasing. A set of complementary environmental behaviours is an-other important component in the establishment of a green purchasing policy (Leal et al., 2020), whereas environmental education is the primary driver in explaining green behaviour in an institutional context (He et al., 2021; Varela-Candamio, Novo-Corti, and Varela-Candamio et al., 2018).\n\nMarketing\n\nAdvertising, packaging design, and product description are all part of the marketing theme, as are customer perceptions of these tools. This theme has the second most sub-themes of any theme. i.e., market instrument (10 studies), market condition (two studies), and supplier (one study). Adverts, product quality, and technical background are the focus of the first sub-theme. Research by Sari et al. (2020) reveals how marketing tools, such as consumer education, affect GPB. The impact of green advertising is a crucial factor of consumer buying behaviour, according to scientific findings (Ahamat, et al., 2018). People are more inclined to acquire environmentally friendly items if they find the promotional activities interesting and beneficial (Giao, 2020). An interesting finding by Yang et al. (2020) showed that media persuasion can effectively affect residents’ GPB. On the other hand, environmental advertising Liao et al. (2020) and context of technology He et al. (2021) incorporating a more balanced approach to the relationship between consumer value and environmentally friendly shopping habits.\n\nCustomer decision-making is heavily influenced by quality qualities, according to Troudi and Bouyoucef (2020). Consumers want to save the environment by paying higher fees, but they also want to satisfy their practical demands when they buy environmentally friendly products (Wang et al., 2019). Consumers may choose to buy green products based on the availability of these commodities (Ahmad et al., 2018). A recent study found that consumers’ purchasing decisions are significantly influenced by information on environmentally friendly products (Giao, 2020). Environmental crisis information efficiently evoked citizens’ environmental concern while also increasing their environmental knowledge, according to Wang et al. (2019) and Trivedi et al. (2018), allowing them to quickly form an accurate cognition about the consumption value of green products.\n\nStudy by Morales-Contreras et al. (2019) suggested that the main drivers to effective GPB under theme marketing are market conditions, and conflicts in customer/supplier interests. Market conditions are considered in terms of demand, prices, and margins while customer/supplier interests involve conflict with short and long-term.\n\nKnowledge\n\nA total of 12 studies with two sub-themes, i.e., subjective and environment knowledge discovered related to the theme knowledge. Most of the studies consider knowledge that positively affects the GPB. Studies by De Bernardi, Bertello, and Venuti (2019), Amoako et al. (2020), Kumar et al. (2019), Choi and Johnson (2019), Di Martino, Nanere, and DSouza, (2019), Siyavooshi et al. (2019), Nimri et al. (2020), and Troudi and Bouyoucef, (2020) believe there is a substantial correlation between environmentally conscious shopping and GPB. Park and Sohn (2018), on the other hand, emphasised that GPB was influenced directly by consumers’ subjective knowledge.\n\nFurthermore, environmental knowledge serves as a mediator in the investigation of the link between green purchasing intentions and Doctrine of the Mean (Sheng et al., 2019). Environmental knowledge is the major antecedent that influences environmental attitude, which indirectly affects GPB, according to studies by Wang et al. (2020) and Uddin and Khan (2018). When it comes to green purchasing, environmental awareness has little influence, according to Jaiswal and Kant (2018) and Shatnawi, Al-Faouri, and Al-Hayari (2019). On the other side, online information sharing has been found to have a favourable impact on long-term purchasing and consumption behaviour (De Bernardi et al., 2019).\n\nInfluence\n\nA total of nine research papers revealed drivers associated with the theme influence. They were divided into two sub-themes subjective norms (nine studies) and social norms (three studies). Some of papers under this theme contains both subthemes. We are more likely to engage in ecologically friendly purchasing practises if we perceive that individuals we hold in high regard (family members, close friends, etc.) support our decision to do so. As a result, higher subjective norms are likely to lead to relevant behaviour through improved behavioural intentions (Onel, 2017). As a result, consumers’ long-term purchasing behaviour might be shaped by reinforcing subjective norms (Joshi and Rahman, 2017). Studies by Laureti and Benedetti (2018) on Italians’ purchasing behaviour toward organic food products has echoed the same notion. However, according to Kumar et al. (2017), the subjective norm has no substantial relationship with purchase behaviour. Behaviour is more represented by social norms in the setting of Indian consumers’ collectivistic culture (Bontempo and Rivero, 1992), and so a favourable norm toward environmental concerns may contribute to the disposition of related behaviour.\n\nAs moderating factors, social norms alter the degree and direction of the link between behaviour intention and actual behaviour (He et al., 2021). The “intention–behaviour” mismatch can be explained in part by factors including social environment, social conformity, and expression language (He et al., 2021). This conclusion was confirmed in a study of Korean university students by Ahn et al. (2020). When it comes to GPB in an emerging market, Germany’s research of organic food consumers revealed that social pressure was a key factor in determining how likely customers were to adopt green shopping habits (Mohd Suki and Mohd Suki 2019).\n\n\nDiscussion\n\nFive themes and 15 sub-themes emerged from a thorough search of two databases for articles related to GPB drivers. Drivers on GPB form in the shape of people, environment, marketing, knowledge, and influence. The most often stated drivers in each theme were reviewed by the authors to emphasise the most common push factors for each type of driver.\n\nWe’ll start with the most frequently cited drivers from the theme people, which are the most frequently cited drivers in the review. The consumer’s behavioural characteristic was mentioned in 14 of the 41 articles. The diversity of the drivers revealed the complexities of human variables. According to our perspective, the most prevalent drivers suggest a widely occurring point, and therefore is the primary driver for long-term purchase behaviour. This corresponds to the findings of Liobikiene et al. (2016), who discovered that internal variables such as environmental attitude and perception of environmentally friendly behaviour are more important drivers than others. As proven in this study, the theme people comprise marketing, knowledge, environment, and influence is the most dominant theme.\n\nAs stated earlier in the descriptive analysis, most of the journals evaluated incorporate features of the Theory of Planned Behaviour (TPB), therefore it is not surprising that this theory dominates this study. According to the TPB, to anticipate an individual’s behaviour (e.g., I buy green items), one must first measure the person’s behavioural intention (e.g., I intend to purchase green products). The TPB has been used to predict and explain environmentally beneficial behaviour. TPB behavioural intentions are determined by three factors: (1) attitudes toward the behaviour, (2) subjective norms, and (3) perceived behaviour control. Furthermore, consumer motivation and characteristics may be regarded as an important factor that impacts an individual’s purchasing behaviour. In understanding green product purchasing behaviours, as part of their investigation into hedonic motives (Choi and Johnson, 2019), they looked at how the need for novelty and adventure affects people. While spirituality acts as a motivation and influences an individual’s behaviour, it is not the same for everyone (Joshi and Rahman, 2019).\n\nAs mentioned in the preceding paragraph, the most frequently referenced drivers in the evaluation are not from the topic influence, but from the theme people; nevertheless, this does not indicate that drivers linked to influence should be overlooked. Subjective norms are a component of external beliefs that may be used to explain public behaviour (Groening, Sarkis and Zhu, 2018). If a person believes that others who matter to him or her approve or disapprove of his or her behaviour, he or she is more or less likely to engage in it. People use social norms as guidelines for what constitutes appropriate behaviour, assisting them in determining whether a particular behaviour is easy to employ or beneficial, and in determining what is decently correct and incorrect, as well as whether a particular behaviour is simple to employ or beneficial (Bamberg and Möser, 2007). As a result, consumer decisions are influenced by personal norms, which are mostly influenced by the social standards of or-ganisations in which a consumer values participation (Gleim et al., 2013).\n\nEnvironmental concern has also emerged as a significant component in the research of purchase intentions (Laureti and Benedetti, 2018), and psychologically, it affects consumer attitudes, their perception of their own power over behaviour, and their own personal standards (Asih et al., 2020). Attitudes, subjective standards, and perceptions of behavioural control are all impacted by environmental concerns (Wang et al., 2020). Teksoz et al. (2016) discovered a substantial relationship between environmental concern and people’s views about the environment and outdoor activities. Another important psychological aspect related to the environment is environmental responsibility (Joshi and Rahman, 2019). Individuals may become more aware of their obligation to safeguard their surroundings if they comprehend the impact of environmental degradation on humans and other living creatures and plants (Lee, 2008). Individual responsibility may be evident in green product purchases, which indicate customers’ willingness to pay a higher price (Verma and Chandra, 2018). Environmental education proves itself to be an effective instrument for instilling green behaviour in individuals. A wide range of elements go into environmental education, such as increasing students’ environmental consciousness, knowledge, and attitudes, as well as their capacity to identify and contribute to the solution of environmental problems (Varela-Candamio et al., 2018).\n\nAs for marketing theme, market instrument was the dominating sub-theme (10 studies). Many organisations have gone green by using green marketing strategies that target eco-conscious customers who are eager to enjoy both personal and environmental benefits. Competitive advantages can be manipulated in driving the GPB by utilising the positive environmental characteristics or the price of the green products. Green advertising is one of the most effective marketing tools for promoting environmentally friendly products and services. Green marketers that use sustainable marketing and communication methods and practises will be able to boost their environmental reputation (Giao, 2020). Promoting environmentally friendly items is more likely to have an impact on consumers’ purchase decisions if they are more attractive and useful. Because of this, marketing campaigns must use the right channels and convenient venues for customers to learn about green products, such as supermarkets and trade events. On top of that, the quality of the products itself was the one of the marketing instruments that plays important factor in predicting GPB (Troudi and Bouyoucef 2020; Wang et al., 2019).\n\nThrough 12 studies, it has been proven that knowledge, as one of the themes, is positively associated with GPB. Several studies have found that a person’s views and behaviours are shaped in part by the information they have about a topic. Contrarily, the results of similar research on the influence of environmental knowledge on supporting behaviour under environmental settings are consistent (De Bernardi et al., 2019; Jaiswal and Kant, 2018; Nimri et al., 2020). Having a positive attitude and feeling of well-being about the environment influences consumers’ shopping decisions, which in turn affects the environment (Kumar et al., 2019; Nimri et al., 2020; Troudi and Bouyoucef, 2020). It has two effects on environmental intention. For starters, it may alter an individual’s environmental attitude, leading to the formation of intentions. People’s attitudes toward environmental care and awareness can be influenced by increased information (Di Martino et al., 2019; Uddin and Khan, 2018). Some researchers have found that people’s attitudes, social norms, and perceptions of behavioural control are influenced by knowledge (Amoako et al., 2020; Kim et al., 2019; Liao, 2019). Green knowledge lowers customer uncertainty because credible environmental information impacts consumers’ views toward green brands (Amoako et al., 2020; Liao, 2019).\n\nSubjective knowledge was more influential than objective knowledge when it came to green purchasing, according to Park and Sohn (2018). To promote environmentally friendly attitudes and behaviours, Park et al. (2018) found that objective information had an impact on subjective information, meaning that objective information should be upgraded to improve subjective information.\n\nThis review has produced a list and description of current GPB that can be used as a knowledge base for future researchers as well as guidelines for policymakers and practitioners. The findings of our study could provide useful insights into managerial decision making, i.e., informing the policy maker about which drivers are likely to influence SPB so that they provide incentives to work. For example, to boost the environment concern and responsibility via SPB, the government could educate people through media social campaigns and community services events. Policymakers and public administrators should set out a variety of effective approaches to gauging public opinion of green purchasing, as well as complementing environmental practises and legislation in place, as well as adequate resources of all sorts to encourage SPB i.e., strengthening the regulations on no plastic bag policy. Environmental conservation should be emphasised in the advertising campaigns of industrial actors, since this instils in customers the idea that they would fulfil their environmental responsibilities by choosing green lodging. SPB should be a societal attitude, not just a ‘marketable’ or ‘advertisable’ notion. In other words, citizens must freely engage in environmental protection actions and have an innate feeling of environmental responsibility while creating and consuming. Long-term improvements would occur only if sustainable consumption became a natural cognitive process and voluntary consumption behaviour. The current study’s emphasis on important psychological elements can change customers’ mindsets and guide them toward green purchasing.\n\nOur study also provides light on current market trends and consumer behaviour in the green industry as market instrument, market condition and suppliers are the key drivers. In this sense, green product marketing strategies must be properly and strategically designed, positioned, and used in order to encourage favourable sales of green products in the market which involves the whole supply chain. Incentives for manufacturers and suppliers to embark and invest in green market should be supported by the government i.e., via grant, loan, and tax exemption. In the end, green advertising is an essential commercial communication tool for increasing customer purchase intentions, which finally leads to environmentally responsible behaviour. Finally. With every method of advertising, customer approval, as well as their subsequent environmental behaviour, are critical aspects in determining its effectiveness.\n\nThis study has certain flaws that have been highlighted. For starters, the results of this study derived from the method of SLR mentioned above. There are many other ways to do the SLR. In this study, we suggest studying the subject from a different SLR perspective. A different SLR method could lead to a better understanding of the drivers of GPB. This analysis excludes unpublished contributions to books, conference papers, and journals. Secondly, the analysis was confined to articles from two databases that were published during the last five years. In presenting the study of journal publications, we purposefully included references that are widely regarded as seminal. This helps to solve some of the limitations of the SLR approach and provides a more comprehensive overview of the developing area of sustainable buying behaviour. All types of articles should be considered for future research. Thirdly, consideration of longer publication period of reviewed journal may show more prominent trend in GPB. Other than that, our eligibility criteria excluded non-English papers—it is plausible that research works written in different languages would have given a salient contribution to this review. Finally, to the best of our knowledge, we considered all the eligible papers given our selection criteria, but it is possible that some papers were missed.\n\n\nConclusion\n\nResults of an extensive literature evaluation on GPB were presented in this study. This review contributes to the literature on GPB by providing a mapping of empirical findings associated with drivers to this action. 41 articles were analysed derived from PRISMA 2020 and MMAT 2018. Five themes and 15 sub-themes were identified. The paper’s contribution is the advancement of knowledge on GPB by highlighting the main drivers, recognising the limits, and pointing the way forward for further research. By reviewing significant publications, theories, techniques, and variables of interest in existing literature, we were able to organise and identify improvements in analytical areas of GPB research. In addition, we created a thematic theme for examining the drivers of GPB.\n\nBased on the existing state of literature, the study proposes several potential directions for further research on the issue. First, our SLR synthesis found that the most dominant theme is about people. Consumer’s motivation, perception, behavioural and characteristic were the most influenced factors on GPB. This theme can be expanded, for example adding personal value as a sub-theme. Personal value orientations have been central to social sciences in explaining people’s motivations and behaviours (Caniëls et al., 2021). It influences environmental behaviours and the link between them. These factors are found to have different degrees of influences in explaining people’s environmental behaviours (Steg and Vlek, 2009).\n\nOur SLR suggests that other important drivers such as environmental concern, environmental responsibility, and environmental practices under the environment theme. Environmental concerns are frequently mentioned under the theme environment, and this is true for both developed and developing countries. In future, it is recommended to do cross-contextual research. As people are greatly influenced by their living settings and surrounding environments, these external factors are equally important as individual’s sociodemographic and socio-psychological factors when we aim to explain people’s complex environmental behaviours (Robertson, 2018).\n\nWe discovered that a substantial number of articles on GPB use theory of planned behaviour as their primary approach. A variety of additional theories are also being utilised to support sustainable buying behaviour, with some combining two or more complementary ideas, such as Value Belief Norm and Attitude-Behaviour-Context. Lastly, the review indicates that there is an increasing trend among developing countries in GPB studies. It shows that green behaviour had gained interest among researchers in developing countries as it was already mature in developed countries. One direction of research on green purchasing intention that has received increasing academic attention concerns the power of consumers’ cultural values (Sheng et al., 2019). We suggest considering the theory of psychographics, as proposed by Wells (1975) in future study. This theory contends that values shape an individual’s lifestyle and, as a result, explain their various purchase behaviour patterns. Cultural values do, in fact, influence customer behaviour when it comes to ecologically friendly items, according to studies (Cordano et al., 2011; Riley et al., 2012). Some researchers have also revealed that consumers’ lifestyles are heavily based in their cultural values (Lee et al., 2015; Nordlund and Gravill, 2002; Stern et al., 1993).",
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}
|
[
{
"id": "219297",
"date": "06 Nov 2023",
"name": "Sallehhuddin Abdullah",
"expertise": [
"Reviewer Expertise Corporate social responsibility",
"ESG",
"ethics",
"governance"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript is recommended for indexing. The chosen focus i.e. green purchasing behaviour is timely and consistent with the development of ESG, UN 30 SDG, as well as the global commitment towards net zero carbon by 2050. The method used to conduct the study and to prepare the report is a common and widely accepted approach for systematic literature review paper. The analysis and the discussion is appropriately and well-explained.\nThe only concern is the discussion on future agenda of research on green purchasing behaviour based on the given analysis. The authors may provide greater explanation and in-depth discussion about the future research agenda or new or innovative research agenda in the area of green purchasing behaviour based on this systematic literature review.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
},
{
"id": "219296",
"date": "08 Jan 2024",
"name": "Muhammad Syukri Abdullah",
"expertise": [
"Reviewer Expertise Human Resource Management",
"Organisational Behavior",
"Social Finance",
"Marketing"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis research is very good. However, there is a little room for improvement that can be made by the authors in order to meet with the journal requirement.\nThe authors should highlight the urgency to conduct the study in the Introduction section.\n\nThe authors should thoroughly discuss each variable in the LR section. The authors are highly advised to put sub-sections in the LR section to discuss and explain further.\n\nIn the analysis part, the authors are highly advised to discuss on theories related to the study too. Grounded theory is very important in every research. Perhaps, one section under the Analysis part can be highlighted.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1286
|
https://f1000research.com/articles/12-525/v1
|
22 May 23
|
{
"type": "Research Article",
"title": "Economic effects of the war in Ukraine and recession",
"authors": [
"belisa korriku",
"AZETA TARTARAJ",
"AZETA TARTARAJ"
],
"abstract": "Background: The economic effects of wars and recessions can have significant impacts on consumer attitudes and behaviors. Understanding how these attitudes and behaviors change impacts during challenging economic times is crucial for financial education and management. Methods: A survey was conducted to investigate the financial attitudes and behaviors of individuals during a recessionary period. The survey was distributed from January 15th to February 28th, 2023 and included questions about age, financial education level, savings behavior, attitudes towards debt, gender and financial management behavior, age and financial education, and income and savings behavior. Data were analyzed using t-tests and ANOVA. Results: Participants with higher income levels had higher levels of savings and investing behaviors than those with lower income levels. Participants with a higher level of formal education in finance had higher levels of budgeting and investing behaviors than those with a lower level of formal education in finance. Additionally, participants who reported higher levels of self-rated financial knowledge had higher levels of all financial management behaviors (budgeting, saving, investing, and debt management) compared to those with lower self-rated financial knowledge. Conclusions: The findings suggest that financial education and management programs should target individuals with lower income levels and less formal education in finance. Additionally, promoting self-rated financial knowledge may be a useful strategy for improving financial management behaviors. Future research could explore the effectiveness of different financial education and management programs on improving financial attitudes and behaviors during recessionary periods.",
"keywords": [
"Ukraine-Russia war",
"recession",
"economy",
"marketing",
"strategy"
],
"content": "Introduction\n\nThe economic effects of war and recession can have significant impacts on consumer attitudes and behaviors towards financial management. (Gathergood and Weber, 2014). During times of economic hardship, consumers may experience financial stress, struggle with debt management, and have difficulty saving for the future (Hurst, Luoh, and Stafford, 2014). As a result, it is important to understand how consumer attitudes and behaviors change during periods of recession and how this information can inform financial education and management during challenging economic times (Alessie, Angelini, and Van Santen, 2018). Research suggests that during times of recession, consumers tend to adopt more conservative financial behaviors, such as reducing spending, increasing saving, and paying down debt (Klapper, Lusardi, and Panos, 2017). These findings highlight the importance of financial literacy and education in helping consumers manage their finances during periods of economic uncertainty.\n\nThe Ukraine-Russia War has significant economic consequences and implications, including the potential increase in electricity production costs. Although war can promote domestic production and use, its damage is unavoidable. The nature and duration of the conflict, the location, and the manner of fighting can also affect its impact. Economic warfare, such as limiting the Russian central bank’s foreign asset access, has been employed to boost the Russian monetary system, support finance, and pay for the invasive damages caused, resulting in severe Russian sanctions (Bechtel and Mihaylov, 2017).\n\nThe effects of suspending Russian energy imports on the European economy depend on resource reallocation, fuel shifting, demand reduction, and substitution of energy sources. Energy consumption in households, industries (heating and cooling), trade and commerce, power providers, and transportation relies heavily on Russian imports (Pirani, 2017). Reducing imports and shifting to alternative energy sources can generate cost savings, which may help alleviate the European economy’s financial burden, provided that industrial power plants transition to alternative input applications. This has been highlighted in recent studies such as the one by Vona and Patriarca (2018), who emphasize the importance of energy transition in reducing the economic burden of carbon taxes in Europe. Similarly, the report by the European Environment Agency (2017) also emphasizes the need to transition to renewable energy sources to reduce the cost of energy imports and improve the European economy’s sustainability.\n\nMilitary conflicts and wars have a significant impact on trade relations among adversaries, often leading to embargoes or reduced consumer demand due to patriotism. However, as tensions ease and the threat of conflict subsides, economies can slowly recover from the damage inflicted during wartime. This has been observed in several studies, such as the one by Malhotra and Russett (2018), which examines the long-term effects of wars on trade relations and finds that trade between former adversaries tends to gradually recover over time. Similarly, the study by Arnold and Mattoo (2016) analyzes the impact of conflict on trade and finds that trade relations tend to recover after peace is established.\n\nThe current situation, including political uncertainty, geographic proximity, and the impact of new sanctions against Russia, has led to negative reactions in European stock markets (Chakravarty and Ghosh, 2016). While a recession was traditionally determined based on gross domestic product (GDP) alone, the National Bureau of Economic Research (NBER) now considers various indicators, such as real GDP, unemployment rates, consumer confidence, manufacturing rates, and inflation rates, to determine an economy’s state according to Mankiw (2019). A decline in real GDP is often accompanied by other shifts, such as a reduction in employment or similar factors. An uptick in unemployment rates is often a harbinger of an impending recession. It’s a signal that businesses are cutting back on labor or decreasing their job openings due to a drop in output and demand. For instance, during the Great Depression, the unemployment rate skyrocketed to 25% in 1933 from 3.2% in 1929. Similarly, during the Great Recession, unemployment peaked at 9% in June 2009 (Williams, 2020). The ripple effects of a rise in unemployment can exacerbate a recession. As more people lose their jobs, their spending power declines, which can dampen retail sales and production rates, and in turn, impact the likelihood of a recession (Fackler and Parker, 2018). Consumer confidence is a crucial barometer of an economy’s wellbeing. It can reveal a consumer’s optimism or pessimism during periods of economic expansion or contraction. Another key indicator of an economy’s health is the manufacturing rate of goods, which is often intertwined with consumer confidence (Hanemann, Huotari, and Reifschneider, 2018).\n\nIn a thriving and sustainable economy, consumers are confident and willing to make significant purchases, while businesses feel optimistic about investing in durable goods. Conversely, in times of recession, the demand for durable goods declines, resulting in stagnation or even a reduction in manufacturing. The manufacturing and service industries have an indicator called the purchase manager index (PMI), which shows whether the sector is expanding or contracting (Isaksson, 2019). The PMI reflects the perspective of purchasing managers in the industry and can provide business owners with insight into present and future business conditions. Typically, the PMI is rated on a scale of 0 to 100, with the upper end indicating an expanding market (Haltmaier and Kwan, 2019).\n\nThis study aims to investigate how consumer attitudes and behaviors change during periods of recession and how this relates to financial education and management. Specifically, the study will explore the age distribution, financial education level, savings behavior, attitudes towards debt, and gender and financial management behavior of participants. Additionally, the study will examine the relationship between income, age, and financial education level on savings behavior and financial management behaviors.\n\nPrevious research has shown that economic crises can have significant impacts on consumer financial behaviors and attitudes. For example, studies have found that during times of economic hardship, consumers may engage in more risky financial behaviors and have greater difficulty managing debt (Gathergood et al., 2014; Lynggaard, 2014). Additionally, research has suggested that financial education can be an important tool for improving financial literacy and management during times of economic hardship (Klapper, Lusardi, and van Oudheusden, 2015). By examining consumer attitudes and behaviors during a recession, this study can provide insights into how financial education and management can be improved to support consumers during challenging economic times. The findings from this study may have implications for financial education programs, policymakers, and financial institutions in developing strategies to support consumers during times of economic hardship.\n\nThe research question of the study is: How do consumer attitudes and behaviors change during periods of recession, and what implications does this have for financial education and management during challenging economic times?\n\nThe main objectives of this study are to investigate how consumer attitudes and behaviors change during periods of recession, and to explore the implications of these changes for financial education and management during challenging economic times. In particular, this study aims to:\n\n1. Examine the demographic factors that may influence financial management behaviors during a recession, including age, gender, income, and financial education level.\n\n2. Assess the relationship between financial education and financial management behaviors, as well as the role of self-rated financial knowledge in shaping financial behaviors.\n\n3. Investigate the savings behaviors and attitudes towards debt of consumers during a recession, and explore the factors that may influence these behaviors.\n\n4. Provide insights and recommendations for financial education programs and financial management strategies that can help consumers better navigate challenging economic times.\n\nThrough these objectives, this study aims to contribute to a deeper understanding of how consumers behave and respond during periods of recession, and how financial education and management can help mitigate the negative impacts of economic downturns.\n\n\nMethods\n\nThis study received restrospective ethical approval from the ethics council of the University Aleksander Moisiu and this study was conducted in accordance with ethical principles and guidelines. Participants were informed about the nature of the study and their rights as participants. Informed consent was obtained from all participants before they completed the survey questionnaire. On the survey they were asked to give consent before filling it out. Participants were assured of confidentiality and anonymity, and their data was stored securely.\n\nThis study aims to investigate how consumer attitudes and behaviors change during periods of recession and what implications this has for financial education and management during challenging economic times, with a focus on the economic effects of the war in Ukraine. The research design used in this study is a quantitative research design that utilizes a survey questionnaire to collect data from a sample of participants.\n\nThe data for this study was collected through an online survey questionnaire that was distributed in English to participants via email and social media platforms from 15 January 2023 to 28 of February 2023. The questionnaire was designed based on the research questions and included questions about consumer attitudes and behaviors during periods of recession, financial education and management, and the economic effects of the war in Ukraine. A copy of the questionnaire can be found under Extended data (Korriku and Tartaraj, 2023).\n\nThe sampling frame for this study consists of individuals who live in countries that have been affected by the war in Ukraine and have experienced periods of recession in the past decade. The sample was selected using a convenience sampling method, which involved recruiting participants through social media platforms, email lists, and online forums. The sample size for this study is 428 participants.\n\nThe data collected from the survey questionnaire was analyzed using descriptive and inferential statistics. Descriptive statistics, such as means, standard deviations, and frequencies, were used to summarize the data and provide a general overview of the participants’ attitudes and behaviors. Inferential statistics, such as regression analysis and t-tests, were used to test hypotheses and determine if there were significant differences between groups.\n\nPatterns and trends in the data will be identified through various techniques of data analysis:\n\nAge distribution: By examining the mean, median, and standard deviation of the age variable, we can determine the central tendency of the sample and the variability of the age distribution.\n\nFinancial education level: By examining the frequency distribution of the financial education variable, we will determine the proportion of respondents with different levels of financial education. We will also cross-tabulate this variable with other variables in the survey (e.g., income, savings behavior) to identify any patterns or relationships between financial education and other variables.\n\nSavings behavior: By examining the mean and standard deviation of the savings rate variable, the average level of savings behavior in the sample and the variability of savings rateswillbe determined.\n\nAttitudes towards debt: By examining the frequency distribution of the debt attitude variable, we will determine the proportion of respondents with different attitudes towards debt. We will also cross-tabulate this variable with other variables in the survey (e.g., income, savings behavior) to identify any patterns or relationships between debt attitudes and other variables.\n\nInferential statistics, including t-tests and ANOVA, were conducted to explore the relationships between different variables. The following are the hypotheses and variables for these analyses:\n\nThere will be significant differences in financial management behaviors between different demographic groups.\n\nVariable 1: Demographic characteristics (independent variable) - including age, gender, education level, income level, and employment status.\n\nVariable 2: Financial management behaviors (dependent variable) - including budgeting, saving, investing, and debt management.\n\nFor this hypothesis, t-tests will be conducted to determine if there are significant differences in financial management behaviors between different demographic groups. For example, a t-test may be used to compare the budgeting behaviors of participants with different income levels.\n\nThe level of financial education will be positively correlated with financial management behaviors.\n\nVariable 1: Financial education (independent variable) - including level of formal education in finance, participation in financial education programs, and self-rated financial knowledge. Variable 2: Financial management behaviors (dependent variable) - including budgeting, saving, investing, and debt management.\n\nFor this hypothesis, ANOVA will be conducted to determine if there are significant differences in financial management behaviors between participants with different levels of financial education. For example, an ANOVA may be used to compare the budgeting behaviors of participants with different levels of formal education in finance.\n\nIn summary, these hypotheses and variables will be used to explore the relationships between demographic characteristics, financial education, and financial management behaviors using inferential statistics in this study.\n\nOne limitation of this study is that the sample size is relatively small and may not be representative of the entire population. Another limitation is that the survey questionnaire relied on self-reported data, which may be subject to bias and inaccuracies.\n\n\nResults\n\nThe purpose of this study was to examine how consumer attitudes and behaviors change during periods of recession and to identify the implications for financial education and management during challenging economic times. To achieve this, demographic data and financial management behavior data were collected from a sample 428 respondents. The full raw data can be found under Underlying data (Korriku and Tartaraj, 2023). The results of the data analysis are presented below.\n\nAge distribution: The age distribution of the respondents was as follows: Under 18 (2%), 18-24 (15%), 25-34 (35%), 35-44 (28%), 45-54 (15%), 55-64 (4%), and 65 and over (1%).\n\nFinancial education level: The financial education level of the respondents was as follows: High level (45%), Moderate level (30%), and Low level (25%).\n\nSavings behavior: The savings behavior of the respondents was as follows: Less than 5% (7%), 5-10% (15%), 11-20% (45%), and More than 20% (33%).\n\nAttitudes towards debt: The attitudes of the respondents towards debt were as follows: Uncomfortable (55%), Neutral (30%), and Comfortable (15%).\n\nGender and financial management behavior: The mean financial management behavior score for male respondents was 4.2 (SD = 0.8), while the mean financial management behavior score for female respondents was 4.1 (SD = 0.7).\n\nUsing a two-sample t-test, we find that the difference in mean financial management behavior scores between males and females is not statistically significant, t(426) = 0.72, p > 0.05. This suggests that there is no significant difference in financial management behavior between males and females in our sample.\n\nAge and Financial Education: Under 25 years old: 30% reported having a high level of financial education, 50% reported having a moderate level, and 20% reported having a low level. 25-34 years old: 40% reported having a high level of financial education, 35% reported having a moderate level, and 25% reported having a low level. 35-44 years old: 35% reported having a high level of financial education, 30% reported having a moderate level, and 35% reported having a low level. 45-54 years old: 25% reported having a high level of financial education, 40% reported having a moderate level, and 35% reported having a low level. 55 years old and above: 15% reported having a high level of financial education, 35% reported having a moderate level, and 50% reported having a low level.\n\nIncome and Savings Behavior: Respondents earning less than $25,000 per year had a mean savings rate of 10% (SD = 5%), while respondents earning $25,000-$50,000 per year had a mean savings rate of 15% (SD = 7%). Respondents earning $50,001-$75,000 per year had a mean savings rate of 20% (SD = 8%), respondents earning $75,001-$100,000 per year had a mean savings rate of 25% (SD = 9%), and respondents earning more than $100,000 per year had a mean savings rate of 30% (SD = 10%).\n\nGender and financial management behavior: The t-test results show (Table 2) that there is no significant difference between males and females in terms of their financial management behavior (t = 0.72, p > 0.05).\n\nThe t-test is used to determine whether there is a statistically significant difference between the means of two groups. In this case, the two groups are male and female respondents, and the variable being measured is financial management behavior.\n\nThe t-value is a measure of the difference between the means of the two groups, standardized by the variability of the scores within each group. A t-value of 0.72 indicates that the difference between the means is relatively small.\n\nThe p-value is the probability of obtaining a t-value as extreme as the one observed, assuming that there is no true difference between the two groups. In this case, the p-value is greater than 0.05, which means that the difference between males and females in terms of financial management behavior is not statistically significant.\n\nTherefore, based on these results, we can conclude that there is no significant difference between males and females in terms of their financial management behavior.\n\nAge and financial education: The ANOVA results indicate that there is a significant difference in financial education levels among different age groups (F = 4.18, p < 0.05). Specifically, older age groups have lower financial education levels than younger age groups.\n\nANOVA table for the Age and financial education data\n\nThe ANOVA table shows that there is a significant difference in financial education levels among different age groups (F = 4.18, p < 0.05). The mean square (MS) for between-groups is 16.30, and for within-groups is 1.87. The F-statistic is 4.18, with a p-value of less than 0.05, which indicates that the null hypothesis of equal means is rejected. Therefore, it can be concluded that there is a significant difference in financial education levels among different age groups.\n\nIncome and savings behavior: The regression analysis results show that income is positively correlated with savings behavior (β = 0.052, p < 0.01). In other words, as income increases, savings behavior also increases.\n\nThe F-statistic is 51.493 and the degrees of freedom are 2,425, indicating a significant relationship between income and savings behavior.\n\nFinally, the F-statistic and its associated p-value provide an overall test of whether the regression model is a good fit for the data. In this case, the F-statistic of 51.49 and its associated p-value indicate that the model is a good fit and that the relationship between income and savings behavior is not due to chance.\n\nIn summary, the regression analysis results show that income is positively correlated with savings behavior, meaning that as income increases, savings behavior also increases. This suggests that higher income individuals tend to save a larger proportion of their income.\n\n\n\nThere will be significant differences in financial management behaviors between different demographic groups.\n\nThe t-test was conducted to determine if there were significant differences in financial management behaviors between different income groups. The results show that there is a significant difference between income groups in terms of their saving and investing behaviors (t = 2.34, p < 0.05). Participants with higher income levels had higher levels of saving and investing behaviors than participants with lower income levels.\n\nIn other words, the results suggest that income is a significant predictor of financial management behaviors. Participants with higher incomes are more likely to engage in saving and investing behaviors than those with lower incomes. This information can be useful for financial planners and educators to better understand the financial behaviors of different income groups and to design effective strategies and interventions to improve financial well-being.\n\nTable 4 shows the t-test results for the comparison of mean savings behavior and mean investing behavior across the three income groups (low, middle, and high). The sample size is 428 for both variables, and the standard deviation is calculated for each income group. The t-value is calculated by comparing the mean savings behavior and investing behavior of each income group to the overall mean for the entire sample.\n\nThe results in Table 1 indicate that there is a statistically significant difference in both savings behavior and investing behavior across the three income groups (p < 0.001). The t-value for savings behavior is 11.06, indicating that the mean savings behavior for the high-income group is significantly higher than the mean savings behavior for the low and middle-income groups. Similarly, the t-value for investing behavior is 7.95, indicating that the mean investing behavior for the high-income group is significantly higher than the mean investing behavior for the low and middle-income groups.\n\nTherefore, it can be concluded that income is positively correlated with both savings behavior and investing behavior as shown in Table 3. The higher the income, the higher the savings and investing behavior.\n\nBased on the analyses performed on the data, we can say that there is evidence to support the hypothesis that there are significant differences in financial management behaviors between different demographic groups\n\nThe level of financial education will be positively correlated with financial management behaviors.\n\nThe ANOVA results in Table 5 revealed that there were significant differences in financial management behaviors between participants with different levels of formal education in finance. Participants with a higher level of formal education in finance had higher levels of budgeting and investing behaviors than those with.\n\nThe independent variables are the levels of formal education in finance and self-rated financial knowledge.\n\nFirst, we can conduct a one-way ANOVA to examine the differences in financial management behaviors among participants with different levels of formal education in finance. We can use the level of formal education in finance as the independent variable and financial management behaviors as the dependent variable.\n\nThe p-value is less than 0.001, which indicates that there is a significant difference in financial management behaviors between participants with different levels of formal education in finance. The F-value of 11.37 also indicates a large effect size.\n\nNext, we can conduct another one-way ANOVA to examine the differences in financial management behaviors among participants with different levels of self-rated financial knowledge. We can use self-rated financial knowledge as the independent variable and financial management behaviors as the dependent variable.\n\nThe p-value is less than 0.001, which indicates that there is a significant difference in financial management behaviors between participants with different levels of self-rated financial knowledge. The F-value of 74.41 also indicates a large effect size.\n\nOverall, in Table 6 these results suggest that both formal education in finance and self-rated financial knowledge are important factors that influence financial management behaviors. Participants with higher levels of formal education in finance and higher levels of self-rated financial knowledge tended to exhibit better financial management behaviors.\n\nTherefore, we can reject the null hypothesis and conclude that the level of financial education is positively correlated with financial management behaviors.\n\n\nDiscussion\n\nThe current study aimed to investigate how consumer attitudes and behaviors change during periods of recession and what implications this has for financial education and management during challenging economic times. The results of the study suggest that there are significant differences in financial management behaviors between different demographic groups, and that the level of financial education is positively correlated with financial management behaviors.\n\nRegarding demographic differences in financial management behaviors, our results showed that participants with higher income levels had higher levels of saving and investing behaviors than participants with lower income levels. This finding is consistent with previous research, which suggests that income is a significant predictor of saving behavior (e.g., Campbell & Mankiw, 1989; Kim & Hanna, 2010). These results highlight the importance of financial education and management programs that are tailored to different income groups, with a particular focus on lower-income individuals and families who may be more vulnerable to economic downturns.\n\nThe study also found that participants with a higher level of formal education in finance had higher levels of budgeting and investing behaviors than those with a lower level of formal education in finance. This result supports the idea that financial education programs can positively influence financial management behaviors (e.g., Lusardi, Mitchell, and Curto, 2010; Shim et al., 2010). However, it is worth noting that the effect size of the relationship between financial education and financial management behaviors may vary depending on the specific content and delivery methods of the educational program.\n\nIt is important to note that the study sample had a relatively high level of financial education, with 45% reporting a high level of financial education and only 25% reporting a low level. This may limit the generalizability of the results to populations with lower levels of financial education. Future research could explore whether the relationship between financial education and financial behavior holds for populations with lower levels of education\n\nAdditionally, participants who reported higher levels of self-rated financial knowledge had higher levels of all financial management behaviors compared to those with lower self-rated financial knowledge. This finding is consistent with previous research that has found that financial literacy is associated with better financial management behaviors (e.g., Huston, 2010; Lusardi, 2017). Financial education programs that focus on increasing financial literacy may be especially beneficial during periods of recession, when individuals may be more vulnerable to financial challenges.\n\nOverall, the findings of this study have important implications for financial education and management during challenging economic times. The results suggest that financial education programs should be tailored to different demographic groups, with a focus on lower-income individuals and families. Additionally, financial education programs that emphasize budgeting, investing, and financial literacy may be particularly beneficial for improving financial management behaviors during periods of recession.\n\nLimitations of this study should also be acknowledged. First, the study was conducted in a specific context of the war in Ukraine and recession, which may limit the generalizability of the findings to other contexts. Second, the data were self-reported and may be subject to social desirability bias. Future research may benefit from using objective measures of financial behavior and management. Finally, the study was cross-sectional in nature, and therefore causal relationships cannot be established. Future research should use longitudinal designs to examine the long-term effects of financial education programs on financial management behaviors during periods of recession.\n\nIn conclusion, this study contributes to our understanding of how consumer attitudes and behaviors change during periods of recession and what implications this has for financial education and management. The results suggest that financial education programs that are tailored to different demographic groups and emphasize budgeting, investing, and financial literacy may be particularly beneficial for improving financial management behaviors during periods of recession.\n\n\nConclusions\n\nIn conclusion, the results of this study suggest that during periods of recession, consumer attitudes and behaviors towards financial management change significantly. Demographic factors, such as income and education level, play a crucial role in shaping financial management behaviors. Higher-income groups tend to save and invest more than lower-income groups, and individuals with a higher level of formal education in finance tend to engage in better financial management practices.\n\nThe study also found that self-rated financial knowledge is a strong predictor of financial management behaviors, suggesting that financial education programs may be beneficial in improving financial management during challenging economic times. Therefore, it is important to continue to develop and improve financial education programs that are accessible to individuals of all income levels and educational backgrounds.\n\nFuture research could focus on exploring the effectiveness of financial education programs in improving financial management behaviors during recessions. Additionally, longitudinal studies could be conducted to investigate the long-term effects of financial education on financial management behaviors. Moreover, given the increasing use of technology in financial services, it would be interesting to investigate the impact of digital financial literacy programs on financial management behaviors during challenging economic times.",
"appendix": "Data availability\n\nFigshare: Economic effects of the war in Ukraine and recession. https://doi.org/10.6084/m9.figshare.22761323.v2 (Korriku and Tartaraj, 2023).\n\nThe project contains the following underlying data:\n\n• Untitled form.csv (raw data from questionnaire).\n\nFigshare: Economic effects of the war in Ukraine and recession. https://doi.org/10.6084/m9.figshare.22761323.v2 (Korriku and Tartaraj, 2023).\n\nThis project contains the following extended data:\n\n• Questionnaire.docx\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nAlessie R, Angelini V, Van Santen P: Saving and wealth effects of economic shocks. Eur. J. Polit. Econ. 2018; 54: 135–150.\n\nArnold J, Mattoo A: Trade and peace: A theory of trade leadership. J. Int. Econ. 2016; 99: 117–132.\n\nBechtel MM, Mihaylov NL: Economic Sanctions and Public Opinion: An Examination of the Russian-Ukrainian Conflict. Foreign Policy Anal. 2017; 13(4): 851–869. Publisher Full Text\n\nCampbell JY, Mankiw NG: Consumption, income, and interest rates: Reinterpreting the time series evidence. NBER Macroeconomics Annual. 1989; 4: 185–246. Publisher Full Text\n\nChakravarty SP, Ghosh S: The impact of sanctions on Russian financial markets: A synthetic control approach. J. Bank. Financ. 2016; 67: 46–63. Publisher Full Text\n\nEuropean Environment Agency: The European environment – state and outlook 2015: synthesis report. Copenhagen: European Environment Agency; 2017.\n\nFackler JS, Parker RP: Macroeconomics: theories, policies, and international applications. Cengage Learning; 2018.\n\nGathergood J, Weber JG: Financial literacy shocks and their long-lasting effects on financial behavior. J. Econ. Behav. Organ. 2014; 107: 447–465.\n\nGathergood J, Weber JG, de Quidt J : How do consumers respond to shocks in credit market liquidity? Evidence from the 2008-2009 financial crisis. Rev. Financ. 2014; 18(6): 2009–2043.\n\nHaltmaier J, Kwan SH: The Role of Consumer Confidence in the Economy. Federal Reserve Bank of San Francisco Economic Letter. 2019; 2019(10). Reference Source\n\nHanemann T, Huotari M, Reifschneider F: Manufacturing our future: How industrialization is driving economic growth across Africa. Brookings Institution Press; 2018. Reference Source\n\nHurst E, Luoh M, Stafford F: The wealth dynamics of American families, 1984–2009. Ann. Am. Acad. Pol. Soc. Sci. 2014; 654(1): 192–216.\n\nHuston SJ: Measuring financial literacy. J. Consum. Aff. 2010; 44(2): 296–316. Publisher Full Text\n\nIsaksson A: The economic impact of military conflicts. J. Peace Res. 2019; 56(2): 161–174. Publisher Full Text\n\nKim J, Hanna SD: Does financial education matter? An empirical analysis of the demand for financial literacy. J. Econ. Psychol. 2010; 31(6): 882–893.\n\nKlapper L, Lusardi A, Panos GA: Financial literacy and the financial crisis. J. Financ. Stab. 2017; 29: 1–13.\n\nKlapper L, Lusardi A, van Oudheusden P : Financial literacy around the world: Insights from the Standard & Poor's Ratings Services Global Financial Literacy Survey. World Bank Res. Obs. 2015; 30(1): 25–51.\n\nKorriku B, Tartaraj A: Economic effects of the war in Ukraine and recession. Dataset. figshare. 2023. Publisher Full Text\n\nLusardi A: The need for financial education and capability. Journal of Retirement. 2017; 4(3): 35–59.\n\nLusardi A, Mitchell OS, Curto V: Financial Literacy Among the Young. J. Consum. Aff. June 2010; 44(2): 358–380. Publisher Full Text\n\nLynggaard K: Struggling to keep afloat: coping strategies of households in debt. J. Econ. Psychol. 2014; 43: 31–44.\n\nMalhotra N, Russett B: The long-term effects of military conflict on trade. Confl. Manag. Peace Sci. 2018; 35(3): 259–279.\n\nMankiw NG: Principles of macroeconomics. Cengage Learning; 2019. Chapter 6.\n\nPirani S: The impact of Russian gas on EU energy security Oxford Institute for Energy Studies (OIES) Gas Programme Research Paper. 2017. Reference Source\n\nShim S, Barber BL, Card NA, et al.: Financial socialization of first-year college students: the roles of parents, work, and education. J. Youth Adolesc. 2010; 39(12): 1457–1470. PubMed Abstract | Publisher Full Text\n\nVona F, Patriarca F: Energy transition, climate policies and the restructuring of the European Union's electricity sector. Energy Policy. 2018; 121: 702–711.\n\nWilliams A: Macroeconomics.Jones S, editor. The Palgrave Encyclopedia of Economics. 2nd ed.Palgrave Macmillan; 2020. Publisher Full Text"
}
|
[
{
"id": "176655",
"date": "04 Jul 2023",
"name": "Michele Pigliucci",
"expertise": [
"Reviewer Expertise Economic Geography",
"Geopolitics",
"regional development"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article provide interesting results of a survey aiming at investigating how personal financial attitudes and behaviors change during crisis periods, namely Russo-Ukrainian war.\nThe results of the survey are organised and summarised in order to give evidence to the different behaviors registered among people according to demographic and financial education elements.\nThe article is well documented, and result well explained. Furthermore, an explanation about the geographic distribution of sampling could be needed to better read the result meaning.\nThe indication about \"countries that have been affected by the war in Ukraine and have experienced periods of recession in the past decade\" looks too much general: every country is actually affected by the war, in different ways.\nDifferent countries register different levels of damage from Ukraine-Russo war, and it can change the result interpretation of the survey.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "175294",
"date": "05 Jul 2023",
"name": "Max Gillman",
"expertise": [
"Reviewer Expertise Macroeconomics",
"monetary economics",
"business cycles",
"asset pricing",
"human capital."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe topic is interesting. The problem is that the authors purport to show what happens during recessions to consumer savings and financial decisions, but then use a panel data study of 428 participants who have been affected by the war in Ukraine and have experienced recessions in the past decade. The sample is taken during the Ukraine wartime period of early 2023.\nLumping together those affected by the Ukraine-Russia war, and those who have experienced a recession in the last decade is an odd combination. It is unclear what is the relation between those affected by the war and those experiencing a past recession. Therefore the results cannot be clearly delineated as to whether this is a wartime result or a recession result, which the authors claim.\nThe results make perfect sense in general, that higher income people have a more sophisticated financial education. But I do not see how this relates to people affected by the war.\nThis sort of question about behavior during recessions should not have anything to do with wartime periods unless there is some different type of hypothesis. Wartime of course creates economic calamity, more of what economists call a negative rare event. This is not a recession, but an economic disaster of untold proportions.\nThe paper needs to somehow untangle the two vastly different effects: being affected by a current ongoing war, and how people behave in recessions in terms of savings and financial decisions.\nIt is also unclear how the sample selection may bias the results: who would be likely to respond to such a study questionnaire? It may be those with a low value of time, or those particularly affected by the war. Either can bias the results, in various directions.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-525
|
https://f1000research.com/articles/12-1283/v1
|
06 Oct 23
|
{
"type": "Case Report",
"title": "Case Report: A rare story of dysmenorrhea and hematuria in a young female with a case of nutcracker syndrome",
"authors": [
"Isha Sahai",
"Benumadhab Ghosh",
"Disha Sahai",
"Shubham Waghulkar",
"Pankaj Banode",
"Isha Sahai",
"Disha Sahai",
"Shubham Waghulkar",
"Pankaj Banode"
],
"abstract": "Nutcracker syndrome (NCS) is a sporadic syndrome due to the compression of the left renal vein (LRV) between the abdominal aorta and the superior mesenteric artery (SMA). This condition may present with unexplainable pain, hematuria, orthostatic hypotension, proteinuria, or dysfunction of the kidneys. These symptoms would be explained by the fact that if a chronically standing venous congestion is there then there could be the development of gonadal vein and pelvic vein collateral drainage pathways. Doppler USG (ultrasound), cross-sectional and invasive imaging modalities are frequently used for the purpose of diagnosis. Here, in this report, there's a female patient in her mid- 20's. She was asymptomatic since birth and presented with a history of abdominal pain and blood in the urine. USG is not the best modality for describing the findings hence a further contrast-enhanced computed tomography was done which reported an NCS. In all cases of unexplained hematuria, after excluding all differential diagnoses, NCS must be taken into account.",
"keywords": [
"Left renal vein compression",
"hematuria",
"vascular compression",
"dysmenorrhoea",
"left flank pain",
"proteinuria",
"nutcracker syndrome."
],
"content": "Introduction\n\nNutcracker syndrome (NCS), which is commonly known as left renal vein entrapment syndrome, is due to hematuria with no glomerular causes and has difficulties in diagnosis.1 NCS is a sporadic vascular compression disease in the left renal vein (LRV) gets compressed, amidst superior mesenteric artery (SMA) and the abdominal aorta. Proteinuria, left lower quadrant of the abdomen pain and presence of blood in the urine are some of the symptoms which might be a presentation in this condition.2 In the year 1937, Grant who was an anatomist detailed the position of the LRV between the SMA and the abdominal aorta and that it shows itself like a nut held between the fangs of a nutcracker.3 de Schepper, in the year 1972, first used the term NCS.4 This sporadic condition may be seen in pediatric or adult patients, with the cause being unknown. It is characterised by the compression of the LRV, which might result in reduced venous drainage thus subsequently dilatating the LRV.5 Inspite of many diagnostic parameters, NCS prevalence is not known, the reason here could be due to the plethora of symptoms, which includes left lower abdomen pain, proteinuria, hematuria, and compression of the pelvis in females (dysmenorrhea, dyspareunia, pelvic pain for a long time), and varicocele might be presented in men.6 Although there’s a study conducted for a 1000 CT abdomen, where anterior NCS was found to be around 4.1% of cases.7\n\nIn this report, we have described a rare presentation of a female patient in her mid 20’s, complaining of pain on left abdominal side for ten days, along with hematuria in the emergency department of Shalinitai Meghe Superspeciality Centre. The patient was undiagnosed until she was of this age before she visited the emergency department of the Shalinitai Meghe Superspeciality Centre, Wardha, India. This is a rare presentation involving several clinical conditions and also involving diagnostic challenges.\n\n\nCase report\n\nA female aged 25 years, college student by profession, resident of a small village in Central India, came with complaints of pain in abdomen for 10 years, painful menstruation (dysmenorrhea), easy fatigability for 5 years and blood in urine for 1 week. The clinician referred the patient for CECT (Contrast enhanced computed tomography) abdomen evaluation. History of vomiting, loose stools, fever, cough or cold is absent.\n\nGeneral examination revealed the patient was conscious and well oriented. Vitals measure were a follows- Fever:absent, pulse rate: 89/min, respiratory rate: 24/minute, blood pressure (BP) was found to be slightly high: 140/96 mm of Hg. 98% (SpO2) was the oxygen saturation. Any other remarkable findings were not seen in the general examination.\n\nOn clinically examining the patient, it was found that the Glasgow Coma Scale score and all the reflexes were normal in the CNS (central nervous system) examination. She was conscious and well oriented to the persons around her. Along with that, the respiratory system (air entry equal bilaterally), cardiovascular system (no abnormal pulsations), and renal system were normal. However, the gastrointestinal system revealed a few abnormalities.\n\nMild tenderness over the lower left quadrant of the- abdomen was present. Any kind of abdominal distension was not seen.\n\n\nDiagnostic assessment\n\nLab findings are shown in Table 1 below.\n\nLab values significantly show low hemoglobin levels, high Erythrocyte sedimentation rate (ESR), presence of albumin in urine and 10-12/hpf (High power field).\n\nUpon Grayscale ultrasound, the proximal left renal vein was grossly distended, as shown in Figure 1. On USG, all the gastrointestinal structures appeared normal in texture, shape and size. Even the findings of the kidney, urinary bladder and the ureters, did not reveal any kind of focal lesions or calculus and were seen normal.\n\nSagittal CECT of abdomen revealed, compression of left renal vein by superior mesenteric artery (SMA), aortomesenteric angle of 21 degrees and a compression ratio of more than 3. As shown in Figure 2.\n\nAn Axial CECT abdomen showed narrowing of Left Renal Vein (LRV) in between the Superior Mesenteric Artery and Aorta with minimal breaking of LRV. There is evidence of pelvic congestion in the form of dilated pelvic veins in the adnexa. As shown in Figure 3.\n\nThe patient had also undergone Coronal CECT abdomen, which showed evidence of dilated left gonadal vein Figure 4. On CT Angiography, SMA-AORTA angle was reduced measuring 21 degrees. SMA-AORTA distance was 4 mm (reduced) Figure 5.\n\n\nTherapeutic intervention\n\nAfter giving a medical therapy consisting of ACE inhibitors, we placed an endovascular stent which is an alternate modality of intervention because there were observable symptoms like hematuria, pain and, dysmenorrhea in the patient. Open surgery is generally not preferred to a stent in these cases as there is increased duration of renal congestion, with higher chances of manifestations. Extensive dissection is usually done in this operation. Other treatments options have been described in the discussion section.\n\n\nOutcome\n\nThe main motive of this case is to exhibit the significance of regular analysis of urine and imaging for the detection of symptomatic and asymptomatic patients suffering from NCS, which is a sporadic reason for hematuria. It is a diagnosis of exclusion. Henceforth, at first, ruling out other possible causes of hematuria is necessary. Patients who are asymptomatic should be assessed through urine analysis for hematuria as a differential fir NCS. This could be established with imaging methods like USG, CT or MRI. NCS, though sporadic can be seen in practice, so it is important to know about it so that diagnosis and management of patients can be done correctly. A broad array of surgical options is available, and the appropriate choice for patients suffering from the syndrome can only be made by possessing a thorough understanding of theory and practicalities of these interventions. Thus, it is important that it is required to upgrade elementary knowledge of the NCS, which is the motive of this report and discussion.\n\n\nDiscussion\n\nThe nutcracker syndrome introduces us to the compression of the LRV within the SMA and abdominal aorta. The pattern in which these three structures are anatomically placed was thought to look like a nut in a nutcracker and thus the name. This phenomenon is defined by extrinsic compression, which obstructs the flow into the inferior vena cava (IVC) from LRV. The titles, NCS and nutcracker phenomenon, are occasionally used as similar words in the writing. The Nutcracker phenomenon states the anatomical findings suggesting the nutcracker when clinical symptoms are absent. The title NCS is applied for those showing manifestations clinically related to nutcracker anatomy.8\n\nThis condition is linked to the development of the LRV within the 6-8th gestational week from the collar of aorta and an improper angle formation of the SMA with the aorta.2 The severity and symptoms of this condition differ, indicating various degrees of compression of the LRV, hypertension, and the compensatory stage, which is associated with the emergence of collateral blood flow. The symptoms include flank and abdominal pain, autonomic dysfunction, dysmenorrhoea, dyspareunia, and fatigue. The pain felt is due to the inflammation pathway activated by venous hypertension. The diagnosis of NCS is possible only when left renal vein compression leads to specific symptoms, like left flank pain, proteinuria, anaemia and varicocele.9 Studies have reported that NCS is more prevalent in females, particularly during their 3rd to 4th decades of life; the same in our case.10,11 People affected by this condition are typically considered slim and tall, having low retroperitoneal and intra-abdominal mesenteric adipose tissue. This results in narrowing the angle between the SMA and the abdominal aorta.11\n\nUltrasonography (USG) can be used as the initial test for diagnosis of patients thought of NCS. In normal cases, the length of the LRV ranges from 6-10 cm, and the average diameter is approximately 4-5 mm. The normal gradient of pressure between the LRV and the IVC is 1 mmHg or lower. However, an elevated gradient exceeding 3 mmHg between the LRV and the IVC can be considered a diagnostic criterion for NCS.12 Imaging plays a crucial role in diagnosing NCS. In CT and magnetic resonance imaging (MRI), the taken average angle between the superior mesenteric artery and the aorta for normal patients is mostly within the range of 38 to 60 degrees, with a mean of approximately 45 degrees.10 There are other studies which also show the same numbers for the aortomesenteric angle (AMA) in CT, which is used for diagnosis of NCS.6,11\n\nAlthough venography, which measures the renal vein pressure gradient, is considered the gold standard for diagnosing NCS, it is an invasive technique that is often not required.5 Thus, CT, USG or MRI are preferred as better non-invasive diagnostic modalities. In our case, we did not use venography because of its invasiveness, although Doppler USG was used. This has the ability to confirm the rise in the pressure gradient of the renal vein. Although, there are studies which suggest using CT as the primary diagnostic tool because of its greater efficiency. CT has the advantage of having a stretched assessment of abdominal structures.13 In our patient, a CT scan was done, revealing a slightly decreased AMA linking the aorta and SMA, measuring 21 degrees, which is suggestive of NCS. Additionally, another significant finding on the CT for diagnosing NCS is the ratio of renal hilar to aortomesenteric left renal vein,14 and in our case, this ratio was 5.12, which further supports the diagnosis of NCS.\n\nThere is a controversy regarding choice for treatment in NCS. This is mostly decided on the condition of the presenting patient. Conservative management is mostly opted for those patients who present with no severe complaints or mild or nil hematuria.15 Surgical modality is mostly opted for cases presenting with severe hematuria due to which patients have severe anemia along with intense pain even after using analgesics or decreased function of kidney.16 In medical therapy, angiotensin-converting enzyme (ACE) inhibitors can be utilized to treat protein in urine. Additionally, the use of acetylsalicylic acid is sometimes thought of, although it remains a subject of controversy, because it is observed to increase kidney perfusion in cases of NCS.15 Placement of endovascular stent is an alternate modality of intervention. In our patient, we used this method of intervention as a treatment modality. Open surgery is generally not preferred to stent in these cases as there is increased duration of renal congestion, with higher chances of manifestations. In this type of operation, there is a necessity for extensive dissection.8 The perfect stent should possess sufficient radial strength so that there is no stenosis, excellent conformability so that it fits to the epithelium of the vessel. It should be also taken care that there should be minimum shrinkage of its length so that proper positioning is established.17,18\n\n\nConsent\n\nThe patient provided written informed consent for the study. The patient consented to the publication of her clinical details and images.",
"appendix": "Data availability\n\nNo data associated with this article.\n\n\nReferences\n\nTago M, Katsuki NE, Hirakawa Y, et al.: Asymptomatic nutcracker phenomenon: entrapment of the left renal vein shown by CT without left flank or pelvic pain, or macroscopic haematuria. BMJ Case Rep. 2020; 13: e233867. Publisher Full Text\n\nDunphy L, Penna M, Tam E, et al.: Left renal vein entrapment syndrome: nutcracker syndrome!. BMJ Case Rep. 2019; 12: e230877. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGrant: A method of anatomy: descriptive and deductive - Google Scholar. Accessed: July 18, 2023. Reference Source\n\nde Schepper A : “Nutcracker” phenomenon of the renal vein and venous pathology of the left kidney. J. Belg. Radiol. 1972; 55: 507–511. PubMed Abstract\n\nde Macedo GL , Dos Santos MA, Sarris AB, et al.: Diagnosis and treatment of the Nutcracker syndrome: a review of the last 10 years. J. Vasc. Bras. 2018; 17: 220–228. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYun SJ, Lee JM, Nam DH, et al.: Discriminating renal nutcracker syndrome from asymptomatic nutcracker phenomenon using multidetector computed tomography. Abdom. Radiol (NY). 2016; 41: 1580–1588. PubMed Abstract | Publisher Full Text\n\nPoyraz AK, Firdolas F, Onur MR, et al.: Evaluation of left renal vein entrapment using multidetector computed tomography. Acta Radiol. 2013; 54: 144–148. PubMed Abstract | Publisher Full Text\n\nGulleroglu K, Gulleroglu B, Baskin E: Nutcracker syndrome. World. J. Nephrol. 2014; 3: 277–281. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOrczyk K, Łabetowicz P, Lodziński S, et al.: The nutcracker syndrome. Morphology and clinical aspects of the important vascular variations: a systematic study of 112 cases. Int. Angiol. 2016; 35: 71–77. PubMed Abstract\n\nOzkurt H, Cenker MM, Bas N, et al.: Measurement of the distance and angle between the aorta and superior mesenteric artery: normal values in different BMI categories. Surg. Radiol. Anat. 2007; 29: 595–599. PubMed Abstract | Publisher Full Text\n\nVelasquez CA, Saeyeldin A, Zafar MA, et al.: A systematic review on management of nutcracker syndrome. J. Vasc. Surg. Venous Lymphat. Disord. 2018; 6: 271–278. PubMed Abstract | Publisher Full Text\n\nVenkatachalam S, Bumpus K, Kapadia SR, et al.: The nutcracker syndrome. Ann. Vasc. Surg. 2011; 25: 1154–1164. Publisher Full Text\n\nZucker EJ, Ganguli S, Ghoshhajra BB, et al.: Imaging of venous compression syndromes. Cardiovasc. Diagn. Ther. 2016; 6: 519–532. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKolber MK, Cui Z, Chen CK, et al.: Nutcracker syndrome: diagnosis and therapy. Cardiovasc. Diagn. Ther. 2021; 11: 1140–1149. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKurklinsky AK, Rooke TW: Nutcracker phenomenon and nutcracker syndrome. Mayo Clin. Proc. 2010; 85: 552–559. PubMed Abstract | Publisher Full Text | Free Full Text\n\nReed NR, Kalra M, Bower TC, et al.: Left renal vein transposition for nutcracker syndrome. J. Vasc. Surg. 2009; 49: 386–394. Publisher Full Text\n\nHulsberg PC, McLoney E, Partovi S, et al.: Minimally invasive treatments for venous compression syndromes. Cardiovasc. Diagn. Ther. 2016; 6: 582–592. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang X, Zhang Y, Li C, et al.: Results of endovascular treatment for patients with nutcracker syndrome. J. Vasc. Surg. 2012; 56: 142–148. Publisher Full Text"
}
|
[
{
"id": "213119",
"date": "08 Feb 2024",
"name": "George Nassar",
"expertise": [
"Reviewer Expertise My areas of research vary but I spent a lot of time on Vascular work in relation to dialysis arteriovenous grafts",
"arteriovenous fistulas and endovascular stents",
"and have some U/S experience with venous structures of the dialysis vascular access and upper extremity veins."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors provide a concise and clear case report of a young female with hematuria and dysmenorrhea who they diagnosed with Nutcraker syndrome (NCS). The case and discussion are interesting and educational. It is well written.\nComments:\nDiagnostic assessment and Table 1: Since the NCS affects the left kidney, it is essential to report the BUN and Creatinine and add to Table 1 data. Also since there is urine albumin, I recommend adding serum albumin to Table 1 Even though this is not a hemolysis case, but since the anemia was severe, do the authors have any data on hemolysis? Such as LDH or Haptoglobin. Or on hemoglobinuria.\nThe authors mention diagnostic tools such as CT scan, U/S or venography. They make a case for less invasive testing. Question to the authors: has anyone used IVUS to evaluate the compression? Is there a role for it?\nOutcome: The authors don't mention the actual clinical outcome of their patient such as resolution of hematuria and dysmenorrhea. Would be useful to outline the time course of the improvement of both gross hematuria, microscopic hematuria and dysmenorrhea, and any residual manifestations.\nDiscussion: I have some questions/comments to the authors: The authors make mention the ratio of renal hilar to aorto-mesenteric renal vein. It would be prudent of the authors to indicate the normal ratio then mention the ratio of their case because the general reader does not know about this ratio and what is normal range.\nIn the last Paragraph: The authors mention that \"Open surgery is generally not preferred to stent in these cases as there is increased duration of renal congestion, with higher chances of manifestations.\" This sentence seems incomplete. Manifestations of what? may be better say 'persistent manifestations' or \"persistent symptoms\". Same comment applies in the paragraph of Therapeutic intervention.\nThe authors mention that the stent should be of sufficient radial strength. Questions to the authors: Is there a risk that the stent in the renal vein compresses on the other vascular structures such as the SMA? Is there a concern? Also, one needs to be careful to avoid the stent protruding into the renal vein. Another question: What imaging should be done after the stent placement to indicate proper location? Also, do the authors recommend any longitudinal follow up of the stent to ensure no stenosis in it is seen long term?\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "11293",
"date": "13 Apr 2024",
"name": "Isha Sahai",
"role": "Author Response",
"response": "Dear Reviewer, Authors appreciate your time and expertise you provided in the report. We appreciate the fact that we needed to add few values in the table such as LDH , haptoglobins and others, however due to lack of information from the patients side, we couldn't add them. We will make the rest of the changes. Thank you for your suggestions in making our report better. Regards Isha Sahai Benu madhab Ghosh"
}
]
}
] | 1
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https://f1000research.com/articles/12-1283
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https://f1000research.com/articles/12-1280/v1
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06 Oct 23
|
{
"type": "Study Protocol",
"title": "Effect of CLX training adjunct to PNF and conventional physiotherapy on pain and balance in patients with chronic lower back pain: A randomised clinical trial protocol",
"authors": [
"Priya Tikhile",
"Deepali Patil",
"Deepali Patil"
],
"abstract": "Lower back pain that has lasted longer than 12 weeks is referred to as chronic lower back pain (CLBP). Lumbar extensor deterioration is a typical characteristic of CLBP. Muscular degeneration could impact proprioception along with reducing strength and endurance, which would further exacerbate concerns about balance. Along with force-matching ability, lower back muscles working together is frequently compromised in CLBP patients. The prime goals of bodily workout in administration of long-lasting lower back ache are advance muscular strength and flexibility, to re-establish injured tissues and to contribute easy engaging in daily tasks. Proprioceptive sense is reduced in CLBP patients due to mechanical alterations in their musculature. Hence, in order to develop an efficient management plan, it is crucial for patients and physiotherapists to understand the alterations that result from the shift in trunk muscular endurance in people with CLBP and how they impact the functional level. Outlined here is a proposed study aiming to evaluate the effectiveness of consecutive loop TheraBand (CLX) adjunct to proprioceptive neuromuscular facilitation (PNF) and conventional physiotherapy exercises on subjects with CLBP in a two-arm parallel superiority randomized clinical trial in reducing pain and enhancing balance. The participants will be split into two groups for equal allocation, after which the intervention CLX adjunct to PNF will be provided to one group and conventional physiotherapy exercises will be provided for another group for six weeks, a total of six days a week, for 50 minutes per day. After six weeks of intervention, the results will be assessed for pain and balance. The implementation of this physiotherapy technique in treatment could occur if the study’s hypothesis is successful in CLBP. Additionally, it will aid in lowering the incapacity in activities of daily living in those recovering from lower back pain. CTRI registration number: CTRI/2023/05/052851",
"keywords": [
"Proprioceptive Neuromuscular Facilitation",
"CLX Thera band",
"Low back pain",
"Balance",
"Strengthening",
"Resistance",
"Disability"
],
"content": "Introduction\n\nWith an incidence as high as 84%, lower back pain is a frequent musculoskeletal issue that mostly impacts adults. Lower back pain (LBP) that lasts for a minimum of 12 weeks is known as chronic lower back pain (CLBP).1 In order to figure out the worldwide impact of low back pain, which is described as” low back pain that limits activities for a minimum of one day”.2 LBP is recognised to have an impact on all affected older and younger individuals, impairing their quality of life and productivity at work.3 As a result, earlier categories of LBP that were generally acute, subacute, or chronic in character are being replaced with an increased understanding of LBP as a chronic, recurrent ailments that may follow one of numerous pathways.4\n\nAbout 60% of Indians experience notable back pain during some period of their life.5 Nociceptors, which are sensors of pain, are numerous in the peripheral tissues, including muscles, tendons, ligaments, fascia, synovium, facet joints, intervertebral disc (IVD), and joint capsules. Deterioration of the aforementioned structures may trigger the nociceptive pathway, swiftly excite nociceptors, and cause a sequence of biochemical events that result in pain.6 It has been reported that chronic nonspecific low back pain (CNLBP) may begin with weakened or insufficient motor control in the deep trunk muscles. Postural and balance issues can result from changes in the way the mechanoreceptors interact and ailments with the paraspinal muscles in peripheral proprioceptive system.7\n\nA major biomechanical definition of balance is the lack of ability to maintain the line of gravity, which is a vertical axis from the body’s centre of mass with minimal postural saying.8 To accomplish everyday physical activities of individuals, balance regulating and maintaining at static and dynamic positions is needed.9 CLBP patients exhibit more impaired balance than unaffected individuals.10 The lumbar extensors, which include the superficial erector spinae and the deep and superficial musculature, are the main muscles associated with lumbar stabilisation in specific. Lumbar extensor deconditioning is a typical characteristic of CLBP. Muscular degeneration may affect proprioception and result in strength and endurance loss, which contributes to balance dysfunction.11 In persons with CLBP, trunk balancing exercises reduced disability and improved function and quality of life.12 Exercises that increase trunk stability aid the body in maintaining its balance and equilibrium.13\n\nProprioceptive neuromuscular facilitation (PNF) makes use of the proprioceptive system and reflexes of the body to either hinder or promote muscle contraction. PNF approaches enhance a patient’s entire ability to function, including their muscular strength, muscular endurance, joint mobility, joint stability, neuromuscular control, balance, and coordination.14 Physical therapists frequently utilise PNF training when treating patients with persistent LBP because it enhances muscle performance by its movement patterns. PNF training uses spiral and diagonal directions, that are better in enhancing human performance and lessening the signs and symptoms of chronic LBP than traditional single-direction exercise programming.15 The bending and extending of the trunk are made possible by the application of rhythmical stabilisation (RS) and a combination of isotonic (COI) strategies while seated.16\n\nConsecutive loops (CLX) are elastic bands in the form of a loop. The participants’ upper and lower limbs both wear CLX. Since CLX includes a loop-shaped gap inside the band, unlike other elastic bands, it is simple to give a holding point during band exercise not having to knot it individually, and it offers simultaneous resistance to numerous joints.17 Advantages that you don't need to fasten them to anything; you can just wind them around your hands or stabilise them on your own body.18 Utilising resistance bands improves spinal extensor stability and strength, reduces lumbar pain, and promotes good posture.19 Balance is improved as a result of strengthening exercises using a TheraBand, which also strengthens the lower extremities.20 Exercise using an elastic band helps decrease joint discomfort while also enhancing balance, walking ability, flexibility, strength, mobility, and performance.21\n\nIn this study, we aim to test the effectiveness of CLX resistance bands adjunct to proprioceptive neuromuscular facilitation and IFT on subjects with chronic LBP in a two-arm parallel superiority randomized clinical trial (RCT), in reducing pain and enhancing balance and reducing disability in end-point results on marginal difference.\n\n\n\n1. To assess the subjects’ pain (Visual Analogue Scale), balance (Balance Error Scoring System, Y – Balance test) due to CLBP treated with CLX resistance bands adjunct to PNF and conventional physiotherapy exercises; to evaluate their effect on reducing pain and improving balance.\n\n2. To assess CLBP subjects’ change in disability (Modified Oswestry Low Back Pain Disability Questionnaire) when treated with CLX resistance bands adjunct to Proprioceptive Neuromuscular facilitation (PNF) and conventional physiotherapy exercises; assess if it can aid in lowering the disability in activities of daily living in overall population.\n\n3. To assess the effectiveness of treatment with CLX resistance bands adjunct to PNF along with interferential therapy (IFT) and conventional physiotherapy exercises with IFT in reducing pain, balance and disability for the population with CLBP.\n\nThis study will be a single-center, two-arm parallel superiority RCT.\n\n\nProtocol\n\nThis is clinical trial research protocol will take place in the Outpatient Department of Ravi Nair Physiotherapy College and Acharya Vinobha Bhave Hospital Sawangi, Wardha, Maharashtra, India. After receiving the Ethical approval from the Institutional Ethical Committee of Datta Meghe Institute of Higher Education and Research. Signed informed participant consent will be obtained, and participants will be selected throughout the region in accordance with the study’s inclusion and exclusion criteria. Participants will be randomly allocated to two groups: Group A (CLX adjunct to PNF and IFT) and Group B (Conventional Physiotherapy exercises and IFT) in a 1:1 allocation. For participant allocation, a randomization approach employing a computer-generated will be used. The allocation blinding mechanism used will be sequentially numbered, opaque, sealed envelopes. Cut-off values at the baseline will be utilised to select participants for the open-label study while taking into account inclusion and exclusion criteria. The interventional group will receive CLX resistance band adjunct to PNF with IFT therapy and the control group will receive conventional physiotherapy exercises with IFT therapy, for reduction in pain and improvement of balance and lowering of disability. Subjects will be enrolled and evaluated at several points throughout the study, including visit 1 for subject enrolment and subject evaluation. Baseline and follow-up visits at six weeks and three weeks after treatment will be carried out, where primary as well as secondary variables will be assessed. The study design is depicted in Figure 1.\n\nBoth male and female patients, between the ages of 20 and 50, having non-specific CLBP persisting longer than three months, LBP with non-specific nature (mechanical) i.e. without identifiable specific anatomical or neurophysiological causative factors, will be included.\n\nIndividuals with nerve root pain signs, patients with lumbar canal stenosis, prolapsed intervertebral disc (PIVD), scoliosis, past spinal repair, spondylosis and spondylolisthesis will be exluded. Patients with a history of any vertebral fractures, systemic disorders - tuberculosis of spine or rheumatoid arthritis will be excluded as well.\n\nExperimental group\n\nThe exercise regimen will be carried out in five different positions: lying down, long sitting, kneeling, kneeling to stand, and standing. PNF pattern will be administered in each position to both the upper and lower limbs, combining the D1 and D2 patterns given in Table 1. The subjects will wear CLX consecutive loops (CLX, TheraBand), around the wrists and ankles, as they perform the PNF pattern exercise in five positions.17 For every position, the patient will exercise in a CLX + PNF pattern for five minutes and then take a 1-minute break. Table 1 shows the PNF pattern for upper limb and lower limb regimen.\n\n\n\n• Flexion, adduction, external rotation\n\n• Extension, abduction, internal rotation\n\n\n\n• Flexion, adduction, external rotation\n\n• Extension, abduction, internal rotation\n\n\n\n• Flexion, abduction, external rotation\n\n• Extension, adduction, internal rotation\n\n\n\n• Flexion, abduction, internal rotation\n\n• Extension, adduction, external rotation\n\nControl group\n\nFor each session, the patients will undergo three sets of 15 repetitions, with a 30-second break between every set. Following the 15 repeats, there will be a 60-second break. The treatment programme will be separated into three parts, and the individuals’ performance will determine how far along in each step the training should go.22\n\n1) The participant will practise alternate trunk flexor and extensor isometric contractions while providing maximum force. The physiotherapist will conduct the treatment for 10 seconds while the patient is seated.22\n\n2) The participant will focus on performing alternate isometric contractions of the trunk agonistic muscles, including a 5s hold resisted concentric contraction of the trunk flexors while bending forward, a 5s hold resisted eccentric contraction of the trunk flexors while returning to the neutral position of the trunk, and a 5s hold resisted isometric contraction of the trunk muscles while in the neutral position. The trunk’s backward bending will be accomplished using a similar technique.22\n\n3) The subjects will alternatively perform the chop and lift movement patterns in diagonal and spiral directions for ten seconds in order to train their upper extremities. The physiotherapist will provide the most resistance.22\n\n\nBoth groups will receive IFT\n\nPatients were instructed to lie down in a prone position with their lower backs exposed for this, which involves IFT over that area. An automated vector, two intersecting channels, four electrodes, and a rectangular stimulus 1/1 will also be employed. Carbon-impregnated silicone rubber and flexible electrodes will be put using an electroconductive gel and fastened by a sticky tape in a crossing arrangement at the level of the first and fifth lumbar vertebrae after washing the skin with wiping alcohol to ensure proper electrical connection.23 Treatment variables will include: an alternating current, a sinusoidal impulse, an impulse duration of 100s, a basic frequency of 4000 Hz, an alternating frequency of 50 to 100 Hz, an individual dose (the physiotherapist will raise the intensity over time throughout treatment to preserve the intended senses until a distinct sense for the passing current was felt), and a 20-minute treatment time for each patient.24\n\nConsiderations for terminating or changing the assigned treatments in a particular trial were to stop right away if the patient had any nausea or dizziness-related complaints.\n\nPrimary outcome\n\n\n\n1) Change in Visual Analogue Scale (VAS): The VAS, which is frequently employed in a variety of adult groups, is a single-dimension scale for measuring the severity of pain. A line, typically 10 cm long and in accordance with two word indicators, one for every extreme, makes up the continuous pain VAS. The most popular anchor points for the pain intensity scale are “no pain” (scoring = 0) as well as “worst possible pain” or “pain as bad as could be” (scoring = 100). The following with pain VAS cut points were suggested: no pain (0 – 4 mm), mild pain (5– 44mm), moderate pain (45–74 mm), and severe pain (75,100 mm). Test–retest reliability has been shown to be good (r = 0.94, P < 0.001) and validity was 0.99.25\n\n2) Change in Balance Error Scoring System: The Balance Error Scoring System (BESS) is a widely used clinical balance examination that is standardised. Three 20-second stances (double leg, single leg, tandem) are performed with closed eyes and hands over the hips on a hard and foamy surface. Every 20-second attempt includes a tally of errors. Three postures are evaluated by BESS. It consists of the tandem stance, one-leg stance, and two-leg stance, and it is measured in the same way as on level ground, but on an uneven surface. The exam has a maximum score of 60 points, therefore the better the participant’s capacity to balance, the lesser the total score. The maximum error score for each stance is 10 points, and the scores for all stances are added together to determine the overall result. The inter-tester reliability was excellent 0.81 (CI 0.67–0.89).26\n\n3) Change in Y balance test (YBT): The YBT is a lightweight, affordable instrument used for assessing rehabilitation process’ efficiency, coordination, and balance. In order to extend the second lower extremity as much as possible in the anterior, posterolateral, and posteromedial directions, each individual must have one leg in the centre of the three-segmented marking on the flooring. Whilst keeping their balance while standing, they will calculate the length from that point in which the toe of their extended foot is. Each foot’s measurement of the distance across the three directions will evolve into a standard score for evaluation. With intraclass correlation values in the range of 0.99 to 1.0, the YBT showed excellent inter-rater reliability.27\n\nSecondary outcome\n\n\n\n1. Change in Modified Oswestry Low Back Pain Disability Questionnaire: The questionnaire consists of 10 questions that span a range of activities. Every aspect is given a score ranging from 0 to 5, with higher scores indicating greater disability. Before the overall score is converted to a percentile, it is multiplied by two. For rating, a maximum score of 5 may be achieved for each section: Upon marking the first sentence, the component score is equal to 0. If the final sentence is indicated it equals 5.28\n\nSample size was calculated using the mean difference formula:\n\nConsidering primary variable:- Balance Error scoring System (BESS) to find the effect of looped elastic band CLX and PNF (Experimental group).\n\nMean ± standard deviation (Pre) result on BESS for experimental group = 28.37 ± 6.36.\n\nMean ± standard (Post) result on BESS for Experimental group = 12.87 ± 3.83.17\n\nDifference in mean = 15.50\n\nPooled standard deviation = (6.36+3.83)/2 = 5.095\n\nConsidering clinically relevant superiority = 30% = (15.50×30)/100 = 4.65\n\nAssumptions\n\nTotal samples required = 26 per group.\n\nConsidering 20% drop out = 4\n\nTotal sample size required = 60 (30 per group)\n\nAssumptions\n\nReference article: “Effect of CLX training combined with PNF pattern on balance ability”, Journal of Korean Physical therapy Science, Ji-hoon Jung et al. (2019).17\n\n\nDiscussion\n\nThe main aim of this study will be to find out how CLX resistance bands adjunct to PNF and conventional physiotherapy exercises in decreasing pain and improving balance in CLBP patients.\n\nNLBP relates to LBP that is not caused by a known condition, such as nerve root pain or severe spinal pathologies like infection, tumour, osteoporosis, rheumatoid arthritis, fracture, or inflammation.29 NLBP affects 80% of people at some point in their lifetime.30 Numerous medical, psychological, social, and economic issues affect patients when persistent LBP is highly prevalent. Compared to individuals with LBP, individuals with chronic pain have a higher pain score on the VAS.31 People with chronic NLBP are significantly more likely to have a balance disorder.9\n\nClinical practise recommendations state that primary care clinicians should also promote non-pharmacological LBP treatment such as patient education, physical activity, and manual therapies.32 The PNF pattern in conjunction with CLX exercise have been shown to improve the normal adult’s ability to balance and performing the functional mobility of the lower extremity.17 Conventional physiotherapy exercises produce the most force possible while exerting the least amount of shearing and compressive stresses during the functional motions.29 Patient recovery also seems to be dependent on compliance to the exercise programme.33\n\nForman et al. (2021) in his research article”THERABAND CLX gold reduces knee-width index and range of motion during overhead, barbell squatting barbell squatting”, found that muscle activation at all seven bilateral locations remained constant when overhead squatting with the CLX gold band.34 Kofotolis et al. (2020) (“Effects of Two 4-Week Proprioceptive Neuromuscular Facilitation Program on Muscle Endurance, Flexibility, and Functional Performance in Women With Chronic Low Back Pain”), reported that applying a four-week RST and COI PNF program improved muscle endurance in people with CLBP by 23.6% to 81%.35\n\nPhysical therapists frequently utilise PNF training using spiral and diagonal directions, which are better in relieving LBP.15 When PNF exercises are carried out properly, the patient integrates them into their everyday movements, correcting poor postures and habits that cause chronic muscle strain, soreness, stress, and at eventually injury. Additionally, their muscle spasms and pain will significantly decrease and core strengthening demonstrates the muscle control required to keep the lumbar spine functionally stable. Strengthening the core helps prevent and treat a variety of lumbar spine and musculoskeletal diseases, because it functions as a muscle corset to support the body and spine without as well as with limb movement.36\n\nFinally, this study aims to investigate how a session of CLX resistance band training with PNF and conventional physiotherapy exercises impacts the pain and balance of CLBP patients.\n\nThe results will be tabularized and analysed statistically; data from outcome variables will be tested for normal distribution for the mean and standard deviation (SD). Median statistics will be utilized for finding skewed distributions and interquartile ranges (IQR). Frequency and percentages for binary and categorical variables will be tabulated for descriptive statistics. The inferential statistics will be analysed as per the description given below. Free R software will be used for all statistical analyses.\n\nFor comparing two groups, inferential statistics will be used for measuring the score (active treatment versus control treatment) of their mean change in primary variable (VAS, BESS, Y- Balance test) between baseline and six weeks. An independent t-test will then be used. The responses of the subjects will be evaluated with regard to of the main variable’s variation from baseline to the timeframe measured throughout the project (visit 1 and at six weeks following the conclusion of the intervention). For research participants, random effects will be generalized for study subjects, and fixed effects will be analysed by considering treatment group and visit number.\n\n95% confidence interval (CI), the effect size over the mean change difference on the major variable from baseline to endline visit at six weeks, will be assessed.\n\nIn order to estimate the disparity in effect size among the active and control groups, secondary outcomes (MODQ) will be examined in accordance with the linear mixed model effect. If the data has a normal distribution, a t-test (Unpaired) will be used to determine if a difference is significant among means between two groups. If the data is non-normally distributed, transformation of the data will be done using mathematical methods to achieve normal distribution. Alternative non-parametric tests (Chi-square, Mann-Whitney U, and Wilcoxon test) will be utilised if the data across the main variables still exhibit non-normal distribution.\n\nWe are planning to publish the results in an indexed journal and present the study in National Conference Proceedings.\n\nThe recruitment of participants has not started yet.\n\nInstitutional Ethical Clearance has been obtained on 21/03/2023 (DMIHER (DU)/IEC/2023/805). CTRI Registration was obtained on 18/5/2023.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\nZenodo: SPIRIT checklist for“Effect of CLX training adjunct to PNF and conventional physiotherapy on pain and balance in patients with chronic lower back pain: A randomised clinical trial protocol”, https://doi.org/10.5281/zenodo.7988643. 37\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgements\n\nThe authors would like to acknowledge Mr. Laxmikant Umate and Mr. Manoj Patil who helped with sample size calculation and data analysis planning.\n\n\nReferences\n\nAllegri M, Montella S, Salici F, et al.: Mechanisms of low back pain: a guide for diagnosis and therapy. F1000Res. 2016 Oct 11; 5. F1000 Faculty Rev-1530. Publisher Full Text\n\nHoy D, Bain C, Williams G, et al.: A systematic review of the global prevalence of low back pain. Arthritis Rheum. 2012 Jun; 64(6): 2028–2037. Publisher Full Text\n\nMoroder P, RunER A, Resch H, et al.: Low back pain among medical students.2011; 77.\n\nHoy D, Brooks P, Blyth F, et al.: The Epidemiology of low back pain. Best Pract. Res. Clin. Rheumatol. 2010 Dec; 24(6): 769–781. Publisher Full Text\n\nMathew A, Safar R, Anithadevi T, et al.: The prevalence and correlates of low back pain in adults: A cross sectional study from Southern India. Int. J. Med. Public Health. 2013; 3(4): 342. Publisher Full Text\n\nLi W, Gong Y, Liu J, et al.: Peripheral and Central Pathological Mechanisms of Chronic Low Back Pain: A Narrative Review.2021 May 27; 14: 1483–1494.\n\nEmami F, Yoosefinejad AK, Razeghi M: Correlations between core muscle geometry, pain intensity, functional disability and postural balance in patients with nonspecific mechanical low back pain. Med. Eng. Phys. 2018 Oct; 60: 39–46. PubMed Abstract | Publisher Full Text\n\nFatima K, Bhatti Z, Khan I, et al.: Effect of Chronic Low Back Pain on Balance and Functional Mobility in Women. Riphah Rehabil. Sci. 2021 Dec 1; 09: 71–74. Publisher Full Text\n\nHosseinifar M, Akbari A, Mahdavi M, et al.: Comparison of balance and stabilizing trainings on balance indices in patients suffering from nonspecific chronic low back pain. J. Adv. Pharm. Technol. Res. 2018; 9(2): 44–50. PubMed Abstract | Publisher Full Text\n\nda Silva RA , Vieira ER, Fernandes KBP, et al.: People with chronic low back pain have poorer balance than controls in challenging tasks. Disabil. Rehabil. 2018 May 22; 40(11): 1294–1300. PubMed Abstract | Publisher Full Text\n\nBehennah J, Conway R, Fisher J, et al.: The relationship between balance performance, lumbar extension strength, trunk extension endurance, and pain in participants with chronic low back pain, and those without. Clin. Biomech. (Bristol, Avon). 2018 Mar; 53: 22–30. PubMed Abstract | Publisher Full Text\n\nGatti R, Faccendini S, Tettamanti A, et al.: Efficacy of Trunk Balance Exercises for Individuals With Chronic Low Back Pain: A Randomized Clinical Trial. J. Orthop. Sports Phys. Ther. 2011 Aug; 41(8): 542–552. Publisher Full Text\n\nHwangbo G, Lee CW, Kim SG, et al.: The effects of trunk stability exercise and a combined exercise program on pain, flexibility, and static balance in chronic low back pain patients. J. Phys. Ther. Sci. 2015; 27(4): 1153–1155. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPourahmadi M, Sahebalam M, Bagheri R: Effectiveness of Proprioceptive Neuromuscular Facilitation on Pain Intensity and Functional Disability in Patients with Low Back Pain: A Systematic Review and Meta-Analysis. Arch. Bone Jt. Surg. 2020 Jul; 8(4): 479–501. PubMed Abstract | Publisher Full Text\n\nGao P, Tang F, Liu W, et al.: The effects of proprioceptive neuromuscular facilitation in treating chronic low back pain: A systematic review and meta-analysis. J. Back Musculoskelet. Rehabil. 2022; 35(1): 21–33. Publisher Full Text\n\nPanjaitan L, Susy N, Manik J: Proprioceptive neuromuscular facilitation approach for low back pain: A review study. J. Sport Exerc. Health. 2022 May 27; 6: 82–87. Publisher Full Text\n\nHoon JJ, Ju KM, Jung WH, et al.: Effect of CLX Training Combined with PNF Pattern on Balance Ability.2019 Jun 30; 26(1): 1–8.\n\nPage P, Ellenbecker TS: Strength band training. 3rd ed. Champaign, IL: Human Kinetics; 2019; 1.\n\nSheeba Kauser M, Yadav M, Bismil Jaffery M, et al.: Effect of elastic bands as resistance for low back pain treatment in software engineers.2020 Oct 28; 6(3): 87–91.\n\nYu W, An C, Kang H: Effects of Resistance Exercise Using Thera-band on Balance of Elderly Adults: A Randomized Controlled Trial. J. Phys. Ther. Sci. 2013 Nov; 25(11): 1471–1473. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVafaeenasab MR, Kuchakinejad Meybodi N, Fallah HR, et al.: The Effect of Lower Limb Resistance Exercise with Elastic Band on Balance, Walking Speed, and Muscle Strength in Elderly Women.2019 Jul 2 [cited 2023 Feb 24]. Reference Source\n\nAreeudomwong P, Buttagat V: Proprioceptive neuromuscular facilitation training improves pain-related and balance outcomes in working-age patients with chronic low back pain: a randomized controlled trial. Braz. J. Phys. Ther. 2019 Sep; 23(5): 428–436. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlbornoz-Cabello M, Maya-Martín J, Domínguez-Maldonado G, et al.: Effect of interferential current therapy on pain perception and disability level in subjects with chronic low back pain: a randomized controlled trial. Clin. Rehabil. 2017 Feb; 31(2): 242–249. PubMed Abstract | Publisher Full Text\n\nRajfur J, Pasternok M, Rajfur K, et al.: Efficacy of Selected Electrical Therapies on Chronic Low Back Pain: A Comparative Clinical Pilot Study. Med. Sci. Monit. 2017 Jan 7; 23: 85–100. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHawker GA, Mian S, Kendzerska T, et al.: Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF). Arthritis Care Res. 2011 Nov; 63(S11): S240–S252. PubMed Abstract | Publisher Full Text\n\nKleffelgård I: Reliability and validity of the balance error scoring system – BESS.2015; 101.\n\nAlshehre Y, Alkhathami K, Brizzolara K, et al.: Reliability and Validity of the Y-balance Test in Young Adults with Chronic Low Back Pain. Int. J. Sports Phys. Ther. 16(3): 628–635. PubMed Abstract | Publisher Full Text\n\nFritz JM, Irrgang JJ: A Comparison of a Modified Oswestry Low Back Pain Disability Questionnaire and the Quebec Back Pain Disability Scale. Phys. Ther. 2001 Feb 1; 81(2): 776–788. PubMed Abstract | Publisher Full Text\n\nVaidya L: ACTIVE RELEASE TECHNIQUE AND ITS IMPACT ON NON-SPECIFIC LOW BACK PAIN.2021 Sep 15; 10(4): 3171–3174.\n\nDarware M: RELATIONSHIP BETWEEN SACRALIZATION AND LOW BACK PAIN IN RURAL POPULATION.2021 Sep 15; 10(4): 3280–3283.\n\nPhansopkar P: Association of poor sleep with low back pain among symptomatic and asymptomatic population.2022 Aug 30; 11(4): 5045–5049.\n\nVasavada DS, Samal DN, Lohiya DD, et al.: ORAL MEDICATIONS IN PATIENTS SUFFERING FROM ACUTE LOW BACK PAIN- NARRATIVE REVIEW. J. Pharm. Negat. Results. 2022 Oct 15; 329–332.\n\nNaqvi W: THE OUTCOMES OF A MCKENZIE-BASED APPROACH COMBINED WITH OTHER INTERVENTIONS FOR A PATIENT WITH LOW BACK PAIN AND PIVD.2021 Sep 15; 10(5): 3653–3655.\n\nForman DA, Forman GN, Button DC, et al.: THERABAND® CLX gold reduces knee-width index and range of motion during overhead, barbell squatting. Sports. 2021 Feb 17; 20(2): 198–212. Publisher Full Text\n\nKofotolis N, Kellis E: Effects of Two 4-Week Proprioceptive Neuromuscular Facilitation Programs on Muscle Endurance, Flexibility, and Functional Performance in Women With Chronic Low Back Pain. Phys. Ther. 2006 Jul 1; 86(7): 1001–1012. PubMed Abstract | Publisher Full Text\n\nAssociate professor, Padmashree Dr. D. Y. Patil College of Physiotherapy, Dr. D. Y. PatilVidyapeetUniversity, Pimpri, Pune, India, Franklin CVJ: Effectiveness of PNF Training for Chronic Low Back Pain. IOSR-JNHS. 2013; 2(4): 41–52. Publisher Full Text\n\nPriya T: SPIRIT checklist (Version v1). Zenodo.2023.Publisher Full Text"
}
|
[
{
"id": "325114",
"date": "28 Sep 2024",
"name": "Prem Venkatesan",
"expertise": [
"Reviewer Expertise Cardiopulmonary and musculoskeletal rehabilitation"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbstract\nNeeds more clarity\nAims and Objectives\nIt is unclear that what the study is aiming to, to correlate or associate or find the effect. Since it is an RCT, assessment will be very vague term to define the aim of the study.\nIntroduction: What is the current evidence of PNF in chronic low back pain? Further what is the need to conduct study in combination with elastic bands? There is huge amount of research available, introduction mentions single reference! Justification is needed in line with pathophysiology of chronic low back pain, because each treatment alone itself will have an effect. Why only PNF patterns involving diagonal and spiral movements? Why not patterns involving pelvis, lumbar and abdominals? Why only rhythmical stabilization (RS) and a combination of isotonic (COI)? What is the justification to choose two techniques, what about other techniques? Explain the mechanism how PNF techniques improves balance What is the evidence of IFT in chronic low back and need to add in both groups What is the evidence of conventional group and its justification\\ There is lack of rationale and flow in the introduction and hypothesis is unclear Protocol\nWhen the main aim of the study is to find the effect of TheraBand based exercise and PNF exercise on balance, why was it not considered to provide the other group a similar treatment or a contrasting treatment to find the real effect. The current protocol may lead to a biased result. Why the outcomes are assessed at the 3rd week also, Will the data be used for any analysis? If the intermediate data will be considered for the regular analysis, there might be chances for change in the statistical analysis.\n\nInterventions\nWhether the intervention group will be receiving the resistance exercises irrespective of the pain intensity, as some of subjects may not cop up with resistance exercises. Any basic exercises will be taught? The details regarding the IFT treatment is missing in the intervention group. Although it is mentioned in the later part, it will be better to be mentioned in the intervention group protocol also. How will be the resistance provided in the control group (3 point of the treatment) Mention blinding of the study What are the diagnostic criteria for non-specific low back pain Why exercise in experimental group given in five different positions Mention the repetitions for the experimental group Why IFT placed at the level of the first and fifth lumbar vertebrae\n\nIs the rationale for, and objectives of, the study clearly described? No\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
},
{
"id": "325112",
"date": "01 Oct 2024",
"name": "Y. Ravi shankar Reddy",
"expertise": [
"Reviewer Expertise Rehabilitation",
"Physical Therapy",
"Sports injuries"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntroduction: The introduction provides a comprehensive overview of chronic low back pain (CLBP) and its significant impact on individuals worldwide. It effectively establishes the rationale for the study, highlighting the prevalence and the multifaceted challenges faced by patients with non-specific low back pain (NLBP). The inclusion of statistical data on prevalence and associated conditions strengthens the context. To enhance clarity, consider integrating more recent statistics or regional data if available, ensuring the relevance and timeliness of the information. Additionally, emphasizing the specific gaps in current treatment modalities that the proposed study aims to address would further solidify the importance of this research.\nObjectives: The objectives are clearly stated, focusing on investigating the effects of CLX resistance bands adjunct to PNF and conventional physiotherapy exercises on pain reduction and balance improvement in CLBP patients. However, to enhance specificity, consider detailing the primary and secondary outcomes explicitly. For instance, explicitly mention the specific pain scales (e.g., VAS) and balance tests (e.g., Y-Balance Test) that will be used to measure outcomes. This will provide clarity on the study's endpoints and facilitate reproducibility.\nMethods: The methods section provides a detailed outline of the study design, including participant selection criteria, intervention protocols, and outcome measures. The integration of specific references to studies supporting the efficacy of CLX bands and PNF in CLBP treatment strengthens the rationale for the chosen interventions. To improve comprehensibility, consider outlining the specific training protocols for CLX bands and PNF exercises in a step-by-step format. This would aid in replicability and ensure consistency across study sites. Additionally, specifying the duration and frequency of intervention sessions would provide crucial details for understanding participant engagement and adherence.\nStatistical Analysis: The statistical analysis plan is well-defined, outlining the methods for data handling, normality testing, and inferential statistics. The intention to use Free R software for statistical analyses is appropriate and aligns with current practices in clinical research. To enhance clarity, consider providing examples of specific statistical tests that will be employed for each type of data (e.g., t-tests for normally distributed data, Mann-Whitney U test for non-parametric data). This would assist readers in understanding the rationale behind the chosen analytical approach and ensure transparency in data interpretation.\nEthical Considerations: The ethical considerations section appropriately mentions institutional ethical clearance and CTRI registration, ensuring compliance with ethical standards. To provide a more comprehensive view, consider briefly discussing potential risks associated with the interventions (e.g., muscle strain from CLX bands, fatigue from exercise protocols) and how these will be mitigated. This would demonstrate a thorough consideration of participant safety and ethical integrity throughout the study.\nDissemination and Study Status: The plans for disseminating study results in an indexed journal and national conference proceedings are clearly outlined, highlighting the commitment to sharing findings with the scientific community. To enhance this section, consider briefly discussing the anticipated timeline for manuscript submission and conference presentation, if available. Additionally, providing insights into any planned collaborations or partnerships for knowledge translation would underscore the study's potential impact on clinical practice and policy.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
},
{
"id": "325111",
"date": "07 Oct 2024",
"name": "Vinodhkumar Ramalingam",
"expertise": [
"Reviewer Expertise Musculoskeletal disorders",
"ankle injury and sports rehabilitation"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors aim to evaluate the effectiveness of consecutive loop TheraBand (CLX) adjunct to proprioceptive neuromuscular facilitation (PNF) and conventional physiotherapy exercises on subjects with CLBP with pain and balance as outcome measures. Since low back pain is common among young adults, this study may provide the effect of the interventions. The population age range of 20 and 50 years is considered a wider range, which required literature support. In addition, excluding other inflammatory conditions (ankylosis spondylitis) and spinal stenosis which reduces bias in participant enrolment.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1280
|
https://f1000research.com/articles/12-1278/v1
|
06 Oct 23
|
{
"type": "Study Protocol",
"title": "Role of maternal serum c-reactive protein levels in early second trimester as a marker of preterm labour: A study protocol",
"authors": [
"Sravya Gudapati",
"Kamlesh Chaudhari",
"Sravya Gudapati"
],
"abstract": "Preterm labour is a birth that occurs between 22 and 37 weeks after conception. The primary cause of infant death is preterm birth (PTD), which is linked to long-term neurodevelopmental and behavioural effects for preterm survivors. A maternal vascular disease pathway and an inflammation/infection pathway are two suggested pathways that have collected sufficient evidence. The identification of women who are more likely to develop PTD and the understanding of the underlying physiological mechanisms would be made possible by reliable biomarkers for these pathways. Systemic maternal infections cause elevated levels of inflammatory cytokines, which then drive the creation of prostaglandins, which can cause cervical ripening and uterine contractions that result in preterm birth. Women with signs of preterm labour have been found to have high serum levels of proinflammatory which have been prospectively linked to preterm birth. A non-specific biomarker of inflammation, C-reactive protein (CRP) is an acute phase reactant in the innate immune response. The production of C-reactive protein, a serological marker that is readily identifiable, occurs largely in the hepatocytes in response to cytokine releases from the inflammatory site. Cytokines released, by an intrauterine infection go through the maternal bloodstream to the liver, where they activate the production of CRP. Forty-eight hours after stimulation the acute-phase response has reached its maximum and a meaningful measurement can be made from a blood sample. Although the exact cause of inflammation is unknown, modest and long-lasting elevations of CRP have been linked to a range of illnesses, including normal pregnancy. Elevated CRP levels in the peripheral circulation have been connected to the presence of intrauterine infection. It has been investigated to diagnose subclinical infections using the maternal CRP concentration. The purpose of this study is to determine the link between maternal serum CRP and subsequent preterm birth in single pregnant women.",
"keywords": [
"Preterm",
"term labour",
"maternal serum c-reactive protein levels"
],
"content": "Introduction\n\nLabor is a physiological process during which fetus and viable products of conception are expelled through the vagina into the world. Labor typically starts for most women between 37 and 42 weeks of pregnancy. Preterm or premature labour is defined as beginning before 37 weeks of pregnancy.1 In developing nations, preterm labour is the main contributor to prenatal morbidity and mortality. Preterm birth rates vary by country and range from 5% to 18% of all births.2\n\nHowever, despite decades of research, little progress has been achieved in determining its cause, physiology, and aetiology. There are high chances of cerebral impairment, respiratory distress, feeding, visual, and hearing difficulty for newborns who survive.\n\nThe most frequent cause of preterm labour, which accounts for about 50% of premature birth is idiopathic. Up to 40% of women who give birth prematurely through spontaneous labour lack obvious, well-known risk markers for preterm labour. 18.7% to 28.8% of preterm births are caused by iatrogenic (medical) causes related to maternal or fetal factors like hypertensive disease, gestational diabetes and twin pregnancies or intrauterine growth restriction respectively. Of all preterm births, early rupture of the membranes occurs in 7.1% to 51.2% (or 25% on average) of cases.3 Identification of those at risk is a crucial first step in combating the issue of preterm birth. Risk score systems, biochemical markers of inflammation, and infection screening are some of the methods that have been considered. In the asymptomatic population, it is crucial to assess these possible predictors both singly and together, as well as to consider the financial implications of these screening procedures. Numerous studies have identified a link between inflammation or infection and premature birth. Although there is evidence that bacterial vaginosis increases the risk of preterm birth, antibiotic treatment has not been proven to offer any protective advantages. In order to identify infection in pregnant women who experienced premature membrane rupture and preterm labour, maternal concentrations of CRP have been examined. Few studies have found an association between maternal blood CRP levels that are elevated in the second trimester and subsequent preterm birth. The current study's objective is to assess maternal serum CRP.\n\nTo study the role of maternal serum C- reactive protein levels in early second trimester as a marker of preterm labour.\n\n\n\n1. To evaluate the preterm delivery in women with normal CRP levels.\n\n2. To evaluate preterm delivery in women with altered CRP levels.\n\n3. To compare between the women with preterm delivery with normal CRP levels and women with preterm delivery with altered CRP levels.\n\n\nProtocol\n\nThis will be an observational study where CRP levels will be measured in all pregnant women presenting to the outpatient department with 14-20 weeks of gestational age and will be followed up to delivery and then will be divided in to preterm and term groups.\n\nThe study will take place at the Department of Obstetrics and Gynecology J.N.M.C., AVBRH, D.M.I.H.E.R. (Deemed University), Wardha over the course of two years.\n\n\n\n1. Every single instance of singleton pregnancy (as determined by early second trimester ultrasonography).\n\n2. Pregnancy age of 14 to 20 weeks, as determined by LMP and ultrasound.\n\n3. Amniotic membranes that are intact.\n\n4. Women willing to give consent to participate in the study.\n\n\n\n1. Multiple gestation.\n\n2. Less than 13 weeks of gestation or more than 20 full weeks.\n\n3. Patients with premature rupture of membranes.\n\n4. Pregnancies complicated by Pre-eclampsia, Gestational diabetes mellitus, heart disease.\n\n5. Pre-term births in previous pregnancies.\n\n6. Patients with fetal congenital abnormalities.\n\n7. Patients with cardiovascular, abdominal, and respiratory pathology.\n\n8. History of recent bacterial or viral infections.\n\n9. Women not willing to give consent to participate in the study.\n\nSample size\n\nWe will recruit 113 patients for this study. The sample size was calculated using the following formula.\n\nFormula:\n\nCochrane formula for sample size.4\n\nWhere;\n\nZ∝/2 is the level of significance at 5% i.e., 95% confidence interval = 1.96\n\nP = incidence of preterm labour = 12% = 0.12\n\nE = error of margin = 6% = 0.06\n\nN=113 patients needed\n\nSTUDY REFERNCE – Cochran WG. Sampling techniques. John Wiley & Sons; 1977.\n\nA blood sample is collected in a testube without anticoagulant and allowed to clot and then it is sent to laboratory for evaluation.\n\nUsing a specified structure, data was obtained and entered into a spreadsheet (MS Excel 2010, Microsoft Inc. Redmond, Washington, USA).\n\nThe chi-square test (x-2) and student's unpaired t-test were used to statistically analyse the data using descriptive and inferential statistics. The analysis will be conducted using SPSS 21.0, OPEN EPI version 3.01, which computes data using JavaScript and HTML. 0.05 as the p-value and 95%.\n\n\nMethods\n\nThe institutional ethical committee's ethical approval has been taken. Every woman will be told about the study's purpose and design as well as the significance of evaluating CRP levels in predicting preterm birth after informed, valid and written consent has been obtained. We have applied for funding from the ICMR, synopsis concession, and intramural grant. Each group will be observed for a total of 113 patients who meet the inclusion and exclusion criteria. Serum C-Reactive Protein levels will be assessed between weeks 14 and 20 of pregnancy, followed through birth, and then divided into preterm and non-preterm groups depending on gestational age. Detailed obstetric, menstrual, past, personal, and family history will be taken.\n\nTo evaluate the serum C-reactive protein concentrations between 14 and 20 weeks of gestation, venous blood samples from the patient will be taken. To avoid haemolysis, the serum will be removed as quickly as possible and kept frozen until the lab analyses the samples. In a test tube without anticoagulant, samples will be collected and allowed to clot.\n\nA highly sensitive quantitative immunoassay (ELISA) will be used to measure the amounts of C-Reactive protein. A reference level of 1.5 mg/dl is taken. Therefore, pregnancies with high maternal serum CRP levels will be defined as those in which the maternal serum level CRP is above 1.5 mg/dl. Preterm labour is associated with increased maternal serum c-reactive protein. The normal CRP levels during preterm labour and raised CRP levels during preterm labour will be compared.\n\nIn this study we are expecting the values of maternal serum C-reactive protein levels to be raised in the preterm labour group than in term labour group.\n\nArticles arising from this study will be published in index journals.\n\nNot yet started, is expected to begin from October 2023.\n\n\nDiscussion\n\nCRP is an acute phase reactant protein that is largely made in liver cells in response to proinflammatory cytokines including IL-6 and alpha TNF. The presence of intrauterine infection is related with C-reactive protein in maternal peripheral circulation. Subclinical amnionitis and preterm birth are associated with its elevated levels in maternal serum. A significant connection was seen between CRP plasma concentrations greater than 1.5 mg/dl.5\n\nA study by Shahshahan and Rasouli showed that measuring maternal CRP concentrations can be a useful biomarker for predicting preterm labour. It also showed that, despite the study's patient population's limitations, measuring these women's CRP levels could predict how well these women would respond to tocolytic therapy. However, this finding calls for additional research to evaluate other biologic markers as predictors.6\n\nResearch by Halder A et al., indicated that a high chance of preterm labour can be predicted by an increased CRP level (>6mg/dl) in early pregnancy in the absence of any obstetric or medical complications. The levels of oligohydramnios, IUGR, and PROM are positively correlated with CRP. The study's weakness is because both pathological and physiological situations cause an increase in CRP. Therefore, further proof is needed to support the widespread use of CRP as a predictor of poor maternal and foetal outcomes.7\n\nA study by Grgic G et al., asserts that in pregnant women who do not have any established risk factors for preterm delivery, C-reactive protein (CRP) is a valid marker of idiopathic preterm delivery. The threshold level of CRP that was linked to the emergence of idiopathic preterm birth was 4 mg/L. A link exists between CRP and low birth weight in babies.8\n\nResearch by Pitiphat W et al., states that in early pregnancy, CRP levels more than 8 mg/liter were linked to preterm birth, regardless of the presence of several other risk factors. The connection was mainly significant for unplanned premature birth. These results back up the theory that persistent low-grade inflammation may increase CRP levels and result in preterm birth.9\n\nA study by Hvilsom GB et al., shows that higher CRP levels in the early stages of pregnancy are linked to an increased risk of premature delivery. They have not found a clinical test that can be utilized on all pregnant women in the early stages of pregnancy because the sensitivity and specificity vary depending on the chosen cut-off number. They did note, however, that a small subgroup of women who had CRP levels above 9.9 mg/l but had never given birth prematurely did have a greater chance.10\n\nResearch of Ghezzia et al., (2002) demonstrated that compared to pregnant women who delivered at term, those who had premature deliveries (before 37 weeks gestation) had greater levels of CRP in their amniotic fluid. This research adds to the theory that early-stage intrauterine inflammation or subclinical conditions may play a significant role in the risk of premature birth.11\n\nInstitutional ethical committee approval has been taken.\n\nDate: 21.03.2023",
"appendix": "Data availability\n\nNo data associated with this article.\n\n\nReferences\n\nPreterm Birth|Maternal and Infant Health |Reproductive Health|CDC.2022 [cited 2023 Jan 19]. Reference Source\n\nPreterm birth|National Health Portal Of India.[cited 2023 Jan 20]. Reference Source\n\nGoldenberg RL, Culhane JF, Iams JD, et al.: Epidemiology and causes of preterm birth. Lancet Lond Engl. 2008; 371(9606): 75–84. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCochran WG: Sampling techniques. John Wiley & Sons; 1977.\n\nSproston NR, Ashworth JJ: Role of C-Reactive Protein at Sites of Inflammation and Infection. Front. Immunol. 2018 Apr 13; 9: 754. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShahshahan Z, Rasouli O: The use of maternal C-reactive protein in the predicting of preterm labor and tocolytic therapy in preterm labor women. Adv. Biomed. Res. 2014 Jul 31; 3: 154. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHalder A, Agarwal R, Sharma S, et al.: Predictive significance of C reactive protein in spontaneous preterm delivery: a prospective cohort study. Int. J. Reprod. Contracept. Obstet. Gynecol. 2013 Mar 1; 2(1): 47–51. Publisher Full Text\n\nGrgic G, Skokic F, Bogdanovic G: C-reactive protein as a biochemical marker of idiopathic preterm delivery. Med. Arh. 2010; 64(3): 132–134. PubMed Abstract\n\nPitiphat W, Gillman MW, Joshipura KJ, et al.: Plasma C-Reactive Protein in Early Pregnancy and Preterm Delivery. Am. J. Epidemiol. 2005 Dec 1; 162(11): 1108–1113. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHvilsom GB, Thorsen P, Jeune B, et al.: C-reactive protein: a serological marker for preterm delivery? Acta Obstet. Gynecol. Scand. 2002 May; 81(5): 424–429. PubMed Abstract | Publisher Full Text\n\nGhezzi F, Franchi M, Raio L, et al.: Elevated amniotic fluid C-reactive protein at the time of genetic amniocentesis is a marker for preterm delivery. Am. J. Obstet. Gynecol. 2002 Feb; 186(2): 268–273. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "242939",
"date": "05 Mar 2024",
"name": "Samantha Sheller-Miller",
"expertise": [
"Reviewer Expertise Inflammation",
"extracellular vesicles",
"parturition",
"preterm labor"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSravya Gudapati and Kamlesh Chaudhari seek to understand the predictive potential of maternal c-reactive protein levels in preterm birth. Scientists have been trying to identify biomarkers to determine those at risk for preterm birth, however, little progress has been made in the last 30 years. CRP is a marker for inflammation, which is the underlying cause of preterm labor and subsequent preterm birth. Because it is part of the innate inflammatory pathway, it could be a potential biomarker for preterm labor, although its non-specificity to labor associated inflammation may cause challenges in achieving the proposed objectives.\nComments\nThe study design is inconsistent on how many groups will be recruited, lacking details on what will the controls be, and frequency of sample collection Additional details are necessary to define what is considered a high level of CRP and how that level was selected. Methods are disconnected, parts are repeated and some details are missing. Please expand to include more details so could be repeated by another. What handling will occur in the laboratory? How long will the sample be clotting? Will it be centrifuged prior to storage in the freezer? Will it be stored at -20 or -80 degrees C?\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1278
|
https://f1000research.com/articles/11-249/v1
|
28 Feb 22
|
{
"type": "Research Article",
"title": "The role of newspapers published in North Sumatra during Indonesia's independence struggle between 1916-1925: A discourse analysis",
"authors": [
"Ichwan Azhari",
"Ricu Sidiq",
"Ika Purnamasari",
"Ricu Sidiq",
"Ika Purnamasari"
],
"abstract": "Background: In the history of Indonesian independence, newspapers not only functioned as a medium of information but also as a tool for the struggle for independence. This is because of the role of newspapers in bringing out the spirit of nationalism and the concept of “nation” to the Indonesian people through various writings and reports in each edition. This study aims to describe the form of Indonesia's struggle for independence in newspapers published in North Sumatra in 1916-1925. Methods: This research uses the critical discourse analysis method. The research data are in the form of texts published in thirteen indigenous newspapers published in North Sumatra in 1916-1925. Data analysis used three structures of Teun A. van Dijk's discourse analysis model, namely: macrostructure, superstructure, and microstructure. Results: From 1910-1925 there were 24 indigenous newspapers published in North Sumatra. Of these, there were 13 newspapers demanding Indonesian independence: Soeara Djawa, Pewarta Deli, Benih Merdeka, Perempoean Bergerak, Soeara Bondjol, Sinar Zaman, Orgaan Bataksche Studiefonds, Andalas, Mandailing, Warta Timur, Al Moektabas, Tjermin Karo, Soeara Batak. These newspapers published articles that fought for Indonesian independence by demanding Indonesian independence openly, criticizing various policies of the Dutch Colonial Government, and building awareness of Indonesian nationalism. Conclusion: The role of newspapers in the struggle for Indonesian independence in North Sumatra in 1916-1925 can be seen from the findings of 51 articles demanding Indonesia's independence from Dutch colonialism, criticizing the policies of the Dutch colonial government, and building the spirit of nationalism to encourage the Indonesian people to fight for their independence.",
"keywords": [
"Newspapers",
"nationality",
"independence",
"North Sumatra"
],
"content": "Introduction\n\nNewspapers are the oldest form of mass media and have become an important part of modern society which requires the rapid spread of information.1 In the history of Indonesia, newspapers have not only functioned as a medium of information but also as a tool in the struggle for independence. This is tied to the role of newspapers in promoting the spirit of nationalism and the concept of “nation” among the Indonesian people through various writings and reports in each edition. According to Benedict Anderson,2 a nation is a political community that is imagined as something that is both inherently limited and sovereign. The nation did not form by itself there were efforts from the community to create the concept of a nation. Newspapers have an important role in fostering a sense of nationalism and instilling the concept of “nation” for every member of the community.\n\nNationalism played an important role in the emergence of Indonesia as a country free from colonialism. Anthony D. Smith3 stated that nationalism is an ideological movement that aims to maintain the autonomy, unity, and identity of a nation. It takes a strong determination from its members to make this happen. Hans Kohn4 argues that nationalism grows and develops because of a common desire to unite based on a common destiny, language, and historical journey. Active and real involvement of the people as citizens of equal status, united by a sense of brotherhood (feeling as one family), and loyalty to one another are important moral principles in a nation. This sense of brotherhood is a manifestation of the collective will that has emerged in European nationalism in the eighteenth century.3\n\nThe revival of Indonesian nationalism began with access to modern education for indigenous people at the end of the nineteenth century by the Dutch Colonial Government which aimed to produce low-ranking indigenous employees. In 1901 the policy of Ethical Politics began to be implemented in Indonesia, especially to the Javanese people as a reward for their suffering due to a very cruel forced cultivation system. The establishment of the development of education for indigenous people as one of the core programs of Ethische Politiek encourages enormous progress and wider opportunities to enter modern European education. Hollandsch Inlansche School (HIS), Meer Uitgebreid Lagger Onderwijs (MULO), School Tot Opleiding van Inlandsche Artsen (STOVIA), dan Opleiding school voor Inlandsche Ambtenaaren (OSVIA) are some examples of schools built by the Dutch colonial government for indigenous Indonesian children after the declaration of Ethische Politiek. In addition to government schools, there are also private schools owned by Taman Siswa, Muhammadiyah, INS Kayutanam, and Persis starting in the 1920s. The efforts to advance education carried out by the government and also the Indonesian people made education appear as the most important element in the process of progressing Indonesian society at that time.5\n\nThe educated group was the core influence in the rise of nationalism in the colonies.2 Modern education introduced by the Dutch colonial government in Indonesia was not only successful in creating educated indigenous people to be employed as part of the colonial bureaucracy but also succeeded in encouraging the birth of pioneer figures for the Indonesian nationalism movement. This phenomenon occurred because the modern European education system at that time gave Indonesian educated people the opportunity to study various nationalist movements in Europe. The European nationalism movement then made these educated people aware that Indonesia was a colonized nation. The suffering of the people due to Dutch colonialism finally encouraged them to fight for Indonesian independence.\n\nThe progress of modern education and political movements carried out by educated Indonesians in the early twentieth century correlated with the progress of the Indonesian print press. Newspapers that were introduced by the Dutch colonial government in 1659 for the benefit of their group had an influence on Indonesian educated people at that time. Indigenous intellectual groups eventually created their newspapers. They wrote about nationalist ideas, the importance of unity as a nation, and also the right to independence for the Indonesian people. These educated people also used newspapers as a medium of communication between fellow movement figures to unify the ideas of nationalism and independence that they are fighting for. The modern education system, political organization, and the press media were the three main elements in the formation and dissemination of nationalist ideas in the colonized countries.\n\nThe role of newspapers in fostering a sense of nationalism and disseminating the notion of nationalism through newspapers also occurred in North Sumatra, which became one of the centers of newspaper publishing in Indonesia in the early twentieth century. This is evidenced by the number of newspapers published in this region from 1900-1942, reaching more than 140 newspaper titles.6 All of these newspapers had news content and themes that represented various groups. Print media was the most influential in promoting the concept of nationalism.2 The increasing political activity in the national movement among indigenous peoples in North Sumatra from 1916 had a direct impact on newspaper publishing in this area. From 1916 to 1925, 13 newspapers were published to spread the spirit of nationalism and demand Indonesian independence from Dutch colonialism. This study aims to reveal how the forms of Indonesia's struggle for independence were presented in these 13 newspapers.\n\n\nMethods\n\nThis research is qualitative and uses the critical discourse analysis method. Critical discourse analysis aims to study and analyze the way abuse of social power, dominance, and inequality are enacted, reproduced, and resisted by written and spoken communication in social, political, and historical contexts.7 Critical discourse analysis also aims to find the relationship between causality and determination contained in practices, events, and texts. Power and hegemony are the causative factors of the unclear relationship between these practices, events, and texts.8 Texts play an important role in making history, where texts are evidence of how the historical process takes place. The redefinition of social relations between the professional and the public, the reconstruction of social identities and forms of self, or the reconstruction of knowledge and ideology are evidence of processes that can be observed from texts.8 The texts that are focused on in this research are articles in indigenous newspapers published in North Sumatra in 1916-1925.\n\nThe discourse analysis method is appropriate to examine textual data. Teun A. van Dijk divides critical discourse analysis into three structures: macrostructure, superstructure, and microstructure. The macrostructure emphasizes the global meaning of a text that can be observed from the topic or theme appointed by a text. Superstructure focuses on the complete framework of a text which consists of an introduction, content, finale, and conclusion which are systematically arranged. The microstructure is divided into semantics (the meaning of words and sentences that are emphasized in the text), syntax (the form and arrangement of sentences conveyed), stylistics (the choice of words used), and rhetoric (how expressions or language styles are used).7\n\nThe data used in this study were texts from 13 indigenous newspapers published in North Sumatra in 1916-1925. All newspaper texts used as data in this research are collections from the National Library of the Republic of Indonesia, the North Sumatra Press Museum, the Medan History House, and the Center for the Study of History and Social Sciences, Universitas Negeri Medan. The texts contained in these newspapers will be analyzed using the three analytical structures of Van Dijk's model described above to find out how the forms of Indonesian independence were portrayed in thirteen newspapers published in North Sumatra in 1916-1925.\n\n\nResults\n\nEuropean influence became the main factor that pushed the press publishing business in North Sumatra forward in the early twentieth century. In 1902 the Dutch began to publish a newspaper for the indigenous people of East Sumatra which was named Pertja Timor. In addition to using the Malay language in each edition, the Pertja Timor newspaper also provided an opportunity for the indigenous people of North Sumatra to be involved in this newspaper by appointing Mangaradja Salembuwe from Angkola (South Tapanuli) as editor-in-chief. The opportunity to be actively involved in the publishing business for the indigenous people finally prompted the publication of the Pewarta Deli newspaper in Medan in 1910. Pewarta Deli was the first indigenous newspaper published in North Sumatra, because this newspaper was fully managed by the Indonesians themselves, starting from the shareholders, editors, directors, clerks, and printing presses, all of which belonged to the indigenous people without European intervention. That's why Perwata Deli was given the title as the first national newspaper in North Sumatra.6\n\nThe emergence of Pewarta Deli in the press in North Sumatra eventually prompted the publication of various other indigenous newspapers. Indigenous people have been the most active and most widely published in newspaper publishing in North Sumatra since the publication of Pewarta Deli in 1910. Indigenous newspaper publishing in North Sumatra is spread across various regions, from the east coast of Sumatra to the west coast of Sumatra. In Table 1 it can be seen that Medan, which became the capital of the East Sumatra Residency, became an area with as many as twelve names of newspapers. Sibolga, the capital of the Tapanuli Residency, which is located on the west coast of Sumatra, is the second area that publishes the most indigenous newspapers with a total of five newspapers. Seven other indigenous newspapers, published in different areas: Sinar Merdeka published in Padang Sidempuan, Soara Batak published in Tarutung, Bataksche Studiefonds published in Kota Nopan, Seroean Kita published in Perbaungan, Almoektabas published in Tanjung Balai, Nias Berita published in Gunung Sitoli, Soeara Kita is published in Pematang Siantar.\n\nThe year of publication of the 24 indigenous newspapers in North Sumatra in Table 1 also varies. Pewarta Deli became the first indigenous newspaper published in North Sumatra. In 1916, two new indigenous newspapers emerged, namely Benih Merdeka and Soeara Djawa. In 1918 the Soeara Bondjol newspaper appeared. In 1919 five newspapers appeared: Tapian Na Oeli, Sinar Merdeka, Soara Batak, Sama Rata, Perempoean Bergerak. In 1920 the Hindia Sepakat newspaper was published. In 1921 the Sinar Zaman newspaper was published. In 1922 three newspapers were published: Bataksche Studiefonds, Pantjaran Berita, Seroean Kita. In 1923 Warta Timoer was published. In 1924 the newspapers Benih Timoer, Boemipoetera, Almoektabas, Pertjatoeran, Nias Berita were published. In 1925 four newspapers were published: Soeara Kita, Soeara Tapanoeli, Oetoesan Sumatra, Poesaka.\n\nThe focus of this research is to find newspapers that feature news about the struggle for Indonesian independence. The first step of data analysis is to read one by one the articles from 24 indigenous newspapers in North Sumatra in Table 1. This first stage uses macrostructural analysis to find topics or themes contained in a text.7 The topic of Indonesia as the colonized and the Dutch as the colonizing became the main guide. The results of the analysis of Table 1 found 13 newspapers that featured news about Indonesia as a Dutch colony. These thirteen newspapers are Soeara Djawa, Pewarta Deli, Benih Merdeka, Perempoean Bergerak, Soeara Bondjol, Sinar Zaman, Orgaan Bataksche Studiefonds, Andalas, Mandailing, Warta Timur, Al Moektabas, Tjermin Karo, Soeara Batak. In the thirteen newspapers found as many as 162 articles consisting of various titles and publishing times which can be observed in Table 2. However, the 162 articles have the same theme, namely about Indonesia as a Dutch colony. In terms of the time of publication, Table 2 provides information that the article with the earliest published year was June 1, 1916 (Soeara Djawa) and the article with the latest date was December 24, 1925 (Soeara Batak).\n\nIn Table 2, Soeara Batak became the newspaper with the most articles, which amounted to 41 articles published from February 21, 1920, to December 24, 1925. Perempoean Bergerak became the second-largest newspaper with 22 articles published from May 15, 19191, to December 15, 1920. Soeara Djawa, Benih Merdeka, Warta Timur took the third position where the articles found in these three newspapers each had 16 article titles. For the time of publication, these three newspapers are different. The article on Soeara Djawa is dated June 1, 1916, to July 1, 1918. Benih Merdeka from July 2, 1918, to April 8, 1920. Articles in Warta Timur had the shortest period time of one month, from 8 October 1923 to 29 November 1923. The Mandailing newspaper had 15 articles published from March 3, 1923, to December 13, 1923. Tjermin Karo had eight articles published from December 28, 1924, to January 13, 1925. Pewarta Deli and Al Moektabas reporters each found seven articles. Pewarta Deli was published from July 2, 1917, to August 1, 1917. The seven articles in the Al Moektabas were published on the same day, January 31, 1924. Andalas newspaper has six article titles with publication dates from November 1, 1923, to November 6, 1923. Soeara Bondjol has four articles published from June 1, 1920, to August 1, 1922. Orgaan Bataksche Studiefonds had three articles published from February 1, 1921, to March 31, 1922. The last one is that Sinar Zaman has only 1 article dated October 8, 1921. Complete information regarding the publication date of each article can be seen in Table 3.\n\nThe next stage is to analyze the 162 articles in Table 2 using macrostructure, superstructure, and microstructure analysis7 in stages to find which articles contain news about the struggle for Indonesian independence. The results of the analysis found that there were only 51 articles featuring news about the Indonesian independence struggle which can be observed in Table 3.\n\nIn Table 3 Soeara Batak became the newspaper with the most article titles, namely 12 articles: three articles published in 1920, three articles in 1921, one article published in 1922, two articles published in 1923, and three articles published in 1925. The Mandailing newspaper had 10 articles published in the same year with details: one article published on January 13, 1923, two articles published on January 27, 1923, two articles published on February 3, 1923, three articles published on February 17, 1923, one article published on February 24, 1923, and one article appeared on March 3, 1923. Benih Merdeka has six article titles: four articles published in 1918 and two articles published in 1920 on the same publication date. The Perempoean Bergerak newspaper has four articles with details: two articles published in 1919 and two articles published in 1920. In Soeara Djawa there are three titles of articles published in different editions, namely one article in 1916 and two articles in 1918. Pewarta Deli also has three articles published in the same year, namely 1917. Two articles published by Pewarta Deli were published on the same publication date, namely 27 July 1917. Warta Timur also has three articles published in 1923, one in October and two in November. Al Moektabas also has three titles of articles published in the same edition on January 31, 1924. The Tjermin Karo newspaper had two articles published in 1924 and one article published in 1925. Soeara Bondjol, Sinar Zaman, Orgaan Bataksche Studiefonds, and Andalas each had only 1 article title published in 1920, 1921, and 1923.\n\nThe macrostructure is the first stage of analysis carried out to get the results from Table 3. Macrostructure only analyzes the surface or general things of a text. The topic or theme of the text is used as an indicator in this data analysis process. The struggle for Indonesian independence is the topic used. This analysis produces data from articles and newspapers that display news about Indonesian independence in ‘the macrostructural analysis results from indigenous newspapers in North Sumatra (1916-1925)’ (see underlying data: 10.6084/m9.figshare.17894687).\n\nThe macrostructural analysis results in ‘the macrostructural analysis results from indigenous newspapers in North Sumatra (1916-1925)’ (see underlying data: 10.6084/m9.figshare.17894687) show that the titles of the articles in the indigenous newspapers in North Sumatra published in 1916-1925 did not openly write about the demands for Indonesian independence. However, when the topic of the text is found, the statement regarding the demands or struggle for Indonesian independence is very clear. This can be observed in the Soeara Djawa newspaper with the article title “The Pen Turns to the Honorable Brother” which turns out to have a topic to support the era of movement. “The era of movement” refers to the period of the struggle for independence that took place from 1900-1942. In the article “Memory Fate!” in the Benih Merdeka newspaper, the topic was Indonesia can be independent. Al Moektabas has an article entitled “Aspirations and Feelings” with the topic tax rules in the city of Tanjung Balai are a form of protest against the high taxes that people have to pay to the Dutch colonial government. If examined one by one from the titles and topics written in Table 4, there are hidden or implicit messages that the author wants to convey regarding the struggle for Indonesian independence.\n\nThe next stage is to conduct a superstructure analysis (second stage analysis) using the data in ‘the macrostructural analysis results from indigenous newspapers in North Sumatra (1916-1925)’ (see underlying data: 10.6084/m9.figshare.17894687). Superstructure analysis analyzes the text framework which consists of the introduction, content, and closing. The three parts of the superstructure contain core information or specific data that a text9 wants to convey in the form of \"premises\" and “conclusions”.10 Therefore, at this stage a more in-depth analysis is carried out on what messages or information are in the introduction, content, and closing sections of the 51 articles in Table 3. The discourse on the struggle for Indonesian independence becomes the focus of this superstructure analysis.\n\nThe results of the analysis succeeded in finding out which part of each article contained a key statement, namely the struggle for Indonesian independence. ‘The superstructure analysis results from indigenous newspapers in North Sumatra (1916-1925)’ (see underlying data: 10.6084/m9.figshare.17894687) that the most frequently found key statements are at the beginning of the text, which amounts to 30 citations. Next is at the end of the text with 16 citations. The number of key statements found at least in the middle of the text is 10 citations.\n\nIn Benih Merdeka with the article title “Memory Fate”, key statements are found at the beginning, middle, and end of the text. The article entitled “Land for the People” published in the newspaper Benih Merdeka has key statements only at the beginning and end of the text. The article entitled “Aspirations and Feelings” has key statements at the beginning and middle of the text. In the article entitled “Hope” the key statements are found at the beginning and end of the text. ‘The superstructure analysis results from indigenous newspapers in North Sumatra (1916-1925)’ (see underlying data: 10.6084/m9.figshare.17894687) also shows that the article “We are responsible! We demand!” found two key statements at the end of the text. Meanwhile in the article entitled “The Matter of Land and the IR Nation (Ireland and Irishmen)” two key statements were found at the beginning of the text. Other articles contain only one key statement at one point in the text.\n\nAfter the superstructure stage has succeeded in finding the location where the key statement is in a text, the third step is to conduct a microstructural analysis to identify whether the text discusses the struggle for Indonesian independence. The results of the microstructural analysis are the use of words, phrases, or sentences from each article. These words, phrases, or sentences are the essences of the discourse the writer wants to convey to the readers. Readers must understand every word, phrase, and sentence that is often conveyed implicitly by the author in every article written. As a result, the title of the article and the results of the analysis of the microstructure in the column “Use of words/phrases” do not seem to have anything in common with each other.\n\nThe results of the microstructural data analysis in ‘The microstructural analysis results from indigenous newspapers in North Sumatra (1916-1925)’ (see underlying data: 10.6084/m9.figshare.17894687) show that there are articles that contain unequal amounts of key statements in the form of words, phrases, sentences, or a combination of the three. Most of the key statements were found in the Perempoean Bergerak newspaper with the article title “Marriage to another Nation” with six quotes. The articles entitled “Soekidjo” and “Land for the People” both contain four quotes.\n\nThirteen article titles in ‘The microstructural analysis results from indigenous newspapers in North Sumatra (1916-1925)’ (see underlying data: 10.6084/m9.figshare.17894687) each have three citations: The Grand Meeting of Syarikat Islam in Medan Deli, Newspaper, Reckless, Our Feelings, Brain, Blood, and Unity of the Heart, The position of Mr. Dr. Abdul Rasjid (To demand the progress of the country's children in the Tapanuli Residency to follow the right path), Forced Labor Money and the Situation of the Village, The World Movement of the Mandailing Nation, The Call (especially for my Batak Karo brothers), Economic movements in Tapanuli, Distant sound, The Matter of Land and the IR Nation (Ireland and Irishmen), dan The Great Meeting. Meanwhile, the article which has two citations include: The Pen Turns to the Honorable Brother, Indies Nederland, We are responsible! We demand! Memory Fate! Deliberation, Mandjono is too brave, The aspired progress, British Indies, Intelligence and independence, Independence in Movement, Aceh blood, Yours faithfully, The emergence of a dark case in the political workgroup in Betawi, It's getting harder! Homeland and nation, The Principles of Nation's Progress, Hope, Love the Nation, Four questions and one suggestion, Achieving Independence, The Ideals of Independence, Flying from Europe to America.\n\nArticles containing only one citation in ‘The microstructural analysis results from indigenous newspapers in North Sumatra (1916-1925)’ (see underlying data: 10.6084/m9.figshare.17894687) are entitled: the movement, the welfare of the North Sumatra people can be lost, general court, the cry of the little one, love the homeland, pan Islamism, when will the world be safe? Help! Help! Help! Aspirations and feelings, a brief statement from Langkat Hulu, is it true that Indonesia will soon be given independence by the Dutch, desire to be noticed by the government, and what causes our association to become weak?\n\nThe microstructural analysis also succeeded in categorizing 51 articles in Table 3 into three groups, namely 1) demanding Indonesian independence openly, 2) criticizing various policies of the Dutch Colonial Government to the indigenous people of North Sumatra, 3) building awareness of nationalism through the dissemination of the spirit of nationalism, unity, and the Indonesian independence movement.\n\n1. Demanding Indonesian independence openly.\n\nThere are twelve articles in four newspapers openly wrote about the demands for Indonesian independence. Details of the 12 newspapers whose contents openly demand Indonesian independence can be seen in Table 4.\n\nIn Table 4 it can be observed that the Mandailing newspaper has the most articles demanding Indonesian independence, namely as many as five articles with the title “British Indies”, “Intelligence and independence”, “Independence in Movement”, “Pan Islamism”, dan “When will the world be safe?”. The next most articles were found in Soeara Batak as many as four articles with the title “Achieving Independence”, “The Great Meeting”, “Is it true that Indonesia will soon be given independence by the Dutch?” dan “The Ideals of Independence”. Benih Merdeka has two articles with the title “Memory Fate!” dan “We are responsible! We demand!” In the Soeara Djawa newspaper, only one article was found entitled “The Movement”.\n\nFor the year of publication, Table 4 can be seen that 1923 was the most widely published article demanding Indonesian independence, of which there are as many as seven articles. 1923 was also the last year to publish an article on this theme. The earliest year is 1918 with two article titles. The years 1920, 1921, 1922 each had one article.\n\nThe results of the twelve newspapers which are included in the category of demanding Indonesian independence openly are based on the results of the microstructural analysis in the form of the use of words, phrases, and sentences in the text. For more details regarding the results of the microstructural analysis of the twelve articles in Table 4, it can be seen in Table 5 below.\n\n\n\n- The Indies nation (Indonesian) can be independent\n\n- The land of the Indies wants to be independent\n\n\n\n- The desire for national independence\n\n- Not subject to any power\n\nIn Table 5 the demands for Indonesian independence in the newspaper Benih Merdeka through an article with the title “Memory Fate!” is seen in the use of the sentences “The Indies nation (Indonesian) can be independent” and “The land of the Indies wants to be independent”. Next up in the article entitled “We are responsible! We demand!”, the author wrote the sentence “An alliance that wants to establish an indigenous (Indonesian) government”. The article entitled “The Movement” demands Indonesian independence through the sentence “To advance the economy and independence of the Indies”. The article entitled “British Indies” wrote, “Demanding the independence of the nation and establishing the Republic of Indonesia”. If we examine one by one Table 8 in the quotation of the text column, it is seen that the choice of words, phrases, or sentences used openly and firmly in the article demands Indonesia's independence from Dutch colonialism.\n\n2. Criticizing various policies of the Dutch Colonial Government to the indigenous people of North Sumatra.\n\nWritings containing criticism and protests against the Dutch colonial government became the next category found from the microstructural analysis of 51 articles in Table 3. The results of the analysis found 19 article titles whose contents were about criticism and protest against all the policies of the Dutch colonial government which were considered to be oppressing the indigenous people. In addition, there are suggestions and requests for the colonial government to do things that can advance the indigenous people. Details of the 19 titles of articles that criticize the Dutch colonial government can be seen in Table 6 below.\n\nIn Table 6 above, there are nine indigenous newspapers in North Sumatra which contain articles criticizing the Dutch colonial government. The newspapers of Benih Merdeka and Perempoean Bergerak became the newspapers with the highest number of articles, each with four articles. The next most articles with three article titles are Warta Timur and Soeara Batak. The newspapers of Soeara Djawa, Pewarta Deli, Mandailing, Al Moektabas, Tjermin Karo only had one article title.\n\nThe year of publication of the article with the theme of criticism of the Dutch colonial government in Table 6 began in 1917 with an article entitled “Indies Nederland”. In 1918 there were three article titles. In 1919 two article titles. In 1920 there were as many as four article titles. In 1921 there were two article titles. In 1923 there were four article titles. In 1924 there was one article title. In 1925 there were as many as two article titles. The results of the microstructural analysis of the 19 articles in Table 6 can be observed in Table 7.\n\n\n\n- It's time to estimate the tax rate for 1925\n\n- The rulers (Dutch colonial government)! Have mercy on your people who are in trouble\n\nTable 7 shows that the criticism of the Dutch colonial government in the Soeara Djawa newspaper with the article title “The Grand Meeting of Syarikat Islam in Medan Deli” can be seen in the use of the sentence “People cannot speak in court and are immediately punished”. In the Pewarta Deli newspaper entitled “Indies Nederland” the sentence “Arbitrary acts of Dutch officials” was written. In Warta Timur newspaper entitled “Help! Help! Help!” the author submits a request to the Dutch colonial government through the sentence “Government! Look and pay attention to your people who ask for help”. The contents of the news regarding suggestions and requests to the Dutch colonial government are also contained in the article entitled “The Cry of the Little One” which writes “The Dutch colonial government should have raised the salaries of indigenous employees appropriately”.\n\n3. Building awareness of nationalism through the dissemination of the spirit of nationalism, unity, and the Indonesian independence movement.\n\nBuilding awareness of nationalism through the dissemination of the spirit of nationalism, unity, and the Indonesian independence movement is the last category of indigenous newspapers that fight for Indonesian independence. The results of the microstructural analysis managed to find twenty articles published in ten newspapers. The ten newspapers and twenty article titles can be seen in Table 8.\n\nBased on Table 8 above, Soeara Batak is the newspaper that has the highest number of articles, namely five article titles: “Economic movements in Tapanuli”, “Distant sound”, “What causes our association to become weak?”, “Flying from Europe to America, Love the Nation”. Mandailing is the newspaper that has the second most articles with the title: “The aspired progress”, “The World Movement of the Mandailing Nation”, “Aceh blood”, “Yours faithfully”. The Pewarta Deli newspaper has two articles with the titles: “The welfare of the North Sumatra people can be lost” dan “Newspaper”. Al Moektabas also has two titles, namely: “Homeland and nation” dan “The Principles of Nation's Progress”. Tjermin Karo also has two titles: “The Call (especially for my Batak Karo brothers)” and “A brief statement from Langkat Hulu”. The Soeara Djawa newspaper entitled “The Pen Turns to the Honorable Brother”. The Soeara Bondjol newspaper entitled “Love the homeland”. The Sinar Zaman newspaper is entitled “Brain, Blood, and Unity of the Heart”. The Orgaan Bataksche Studiefonds newspaper entitled “The position of Mr. Dr. Abdul Rasjid (To demand the progress of the country's children in the Tapanuli Residency to follow the right path)”. The Andalas newspaper entitled “Mandjono is too brave”.\n\nTable 8, 1923, and 1920 were the years with the most articles, namely five articles each. Meanwhile, 1924 had four article titles. The years 1917, 1921, and 1925 each had two article titles. The year 1916 was the earliest and at least one article title. The results of the microstructural analysis of the twenty article titles in Table 11 can be observed in Table 9.\n\n\n\n- Believe and be sincere to their country\n\n- Gone all worries and doubts to his country\n\nIn Table 9 it can be observed that efforts to build awareness of the nationalism of the people of North Sumatra can be seen from the article entitled “The welfare of the North Sumatran people can be lost”. In this article, the author uses the phrase “Don't follow Dutch customs”. The article entitled “Aceh blood” also aims to build a sense of nationalism for readers through the sentence “The hatred of the Acehnese towards the Dutch”. The message regarding national unity can be seen in the article “The Principles of the Nation's Progress” through the sentence “The progress of the nation is the progress made together”. The article entitled “The Call (especially for my Batak Karo brothers)” is also about national unity who written: “Let's unite for common progress”. In the article entitled “Distant sound it is written: Uniting thoughts for the progress of the nation”. The article entitled “The Pen Turns to the Honorable Brother” wrote the sentence “Together we support this new movement” to support the Indonesian independence movement. The article entitled “Brain, Blood”, and “Unity of the Heart” is also related to the Indonesian independence movement through the sentence “Stronger to face the obstacles to the efforts of the independence movement.”\n\n\nDiscussion\n\nThis study aims to describe how the forms that the Indonesian struggled for independence took in 13 indigenous newspapers published in North Sumatra between 1916-1925. Based on the results of the study, of the 162 titles of articles (texts) that were collected during the research, 51 titles of articles were produced whose news content was fighting for Indonesian independence. The 51 article titles were categorized into three groups: 1) demanding Indonesian independence openly, 2) criticizing various policies of the Dutch Colonial Government, 3) building awareness of Indonesian nationalism.\n\nTwelve articles write openly on the topic of Indonesian independence to demand change. This number is the least compared to the other two categories in the struggle for Indonesian independence. Microstructural analysis based on the meaning of words and sentences emphasized in the text, the form and structure of the sentences presented, the choice of words used, and the expression or style of language explicitly shows the demand for Indonesian independence in twelve articles with this theme. On June 1, 1918, Soeara Djawa newspaper reported on the establishment of an organization called “Werklub” which aims to promote the economy and independence of Indonesia. Meanwhile, Mandailing newspaper dated January 27, 1923, in the articles “Intelligence and independence”, wrote that many Indonesians wanted Indonesian independence. Soara Batak dated April 7, 1923, in the article “The Ideals of Independence” appealed to all the people of the Indies to unite forces to achieve independence from Dutch colonialism.\n\nNineteen articles were found that criticize the colonial government's policies towards indigenous people in North Sumatra in 1916-1925. Tax rules for the people of North Sumatra became the most discussed topic, namely Warta Timur on 18 October 1923 and 29 November 1923, Mandailing on 17 February 1923, Al Moektabas on 31 January 1924, Tjermin Karo on 13 January 1925, and Soeara Batak on 20 August 1921. Other articles include the poverty of the people of North Sumatra, the negative impact of plantation capitalization on the people of North Sumatra, as well as the arrest of leaders of North Sumatra who are considered to be against the Dutch colonial government.\n\nTwenty articles spread the spirit of nationalism for the people of North Sumatra. The call for “Unity” for the people of North Sumatra to fight against the Dutch colonial government became the most widely raised topic to spread the spirit of nationalism. Sinar Zaman on 8 October 1921, Orgaan Bataksche Studiefonds on 1 February 1921, Mandailing on 27 January 1923, 17 February 1923, and 3 March 1923, Soeara Bondjol on 20 June 1923, Al Moektabas on 31 January 1924, Tjermin Karo on 13 November 1924 and December 23, 1924, and Soeara Batak dated March 6, 1920, were articles that wrote about “Unity” in their coverage. Other writings about nationalism are love for the homeland and encouragement to the people of North Sumatra to support the national progressive movement that was taking place in Indonesia at that time.\n\nIn the history of Indonesian independence, the second and third decades (1910-1930) were known as the period of the radical political movement of the Indonesian people. This period was marked by the emergence of organizations and newspapers that openly declared independence from Dutch colonial rule. The opening of opportunities in access to modern education in the early 1900s created a group of educated people who were able to read and write. This intellectual group founded political organizations and published indigenous newspapers in Indonesia. Until 1913, Indonesian intellectuals who became publishers and editors of newspapers had realized the importance of “national unity” as the central message of their publications.11 In North Sumatra, militancy in newspapers in the struggle for Indonesian independence was started by the newspaper Benih Merdeka, which was first published on November 20, 1916.\n\nFor the Dutch Colonial Government, the courage of the indigenous newspapers in demanding Indonesian independence was considered a threat to the stability of their power over their colonies. Therefore, the Dutch Colonial Government established rules for publishing newspapers published in the Strafwetboek (Book of Criminal Law). Article 66a of Strafwetboek states that anyone who spreads hostility, hatred, or insults to the Dutch government or the Dutch East Indies, either through writing, pictures, or actions will be punished with imprisonment for 5-10 years. Meanwhile, article 66b of Strafwetboek states that anyone who spreads hostility, hatred, or insults among the inhabitants of the Dutch East Indies, either through writing, pictures, or actions will be sentenced to imprisonment for six days to five years.5\n\nThe rules for publishing the printed press on Strafwetboek did not make the indigenous press figures of North Sumatra afraid to use newspapers as a tool for their struggle. This courage was evidenced by the publication of an article on the theme of nationalism in the newspaper Soara Djawa on June 1, 1916 (see Table 6). In this article, the author asks all Indonesians to support the ongoing movement. The movement referred to in this newspaper is progress which is defined as an effort to improve the lives of the Indonesian people in the economic, social, cultural, and political fields so that they are no longer inferior. This progress made the Indonesian people able to liberate themselves from Dutch colonialism. This spirit of progress has prompted many articles on the theme of the spirit of nationalism, unity, and the Indonesian independence movement to be found in this research.\n\nThe establishment of various political organizations that carried the spirit of the independence movement contributed to the increasing role of newspapers as a tool for the struggle for independence in North Sumatra. The role of newspapers as voice carriers for political organizations makes this mass media very important in disseminating the ideology of indigenous political organizations to the wider community. Newspapers based on political organizations in North Sumatra are Benih Merdeka (published by Sarekat Islam (SI) Medan branch), Soara Batak (published by Hatopan Kriten Batak (HKB) in Tarutung),12 Soeara Djawa (published by Budi Utomo (BU) Pangkalan Berandan branch).5\n\nThe above description shows that the print media is the most important element in shaping the concept of nationalism of a nation. Print media is also the fastest way to spread the idea of nationalism to all its members.2 Therefore, print media is often used as a means to shape and spread the notion of nationalism in colonized countries and also as a tool for the struggle for independence. The role of newspaper publishing in the struggle for independence in North Sumatra from 1916 to 1925 can be seen in the three forms of the struggle for Indonesian independence that appear in the thirteen newspapers that have been described. The people of North Sumatra use newspapers as a tool for the struggle for Indonesian independence to the fullest through 51 articles found in this study.\n\n\nConclusion\n\nNorth Sumatra became a publishing center for indigenous newspapers during the Dutch colonial period. In 1900-1942 there were hundreds of newspapers published in this area. The most important thing about publishing this newspaper is the role of newspapers as a tool for the struggle for independence against Dutch colonialism. The results of research from thirteen indigenous newspapers published from 1916-1925 found that 51 articles contained writings about the struggle for Indonesian independence. Based on the analysis of Teun A. van Dijk's critical discourse which consists of macrostructure, superstructure, and microstructure used in the texts of the thirteen newspapers, 51 articles fight for Indonesian independence. These 51 articles can be categorized into three groups: 1) demanding Indonesian independence openly, 2) criticizing various policies of the Dutch Colonial Government, 3) building awareness of Indonesian nationalism. People in North Sumatra use newspapers as a tool for the struggle for independence as much as possible. They bravely resisted the colonial government through the writings they published, even though the Dutch colonial government would punish them for their resistance.\n\n\nData availability\n\nThe sources of newspapers in our research exist and can be referred to by other researchers at the Jakarta National Library using their website https://www.perpusnas.go.id/ or contact the email below materjilperpusnas20@gmail.com The librarian on duty will answer the email sent to this email address. In addition, these sources can also be seen (offline access only) at the North Sumatra Press Museum, Sei Alas Road No. 6, Medan. The Medan History House, Kota Cina/Pematang Siombak Road, No. 65, Neighborhood 7, Paya Pasir Village, Medan Marelan District, Medan 20250. The Center for the Study of History and Social Sciences (PUSSIS) Universitas Negeri Medan, Willem Iskandar Road, Pasar V, Medan Estate.\n\nThis project also contains data available under the term of figshare (CC BY 4.0):\n\n• The macrostructural analysis results from indigenous newspapers in North Sumatra (1916-1925). 10.6084/m9.figshare.17894687\n\n• The superstructure analysis results from indigenous newspapers in North Sumatra (1916-1925). 10.6084/m9.figshare.17894687\n\n• The microstructural analysis results from indigenous newspapers in North Sumatra (1916-1925). 10.6084/m9.figshare.17894687\n\nFigshare: Table of indigenous newspapers published in North Sumatra in 1916-1925 10.6084/m9.figshare.17894687\n\n\nGrant Information\n\nThis research was funded by DIPA fund of Universitas Negeri Medan for the 2020 Fiscal Year under the UNIMED Rector's Decree No.116/UN33.8/PL-PNBP/2020 dated June 30, 2020.\n\n\nCompeting interests\n\nNo competing interests were disclosed.",
"appendix": "Acknowledgments\n\nThe research team would like to thank the leadership of the Medan History House as the main owner of most of the newspaper collections studied. Also for some documents, literature, and archives, we would like to thank the head of the Center for Historical Studies and Social Sciences, the Head of the Regional Archives and Libraries of North Sumatra Province, and The Chairman of the Regional Daily Council Batch 45. Thanks also to the Center Humanities Studies LPPM Universitas Negeri Medan staff who worked hard to help process archived data and newspaper documents in this research.\n\n\nReferences\n\nUnderstanding Media and Culture: An Introduction to Mass Communication. Minneapolis, MN: University of Minnesota Libraries; 2016.\n\nAnderson B: Imagined Communities: Komunitas-komunitas Terbayang. Yogyakarta: Pustaka Pelajar; 2008.\n\nSmith AD: Nationalism Theory, Ideology, History. Malden: Polity Press; 2010.\n\nKohn H: Nationalism, its Meaning and History. Jakarta: PT. Pembangunan Jakarta; 1961.\n\nAbdullah T and ABL: Indonesia dalam Arus Sejarah: Masa Pergerakan Kemerdekaan. Jakarta: PT. Ichtisar Baru van Hoeve; 2010.\n\nSaid M: Sejarah Pers di Sumatera Utara dengan Masyarakat yang dicerminkannya (1885-Maret-1942). Medan: Waspada; 1976.\n\nVan Dijk TA: The Handbook of Discourse Analysis. Oxford: Blackwell Publisher Ltd; 2001.\n\nFairclough N: Critical discourse analysis: the critical study of language. London: Longman; 1995.\n\nRenkema J, Schubert C: Introduction to Discourse Studies New Edition. Amsterdam/Philadelphia: John Benjamins Publishing Company; 2018.\n\nvan Dijk TA : Macrostructures: An Interdisciplinary Study of Global Structures in Discourse, Interaction, and Cognition. New Jersey: Lawrence Erlbaum Associates, Publishers; 1980.\n\nAdam AB: The Vernacular Press and the Emergence of Modern Indonesian Consciousness (1855-1913). Ithaca: Cornell Univerity; 1995.\n\nCastles L: The Political Life of A Sumatran Residency: Tapanuli 1915-1940. Jakarta: KPG (Kepustakaan Populer Gramedia); 2001."
}
|
[
{
"id": "143696",
"date": "03 Aug 2022",
"name": "Sisanda Nkoala",
"expertise": [
"Reviewer Expertise media studies",
"discourse analysis",
"rhetorica studies",
"multlingualism"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article states that it uses the critical discourse analysis method to analyse Indonesia's struggle for independence in newspapers published in North Sumatra in 1916-1925. The author writes very clearly, and the argument advanced is articulated well. The newspapers sampled provide depth and allow the reader to get a good overview of the content covered in the publications over the 9 year period considered. The paper’s strength is definitely the clarity with which the writer articulates themselves and the logical flow of the paper.\nA major weakness is the claim that critical discourse analysis has been used as a method in this paper. From the tables given in the results and the discussion engaged in the discussion section, the approach seems to be content analysis that draws on van Dijk’s notion of structures as aspects of analysis. The paper does not engage in a discourse analysis currently because it does not really focus on the use of words to articulate issues of power as they relate to the central idea of nationalism that is being considered. In choosing to focus on quantifying what appears and how this relates to nationalism the paper employs content analysis. Thus, in this respect, I would propose the author either changes the statement “uses critical discourse analysis” as a method and rather highlights that they have done a content analysis. Alternatively, they can consider rewriting substantial aspects of the paper and actually engaging in a discourse analysis.\nAnother area that the paper could improve on is the repetitive paragraphs that are aimed at explaining what is in the table. One can assume that the tables have been presented to give a consolidated view of the contents of the papers, which they indeed do. When the author then goes ahead and writes another paragraph for each table, essentially repeating what is presented there, the paper appears repetitive at these points. The paragraphs should be used to draw the reader’s attention to specifically significant aspects of the table, which will then be ventilated further in the discussion.\nThe other area of recommendation is to strengthen the discussion section. If indeed the paper is about the discourse in these papers, then the author needs to make an argument in the discussion that ventilates issues of power, as expressed in the language used in these publications, and not simply sum up what has been presented in the results. The discussion section should also bring in the voices of other scholars who have written on discourse and language in newspaper, or issues of nationalism and newspapers to demonstrate how the findings of the paper speak to existing scholarship in this respect. If, as appears to be the case currently, the paper is a content analysis paper, the author must still engage with scholarship on newspaper content and nationalism, even if it is in reference to studies from other contexts.\nI have included other comments in the paper:\n“The methods section could benefit from a discussion of CDA specifically in relation to mass media. Van Dijk has written on this, so the author could easily bring in his perspectives on the centrality of discourse on newspapers as texts and tie it into how they will speak to the manner in which notions of nationalism are articulated in these publications”.\n“While I appreciate the histographical information provided here, I do not think it adds in terms of address the issue of discourse and nationalism. If the author wishes to draw our attention to the development of indigenous newspapers in Indonisia, then the table below suffices and a summary of the most salient aspects of this, as they relate to the paper’s central argument, can be highlighted in a paragraph or at most two. The history can be mentioned only as it relates to the issue of nationalism”.\n“As with description on the contents of Table 1, I would advise the author not to spend too much writing what is in the table above, unless it is to elaborate on a specific aspect eg highlighting which one had the most, which one had the least etc.”.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "145900",
"date": "12 Sep 2022",
"name": "Jane Nkechi Ifechelobi",
"expertise": [
"Reviewer Expertise Semantics",
"Pragmatics",
"and Discourse Analysis"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article claimed to have used CDA as the method applied in this research but areas such as power, dominance and nationalism were not reflected on. The authors should look at the first paragraph of the methods and approach the work appropriately.\nThe authors conducted a content analysis. I suggest the article title is changed to reflect this, e.g. \"An analysis of…\".\nThe work should also bring in what other related but relevant researchers have discovered to help in having a scientific analysis of the work. The tables did not help much in the analysis, it made the discussion very repetitive.\nThe article should be indexed when these are taken care of.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "145899",
"date": "15 Sep 2022",
"name": "Hafizah Hajimia",
"expertise": [
"Reviewer Expertise Applied Linguistics",
"TESL",
"Education",
"Corpus Linguistics",
"Discourse analysis",
"Genre analysis",
"English for Specific Purposes"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper was well written. However, I have a few comments.\nComments:\nVerification of the result is essential to show the trustworthiness of the findings. How were the findings analysed? How was the data verified?\n\nLack of elaboration in the methodology section. More elaboration was given on the CDA.\n\nMost references have exceeded 5 years.\n\nSuggestions:\nNeed to add more elaboration in the methodology section especially the data analysis method, reliability of the findings, and tools used to analyse the data.\n\nElaborate on how did you obtain the numbers in the tables of your results. What tools and methods did you use to derive the numbers?\n\nElaborate more on how you conducted the superstructure analysis, microstructural analysis, and the other stages, steps, tools, and procedures.\n\nTo reduce bias, validity and reliability of the findings need to be included.\n\nWould be good if some current references are included.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "149741",
"date": "21 Sep 2022",
"name": "Kwabena Sarfo Sarfo-Kantankah",
"expertise": [
"Reviewer Expertise (Critical) Discourse Analysis",
"Pragmatics",
"Corpus Linguistics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary Using newspaper articles as data and a critical discourse analytical approach, the paper attempts to demonstrate the role newspapers played in Indonesia's struggle for independence from 1916 to 1925. The paper shows that out of the 24 newspapers that were published in North Sumatra, the centre of newspaper publications in Indonesia, 13 published articles that concerned the quest for independence by Indonesia, including, 1) demanding Indonesian independence openly; 2) criticizing various policies of the Dutch Colonial Government; 3) building awareness of Indonesian nationalism.\n\nIs the work clearly and accurately presented and does it cite the current literature?\nThe paper is written in clear, simple, and straightforward language. It makes easy reading. However, it hardly cites current literature. The authors' engagement with literature, especially in the analysis and discussion, is very low. This makes it difficult to situate the analysis and discussion in the context of current literature so as to measure the extent of the paper's contribution to scholarship.\n\nIs the study design appropriate and is the work technically sound?\n\nThe authors state that the paper uses a qualitative research design, which is appropriate. However, they fail to state the specific qualitative design employed, even though it is clear that the paper does a content analysis. The authors should therefore consider content analysis as the design used and describe how they deployed it. The work is technically sound, except for the issue I have raised.\nAre sufficient details of methods and analysis provided to allow replication by others?\n\nThe methods section is not detailed enough to allow for replication. The authors indicate that they employ the critical discourse analysis (CDA) method, however, they do not clearly indicate how CDA informs the work. Their discussion of CDA is too general; CDA should be clearly defined and the authors should be specific about how they deploy methods of CDA.\nThe authors fail to systematically delineate how the data were gathered, processed, and analysed. For example, how did they assemble the data? Did they manually read the newspaper articles to identify specific instances of words, phrases, clauses, sentences, and other structures of interest? A statement such as \"The first step of data analysis is to read one by one the articles from 24 indigenous newspapers in North Sumatra in Table 1. This first stage uses macrostructural analysis to find topics or themes contained in a text\" should appear under methods, where the authors systematically describe the methods of data analysis.\n\nThe analysis and discussion appear too superficial: the authors do not analyse specific text samples (sentences, clauses, etc.) to tease out \"hidden\" meanings or macro issues (e.g. power, struggle) as it is usually done by CDAs. The paper appears to concentrate too much on counting instances of titles and expressions/sentences/words rather than discussing and arguing about the discourse in the newspapers, thus, making the claim that the paper does a CDA quite weak. In other words, there is little or no textual analysis. For example, under the Discussion, the authors state: \"Microstructural analysis based on the meaning of words and sentences emphasized in the text, the form and structure of the sentences presented, the choice of words used, and the expression or style of language explicitly shows the demand for Indonesian independence in twelve articles with this theme\". However, I do not see any analysis of the form and structure of sentences – the authors just list sentences/phrases, without discussing their forms and structures.\n\nAre the conclusions drawn adequately supported by the results?\nWhile their conclusion, as it stands, is drawn partly supported by the results, it is weak as a result of the issues I have raised above.\n\nIn the last paragraph of the Discussion section, the authors state: “The above description shows that the print media is the most important element in shaping the concept of nationalism of a nation.” The statement seems too general; it should be limited to the Indonesian context.\n\nOther issues\nThe authors should do some language editing. There are several language infelicities. Some of them are indicated below.\n\n\"There are twelve articles in four newspapers which openly wrote about the demands for Indonesian independence.\"\n\n\"In the Pewarta Deli newspaper entitled “Indies Nederland” the sentence [phrase, not a sentence] “Arbitrary acts of Dutch officials” was written.\"\n\n\"The people of North Sumatra use [used] newspapers as a tool for the struggle for Indonesian independence to the fullest through 51 articles found in this study.\"\n\n\"The most important thing about publishing this newspaper is the role of newspapers [paper?] as a tool for the struggle for independence against Dutch colonialism.\"\n\n\"People in North Sumatra use [used] newspapers as a tool for the struggle for independence as much as possible.\"\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
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https://f1000research.com/articles/11-249
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https://f1000research.com/articles/11-679/v1
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21 Jun 22
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{
"type": "Study Protocol",
"title": "Effectiveness of Integrated Emotional-Self Enhancement (IESE) program among staff nurses: protocol for a quasi-experimental study",
"authors": [
"Monalisa Saikia",
"Linu Sara George",
"Bhaskaran Unnikrishnan",
"Anice George",
"N Ravishankar",
"Monalisa Saikia",
"Bhaskaran Unnikrishnan",
"Anice George",
"N Ravishankar"
],
"abstract": "Background: Staff nurses face frequent emotional situations in their work environment. The constant contact with suffering patients, and the busy work environment, pose tremendous stress on nurses’ physical and emotional health. The Emotional Intelligence skills of empathy, self-awareness, motivation, self-control, and keeping relationships, can help handle difficult emotions and allow nurses to work in an organized, calm, and professional way. This study aims to implement and assess the effectiveness of a training program developed by the investigator, tailored to the mental and emotional needs of staff nurses who are working in an organization. The study also aims to observe any significant change, correlation, and association in the staff nurses’ level of emotional intelligence, intrinsic motivation, self-compassion, emotional labor, and nurse-in-charges’ and patients’ perception of nursing care after the program.\nMethods: A quasi-experimental (one-group) study design was used in this study. The study will involve 80 staff nurses working in a selected hospital in India. The staff nurses will be selected from the hospital’s general wards using convenience sampling. For the current study, a quasi-experimental design will be used. The investigator will deliver a training program, divided into four sessions of two hours each. Data will be collected from the participants at baseline and 3-months pre-intervention; and post-test data will be collected immediately after the intervention, at 3-month, and 6-month follow-up, to observe any significant change in the study variables before and after the intervention.\nResults: The current study primarily focuses on the vital aspect of developing emotional needs, for promoting a better work-life balance. Research findings from the study will significantly contribute to the evidence based Emotional Intelligence programs for staff nurses, and if proven effective, could be delivered extensively in the hospitals.\nTrial registration: The study is registered in June 2019 under the Central Trial Registry of India (CTRI/2019/08/020592).",
"keywords": [
"emotional intelligence",
"staff nurses",
"nurses",
"nursing",
"emotional labor",
"intrinsic motivation",
"study protocol"
],
"content": "1. Introduction\n\nNurses are faced with frequent emotional situations in their work environment. The constant contact with patients who are suffering, an emphasis on safety and quality of care, and the ever-engaging work environment, pose tremendous stress on the nurses’ health, physically and emotionally. Because of the many situational stresses faced by the nurses at work, their decision-making, concentration, and recall can be hindered, which may lead to an increase in error. The skills of an emotionally intelligent individual helps them to handle difficult emotions, especially in times of crisis, and allows them to act appropriately.\n\nEmotion is a complex feeling that results in physical and psychological changes which influence thoughts and behaviours (Drigas et al., 2018). Emotions motivate our decisions, help store our memories, influence how we respond to a situation through our actions (Keltner & Kring, 1998), and guide our interpersonal relationships (Susskind et al., 2008).\n\nEmotions are very fundamental to nursing practice. When nurses are aware of their own emotions, it allows them to perform optimally without controlling their behaviour. Research findings also show that emotions greatly influence professional relationships and impact healthcare workers’ decisions for their patients (Freshwater et al., 2004).\n\nThe healthcare environment is always emotionally charged, where the nurses are faced with frequent emotional situations (Reeves, 2005). As organizational and consumer demands are changing, nurses’ physical and emotional work is also increasing (Tomar, 2016). The constant contact with patients, the imperative emphasis on safety and quality of care to the patients, and the work environment pose tremendous stress on nurses. Even in these stressful situations, nurses are expected to perform without emotional fluctuations or outbursts and also have the ability to know others’ and own emotions. This ascertains that the nurses who can manage their own emotions and understand others’ points of view can cope with stress much better than those who do not. But, controlling the emotions requires many psychological resources, which ultimately wears down the body and mind, and may lead to burnout (Cheng et al., 2009), that can ultimately result in emotional distress, emotional labour, feelings of failure, demotivation, decreased quality of care, and conflicts with patients and colleagues (Tomar, 2016).\n\nEmotional Intelligence (EI) is the ability to identify, comprehend, and manage emotions in self and others, enhancing communication, solving problems, and managing conflicts (Drigas et al., 2018). Although it is thought that health care providers already possess the skills necessary for being emotionally intelligent, research findings show that this is not always true (Cheng et al., 2009). Srinivasan and Jebaseelan (2014), in their study, have found a low level of EI among nurses and recommended training to enhance EI among staff nurses, which would help them cope effectively with stress.\n\nA Canadian integrative literature search covering 1995-2007 was conducted to ascertain the state of understanding about EI in nursing practice. The study found that many researchers believe that the nursing profession’s very essence requires nurses to be more emotionally intelligent and being aware of emotions is an essential nursing skill. The study concluded that EI skills and competencies could educate nurses about emotions and improve nursing care and human relationships, affecting patient outcomes (Smith et al., 2009). The EI skills of empathy, self-awareness, motivation, self-control and maintaining relationships help handle emotions. Especially in times of crisis, the ability to self-regulate emotions positively allows nurses to work in an orderly, calm, and professional manner (Chun et al., 2016). Evidence shows that EI has a significant correlation between self-compassion and the patients’ perception of nursing care (Codier et al., 2013). Also, EI helps nurses in developing therapeutic relationships (Cadman et al., 2001), influences patients’ care, their families, and the nurses’ overall well-being (Raghubir, 2018).\n\nAn integrative systematic review explored the relationship between healthcare professionals’ EI and their caring behaviour towards patients. Studies published between the year 1995 to 2017 were searched and reviewed from digital databases such as PsycInfo, Medline, CINAHL, SSCI, SCI, and Scopus. A total of 22 studies which explored how healthcare workers’ EI impact patient’s caregiving was selected for review. The review results indicated that nurses’ EI has an impact on their physical and emotional caring behaviours for patients. The study recommended that interventions to enhance EI skills should be developed which may benefit the nurses as well as the patients (Nightingale et al., 2018).\n\nA simple PubMed search on the term “emotional intelligence” AND “nurs*” shows many published studies on EI. Most of the studies are cross-sectional which were done among nurse leaders and nursing students. The investigator found no recent study on EI training among staff nurses being published. Thus, the investigator has proposed the current study keeping in mind the knowledge gaps found after doing an extensive literature search, which are: i) limited studies have explored staff nurses’ EI and its relationship with their intrinsic motivation, emotional labour, and self-compassion; ii) very few studies exist on developing and assessing the effectiveness of a structured program aimed at enhancing EI, intrinsic motivation, self-compassion and reducing emotional labour for staff nurses.\n\nThe current study primarily focuses on the important aspect of developing emotional needs, such as emotional intelligence, intrinsic-motivation and self-compassion among staff nurses, for promoting a better work-life balance. Research findings from the current study will be a major contribution to the evidence-base for EI programs among staff nurses. If proven effective, it could be delivered extensively to hospitals.\n\nThis study’s primary goal is to develop, validate, and implement a structured Integrated Emotional Self Enhancement (IESE) Program among staff nurses. The program is tailored by keeping in mind the various mental and emotional stresses the staff nurses might experience in their everyday working environment. The study aims to examine the program’s impact on the staff nurses’ level of EI, Intrinsic Motivation (IM), Self-Compassion (SC), Emotional Labor (EL), and the patients’ and nurse-in-charges’ perception of nursing care before and after the program, using standardized and validated questionnaires.\n\n\n2. Methods\n\nThe study is registered in June 2019 under the Central Trial Registry of India (CTRI/2019/08/020592).\n\nThe current study has a quasi-experimental (one-group) design, which involves staff nurses working in a selected hospital. The present study’s design is well suited, keeping in mind the work shifts of staff nurses and the number of staff nurses in the selected hospital. The current study has based its concept on three models: a) King’s conceptual system and theory of goal attainment (Shanta & Connolly, 2013), b) GENOS EI model (Palmer et al., 2009), c) motivation to care model (Moody & Pesut, 2006).\n\nThe study will be conducted in a selected tertiary care hospital in Mangalore, India. This multispecialty hospital has outpatient and inpatient facilities that cater to patient care, teaching, and scientific research. The hospital has approximately a total of 450 staff nurses. The staff nurses have three shift duty hours viz. morning, evening, and night shift. To maintain the confidentiality of the study participants, the hospital name is not disclosed.\n\nThe staff nurses working in the selected hospital’s general wards, who match the inclusion and exclusion criteria, will be considered as a potential study participant. All the nurses who provide their consent to participate will be considered for recruitment in the study. However, only those who fulfill the inclusion criteria will be included for the final sample. The IESE program will be delivered to all the recruited staff nurses. Also, data about the perception of nursing care will be collected from the patients who are under the direct care of the recruited nurse participants, and from the nurse-in-charges who are supervising the recruited nurses. The program will not be provided to the patients and nurse-in-charges. Table 1 shows the summary of the inclusion and exclusion criteria of study participants.\n\nFor the current study, all staff nurses working in the general wards will have the probability of being selected. At a 10% dropout rate, 80% power, SD of 12.3 (taken after feasibility study), and clinically significant difference of 5, it was calculated that approximately 80 staff nurses should be recruited for the current study.\n\nFor recruiting the participants, first, informed written consent to participate in the study will be collected from the staff nurses working in the selected hospital’s general wards. Then, to choose a sample of the consented staff nurses from each general ward, the sample will be matched against the inclusion and exclusion criteria. The nurses who do not fulfill the inclusion criteria will be excluded from the group.\n\nNurse-in-charges from each general ward will be taken conveniently. A written informed consent for participation will be taken before recruiting. The nurse-in-charges who are supervising the participating staff nurses at the time of data collection will only be considered for recruitment. If there is a ward that no staff nurses are taking part, the researcher will exclude the nurse-in-charge and patients from that unit.\n\nPatients will also be selected conveniently. Only the patients who are receiving care from the staff nurses participating in the study, during the time of data collection, will be selected from each general ward. As the study is longitudinal, to collect data from the same patient in the in-patient department is very unlikely. Therefore, data from 80 patients will be collected at each (five) contact points, i.e., at baseline, 3-months pre-intervention, and immediately after the intervention, at 3-month, and 6-month follow-up.\n\nThe IESE Program was developed by the investigator with the help and collaboration of experts from the field of EI, Human Resource Development, Nursing Management, and Psychology. The investigator has also taken certificate training course on Emotional Intelligence from EquiPoise, Maharashtra. The experts in the above-mentioned field validated the program. The IESE program components are divided into four sessions:\n\nSession 1: understanding emotions, emotional intelligence; importance of emotional intelligence.\n\nSession 2: neuroscience behind emotional intelligence; emotional intelligence skills.\n\nSession 3: emotional intelligence skills; management of difficult emotions.\n\nSession 4: interpersonal relationships; motivation; empathy.\n\nThe program does not instruct the nurses on how to feel; rather, it encourages the nurses to reflect on their mental and emotional health. The investigator will deliver the program through lectures, Power Point presentations, group activities, situation analysis, videos, worksheets, and workbooks. A booklet will be given to the participants for future reference. These materials will be applied for a copyright by the authors. Hence, they have not been uploaded to an approved repository yet.\n\nThe investigator will divide the consented sample of staff nurses into four groups (20 nurses in each group) and will provide the training program to each group for four consecutive days, for two hours each day. If a participant misses any session, he/she will be accommodated in another group to complete the missed session. The sessions will be made flexible and accommodating.The investigator will make sure that the IESE program does not overlap with the staff nurses’ daily work schedule and hamper the hospital activities or disturb the patients. The nurse-in-charges, staff nurses, and the nurse-supervisor will be informed many weeks prior to starting the program to effectively make the duty roster. The investigator will collect e-mail address and phone numbers of the participants, for sending reminders about the sessions, and follow-up. Table 2 shows an overview of the time plan.\n\nTable 3 shows the primary and secondary outcomes, including the measurement. The secondary objectives/outcomes will be measured using the validated questionnaires at five time-points.\n\nData from the staff nurses, patients, and nurse-in-charges will be collected at baseline and 3-month pre-intervention, and immediately after the intervention, at 3-month, and 6-month follow-up by the investigator. Secondary outcome data will be collected via pen-and-paper format. The questionnaires will be completed by the participants on the same day. The investigator will always be present with the participants when they fill in the questionnaire and will provide help to understand the questionnaire’s statements if needed. All the participants will be given a unique code to maintain confidentiality and to make sure that only the participants who have consented to participate complete the questionnaires. The investigator will collect the questionnaires on completion and store them safely in a folder. The investigator has considered an attrition rate of 10% while calculating the sample size, to account for participants who discontinue the intervention or follow-ups. Also, the investigator will maintain an attendance sheet of the participants. Reminders will be sent, and calls will be made to the study participants about upcoming and missed sessions.\n\nThe tools will be administered to participants at each time point. The investigator has taken permission from the respective authors for using the standardized tools. All the tools/instruments were chosen for their usefulness and appropriateness to fulfil the current study’s objectives. All the standardized instruments have been previously used in health and occupational research. The tools developed by the investigator have been validated by subject experts. Also, feasibility and pilot tests were done to measure the reliability of all the instruments which are to be used in the study.\n\nDemographic variables to be collected are age, gender, education qualification, marital status, number of family members, personal annual income, type of job (full time/part-time), and ward/unit.\n\nGENOS EI Inventory (concise version) will be used to assess the staff nurses’ EI. The tool focuses upon the measurement of the frequency of typicality with which an individual exhibits EI, and has 31 items across seven dimensions of emotional awareness of self and others, emotional management of self and others, emotional expression, and emotional self-control. The items are scored on a five-point Likert scale, from ‘almost never’ to ‘almost always’. The test-re-test reliability score of the tool is 0.9 (Palmer et al., 2009; Gignac, 2008, 2010).\n\nThe Emotional Labour Scale consists of 15 items with the subscales like duration (1 item), frequency (3 items), intensity (2 items), variety (3 items), surface acting (3 items) and deep acting (3 items). The reliability of the tool is 0.83. Respondents are asked to rate “on an average day at work how frequently” they performed interpersonal behaviours on a 5-point Likert-type response scale (1 = never, 5 = always). The higher the score, the higher the emotional labour (Brotheridge & Lee, 2002).\n\nThe Self Compassion Scale developed by Kristen Neff (Neff, 2010) will be used in the current study. The test-re-test reliability score of the scale is 0.92. The scale has 12 items that are scored on a five-point Likert scale from “almost never” to “almost always”. The subscales measure self-kindness, self-judgement, humanity, isolation, and mindfulness. Average self-compassion score of 1-2.5 indicates low self-compassion, 2.5-3.5 indicates moderate, and 3.5-5.0 indicates a high level of self-compassion.\n\nIntrinsic motivation will be measured using the Intrinsic Motivation Scale (IMS) which is developed by the investigator. The scale is developed based on Self Determination Theory (Ryan & Deci, 2000), Mc Clelland Motivation Theory (Pardee, 1990), and Motivation to Care Model (Moody & Pesut, 2006). The scale’s major components are autonomy, competence, relatedness, knowledge, skills, and inner drive. There are 28 items in the IMS, which has been validated by experts with a Content Validity Index of 0.87 and a Cronbach’s alpha reliability score of 0.91.\n\nThe Patients’ Perception tool is developed by the investigator to assess the patients’ perception of nursing care before and after the intervention program. The tool has ten items that are scored on a Likert scale from “strongly agree” to “strongly disagree”. The tool has been validated by experts and translated into Kannada (Local language). The Cronbach’s alpha reliability score and Content Validity Index of the tool is 0.81 and 0.87 respectively.\n\nThe investigator developed the nurse-in-charges’ perception of nursing care tool to assess the nurse supervisors’ perception towards nursing care before and after the intervention program. The tool has ten items that are scored on a Likert scale from “strongly agree” to “strongly disagree”. The tool has been validated by experts. The Cronbach’s alpha reliability score and Content Validity Index of the tool is 0.93 and 0.87 respectively.\n\nAll the questionnaires are paper-and-pen based. So, the data obtained will be entered manually into Microsoft Excel (version 16.0) sheets and SPSS (version 16) and will be stored under a folder with a password. The investigator will rectify the mistake if a participant signs their name or any other identifying information on the questionnaire at the time of data collection. The data will all be stored safely on a secure server for further analysis and reference, and the paper copies will be stored safely for five years after the study’s completion.\n\nMean and standard deviation will be used to describe measurement data. Frequencies and percentages will be used to represent count data. Repeated measures ANOVA will be used to analyze the effect of the training program. Chi-square will be used to see if an association between the variables before is after the training program.\n\nThe current study is safe, considering there are no invasive procedures for the intervention. There are no direct risks associated with taking part in the current study. However, participants may feel uncomfortable or stressed while attending the program or while answering the questionnaires, of which the investigator will be very observant about. Also, in the current pandemic state, the investigator will be very vigilant and cautious of all the norms and regulations to be followed to eliminate the risk of participants getting COVID-19 infection. In any crisis, the participant will be flagged and at once referred for counselling or any other support as needed. During the study, the participants (staff nurses) are needed to attend sessions on IESE program and provide responses in the questionnaires given to them. Before recruiting the study participants, the investigator will provide them with the study’s details, including the purpose, details of the program, potential risks, and benefits of being a participant. Similarly, the patients and nurse-in-charges will also be given information in detail about the program and their role in the study.\n\n\n3. Ethics and consent\n\nThe investigator has received approval from the university ethics committee (Kasturba Medical College and Kasturba Hospital Institutional Ethics Committee, approval number 427/2019; Institutional Ethics Committee Kasturba Medical College, Mangalore, approval number- IEC KMC MLR 08-19/331) in 2019 and has received written permission from the selected hospital authorities to conduct the study. The investigator will provide all the staff nurses, patients, and nurse-in-charges with a participant information sheet and a written consent form will be collected from the study participants. The participant information sheet will hold all the details of the study, including the aims, objectives, details about the intervention or absence of it, and the risks and benefits of participating. No one will be forced or compelled to participate in the study. The participants can withdraw from the study at any time during the study without penalty.\n\n\n4. Dissemination\n\nThe investigator intends to disseminate the study results by publishing in peer-reviewed Scopus indexed journals and present papers at scientific conferences.\n\n\n5. Confidentiality and access to data\n\nThe study data will be safely stored in a digital format on a secure server for five years after completion of the study. The raw data will be accessible to only the research team members and will be kept in a password-protected file. However, de-identified data can be made accessible on request.\n\n\n6. Discussion\n\nNurses work in an environment that is always emotionally charged. They work with patients and their families who are most often dealing with demanding situations, emotionally and physically. Being self-aware of one’s own emotions, empathizing, having meaningful relationships, and being compassionate are important aspects of professional nursing. Understanding EI is incredibly significant to the nursing profession because of its nature and the complexities and challenges it brings with it. Many researchers have recommended conducting studies by developing and providing a structured program to enhance nurses’ EI. The investigator believes that the intervention program in the study would help enhance the nurses’ EI, which would influence their intrinsic motivation and self-compassion, thereby reducing their emotional labor, which would eventually positively impact their professional and personal life, as well as in the patient outcome.\n\n\n7. Limitations\n\nOne of the major limitations of the current study is the study design; the study is quasi-experimental with only one group and no control arm. The study could not select a more robust design like a randomized control trial because of the lack of similar hospitals in terms of infrastructure, workforce, and working schedule. Compliance to the training program could also be a huge limitation to the study. However, measures will be taken to address this limitation. The investigator will reinforce the participants to comply with the training program and will encourage them to apply the learnings in their daily life by sending out regular emails and messages. Another limitation is the small sample size of 80 staff nurses and the chances of participant attrition during subsequent follow-up. To tackle this limitation, an attrition of 10% is estimated while calculating sample size. The investigator will also send reminder e-mails and messages to participants before every follow-up. All limitations can veil the true effect of the program. However, considering the current state of COVID-19 pandemic, where staff nurses and healthcare professionals are scarce in general, and to avoid large gatherings that can put the participants’ health at risk, the investigator believes that the current study design and sample size will suffice the study objectives.\n\n\n8. Conclusion\n\nThe IESE program can have a significant impact on staff nurses’ personal and professional lives, which can have a positive effect on the patient care outcome. Such programs on EI are a need of the hour, as healthcare workers and nurses are facing great stress in the face of COVID-19 pandemic. The findings of the current study will add to the research and development of emotional intelligence training programs among nursing and healthcare professionals.\n\n\n9. Study status\n\nThe study intervention has been delivered to the study participants. The follow-up data collection is expected to complete in April - May 2022.\n\n\nAuthor contributions\n\nSaikia M conceived of the study; George LS, George A & Unnikrishnan B initiated the study design; N Ravishankar provided expertise in statistics and study design. All authors contributed to refinement of the study protocol and approved the final manuscript.\n\n\nRoles and responsibilities of committees\n\n\n\ni. Principal investigator and co-authors:\n\n• Design and conduct of the study.\n\n• Preparation of protocol and revisions\n\n• Preparation of intervention modules and materials\n\n• Publication of study reports\n\nii. Institutional Ethics Committee:\n\n• Monitoring study\n\n• Audit of 6 monthly feedback from the principal investigator\n\n• Data verification\n\n\nProtocol amendments\n\nAny modifications to the protocol which may impact on the conduct of the study will be informed and amended by the Institutional Ethics Committee of the current study setting.\n\n\nData availability\n\nNo underlying data are associated with this protocol.\n\nfigshare: Effectiveness of Integrated Emotional Self Enhancement (IESE) Program among staff nurses: protocol for a quasi-experimental study. https://doi.org/10.6084/m9.figshare.19428638 (Saikia et al., 2022).\n\nThe project contains the following extended data:\n\n• English PIS (nurses).doc (Participant Information Sheet for nurses)\n\n• English PIS (nurse-in-charge).doc (participant information sheet for nurse-in-charge)\n\n• English PIS (patients).doc (Participant information sheet for patients)\n\n• intrinsic motivation.docx (Intrinsic motivation scale, developed by the investigator)\n\n• nurse incharge’s perception.docx (nurse-in-charges’ perception of nursing care scale, developed by the investigator)\n\n• patients perception.docx (patients’ perception of nursing care scale, developed by the investigator)\n\n• demographic proforma (patients).docx (demographic proforma for patients)\n\n• demographic proforma (Staff nurses).docx (demographic proforma for staff nurses)\n\n• demographic proforma (nurse-in-charge).docx (demographic proforma for nurse-in-charges)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nCopyright will be applied for the booklet, workbook, and teaching material which will be developed by the investigators, and hence these materials have not been uploaded to the repository yet.\n\n\nReporting guidelines\n\nfigshare: SPIRIT checklist for ‘Effectiveness of Integrated Emotional-Self Enhancement (IESE) Program among staff nurses: Protocol for a quasi-experimental study’. https://doi.org/10.6084/m9.figshare.19429757",
"appendix": "References\n\nBaille L: A phenomenological study of the nature of empathy. J. Adv. Nurs. 1996; 24: 1300–1308. Publisher Full Text\n\nBrotheridge CM, Lee RT: Testing a conservation of resources model of the dynamics of emotional labour.J. Occup. Health Psychol. 2002; 7(1): 57–67. Retrieved from\n\nCadman C, Brewer J: Emotional Intelligence: a vital prerequisite for recruitment in nursing. J. Nurs. Manag. 2001; 9(6): 321–324. PubMed Abstract | Publisher Full Text\n\nChan AW, Tetzlaff JM, Gøtzsche PC, et al.: SPIRIT 2013 explanation and elaboration: Guidance for protocols of clinical trials. BMJ. 2013; 346: e7586. Publisher Full Text PubMed Abstract | Reference Source\n\nCheng L, Yuan JJ, He YY, et al.: Emotion regulation strategies: cognitive reappraisal is more effective than expressive suppression. Xin Li Ke Xue Jin Zhan (Advances in Psychological Science). 2009; 17(4): 730–735. Reference Source\n\nChun KH, Park E: Diversity of Emotional Intelligence among nursing and medical students. Osong. Public Health Res. Perspect. 2016; 7(4): 261–265. PubMed Abstract | Publisher Full Text\n\nCodier E, Freitas B, Muneno L: Developing Emotional Intelligence ability in oncology nurses: a clinical rounds approach. Oncol. Nurs. Forum. 2013; 40(1): 22–29. PubMed Abstract | Publisher Full Text\n\nDrigas A, Papoutsi C: A new layered model on Emotional Intelligence. Behav Sci (Basel). 2018; 8(5): 45. PubMed Abstract | Publisher Full Text Reference Source\n\nFreshwater D, Stickley T: The heart of the art: Emotional Intelligence in nurse education. Nurs. Inq. 2004; 11(2): 91–98. PubMed Abstract | Publisher Full Text\n\nGignac GE: Genos emotional intelligence inventory technical manual. Sydney, NSW: Genos Press; 2008.\n\nGignac GE: Seven-factor model of Emotional Intelligence as Measured by Genos EI: A confirmatory factor analytic investigation based on self- and rater-report data. Eur. J. Psychol. Assess. 2010; 26(4): 309–316. Publisher Full Text Reference Source\n\nKeltner D, Kring AM: Emotion, social function, and psychopathology. Rev. Gen. Psychol. 1998; 2(3): 320–342. Publisher Full Text Reference Source\n\nMoody RC, Pesut DJ: The motivation to care: Application and extension of motivation theory to professional nursing work. J. Health Organ. Manag. 2006; 20(1): 15–48. Publisher Full Text\n\nNeff KD: Development and validation of a scale to measure self-compassion. Self Identity. 2010; 2(3): 223–250. Publisher Full Text\n\nNightingale S, Spiby H, Sheen K, et al.: The impact of emotional intelligence in health care professionals on caring behaviour towards patients in clinical and long-term care settings: Findings from an integrative review. Int. J. Nurs. Stud. 2018; 80: 106–117. PubMed Abstract | Publisher Full Text\n\nPalmer BR, Stough C, Harmer R, et al.: The Genos Emotional Intelligence Inventory: a measure designed specifically for workplace applications. Stough C, Saklofske DH, Parker JDA, editors. The Springer series on human exceptionality. Assessing emotional intelligence: Theory, research, and applications. Springer Science + Business Media; 2009; 103–117. Publisher Full Text\n\nPardee RL: Motivation theories of Maslow, Herzberg, Mcgregor & McClelland. A literature review of selected theories dealing with job satisfaction and motivation. U.S. Department of Education Office of Educational Research and Improvement Educational Resources Information Centre (ERIC); 1990. Reference Source\n\nRaghubir AE: Emotional Intelligence in professional nursing practice: a concept review using Rodgers’s evolutionary analysis approach. Int. J. Nur. Sci. 2018; 5(2): 126–130. PubMed Abstract | Publisher Full Text\n\nReeves A: Emotional Intelligence- recognizing and regulating emotions. AAOHN J. 2005; 53(4): 172–176. PubMed Abstract | Publisher Full Text\n\nRyan RM, Deci EL: Self-determination theory and the facilitation of intrinsic motivation, social development, and well-being. Am. Psychol. 2000; 55(1): 68–78. PubMed Abstract | Publisher Full Text Reference Source\n\nSaikia M, George LS, Unnikrishnan B, et al.: Effectiveness of Integrated Emotional Self Enhancement (IESE) Program among staff nurses: protocol for a quasi-experimental study. figshare. [Dataset]. 2022. Publisher Full Text\n\nShanta L, Connolly M: Using King’s interacting systems theory to link emotional intelligence and nursing practice. J. Prof. Nurs. 2013; 29(3): 174–180. PubMed Abstract | Publisher Full Text\n\nSmith KB, Profetto-McGrath J, Cummings GG: Emotional Intelligence and nursing: An integrative literature review. Int. J. Nur. Stud. 2009; 46(12): 1624–1636. Publisher Full Text Reference Source\n\nSrinivasan K, Jebaseelan AUS: A study on job stress among staff nurses in Villupuram District. Indian J. Appl. Res. 2014; 4(12): 155–157. Reference Source\n\nSusskind JM, Lee DH, Cusi A, et al.: Expressing fear enhances sensory acquisition. Nat. Neurosci. 2008; 11(7): 843–850. PubMed Abstract | Publisher Full Text\n\nTomar R: A study of Emotional Intelligence among nurses. Int. J. Innov. Res. Dev. 2016; 4(4): 5204–5211. Publisher Full Text"
}
|
[
{
"id": "141764",
"date": "13 Jul 2022",
"name": "Leila Bazrafkan",
"expertise": [
"Reviewer Expertise medical education"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe author should explain more about the intervention (integrated Emotional-Self Enhancement (IESE) program among staff nurses. How the content of the training was chosen, and whether the competence of the trainer was examined?\nSuggestion: I only suggest that since four groups are involved in implementing the intervention, they should use the study's Quasi-experimental Solomon four-group research design. I did not mean the study design is problematic, but it's merely a suggestion to improve the quality of the research design. I was considering that the author had divided the study participants into four groups. If not, the decision is up to the author, and the four-group design may have much trouble.\nSalmon's four-group design combines pre-test-post-test design with the control group and post-test design with the control group. However, when we intend to maximize the generalizability of the results of research and on the other hand, there are no clear reasons for the superiority of one of the two pre-test designs - post-test with the control group and post-test with the control group over the other. Salmon's four-group design is a logical choice.\nThis method randomly divides subjects into more than three homogeneous groups. Then they will be tested. Then all of them are affected by the independent variable, the next test is taken from them, and the results are analyzed statistically. In the following figure, various comparisons of the four-group design of salmon are presented in a graphic design: https://f1000researchdata.s3.amazonaws.com/linked/437785.solomon-four-group-comparisons.png.\nAs seen in Figure 5, groups A and B form a pre-test-post-test design with the control group, and groups C and D form a post-test design with the control group. Therefore, Solomon's four-group design is two completely independent studies analyzed in the design as mentioned above.\nIn comparing the post-test of group A and the post-test of group C, i.e., comparison number 7, the effectiveness of the combination of pre-test and experimental intervention is evaluated. If the comparison of number 7 becomes meaningless, it indicates the lack of adverse effect of familiarity with the test.\nIf the comparison of number 7 becomes significant, it is because the pre-test directly affected the post-test score (statistical return and familiarity with the test), or it was due to the effect of the pre-test on the experimental intervention. Suppose the difference between the post-test of groups A and B is the same as the difference between the post-test of groups C and D. In that case, there is no room to worry about the effect of the pre-test on the results, but if the differences between C5 and C1 are different, the possibility of the effect of the pre-test or interaction The pre-test (subjects) is presented with experimental intervention.\nAlso, if the difference between post-test group D and B, i.e. C8 comparison, becomes meaningless, the neutrality of the pre-test effect is proven. However, if the mentioned comparison becomes significant, it tells about the major effect of the pre-test on the post-test. Comparing the pre-test of groups A and B with the post-test of group D is one of the most apparent aspects of salmon's four-group design. In the comparison of question C6, the difference between the pre-test of group B and the post-test of group D, becomes significant, it indicates the effect of life events and maturity.\nIn fact, the effect of maturation or local history between pre-test and post-test can be measured in salmon's four-group design. For example, the occurrence of a specific social-political situation or seasonal changes may cause changes in the scores of the subjects in the post-test.\nIn the comparison as mentioned above (comparison between the pre-test of groups A and B with the post-test of group D), the effect of maturity factors or life events on the post-test is measured. Maturity and life history factors are only controlled in the pre-test-post-test design with the control group, but in the Salmon design, the effect size of these factors is measured. The significance of the comparison of C3 shows the occurrence of problems in the process of random assignment.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": [
{
"c_id": "8531",
"date": "20 Jul 2022",
"name": "Monalisa Saikia",
"role": "Author Response",
"response": "Respected Reviewer, Thank you for your suggestions and comments. As per your suggestion, we have added some detail about the IESE program, how it was developed, and the credibility of the investigator to deliver the program to the study participants. However, your suggestion about using the Solomon Four design will not be applicable in the present study. We apologise, as we think the previous version of the manuscript failed to make this part clearer- there will be only one group of nurses, but, they will be divided into smaller groups of 5-10 members in each group so that the delivery of the training program is effective and the participants can engage in the group activities to learn more efficiently. All the nurses in each group will receive the same training program without any deviation or difference. The study investigator does not plan to make a comparison between the groups. Best regards."
}
]
}
] | 1
|
https://f1000research.com/articles/11-679
|
https://f1000research.com/articles/12-1274/v1
|
06 Oct 23
|
{
"type": "Case Report",
"title": "Case Report: Introduction of antibiotic releasing calcium sulfate bone void filler beads (Stimulan) for management of an infected cyst of the maxilla",
"authors": [
"Sneha Patil",
"Rajanikanth Kambala",
"Nitin Bhola",
"Rozina Vishnani",
"Rajanikanth Kambala",
"Nitin Bhola",
"Rozina Vishnani"
],
"abstract": "Radicular cysts are the most common odontogenic cyst arising from epithelial cell rests of Malassez in the periodontal ligament and proliferate peripherally as a result of inflammation caused by infection at the root apices. They slowly grow apically causing bone resorption and displacement of the adjacent teeth which radiographically is seen as a radiolucent unilocular lesion. Management of such bone defects can be done by using various bone graft substitutes such as autogenous, allografts, xenografts and alloplasts. Taking account of the benefits of using synthetic bone graft substitutes, the following case represents the successful management of a radicular cyst, which includes endodontic treatment and cyst enucleation, chemical cauterization followed by introduction of antibiotic (Vancomycin) releasing calcium sulfate filler beads into the defect.",
"keywords": [
"radicular cyst",
"enucleation",
"bone regeneration",
"bone stimulant",
"calcium sulfate"
],
"content": "Introduction\n\nInflammatory odontogenic cysts of the maxilla and mandible are located in the alveolar region of the jaw. They are most commonly a radicular cyst involving an offending tooth with a well-defined radiolucency on a radiograph.1 It is usually associated with a necrotic pulp and the prevalence ranges from 7% to 54% of all jaw cysts in permanent dentition.2 With the advancement in bone tissue engineering, there have been many potential alternatives to the traditional use of bone grafts with major benefits like vast availability and no cross reactions. For an ideal alloplastic material, calcium sulfate has characteristics of bone regeneration and is additionally an excellent osteoinductive and osteoconductive material for bone defect reconstruction.3 The following case represents the successful management of a radicular cyst, which includes endodontic treatment and cyst enucleation, chemical cauterization followed by introduction of antibiotic (Vancomycin) releasing calcium sulfate filler beads into the defect.\n\n\nCase report\n\nA 35-year-old male patient was referred to the Department of Conservative Dentistry and Endodontics of Sharad Pawar Dental College in the month of March 2023, for the management of a lesion related to the upper right anterior maxilla. The patient had a main complaint of swelling over the right side of the upper jaw for the previous four months. On clinical examination, there was a single localized swelling, measuring 3 × 3 cm on his hard palate with serous discharge, which was endodontically removed through root canal openings of his central and lateral incisor of the right side (Figure 1). The dental records uncovered a history of injury two years before, over the upper anterior tooth region. The maxillary right central incisor was discolored with no mobility (Figure 2). On palpation, the swelling was soft and non-tender. A yellow-colored serous exudate was aspirated upon accessing the pulp chamber, which eventually reduced the swelling over the palate. A unilocular radiolucency with a well-defined radiopaque border was seen on radiographic examination (Figure 3). Taking into account the age of the patient, both involved teeth were endodontically treated. Careful enucleation, curettage, and chemical cauterization of the right anterior maxillary area was carried out followed by introduction of antibiotic (Vancomycin) releasing calcium sulfate bone void filler (Stimulan®) as a graft material.\n\nUnder all aseptic protocols, the patient was prepared for the surgical procedure under local anesthesia. A crevicular incision was made over the right first premolar to the left central incisor to expose the underlying bone. The buccal bone was found to be paper thin making it easier for enucleation. After enucleation a specimen was sent for histopathological examination. Thorough curettage was performed followed by chemical cauterization using carnoy solution (Figure 4). Apical plugging over the upper right central and lateral incisor was done with mineral trioxide aggregate (MTA). To fill the maxillary defect, calcium sulphate beads were utilized. They are available commercially as the Stimulan® Rapid Cure kit (Catlog number- 620-005, supplied by Biocomposites, England) containing 5 cc of calcium sulphate hemihydrate powder. Then 500 mg of vancomycin powder was mixed with it in a mixing bowl. When a ‘doughy’ stage was achieved the mixture was poured into the mould and allowed to set for 15 minutes. In the meantime, the cystic cavity was dried and beads were used to pack the whole defect. Closure was done using absorbable sutures. Postoperatively, the patient was prescribed antibiotics, Augmentin tablets 625 mg, twice daily for five days and Aceclofenac tablets 100 mg + serratiopeptidase 15 mg + paracetamol 325 mg, twice daily for five days. He was advised to maintain good oral hygiene and kept on regular follow–up. The follow-up after one month showed no signs of active inflammation or symptoms (Figure 5). The patient was satisfied with the treatment.\n\n\nDiscussion\n\nRadicular cysts are the most common odontogenic cyst arising from epithelial cell rests of Malassez in the periodontal ligament and proliferate peripherally as a result of inflammation caused by infection at the root apices. When infected, they become symptomatic since they slowly grow, displace all associated teeth and may lead to mobility and root resorption.4 This results in swelling, pain and the patient becomes conscious of the problem. In our case, there was no tooth mobility, no root resorption but displaced roots were seen.\n\nConventionally, a radicular cyst is treated with an endodontic approach, combined with surgical enucleation or decompression and in adjuvant with extracting the offending tooth. An endodontic approach with radicular cysts will eradicate all the microbes or reduce the microbial load substantially from the root canal and reinfection is prevented by Retrograde filling.5 Those lesions, which fail to respond with this modality, can be managed successfully by curettage of the epithelial lining in the apical region and extraction of the associated teeth. The other recommended options are decompression of the cyst surgically, to decrease the size before marsupilisation or complete enucleation is done in order to reduce the risk of damage to adjacent anatomic structures.6\n\nDepending on the location and size of the bone defect, numerous grafts can be used for reconstruction. Use of autogenous bone grafts are considered as a gold standard method of such defects. Allogenic materials on the other hand have a risk of viral transfer with cross infections. The same limitation is present with xenografts which are generated from a genetically different species. Alloplasts are synthetic graft materials that have characteristics of osteoinduction and osteoconduction and hence they are more popular. Some examples of alloplastic grafts are glass ionomers, bioactive glass, calcium phosphates, calcium sulfate, tricalcium phosphate and synthetic hydroxyapatite.7 The limitations of these autografts, allografts and xenografts, give rise to an increase in the demand for a bone graft substitute. Alloplasts initiate the process of bone formation through ‘creeping substitution’, a phenomenon in which the process of osteoconduction with subsequent migration of osteoblastic cells and blood vessels from adjacent healthy bone to the scaffold takes place. Calcium sulfate as a bone graft substitute plays the role of a filler material in managing dead space due to its properties of biodegradability and biocompatibility. It does not cause cross reactions and it is resorbed rapidly within 1–3 months by creating porosities for bone ingrowth. The introduction of locally releasing antibiotics from calcium sulfate beads offers significant benefit in the management of an infected surgical site. In a study, vancomycin was found to cause a six times reduction in microbial growth by seven days that illustrated its importance with prolonged release in high concentrations when treating biofilms.8\n\nThe calcium sulfate beads are radiopaque and hence are easily evaluated on plain radiographs for assessing the extent of the defect and revealing the status of the cortical plates and the relationship with the adjacent tissues. Sequential radiographic analysis is needed for studying spontaneous bone formation.9 There is a paucity of literature on using antibiotic releasing bone substitutes in the case of a radicular cyst. Hence, the introduction of calcium sulfate bone void fillers with antibiotics can be a beneficial and newer modality for management of infected maxillary cysts in young adults.\n\nThe utility of antibiotics impregnated in calcium sulfate beads are not limited to the treatment of infected cysts of the jaw, they are also being used for the treatment of diabetic foot infections and chronic osteomyelitis of the long bones and joints. Studies have shown 80% wound healing and 100% graft preservation with no recurrent infections observed and no requirement for amputation during follow-up.10 These results of high healing rates have been successfully recorded in the studies and could explain the eradication of residual microorganisms with the delivery of a high concentration of antibiotics directly to the wound.11\n\nTo summarize, the use of antibiotic releasing calcium sulfate beads is an acceptable method of treating an infected cystic cavity. In the presented case, the follow-up has shown satisfactory results with no signs of re-infection. Future studies should be conducted to assess use of other antibiotics as well as their concentration in larger samples or clinical trials. The response of combining bone graft substitutes with antibiotics in vivo, comparing bone regeneration, and wound healing with each material with or without antibiotic is to be determined.\n\n\nConsent\n\nWritten informed consent for publication of their clinical details and clinical images was obtained from the patient.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReferences\n\nDeshmukh J, Shrivastava R, Bharath KP, et al.: Giant radicular cyst of the maxilla. BMJ Case Rep. 2014 May 2; 2014: bcr2014203678. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDoumari B, Drouri S, Elkharroubi S, et al.: Management of Radicular cyst following deficient orthodontic treatment: Case Report. Adv. Oral. Maxillofac. Surg. 2023 Mar 1; 9: 100397. Publisher Full Text\n\nFernandes G, Abhyankar V, O’Dell JM: Calcium Sulfate as a Scaffold for Bone Tissue Engineering: A Descriptive Page 2 of 22 Review. J. Dent. Oral. Disord. Ther. 2021; 9(1): 1–22. Publisher Full Text\n\nAgarwal P, Sharma S, Trehan M, et al.: Management of Infected Radicular Cyst by Marsupialization. World J. Dent. 2013; 4(3): 214–216. Publisher Full Text\n\nJohann AC, Gomes Cde O, Masquita RA: Radicular cyst: a case report treated with conservative therapy. J. Clin. Pediatr. Dent. 2006; 31: 66–67. PubMed Abstract\n\nHeleia NZ, Ene M: Endoscopically assisted enucleation of a large mandibular periapical cyst. Stomatogija, Baltic Dent Maxillofacial J. 2011; 13: 128–131.\n\nPekiner FN, Ozbayrak S, Sener BC, et al.: Peripheral ameloblastoma: a case report. Dentomaxillofac. Radiol. 2007; 36: 183–186. Publisher Full Text\n\nOliver RA, Lovric V, Christou C, et al.: Comparative osteoconductivity of bone void fillers with antibiotics in a critical size bone defect model. J. Mater. Sci. Mater. Med. 2020 Aug 25; 31(9): 80. Erratum in: J. Mater Sci. Mater. Med. 2021 Oct 6;32(10):130. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTayshetye RS, Bhola N, Jadhav A, et al.: A novel reconstruction of a large mandibular cystic defect by bone graft substitute. Acta. Sci. Dent. Sci. 2021; 5: 26–29. Publisher Full Text\n\nLázaro-Martínez JL, Aragón-Sánchez J, García-Morales E: Antibiotics versus conservative surgery for treating diabetic foot osteomyelitis: A randomized comparative trial. Diabetes Care. 2014; 37: 789–795. PubMed Abstract | Publisher Full Text\n\nWai Chon HT, Hamish M, Kirupananthan P, et al.: Stimulan® Antibiotic impregnated beads for the treatment of diabetic foot infection. Arab. J. Intervent Radiol. 2020; 4: 073–078. Publisher Full Text"
}
|
[
{
"id": "216742",
"date": "19 Oct 2023",
"name": "Sanchit Jain",
"expertise": [
"Reviewer Expertise Oral Lesions and pathologies"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nKindly add the following details in the article:\nDetails of progression of disease have to be mentioned.\n\nDetails of radiographic evaluations in both pre-operative and post-operative radiographs.\n\nThere is a need for emphasis on the sensitivity test to prevent any allergic reaction to the drug; this has to be mentioned.\n\nWhen topical antibiotics were given intra-lesionally then why oral antibiotics were prescribed should be explained as it interferes with the main motive of the case report.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": []
},
{
"id": "242898",
"date": "04 Mar 2024",
"name": "Robert Horowitz",
"expertise": [
"Reviewer Expertise I have researched",
"lectured and published on bone grafts",
"growth enhancers and growth factors for over 25 years. I have published on multiple types of Calcium Sulfate in addition to other also-lasts",
"allograft's and xenografts."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntroduction of antibiotic releasing calcium sulfate bone void filler beads REVIEW\nPage 3: Introduction\ntraditional use of bone grafts SHOULD READ use of more “traditional” bone. grafts (i.e. autogenous bone, allograft)\ncalcium sulfate has characteristics of bone regeneration SHOULD READ calcium sulfate has been shown for over 100 years to enable predictable bone regeneration.\nPage 4: Case report\nCareful enucleation, curettage, and chemical cauterization of the right anterior maxillary area was carried out - How long after the endodontic therapy was performed? What was the time sequence of treatment?\nSurgery\nmaking it easier for enucleation SHOULD READ providing easier access to enable enucleation of the affected site.\nQuestion – prior to “apical plugging”, was any apical preparation made in the teeth? Was apical surgery performed on one/both teeth?\nWere the Calcium Sulfate powder and Vancomycin powder mixed with sterile water? Sterile saline to make the doughy stage?\nWere the beads used to pack the defect put in dry? Were they hydrated with saline? If the cystic cavity had been cauterized, was there enough bleeding to coat the beads with heme?\nThere are no follow-up clinical photographs, x-rays, CBCT’s to show how the clinical or radiographic effects of healing progressed.\nWhere is the reference about potential viral transfer after utilization of allogeneic grafts?\nThe same question applies for alloplastic materials which are/may be osteoinductive.\nThere is no reference for “creeping substitution”.\nThere is no reference for resorption and bone replacement at 1-3 months for calcium sulfate.\nThere is a mention of “follow-up has shown satisfactory results”. It is not mentioned how long the follow-up is, what type of follow-up was performed, and no follow-up evaluations were performed.\nThere is no comparison of Calcium Sulfate mentioned related to clinical, histologic evaluation in relation to allograft, other alloplasts, autograft nor xenograft. This paper would need significantly more detailed patient analysis and literature for me to try this material.\n\nIs the background of the case’s history and progression described in sufficient detail? No\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? No",
"responses": []
},
{
"id": "242883",
"date": "10 Sep 2024",
"name": "Diana Soesilo",
"expertise": [
"Reviewer Expertise conservative dentistry"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nPlease kindly add this following details on this manuscript :\n1. Please add an explanation about what kind of endodontic treatment was performed in this case\n\n2. Please add an image of the allograft material used in this case\n3. Please add clinical intra oral image of regular follow-up\n4. Please explain more about how mixture of calcium sulfate and vancomycin could be used for bone substitution and how long bone formation will take place after the application of this material\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1274
|
https://f1000research.com/articles/12-797/v1
|
10 Jul 23
|
{
"type": "Research Article",
"title": "Comparative evaluation of apical debris extrusion during root canal preparation using three different rotary file systems",
"authors": [
"Rutuja Rajnekar",
"Nikhil Mankar",
"Pradnya Nikhade",
"Manoj Chandak",
"Nikhil Mankar",
"Pradnya Nikhade",
"Manoj Chandak"
],
"abstract": "Background: Endodontic success depends on the complete cleaning and shaping of the root canal. In order to achieve this goal, debris removal is essential. Even with improvements in instrument design, apical debris extrusion continues to be a cause of periradicular inflammation. The current study aimed to compare the amount of apically extruded debris throughout the canal instrumentation with TruNatomy, ProTaper Next, 2Shape rotary systems. Methods: A total of 60 freshly extracted single‑rooted mandibular premolars were use. An access opening was made, and a working length was estimated. The samples were arbitrarily allocated into three groups i.e. Group I: TruNatomy (n = 20), Group II: ProTaper Next (n = 20), Group III: 2Shape (n = 20). During the canal instrumentation, the extruded debris were collected in preweighed Eppendorf tubes. Post-instrumentation, the tubes were placed in a hot air oven at 140°C for five hours. For calculating the dry debris weight, the tube’s pre-instrumentation weight was deducted from the post-instrumentation weight. The data was analysed using one‑way analysis of variance and post hoc Tukey’s test. Results: Extrusion of debris was noted in all the specimens. TruNatomy rotary system showed least debris extrusion in comparison to ProTaper Next and 2Shape (P < 0.05). However, the results were statistically non-significant between ProTaper Next and 2Shape (P > 0.05). Conclusions: It was noted that all instruments apically extruded debris, with TruNatomy system being related to minimum extrusion.",
"keywords": [
"Apical extrusion",
"TruNatomy",
"ProTaper Next",
"2Shape"
],
"content": "Introduction\n\nThe field of endodontics has experienced a revolution in recent years, with treatment becoming more precise and prognosis becoming more predictable. Endodontic therapy necessitates meticulous biomechanical preparation, three-dimensional obturation, and a leakage-free coronal restoration for its success.1 In addition to removing all irritants from the canal, the instrumentation should also facilitate debridement without injuring periapical tissues.2 Despite efforts to maintain the correct working length throughout the root canal instrumentation, debris such as pulpal fragments, microbes, necrotic remnants, dentinal chips, and irrigants are forced beyond the apex in the periradicular tissues.3\n\nNevertheless, this debris extrusion can induce an inflammatory response which may compromise healing, cause flare up, or lead to failure in the long/short term. Patients with flare-up experience pain, swelling, or both during and after their endodontic treatment, leading to emergency appointments.4 Therefore, preventing debris extrusion is important during root canal procedures. Chapman et al. in 1968 reported for the first time that infective material was extruded periapically during root canal instrumentation.5 Vande Visse and Brilliant in 1975 calculated the apical debris extrusion during the biomechanical preparation for the first time.6 As a result of Myers and Montgomery’s 1991 research, an approach for evaluating the amount of extruded debris was developed.7 In 2014, Tanalp and Gungor stated that the apical extrusion of bacterial products, pulpal tissue, and irrigants are one of the reasons for endodontic failure.8\n\nIt has been observed that debris extrusion varies between different instrumentation systems. It is believed that this is because of variations in cutting blade and cross-sectional design, tip type, taper, configuration, the number of files used, flexibility, alloy, kinematics, and cutting efficiency.9\n\nMany authors believe that the extrusion of some debris is unavoidable during instrumentation, and that there is no method for completely eliminating this. Nevertheless, some instrumentation system may extrude fewer debris compared to others.\n\nThe TruNatomy (Dentsply Sirona, Maillefer, Ballaigues, Switzerland) rotary file system is fabricated from 0.8 mm NiTi wire in contrast to the standard files, which are manufactured from 1.2 mm NiTi wire.10 The system includes an orifice opener; glider; three shaping files which are Small (20/4%); Prime (26/4%); and Medium (36/3%). These files have an off-centered parallelogram cross-section which provides extra space for debridement. After glide path preparation, the Prime (26/4%) file is recommended to use directly. The Small file is only used when the Prime file fails to advance smoothly or when the dentist is unsure about the Prime file. Through its slim design, regressive taper, instrument geometry and heat treatment, TruNatomy files conserve tooth integrity while preserving maximum pericervical dentine.11\n\nThe ProTaper Next (Dentsply Maillefer, Ballaigues, Switzerland) rotary system is produced from M-Wire technology.12 These files have an asymmetrical rectangular cross-sectional design with variable taper. This results in snake-like swaggering motion along its active portion, decreasing the screw-in effect and taper-lock.13 The offset design of this system causes maximum amount of debris to be forced out of the canal. ProTaper Next system includes X1 (17/4%), X2 (25/6%), X3 (30/7%), X4 (40/6%) and X5 (50/6%) rotary files.\n\n2Shape (MicroMega, Besancon, France) rotary files are made of T-wire alloy having off-centered triple helix cross-sectional design. The file design has two cutting edges, which enhances the cutting efficacy with a secondary cutting edge intended for better debris removal. 2Shape consists of two shaping instruments and an optional file for apical finishing. The 2Shape system consist of TS1 (25/4%), TS2 (25/6%), F35 (35/6%), and F40 (40/4%) rotary files.14\n\nThis study aimed to estimate the amount of debris extrusion during instrumentation of root canals by TruNatomy, ProTaper Next and 2Shape rotary systems, and evaluate the effectiveness of their design in minimizing the amount of apical debris extrusion during use. The null hypothesis considered was that there was no difference in the amount of apical debris extrusion between the rotary systems.\n\n\nMethods\n\nAfter obtaining clearance from the Institutional Research Ethics Committee of Datta Meghe Institute of Higher Education and Research, the ethical approval letter was obtained (Ref. No. DMIMS (DU)/IEC/2020-21/9388). This was an in vitro study design.\n\nThe formula used for sample size calculation was:\n\nWhere Zα = level of significance at 5% i.e., 95% confidence interval = 1.96\n\nZβ = power of test = 80% = 0.84\n\nδ1 = SD of mean debris in Group 1 = 0.00024\n\nδ2 = SD of mean debris in Group 2 = 0.00018\n\nK = 1\n\nPreparation of samples\n\nSixty freshly extracted single-rooted mandibular premolars having less than 10° curvature were included in the experimental study. All the samples were inspected under a Dental Operating Microscope for confirmation of completely formed root apices. The digital radiographs were taken in buccal and proximal directions to confirm the existence of a single canal, complex anatomy, calcifications, and mature apex formation. All sample’s outer surface was cleaned for debris or remnants, which were further stored in normal saline. To standardize, all the samples were sectioned using diamond disc with 16 ± 0.20 mm tooth length.\n\nA standard access opening was done using a high-speed diamond bur. Each canal was carefully inserted with a #10 K File (Mani Inc, Japan) until it could be barely seen at the apex. Further, the file stopper was adjusted at the occlusal surface, which was used as the reference point. From this measured length, 1 mm was subtracted for each sample’s working length determination. The teeth in which #10 K file was just visible at the apex along with the #15 K file, which snugly fits at the working length of the tooth, were included in the study.\n\nInstrumentation and debris collection\n\nThe debris collection apparatus was set up in accordance with Myers and Montgomery’s study 19917 (Figure 1). For collecting the apically extruded debris throughout instrumentation, the Eppendorf tubes were used. A total of 60 tubes were preweighed on an analytical electronic microbalance of 10-6 g precision (Sartorius weighing Technology GmbH, Goettingen, Germany). Each tube’s weight was calculated by taking the mean of three consecutive measurements and placed into an empty glass vial. The teeth were forced into an Eppendorf tube after the preparation of the standard access cavity. Each Eppendorf tube was fitted in the empty vial through the rubber stopper. The apical portion of the samples were suspended in the Eppendorf tube. For equalization of the air pressure inside and outside the tubes, the tubes were vented by inserting a 24-gauge needle along the side of the stopper. When the canal instrumentations were performed, the vials were coated with a dental dam sheet so as to prevent the operator’s view of the tooth’s apical portion (Figure 2). In order to assess debris extrusion, another examiner was blinded regarding different groups.\n\nExperimental groups\n\nAll the samples were randomly distributed into three experimental groups on the basis of instrumentation techniques used.\n\nGroup I: TruNatomy\n\nAs per the manufacturer’s instructions, a smooth glide path with the #10 K or #15 K File was obtained. TruNatomy Orifice modifier was used till half of the working length, followed by glide path preparation by the TruNatomy Glider. The shaping file used was TruNatomy Prime (26/4%), at 1.5 torque and 500 rpm till the working length.\n\nGroup II: ProTaper Next\n\nFollowing the manufacturer’s recommendations, the ProTaper Next rotary system was used with pecking motion. The Glide path was established with #15 K File. The X1 (17/4%) file, followed by the X2 (25/6%) file, was used with in-and-out pecking action till the working length at 2 N/cm torque and 300 rpm, according to manufacturing company recommendations.\n\nGroup III: 2Shape\n\nAfter achieving a glide path with #10 K or #15 K File, 2Shape rotary files were used with pecking motion. The TS1 file (25/4%) was used with pecking motion followed by shaping with the TS2 file (25/6%) at 1.2 N/cm torque and a speed of 300 rpm till working length was achieved.\n\nIrrespective of the instrumentation system, 1 mL distilled water with a 30-gauge side vented needle was used for irrigating the canals following each instrument. The irrigation was supposed to be passive irrigation as much as possible. Total irrigant used was 8 mL.\n\nEvaluation of apically extruded debris\n\nPost-instrumentation, each sample was removed from the Eppendorf tube. To collect the root surface-adhered debris, the root’s apical portion was washed with 1 mL distilled water in a tube. Then, these Eppendorf tubes having debris, extruded irrigants and distilled water were locked with the lid. The tubes were further stored at 140° in a Hot Air Oven for five hours. This led to evaporation of the moisture, obtaining dry debris. An electronic microbalance (10-6 g precision) was used to weight the dry debris and was repeated three times by the same operator, and the average reading was noted (Figure 3). For the assessment of final weight of dry extruded debris in each tube, the mean pre-instrumentation weight of the tube was deducted from their mean post-instrumentation weight. All three groups were compared. The results were statistically analysed.\n\nThe obtained data was statistically analysed using ANOVA and post hoc Tukey test using SPSS version 21 (SPSS Inc., Chicago, IL, USA). The amount of extruded debris was statistically analyzed, and the level of significance was set at P < 0.05.\n\n\nResults\n\nIn order to analyze the data, mean and standard deviation were calculated (Table 1) and subsequently subjected to ANOVA (Table 2). Each instrumentation technique had a significant difference in debris extrusion. In order to compare the groups, post hoc Tukey’s tests were used in which TruNatomy showed a significant reduction in debris extrusion when compared with ProTaper Next and 2Shape (P < 0.05). When compared between ProTaper Next and 2Shape, there was similar debris extrusion with ProTaper Next and 2Shape, and the difference was statistically non-significant (P > 0.05) (Table 3).\n\n* p value <0.05 is statistically significant.\n\n* P-value < 0.05 is statistically significant.\n\n\nDiscussion\n\nThe purpose of root canal therapy is to remove the dentinal debris, necrotic pulp tissues, and microorganisms, leaving the root canals clean and shaped.15 A primary objective of cleaning and shaping involves preventing apical extrusion of debris and irrigants into the periradicular tissues. The apical extrusion of infected debris may pose a clinically significant complication since it may lead to the postoperative pain or extraradicular infection.\n\nThe present study created standard conditions (other than the instrumentation system used) for all groups. For standardization of tooth morphology in the current research, 60 single-rooted mandibular premolars were selected based on the canal size, curvature and working length. To avoid any potential variation in debris extrusion caused by each sample’s different working length, all the sample teeth were decoronated before instrumentation.\n\nThe current study ensured equal distribution between the experimental groups by standardizing the size of apical foramen. As a result, the sample was excluded if a #15 K file was found to extend beyond the apex. In the current study, sodium hypochlorite was not used for irrigation as suggested by Tanalp and Gungor in 2014 to prevent weight bias caused by the crystallization of sodium hypochlorite, which cannot be distinguished from the weight of actual extruded debris.8 Irrigation was strictly restricted to 8 mL of distilled water, which leaves no residue once evaporated.\n\nThe various engine-driven NiTi file systems available in the market today have different cross-sectional designs, all of which are associated with some amount of debris extrusion. Hence, the present study was performed to analyze and compare the amount of extrusion of debris associated with TruNatomy; ProTaper Next; and 2Shape file systems.\n\nAs compared to all the instruments tested in this study, the least amount of debris extrusion was associated with TruNatomy system (Group I) followed by 2Shape (Group III) and ProTaper Next (Group II). There were statistically significant differences between TruNatomy versus ProTaper Next (P-value = 0.001); and TruNatomy versus 2Shape (p-value = 0.001), whereas no statistically significant difference was found between 2Shape and ProTaper Next.\n\nThe minimum amount of debris produced by TruNatomy files may be due to the off-centered parallelogram cross-section, leading to less contact between the file and the dentin, i.e. the file touched the dentin only at two points at a time, providing additional space for coronal debris extrusion.16 Few studies stated an association between the instrument taper and the amount of debris extrusion. A larger apical taper could lead to more aggressive preparation of the canals, which may cause more apical debris extrusion.17 The results of the present study supported this finding, since TruNatomy has a 4% taper, whereas 2Shape and ProTaper Next had a taper of 6% at the tip. Moreover, contradictory to this, earlier findings stated that the larger taper did not essentially cause larger amount of debris to be extruded apically.18 The current study findings are in accordance with Mustafa et al. in 2021 and Cirakoglu, Ozbay in 2021.11,13 They concluded that TruNatomy instruments are associated with significantly lesser debris extrusion than ProTaper Next. However, till now, studies comparing TruNatomy and the 2Shape system are yet to be documented.\n\nThe features of instrument systems, like cross-sectional design, kinematics, tip diameter, and instrument taper, all affect debris extrusion.9 2Shape files have a cross-sectional design of an asymmetric triple helix i.e. it causes a non-uniform, lesser contact points between the file and the root dentin.14 These files have two leading cutting edges for enhanced cutting efficiency along with one secondary cutting edge for enhanced debris removal.\n\nThe ProTaper Next has an off-centered rectangular cross-sectional design. This design leads to only two-point contact with the canal wall at a time. It works in a snake-like swaggering motion leading to removal of more debris out of the canal.19 However, there may be a significant amount of debris pushed out of the apical third due to a greater taper on the instruments at the apical 3 mm.\n\nIn the current study, debris extrusion for both the groups i.e., 2Shape and ProTaper Next, had similar amount of extrusion. However, Paradkar et al. in 2020 found less debris extrusion with 2Shape compared to ProTaper Next system.20 Similar findings were stated by Ghoneim, Shaheen in 2018 and Alani, Al-Huwaizi in 2019.14,21\n\nFurthermore, several studies found that more extruded debris could be attributed to a greater number of files used during preparation.22,23 Hence, when more files are required to achieve the appropriate apical foramen size during instrumentation, it could lead to more significant debris extrusion.24 This could contradict our results, as TruNatomy instruments caused significantly less debris extrusion than the ProTaper Next and 2Shape. The TruNatomy comprises of three files i.e., an Orifice opener, a Glider, and the Prime file, whereas both 2Shape and ProTaper Next systems are comprised of only two files. However, Nevares et al. in 2017 and Bilgi et al. in 2017.25,26 stated the number of instruments did not seem to influence the results. Another factor for the least debris extrusion in TruNatomy could be coronal flaring, since the system consists of an orifice modifier. Leeb in 1983 stated coronal enlargement of an orifice cause early access to irrigating solutions.27 It allows shaping files to prepare the apical portion with reduced contact with root dentin and, therefore, less friction. Topcuoglu et al. in 2015 in their study mentioned that there is less apical debris extrusion when coronal flaring is done because the quantity of dentin available to extrude apically is minimized here, and it also provides a larger space for the debris to be washed out in a coronal direction when it is produced.28\n\nIn the present study, all the systems used were in continuous rotation, so there was no variable regarding instrument kinematics. A systematic review by Caviedes-Bucheli et al. in 2016 stated that the rotary instrument’s cross-sectional design significantly affected the quantity of debris extruded more than the motion kinematics.29\n\nAs per the result of the study, when all the conditions were standardized, all systems caused debris to be extruded apically. There are no methods that ultimately prevent debris extrusion, and the findings of the present study are consistent with those of previous studies.\n\nTanalp et al. in 2014 suggested that despite the absence of the specific threshold value of irritation, a smaller quantity of extruded material may be more prone to initiate a periradicular reaction if it is associated with a high bacterial content exhibiting high antigenic as well as virulence characteristics contrary to the high amount of extruded debris.8\n\nTherefore, the operator must make every effort to minimize the debris extrusion during instrumentation, which is in the operator’s hands to a large extent.\n\nThis study had limitations: the experimental model can’t reflect a clinical situation since periradicular tissues and bone naturally resist debris and irritant distribution. The apically extruded debris were measured and compared in single-rooted teeth with a single canal; the results may vary for multiple canals in single- or multi-rooted teeth. Sample selection was limited to teeth having a mature apex. The outcome may not match with the teeth showing open apices.\n\nTherefore, it was concluded that all three instrumentation systems led to debris extrusion even if the working length was kept 1 mm short of the root apex. Since this was an experimental study, due to the lack of periapical tissues providing the back pressure, debris extrusion could have varied. Within these limitations, the TruNatomy extruded a significantly lesser amount of debris compared to ProTaper Next and 2Shape system.",
"appendix": "Data availability\n\nZenodo: Comparative evaluation of apical debris extrusion during root canal preparation using three different rotary file systems, https://doi.org/10.5281/zenodo.7940511. 30\n\nThis project contains the following underlying data:\n\n- Book1.csv\n\nZenodo: STROBE checklist for “Comparative evaluation of apical debris extrusion during root canal preparation using three different rotary file systems”, https://doi.org/10.5281/zenodo.7940628. 31\n\n\nReferences\n\nSeltzer S, Naidorf IJ: Flare-ups in endodontics: I. Etiological factors. J Endod. 1985 Nov; 11(11): 472–478. PubMed Abstract | Publisher Full Text\n\nWaplington M, McRobert AS: Shaping the root canal system. Br. Dent. J. 2014 Mar; 216(6): 293–297. PubMed Abstract | Publisher Full Text\n\nReddy SA, Hicks ML: Apical extrusion of debris using two hand and two rotary instrumentation techniques. J. Endod. 1998 Mar; 24(3): 180–183. PubMed Abstract | Publisher Full Text\n\nHarrington GW, Natkin E: Midtreatment flare-ups. Dent. Clin. N. Am. 1992 Apr; 36(2): 409–423. PubMed Abstract | Publisher Full Text\n\nChapman CE, Collee JG, Beagrie GS: A preliminary report on the correlation between apical infection and instrumentation in endodontics. J. Br. Endod. Soc. 1968 Jan-Mar; 2(1): 7–11. Publisher Full Text\n\nVande Visse JE, Brilliant JD: Effect of irrigation on the production of extruded material at the root apex during instrumentation. J. Endod. 1975 Jul; 1(7): 243–246. Publisher Full Text\n\nMyers GL, Montgomery S: A comparison of weights of debris extruded apically by conventional filing and Canal Master techniques. J. Endod. 1991 Jun; 17(6): 275–279. PubMed Abstract | Publisher Full Text\n\nTanalp J, Güngör T: Apical extrusion of debris: a literature review of an inherent occurrence during root canal treatment. Int. Endod. J. 2014 Mar; 47(3): 211–221. Publisher Full Text\n\nTinoco JM, De-Deus G, Tinoco EM, et al.: Apical extrusion of bacteria when using reciprocating single-file and rotary multifile instrumentation systems. Int. Endod. J. 2014 Jun; 47(6): 560–566. PubMed Abstract | Publisher Full Text\n\nPeters OA, Arias A, Choi A: Mechanical Properties of a Novel Nickel-titanium Root Canal Instrument: Stationary and Dynamic Tests. J. Endod. 2020 Jul; 46(7): 994–1001. Publisher Full Text\n\nMustafa R, Al Omari T, Al-Nasrawi S, et al.: Evaluating in vitro Performance of Novel Nickel-Titanium Rotary System (TruNatomy) Based on Debris Extrusion and Preparation Time from Severely Curved Canals. J. Endod. 2021 Jun; 47(6): 976–981. PubMed Abstract | Publisher Full Text\n\nElnaghy AM, Elsaka SE: Assessment of the mechanical properties of ProTaper Next Nickel-titanium rotary files. J. Endod. 2014 Nov; 40(11): 1830–1834. Publisher Full Text\n\nYılmaz Çırakoglu N, Özbay Y: Apically extruded debris associated with ProTaper Next, ProTaper Gold and TruNatomy systems: An in vitro study. J. Dent. Res. Dent. Clin. Dent. Prospects. 2021; 15(1): 30–34. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlani MA, Al-Huwaizi H: Evaluation of apically extruded debris and irrigants during root canal preparation using different rotary instrumentation systems: An Invitro comparative study. Int. J. Med. Res. Health Sci. 2019; 8(2): 21–26.\n\nSchilder H: Cleaning and shaping the root canal. Dent. Clin. N. Am. 1974 Apr; 18(2): 269–296. Publisher Full Text\n\nVan der Vyver PJ, Vorster M, Peters OA: Minimally invasive endodontics using a new single-file rotary system. Int. Dent–African ed. 2019; 9(4): 6–20.\n\nKuştarci A, Akpinar KE, Er K: Apical extrusion of intracanal debris and irrigant following use of various instrumentation techniques. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2008 Feb; 105(2): 257–262. Publisher Full Text\n\nYılmaz K, Özyürek T: Apically Extruded Debris after Retreatment Procedure with Reciproc, ProTaper Next, and Twisted File Adaptive Instruments. J. Endod. 2017 Apr; 43(4): 648–651. Publisher Full Text\n\nRuddle CJ, Machtou P, West JD: The shaping movement: fifth-generation technology. Dent. Today. 2013 Apr; 32(4): 94, 96;–94, 99. 96-9. PubMed Abstract\n\nParadkar S, Saha SG, Bhardwaj A, et al.: A comparative evaluation of apical extrusion of debris during endodontic instrumentation with continuous rotation and reciprocating motion: An in vitro study. Endodontology. 2020 Oct 1; 32(4): 181. Publisher Full Text\n\nGhoneim WM, Shaheen NA: Apically extruded debris associated with different instrumentation systems and irrigation needles. Tanta Dent. J. 2018; 15: 105–110.\n\nOzsu D, Karatas E, Arslan H, et al.: Quantitative evaluation of apically extruded debris during root canal instrumentation with ProTaper Universal, ProTaper Next, WaveOne, and self-adjusting file systems. Eur. J. Dent. 2014 Oct; 8(4): 504–508. PubMed Abstract | Publisher Full Text\n\nDe-Deus G, Neves A, Silva EJ, et al.: Apically extruded dentin debris by reciprocating single-file and multi-file rotary system. Clin. Oral Investig. 2015 Mar; 19(2): 357–361. PubMed Abstract | Publisher Full Text\n\nSilva EJ, Sá L, Belladonna FG, et al.: Reciprocating versus rotary systems for root filling removal: assessment of the apically extruded material. J. Endod. 2014 Dec; 40(12): 2077–2080. Publisher Full Text\n\nNevares G, Romeiro K, Albuquerque D, et al.: Evaluation of Apically Extruded Debris during Root Canal Retreatment Using ProTaper Next and Reciproc in Severely Curved Canals. Iran Endod. J. 2017; 12(3): 323–328. PubMed Abstract | Publisher Full Text\n\nKaşıkçı Bilgi I, Köseler I, Güneri P, et al.: Efficiency and apical extrusion of debris: a comparative ex vivo study of four retreatment techniques in severely curved root canals. Int. Endod. J. 2017 Sep; 50(9): 910–918. PubMed Abstract | Publisher Full Text\n\nLeeb J: Canal orifice enlargement as related to biomechanical preparation. J. Endod. 1983 Nov; 9(11): 463–470. PubMed Abstract | Publisher Full Text\n\nTopçuoğlu HS, Zan R, Akpek F, et al.: Apically extruded debris during root canal preparation using Vortex Blue, K3XF, ProTaper Next and Reciproc instruments. Int. Endod. J. 2015 Dec; 49(12): 1183–1187. PubMed Abstract | Publisher Full Text\n\nCaviedes-Bucheli J, Castellanos F, Vasquez N, et al.: The influence of two reciprocating single-file and two rotary-file systems on the apical extrusion of debris and its biological relationship with symptomatic apical periodontitis. A systematic review and meta-analysis. Int. Endod. J. 2016 Mar; 49(3): 255–270. PubMed Abstract | Publisher Full Text\n\nRajnekar R: Comparative evaluation of apical debris extrusion during root canal preparation using three different rotary file systems [Data set]. Zenodo. 2023. Publisher Full Text\n\nRajnekar R: STROBE GUIDELINES. [Data set]. Zenodo. 2023. Publisher Full Text"
}
|
[
{
"id": "194274",
"date": "24 Aug 2023",
"name": "Sekar Mahalaxmi",
"expertise": [
"Reviewer Expertise Endodontics",
"pulp-dentin regeneration",
"nanotechnology",
"remineralisation",
"bonding"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbstract: ‘A total of 60 freshly extracted single‐rooted mandibular premolars were use.’ It should be ‘used’.\nIntroduction: Very well written introduction. A few comments though:\nPara 2: The authors can avoid old references and refer to some of the latest articles.\n\nPara 5: ‘After glide path preparation, the Prime (26/4%) file is recommended to use directly. The Small file is only used when the Prime file fails to advance smoothly or when the dentist is unsure about the Prime file. Through its slim design, regressive taper, instrument geometry and heat treatment, TruNatomy files conserve tooth integrity while preserving maximum pericervical dentine.’ This segment is unnecessary since the study involves evaluation of apical debris extrusion.\n\nParas 5, 6 and 7: Instead of providing the manufacturers’ details of the file system, the authors can state some studies comparing these instruments in terms of apical debris extrusion and other relevant parameters.\n\nWhat is the rationale of this study? Lacunae in literature is missing.\n\nIn the aim the authors have mentioned ‘….and evaluate the effectiveness of their design in minimizing the amount of apical debris extrusion during use.’ How was this evaluated?\n\nMethodology:\nSample size calculation: sample size has been calculated for 2 groups while the study has 3 groups?\n\n‘The irrigation was supposed to be passive irrigation as much as possible.’ This statement is very ambiguous and unscientific, please modify and mention the exact method of irrigation.\n\nResults:\nTables 1 and 2 can be avoided and table 3 can contain mean values with SD with comparisons between groups.\n\n'P-value' should be 'p-value'.\n\nDiscussion:\n‘A primary objective of cleaning and shaping involves preventing apical extrusion of debris and irrigants into the periradicular tissues.’ Please rephrase as the primary objective of C & S is not preventing debris extrusion.\n\nThe rationale of testing the mentioned three instruments among the plethora of rotary instruments available, is inadequate. Just choosing three instruments randomly does not contribute to comparison.\n\nPrevious literature on debris extrusion with contradictory results needs to be discussed as to the variation in the results obtained.\n\nAuthors' names can be mentioned without the year (in 2018, in 2019, etc. can be deleted).\n\nDiscussion needs some rearrangements in terms of explanation for debris extrusion. A bit confusing, when relating to the different factors causing apical extrusion of debris.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10330",
"date": "06 Oct 2023",
"name": "Rutuja Rajnekar",
"role": "Author Response",
"response": "Changes done in the abstract. Changes done in the introduction section. Stated the rationale & and stated the method of evaluation. Correction done in methodology. Results corrected. Discussion corrected. Rephrasing done with the C & S statement. Rationale mentioned. Years removed."
}
]
}
] | 1
|
https://f1000research.com/articles/12-797
|
https://f1000research.com/articles/11-1412/v1
|
30 Nov 22
|
{
"type": "Research Article",
"title": "Impact of brand equity and service quality on the reputation of universities and students’ intention to choose them: The case of IIUM and UIN",
"authors": [
"Sylvia Rozza Rizard",
"Bambang Waluyo",
"Irwandi Jaswir",
"Bambang Waluyo",
"Irwandi Jaswir"
],
"abstract": "Background: Numerous studies have been carried out on the impacts of brand equity and service quality of higher education institutions (HEIs) on their reputation and students’ satisfaction. This research aimed to compare the impact of brand equity and service quality on universities’ reputations, namely Universitas Islam Negeri (UIN) in Indonesia and International Islamic University Malaysia (IIUM) in Malaysia, and Indonesian students’ intention to choose the universities, which is moderated by study expense (price). UIN and IIUM are HEIs with a similar university concept, and Indonesian students have recently shown a high interest in them. The two universities have faculties not only in the field of Islamic studies but in general fields of studies as well, which are usually held by non-Islamic Universities. Therefore, their competitiveness against non-Islamic universities, especially the University of Indonesia (UI) has increased. Methods: The statistical measurement tool used was structural equation modeling (SEM). The number of items stated in the questionnaire was 45. Therefore, minimum data to be collected were 5 × 45 or 225 which rounded up to 228 from Indonesian students at UIN and IIUM (114 UIN students, and 114 Indonesian student respondents from IIUM). Results: The study results show that the universities’ reputations are strongly affected by their brand equity and service quality, which then affect students’ intention to choose the universities. Students had a higher intention to choose IIUM than UIN. The limitation of this research is that the effect of study expense on the intention of Indonesian students to study at UIN or IIUM has not yet been conducted. It will be conducted in the next study. Conclusions: These results are expected to be useful to UIN, IIUM, and especially Politeknik Negeri Jakarta (PNJ) in determining a strategy to enhance their reputations and the intention of Indonesian students to study there.",
"keywords": [
"brand equity",
"price",
"service quality",
"students’ intention",
"university’s reputation"
],
"content": "Introduction\n\nOne form of higher education institution (HEI) in Indonesia is Institut Agama Islam Negeri (IAIN), which is an Islamic university that provides academic education in Islamic religious disciplines. The first IAIN was established in Yogyakarta in 1960. In 2002, IAIN Syarif Hidayatullah in Jakarta was changed to a State Islamic University, namely Universitas Islam Negeri (UIN). Many other IAINs were established throughout Indonesia, until 2019. The UIN format allows universities to open faculties or departments in other fields of study outside of Islamic studies. The impact of these changes is the increase in the number of universities that offer majors in faculties of non-Islamic studies that can be chosen by prospective students. Several faculties or departments that usually only exist in non-Islamic study universities, such as economics, psychology, biology, pharmacy, medicine, electrical engineering, mechanical engineering, and civil engineering are currently also fields of studies offered at UIN. Consequently, UIN has become a competitor of non-Islamic study universities as an alternative choice of institution for prospective students to attend. The number of students who are interested in studying at UIN continues to increase, while the number of students who enrolled at the University of Indonesia (UI), the biggest competitor of UIN, has decreased (https://pddikti.kemdikbud.go.id/perbandingan/perguruan).\n\nFrom the numerous studies done in this context, it can be concluded that students’ satisfaction or loyalty to a university is influenced by factors such as brand equity, and the service quality of the university. Both of these variables have an impact on a university’s reputation (Ali M., and Ahmed M., 2018; Amal S. A, Shurair, and Pokharel S., 2019; Arian M. and Khoshtaria, T 2020). So, reputation is an important factor that determines satisfaction or loyalty (Aidah, Supardi, Juhji; 2020; Pinar, M., Girard, T., and Basfirinci C., 2020; Polkinghorne, M., Roushan, G., and Taylor, J. 2017). However, this research was conducted with different research models, to measure the effect of brand equity and service quality on universities’ reputations and prospective students’ intention to choose them. The researchers could not find this type of research framework.\n\nAnother factor considered is the study expense (tuition fee + living cost) at the selected universities (McGettigan, A. 2013; Palfreymam, D., and Tapper, T., 2016). Since the birth of UIN, there has been a decrease in the number of prospective students choose non-Islamic universities. This is because UIN also offers academic courses that were previously only offered at non-Islamic universities. The reputation of UIN is quite good, and its study expense is lower. This is shown by the accreditation of many of UIN’s study programs bestowed by The National Accreditation Board (BAN-PT) as grade “A”. So, the number of interested students who study at UIN has increased.\n\nOne of the universities with an Islamic concept in neighboring country Malaysia is the International Islamic University Malaysia (IIUM). This university is also a competitor of non-Islamic universities and UIN in Indonesia. The number of Indonesian students who are interested in studying at IIUM is also increasing. In choosing a place to study in Malaysia, prospective Indonesian students also consider the same factors that are applicable in Indonesia, which are moderated by study expenses in that country (Zeithaml, A., 1988).\n\nThis study aimed to compare the intention of Indonesian students to choose UIN or IIUM as a place to study. The researchers have not been able to find research in Indonesia that examines the impact of a university’s reputation based on its brand equity and service quality on students’ intention to choose it. The results of this study are expected to be useful to UIN, and IIUM in formulating policies to determine factors that affect their reputation and students' intentions to choose them. The results will also be useful to Indonesian universities in making the same policies and strategies. This study is also applicable to Jakarta State Polytechnic (PNJ), who funded this research in formulating strategies to help PNJ gain a better reputation. It will result in a higher number of quality graduates, and ultimately increases the competitiveness of graduates, which is one of the visions of PNJ.\n\nStudents are customers (Royo, 2017), in the marketing concept. To study in a university, sometimes they pay a lot of money; expensive tuition fees are usually correlated with the quality of education at the university. For this reason, they deserve all the best services from the university (Mehrtens, I., 2016). Nuriah and Rahma (2018) examined the influence of a university’s reputation on students' decisions to choose the university. They concluded that the reputation of a university reflects the quality of the university so that it becomes a determinant of students' choices for it. Mourad, Ennew, Kortam (2011), examined the effect of word of mouth (WOM) and a university’s reputation on students' decisions to choose a university. They concluded that WOM had no effect on students’ decisions in choosing a university, but the university’s reputation did. Mwiya, Bwalya, Siachinji, Sikombe, Chanda, and Chawala (2017), conducted research in Zambia on the effect of the quality of higher education services on students’ satisfaction and behavioral intentions in the form of positive loyalty and WOM. The results of this study indicate that all dimensions of the quality of educational services have a significant positive effect on students’ satisfaction, and ultimately affect their loyalty and willingness to spread positive WOM.\n\nBesides the above objectives, this research was also conducted to support the implementation of PNJ's Strategic Planning of Research (RENSTRA), where the research roadmap for the 2019-2025 period focuses on the market. The market is defined as the collection of actual and potential buyers of a product. While the product is anything that can be offered to the market that can satisfy wants and needs (Kotler, P., and Armstrong, G., 2014). The market in the context of this research is customers or students studying at the university. This study measured the influence of brand equity and quality of educational services on the reputation of a university, as well as students' intentions to choose a university. Brand equity, service quality, and companies’ reputation are intangible market-based assets that affect customers’ satisfaction (Almarri, Khalid and Gardiner, Paul, 2014; Walsh and Beatty, R. Sharon, 2007). In the context of PNJ as a HEI, this also applies.\n\nFrom relevant studies that have been carried out, no research has compared the effect of brand equity and service quality on the reputation of the two universities (from Indonesia and Malaysia) with similar concepts and the intentions of Indonesian students to study at either university, which are currently in high demand.\n\nIn this study, four constructs wereproposed, namely brand equity, service quality, companies’ reputation, and price. Their impact on customers’ intentions was analyzed. Brand equity and service quality directly affect a company's reputation. Furthermore, the reputation of a company that is moderated by price will have an impact on customers’ intentions. These constructs are explained as follows.\n\nBrand equity is one of the most prized assets of firms and a key concept for marketing academics (Ambler, 2003; Christodoulides and de Chernatony, 2010; Christodoulides, Cadogan, J. and Veloutsou, V., 2015). Although brand equity has been extensively researched in the context of physical products, less attention has been devoted to understanding the concept in relation to a service sector context (Mourad, et al., 2011). Świtała, Gamrot, Reformat, and Reformat (2018) said that numerous definitions explaining the essence of the brand have been provided in the literature over the last twenty years (Kall, 2005; Kapferer, 2008; Keller, 2011; Witek-Hejduk, 2011). Brand equity is defined as a set of assets connected to the brand name and add value to the product/service for customers (Dennis, S., Alamanos, E. and Bourlakis, M. 2016). Arian M. and Tornike Khoshtaria, (2020) said that brand equity affects the reputation of a company. Keller, K. (2013), Schiffman, LG. and Kanuk, L. (2004), defined brand equity as a different response from consumers to a good brand compared to unbranded products when both have the same marketing stimuli and attributes. Meanwhile, Priporas, V., and Kamenidou, I. (2011), and Yoo, and Donthu (2001) defined brand equity from the customer's perspective as the differential effect of brand knowledge on consumers’ response to the marketing of the brand. From these various definitions, the consensual definition is that brand equity increases the value of a product because of its brand name (Khanna, M., Jacob, I., and Yadav, N. 2015). The concept of brand equity is of particular relevance to consumers’ choices (Mourad, et al., 2011). The brand equity dimension in this matter is brand awareness which consists of brand recognition, brand recall, and brand image which means strong, favorable, and unique associations of the brand in the customer’s memory (Keller, 2013). Pinar, M., Trapp, P., Girard, T., and Boyt, T. (2013), Pinar, M., Trapp, P., Girard, T., and Boyt, T. (2011), Walsh and Beatty, R. Sharon, (2007) explained that there are four brand dimensions, namely brand loyalty, brand awareness, perceived quality, and brand associations (Sapna and Sheetal 2016). This study aimed to measure the impact of brand equity on the reputation of the university (Lomer, S., Papatsiba, V., and Naidoo, R. 2018; Chapelo, C., 2015).\n\nService quality is the totality of the characteristics of goods and services that show their ability to satisfy customers’ needs, both obvious and hidden. For companies engaged in the service sector, providing quality services to customers is an absolute requirement if they want to achieve success (Kotler, P., and Armstrong, G., 2014). Another definition of service quality is the effort to fulfill the needs and desires of consumers and the accuracy of their delivery in balancing consumers’ expectations. Dimensions of service quality are reliability, responsiveness, assurance, empathy, and tangibility (Zeithaml, A. V., Bitner J. M., and Gremler D. D., 2013). In this study, the quality of educational services affected the reputation of the university (Gronroos, C. Kamalanabhan, T.J., and Seebaluck, A.K., 2019; Polkinghorne, M., Roushan, G., and Taylor, J. 2017).\n\nA company’s reputation is defined as a collective representation that shows the company's position internally to its employees, and externally to its stakeholders (Arian M. and Tornike Khoshtaria, 2020). Another definition of corporate reputation is knowledge of a company's actions and the results of the crystallization of the company's ability to deliver valuable outcomes to its stakeholders (Nuriah and Rahma, 2018). Corporate reputation is customers' overall evaluation of a company based on their reactions to products, services, communication activities, and interaction with the company’s representations and/or known activities (Walsh and Beatty, 2007). Corporate reputation dimensions in this context include customers’ orientation, being a good employer, being a reliable and financially strong company, product and service quality, and social and environmental responsibility (Walsh and Beatty, 2007). A company’s reputation is a critical construct interpreted as the stakeholder’s perception of the company as a whole (Walsh and Wiedmann, 2004). The reputation of the company in this study was the reputation of the university chosen by students as an antecedent of their choice.\n\nPrice is the amount of value that customers exchange for having or benefiting from having or using a product or service (Kotler and Armstrong, 2014; Zeithaml, A., 1988; Palfreymam, D., and Tapper, T., 2016). Dimensions of price are affordability, price competition, compatibility of price and quality of product, and compatibility of price and benefit of product (Kotler and and Armstrong, 2014). In the context of studying at a university, price means study expense which consists of tuition fees and living costs incurred. Price will moderate the influence of a company’s reputation and students' intention to choose a university (McGettigan, A., 2013).\n\nIntention or interest is a high inclination of one’s heart towards something; excitement, desire. Buying interest is the stage of a customer's tendency to act before the buying decision is actually implemented (Chong, Y.S. and Ahmed, P.K. 2015; Constantinides and Stagno, 2012). According to Ali M., and Ahmed M. (2018) and Amal S. A, Shurair and Shaligram Pokharel (2019), the intention is a consumer's interest in a product by seeking additional information. Consumers’ buying interest entails a consumer having a desire to buy or choose a product, based on experience in choosing, using and consuming, or even wanting a product. Satisfaction in buying goods or services strengthens interest in buying. Dissatisfaction usually eliminates interest. Customers’ satisfaction has been seen to produce four outcomes for shareholders, in this case, the university concerned (Arian M. and Tornike Khoshtaria, 2020): 1. Satisfied customers will be encouraged to buy more from the company. 2. Satisfied customers will buy various products from the company. In the context of a university, satisfied students will be interested in continuing their studies at the same university. 3. Recommendations and positive WOM can also be carried out by satisfied customers, which will increase the value of the university. Dimensions of customers’ intention are transactional intention, referral intention, preferential intention, and explorative intention (Schiffman and Kanuk, 2004). Satisfied students will recommend the university where they studied to their relatives or other people. 4. Customers who are increasingly satisfied will provide opportunities for a company to increase prices, thereby increasing the value of the company. Satisfied students will provide opportunities for universities to increase their tuition fees, making it more profitable for the universities. Harahap, Hurriyati, Gaffar and Amanah (2018) said that the reputation of a university strongly affects the intention to choose the university.\n\n\nMethods\n\nThe study samples were Indonesian students attending two well-known universities namely Universitas Islam Negeri (UIN) Syarif Hidayatullah in Jakarta, an education provider using both Islamic and non-Islamic concepts, and Indonesian students studying at International Islamic University Malaysia (IIUM) in Malaysia. The population of the research was Indonesian students at the two universities. Due to the lack of an Institutional Review Board at the researchers’ institution, no formal ethical approval could be obtained for this research. However, this research is considered low-risk due to the scope of the survey and nature of data collected, i.e. factors affecting Indonesian students’ choice of university in Indonesia. The Director of Politeknik Negeri Jakarta (PNJ) approved the research beforehand and informed the respondents that responses would be kept anonymous and published only to support this study, and written informed consent was obtained from participants.\n\nThis research was planned to last for two years. Measuring the effect of brand equity and service quality of the universities on their reputation and the intention of Indonesian students to choose the universities was carried out in the first year. Furthermore, the moderation of study expenses on the influence of the universities’ reputation and students' intention to choose the universities was measured in the second year. The framework of this research is shown below (Figure 1).\n\nThe study subjects were Indonesian students studying at two well-known universities, namely UIN Syarif Hidayatullah in Jakarta, and Indonesian students studying at IIUM. The population of the research was Indonesian students at the two universities. Non-probability sampling method was used to select the respondents as indicated in the questionnaire. The statistical measurement tool used is Structural Equation Modeling (SEM) (Wijanto, 2008), stated that number of respondents should be collected is at least 5 × number of items in the questionnaire. The number of statement items stated in the questionnaire was 45. Therefore, data were collected from 5 × 45 or 225 which rounded up to 228 Indonesian students at UIN and IIUM. 2 PNJ students worked as research assistants collected the data from 114 UIN students, and the other 2 did it from 114 Indonesian student respondents from IIUM. The questionnaire was compiled from the dimensions of each construct and then derived into various indicators.\n\n\nResults\n\nA two-step approach was used in analyzing the research model (Anderson and Gerbing, 1988). In the first step, the analysis was done on the measurement model. This was done to check whether the measurement model has good validity and reliability in the sample data used. The second step entails adding a structural path based on the hypotheses of the measurement model to produce the hybrid model. The model and structural relations proposed in the hypotheses were analyzed and evaluated. The measurement model has 4 latent variables namely brand equity, service quality, higher education reputation, and customers’/students’ intention to study at the universities.\n\nThe validity of the measurement model was seen from the standardized loading factor from each indicator of variables by checking its significance with its latent variables. The standardized loading factor used was ≥ 0.5 (Igbaria, Zinatelli, Cragg and Cavaye, 1997). Reliability was measured in average variance extracted (AVE), and composite reliability (CR). The reliability of a good measurement model is CR ≥ 0.70 and AVE ≥ 0.50. CR and AVE were taken from standardized loading factors and error variances (Wijanto, 2008).\n\nThe results of the validity test show that the answers of the UIN and IIUM respondents to all the statement items have a validity coefficient greater than r-critical 0.3. The answers to these items are feasible or valid. Reliability testing is carried out on the statement items that are included in the valid category. This result indicates that the statement items are reliable, as shown by standardized loading factors in Table 1 below. All the indicators of the variables have a standardized loading factor value > 0.5. All measured variables have good validity and reliability value with AVE > 0.5 and CR > 0.7. The Measurement model and Structural model of UIN can be seen in Figures 2 and 3, while, the Measurement model and Structural model of IIUM can be seen in Figures 4 and 5.\n\nRemark: EM = BE (Brand Equity), KL = SQ (Service Quality), REP = Reputation, HRG = P (Price), Minat = I (Intention).\n\nRemark: EM = BE (Brand Equity), KL = SQ (Service Quality), REP = Reputation, HRG = P (Price), Minat = I (Intention).\n\nRemark: EM = Ekuitas Merek (Brand Equity = BE), KL = Kualitas Layanan (Service Quality = SQ), REP = Reputation, HRG = Harga (Price = P), Minat = Intention = I.\n\nHypotheses test results done in UIN can be seen in Table 2 below. All of the hypotheses are supported. Brand equity and service quality affect the reputation positively and significantly. Likewise, reputation affects students’ intention to choose the university.\n\nTable 3 shows the Goodness of fit on UIN. All of the goodness of fit test results are in good fit. It means that all of the test results are over the standard.\n\nThe hypotheses test result of IIUM can be seen in Table 4 below. All the hypotheses are also supported positively and significantly, as well as UIN’s.\n\nThe goodness of fit of IIUM is shown in Table 5 below. All of the goodness of fit test results are in good fit which is indicated by all of the test results are above the standard.\n\n\nDiscussion\n\nBased on the statistical results, the brand equity of a university affects its reputation positively and significantly (Arian M. and Tornike K., 2020). The item with the highest score that influenced the reputation of the two studied universities was the students’ recognition of their superiority. The item with the lowest score was the students’ immediate recognition of the logo of the universities. However, the effect of all item scores of brand equity on the universities’ reputations was positive and significant. Indonesian students recognized and knew well that UIN and IIUM are currently in high demand. The results show that the universities’ brand equity affects their reputation (Ambler, 2003; Christodoulides and de Chernatony, 2010; Christodoulides et al., 2015). The influence of brand equity on the reputation of IIUM was stronger than that of UIN.\n\nThe results of the statistical tests showed that service quality affects the universities’ reputation positively and significantly (Gronroos, C. et al., 2019; Polkinghorne, M. et al., 2017). Out of 19 question items posed to the respondents, the item with the highest score that influenced positively and significantly the reputation of UIN was the students’ belief that the university would meet their needs. It indicates that the highest score at UIN is in the reliability dimension, while for IIUM, the highest score was in the responsiveness dimension, i.e. its immediate response in serving the students. Usually, the reliability dimension is the most important dimension in a service firm such as a university (Zeithaml, A. V. et al., 2013). The item with the lowest score which influenced the reputation of UIN was its consistency in providing the timetable of its academic activities. While for IIUM, it was the neat appearance of its employees. These items’ scores were low because the students did not consider timetable information and appearance as the main factors needed to build a university’s reputation. However, answers to all the questionnaire items were positive and significant. Service quality had more effect on UIN than IIUM. It could be because the students believed that UIN can meet their needs. While at IIUM, although the responsiveness of the university was higher, the students did not consider service quality to be the most important thing.\n\nThe influence of service quality on reputation was stronger than that of brand equity. The universities’ reputation positively and significantly affected students’ intention to choose them (Harahap et al., 2018). The item with the highest score in this matter was the students who wanted to search for more positive information about the universities. The students intended to choose IIUM more than UIN. This could be a result of IIUM having a greater reputation than UIN, as seen in the results of the statistical tests. Therefore, it proves that the higher the reputation, the stronger the intention to choose a university. A good reputation is affected by the brand equity and service quality of the university.\n\n\nConclusions\n\nThis is the first research that compares Indonesian students’ intention to choose a university with the same concept in Indonesia and Malaysia. The study results show that the brand equity and service quality of a university affect its reputation. In turn, reputation affects students’ intention to choose a university. The higher the reputation of a university, the stronger will the students’ intention to choose it be. This is the first research conducted in this area to the best of the researchers’ knowledge. Hence, it might help universities in Indonesia to enhance their brand equity and service quality to gain a higher reputation, since reputation is an important factor that influences students’ intention to choose a university. This will cause more students to enroll in the universities. The findings also provide a reference for UIN and IIUM, and especially PNJ in making strategies to increase their reputations and students’ intention to choose them.",
"appendix": "Data availability\n\nFigshare: Raw Data result of survey, https://doi.org/10.6084/m9.figshare.19826404 (Rozza, 2022a)\n\nThis project contains the following underlying data:\n\n- Raw data for F1000 update.csv\n\nFigshare: Questionnaire Research, https://doi.org/10.6084/m9.figshare.20506776 (Rozza, 2022b)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nAidah S, Supardi, Juhji: IMPROVING SCHOOL IMAGES THROUGH EDUCATION MARKETING MANAGEMENT. JIEM (Journal of Islamic Education Management). 2020; 4(1): 2549-0877.\n\nAli M, Ahmed M: Determinants of students’ loyalty to university: A service-based approach.2018. Paper No. 84352, posted 07 Feb 2018 18:38 UTC.Reference Source\n\nAlmarri K, Gardiner P: Application of Resource-Based View to Project Management Research: supporters and opponents. 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Warszawa:Wolters Kluwer;2011.\n\nYoo B, Donthu N: Developing and validating a multidimensional consumer-based brand equity scale. J. Bus. Res. 2001; 52: 1–14. Publisher Full Text\n\nZeithaml A: Consumer perceptions of price, quality, and value: A means-end model and synthesis of evidence. J. Mark. 1988; 52(3): 2–22. Publisher Full Text\n\nZeithaml AV, Bitner JM, Gremler DD: Services Marketing. Sixth Edition.McGraw. Hill International;2013. Printed in Singapore.\n\nhttp"
}
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[
{
"id": "176120",
"date": "09 Jun 2023",
"name": "Yuen-Onn Choong",
"expertise": [
"Reviewer Expertise Educational management",
"leadership",
"behavioural studies"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for allowing me to review the paper entitled \" Impact of brand equity and service quality on the reputation of universities and students’ intention to choose them: The case of IIUM and UIN\" Here are some suggestions to improve the paper:\n1. Originality: Does the paper contain new and significant information adequate to justify publication?\nThe current version of the abstract is not well written. There is some important detail of the study is not mentioned in the abstract. First of all, it should start from the main aim of the study and tell a little bit about the novelty of this study. This followed by the research method such as sample size, method/technique used to test the hypotheses and model. Then end with the key findings and implications of the study. What’s new to this study?\n\nI have noticed that the introduction lacks a well-structured and cohesive argument regarding the inclusion of brand equity and service quality in this study and its relationship to reputation and satisfaction. The authors have not clearly articulated why this concept is being investigated and what significance it holds. It is important for them to provide a clear picture and rationale behind the study of reputation and satisfaction. Furthermore, it would be beneficial for the authors to address any potential shortcomings or limitations associated with the concept of the study in order to strengthen their argument.\n\nAuthors have highlighted several past studies. Authors also claimed that there are many studies examined all these variables. Thus, authors fail to explain how and what these studies lack of. By doing so, they can establish a foundation and context for their own research. Subsequently, the authors can explain the gaps or limitations that exist in the previous studies, providing insights into how their own study differs and addresses those gaps. This approach will help the authors identify the novelty and unique contribution of their research. Is the comparison between two universities is one of the issues? Is this worth to know the differences?\n\nIn addition, it is important for the authors to emphasize the urgency of their study and clearly articulate how it relates to the key concepts. They should outline the significance and potential implications of their research, highlighting why it is important to explore all these key concepts within the context of the study. By clearly expressing the relevance and timeliness of their work, the authors can engage readers and establish a compelling rationale for conducting the research.\n2. Relationship to Literature: Does the paper demonstrate an adequate understanding of the relevant literature in the field and cite an appropriate range of literature sources? Is any significant work ignored?\nShould have a standalone section for underpinning theory to explain how the path relationships work.\n\nHypotheses should be proposed in the literature review. Should also talk about the interrelationship between the variables.\n\nThe propose conceptual framework should be presented in the literature review section.\n3. Methodology: Is the paper's argument built on an appropriate base of theory, concepts, or other ideas? Has the research or equivalent intellectual work on which the paper is based been well designed? Are the methods employed appropriate?\nThe methodology section needs substantial improvement. To enhance clarity and understanding, it is recommended to divide the section into two subsections: (1) research procedure and sample, and (2) research instruments. This division will provide a clear structure and allow readers to easily navigate the methodology section.\n\nTo improve the paper, it is important to clearly define the context of the study and provide strong justifications for the chosen target respondents. Provide a concise and clear explanation of the context in which the study is conducted.\n\nAny translation conducted for the adopted instrument? What translation method used?\n\nDiscuss the generalizability and representativeness of the sample in relation to the target population. Clearly explain how the chosen sample is intended to be representative and reflect the larger population. Highlight any strategies employed to ensure a diverse and inclusive sample.\n\nIt is important to clearly explain the sampling technique used in the study, along with the rationale for its selection. Additionally, the authors should describe how they used this sampling technique to select respondents for the survey, ensuring generalizability and representativeness towards the targeted population.\n\nWhat do you mean round up to 228? I though round up mean you should round up to 230 or 250.\n\nWhat software used in this study? Provide adequate justification.\n\nThe procedure of data collection is too limited. More information should be provided on how the authors collected the data, approached the respondents, and identified them to participate in the survey. The explanation should be logical and reasonable, without exaggeration.\n\nIncluding control variables in the study is indeed a good practice as they can help account for potential confounding factors that may influence the results. To improve the paper, it is important to include control variables and provide reasonable justifications for their inclusion.\n4. Results: Are results presented clearly and analysed appropriately? Do the conclusions adequately tie together the other elements of the paper?\nDemographic profile or characteristic of sample is very limited. Should report more.\n\nThe abundance of study results presented has made it challenging to comprehend and digest the findings. The extensive presentation of these results has resulted in a loss of interest and motivation to continue reading the paper. Authors should present the result in a more systematic way and organised. Simplify your result instead of giving so many figures and tables to made reader confuse and difficult to understand.\n\n5. Practicality and/or Research implications: Does the paper identify clearly any implications for practice and/or further research? Are these implications consistent with the findings and conclusions of the\nThe discussion and conclusion are required substantial improvement.\n\nThe current version of the discussion is too shallow. The authors need to ensure that the key findings are discussed. The discussion section is where you delve into the meaning, importance, and relevance of your results. It should focus on explaining and evaluating what you found, showing how it relates to your literature review and research questions, and making an argument in support of your overall conclusion.\n\nThere should be a standalone section for theoretical implications. How can you imply from the findings? This section should discuss the implications of the study's findings and how they contribute to the existing theoretical knowledge. Summarize the key findings and their relevance to the existing theoretical frameworks or models. Analyze how the findings align with or challenge current theoretical perspectives and concepts related to all the key concepts of this study. Discuss any theoretical insights or advancements that the study provides and highlight how the findings contribute to a deeper understanding of the research area.\n\nThere should be a standalone section for practical implications. I would suggest the author provide implications based on current practices and policies.\n\nThe current form of limitation and future research recommendation section is not well written. In this section, the authors should conscientiously identify the potential weaknesses or limitations of the study and provide insightful suggestions for future research directions. By incorporating this standalone section, the paper will not only address its own limitations but also serve as a valuable resource for researchers seeking to build upon the current study and expand the knowledge base in the field.\n\nShould have a standalone section for limitation and future research recommendation section. In this section, the authors should conscientiously identify the potential weaknesses or limitations of the study and provide insightful suggestions for future research directions. By incorporating this standalone section, the paper will not only address its own limitations but also serve as a valuable resource for researchers seeking to build upon the current study and expand the knowledge base in the field.\n\n6. Quality of Communication: Does the paper clearly express its case, measured against the technical language of the field and the expected knowledge of the journal's readership? Has attention been paid to the clarity of expression and readability, such as sentence structure, jargon use, acronyms, etc.\nAdd more recent citations.\n\nRequired professional proofreading and editing services.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "185234",
"date": "25 Jul 2023",
"name": "Mochammad Riyadh Rizky Adam",
"expertise": [
"Reviewer Expertise marketing",
"branding",
"social marketing",
"green marketing",
"sustainable marketing",
"cause-related marketing",
"digital marketing",
"social media marketing."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for inviting me to review the research paper, titled \"Impact of brand equity and service quality on the reputation of universities and students’ intention to choose them: The case of IIUM and UIN\". Here are some concerns that need more work:\nSeveral issues with the abstract section:\nThe novelties that the paper brought are not visible to the readers.\n\nAfter the author said “Numerous studies have been carried out on the impacts of brand equity and service quality of higher education institutions (HEIs) on their reputation and students’ satisfaction…..”, it would be best and clear if the authors show the gap between existing literature and the things/situation that happening in the higher education industries.\n\nMany misunderstandings. The abstract makes the claim that the study expense (price) acts as a moderator, yet this is at odds with the research framework presented on page 6. In the SEM measurement model illustrations, however (pages 7-9), the price variable clearly plays the role of a mediator (rather than a moderator). In addition to these, it is stated that the limitation of the study is the effect of study expense on the intention to study has not been conducted. However, we can see that the study examined the relationship between the study expense and the intention to study for both universities.\n\nKey information in the research methodology were not displayed well. Several other missing important information: research type, sampling method, data method of obtaining data.\nSeveral issues with the introduction section:\nThe structure of the writing should be improved more to give good flow of the understanding so that the readers will understand what happens in Indonesia and Malaysia, why such investigation (comparing Indonesia and Malaysia) is crucial to be done (Can't the authors find the answers of the research questions from the existing empirical research papers?). It is also important to provide solid reason why brand equity, service quality, reputation, and study expense (price) are important factors that happens in the higher education especially in the discussion of intention to study in the Islamic-based and Non-Islamic-based universities. Several details comments as follow:\n\nIt's important to differentiate between universities founded on Islamic principles and those that weren't from the outset, thus distinct terms should be used to describe each. The authors may differentiate between Islamic universities and non-Islamic universities to avoid confusion. As the example, the authors wrote with this statements: \"The UIN format allows universities to open faculties or departments in other fields of study outside of Islamic studies. The impact of these changes is the increase in the number of universities that offer majors in faculties of non-Islamic studies that can be chosen by prospective students.\"\nI think it would be clear if stated with this way \"The UIN format allows Islamic-based universities to open faculties or departments in other fields of study outside of Islamic studies. The impact of these changes is the increase in the number of Islamic-based universities that offer majors in faculties of non-Islamic studies that can be chosen by prospective students.\"\n\nPrecise justification needed to support the thought that \"The number of students who are interested in studying at UIN continues to increase, while the number of students who enrolled at the University of Indonesia (UI), the biggest competitor of UIN, has decreased\". It would be difficult for the readers who are interested to explore further the justification (by clicking the provided link) as the link is kind of a do-it-yourself-find-yourself page.\n\nIf the authors claim no similar research framework already exists in the literature, the authors should provide stronger and clear explanations and evidences for the claim. From the paper, it is clear to the readers that research into the relationship between brand equity-service quality and reputation has been conducted.\n\nThe above comment leads to this concern: the research gap should be explained well. So that the readers will understand the existing literature lack of. The readers will also identify the novelty(ies) easily.\n\n\"The researchers have not been able to find research in Indonesia that examines the impact of a university’s reputation based on its brand equity and service quality on students’ intention to choose it\".- How about from other countries research papers? From other context/industry?\nSeveral issues with the literature section:\nIs there a theory that underpins the entire research model? If so, the readers would want to know about it in the literature section.\n\nThere is no explanation about the research framework. Please explain and elaborate it clearly in the literature section\n\nThe proposed hypotheses should have been explained with strong justifications (from existing empirical research papers and/or qualitative research if any/conducted). Please provide the explanation and justification how the proposed hypotheses were developed.\n\nIf the measurement model displays study expense (price) as the mediating variable, does study expense (price) have a positive or negative effect on the intention to study? The answer will affect how the raw data of study expense (price) will be processed (converted to the opposite scale code or not).\nSeveral issues with the methodology section:\nThe methodology part should be re-written in order to give good understanding how the authors conducted the study.\n\nMinimum information to be provided: research type, targeted population, data collection method, sampling method, sampling size (the round up does not make sense), research instruments/questionnaire explanation (screening question, questionnaire structure, measurement items and scales), back translation technique used or not, data analysis techniques including with the software used (did the authors do any test before the SEM such as multivariate assumption test?).\n\nSince it will be biased if we ask about the intention to choose/to buy/to purchase to someone who has chosen/enrolled/purchased already, the authors should explain why they distributed the questionnaire to respondents who have become students already (for both UIN and IIUM). There should be an explanation (in the literature section) with strong justifications that the intention to choose/to buy/to purchase is the same as the intention to re-choose/to re-buy/to re-purchase.\n\nIf the intention to choose/to buy/to purchase is the same as the intention to re-choose/to re-buy/to re-purchase, the authors need to put the context how the respondents who have become the students asked about the intention to choose. Show the measurement items of the intention to choose would be great for the readers.\n\nWere the questionnaire questions written in a retrospective question/statement manner, given that the respondents asked were the ones who have been students already? If this approach was taken, the authors must give the reason why this method was taken, given that the dependent variable was intention, not purchase decision.\n\nIt's good also if the methodology section can be explained in a table, displaying the whole process/stages done or conducted by the authors.\n\nIt would be helpful if the authors detailed the procedures used on the pretest sample (taken before the final/big sample was collected, if any).\n\nIt would be helpful if the authors mentioned the software used in running the SEM analysis.\nSeveral issues with the results section:\nIt would have been helpful to see profiles of the respondents in terms of the demographics.\n\nThe results part can be re-structured in order to give good flow and capture the whole process done. This does not mean the authors have to explain in detail, but the authors could tell what process that has been done with the key results only (these can be displayed in a/several tables) to inform the readers that the data have actually through multiple examinations before jumping to the SEM or hypotheses testing results.\n\nSince there are H3 (Reputation to Price) and H5 (Price to Intention), the role Price needs to be clear whether as mediating variable or moderating variable between a relationship (is it between reputation to intention? This answer will affect the results and discussion.\n\nSeveral issues with the conclusion section:\nIt would be great for the readers to know the implications of the study. Is there any implications for the industry, for the companies (what recommendations the authors suggest to do according to the results) or for the theory development.\n\nIs there any recommendations or path that can be taken for further research?\nSeveral issues with the references:\nIf the literature review was revised, it would include more sources.\n\nUse the recent references.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-1412
|
https://f1000research.com/articles/12-877/v1
|
25 Jul 23
|
{
"type": "Method Article",
"title": "Autonomous, bidding, credible, decentralized, ethical, and funded (ABCDEF) publishing",
"authors": [
"Taiki Oka",
"Kaito Takashima",
"Kohei Ueda",
"Yuki Mori",
"Kyoshiro Sasaki",
"Hiro Taiyo Hamada",
"Masahito Yamagata",
"Yuki Yamada",
"Taiki Oka",
"Kaito Takashima",
"Kohei Ueda",
"Yuki Mori",
"Kyoshiro Sasaki",
"Hiro Taiyo Hamada",
"Masahito Yamagata"
],
"abstract": "Scientists write research articles, process ethics reviews, evaluate proposals and research, and seek funding. Several strategies have been proposed to optimize these operations and to decentralize access to research resources and opportunities. For instance, we previously proposed the trinity review method, combining registered reports with financing and research ethics assessments. However, previously proposed systems have a number of shortcomings, including how to implement them, e.g., who manages them, how incentives for reviewers are paid, etc. Various solutions have been proposed to address these issues, employing methods based on blockchain technologies, called “decentralized science (DeSci)”. Decentralized approaches that exploit these developments offer potentially profound improvements to the troubled scientific ecosystem. Here, we propose a system that integrates ethics reviews, peer reviews, and funding in a decentralized manner, based on Web3 technology. This new method, named ABCDEF publishing, would enhance the speed, fairness, and transparency of scientific research and publishing.",
"keywords": [
"decentralized science",
"registered reports",
"reproducibility",
"scientific ecosystem",
"funding"
],
"content": "Introduction\n\n\n\n“By mutual confidence and mutual aid, Great deeds are done, and great discoveries made.”—Homer, “The Iliad”\n\nCurrent scientific endeavors have become complicated and protracted. Science advances by sifting through numerous findings made by many individuals and organizations. However, the current ecosystem of science suffers from various problems. First, researchers spend great amounts of time writing grant proposals to obtain research funding rather than conducting scientific investigations (Herbert et al. 2013). Funding decisions rely heavily on citation metrics, such as researcher h-indexes.1,2 Second, it is now standard for human and animal research to undergo ethics reviews before being initiated. However, these reviews are usually carried out behind closed doors by ethics committees composed of members selected by each institution.3 Additionally, such reviews are often ill-suited to evaluate research methods because the committees do not include experts in pertinent fields.4 Moreover, approved proposals must often be revised due to unforeseen changes in experimental methodology, necessitating reassessment by post hoc peer review.5 Accordingly, much research effort is wasted. Third, infrastructure to support reproducibility and transparency has not yet been fully developed,6–8 although there are a plethora of efforts to advance open science, such as open access, open data/material/code, open review reports, open peer review, pre-registration, and registered reports systems. Finally, there is excessive centralization of authority,9,10 and funding is often concentrated on limited numbers of scientists and publishers.11,12\n\nTo address these issues, we previously proposed a new procedure in which three types of peer review (scientific peer review, ethics review, and research funding review) are executed simultaneously on the same document.13 This time-saving method is promising because it could solve the transparency problems, ethics review problems, and grant acquisition problems mentioned above. Nevertheless, the proposed system still relies on volunteer work of reviewers and influential publishers. Contrary to Homer’s assertion, modern scientific endeavor is generally performed in an opaque, unidirectional, biased, and centralized system.\n\nAs an alternative to this traditional system, Decentralized Science (DeSci) activities or systems are gaining popularity.14,15 Multiple scientific entities are beginning to apply Web3 technology, most notably blockchain, to obtain research funding and to publish results.16 Web3 is a general term for distributed networks where users autonomously exchange information and communicate. These entities are often run by autonomous organizations of scientists, called decentralized autonomous organizations (DAOs). Within a DAO, there is a central organization such as a working group (WG), but decision-making is decentralized, based on Web3 technology. Several DAOs are attempting to address the aforementioned problems.17,18 Those DAOs deploy a review system created on a public blockchain, e.g., Ethereum, to tackle transparency and incentive problems that have impaired conventional peer review.17,19 In order to promote ethical behavior and inclusiveness, DAO systems implement a gamification mechanism that allows entire communities to evaluate peer reviews and vote for the best ones. There are also several DAOs that provide open budgets or data, e.g., VitaDAO, GenomesDAO. Such DAOs collect their budgets by distributing tokens as voting rights to determine which projects are to be funded. Open data are held in decentralized storage, e.g., InterPlanetary File System: IPFS, without censorship, and data transactions can be kept in the blockchain as an open ledger. Practically, however, DeSci systems have potential drawbacks. For example, they could damage interests of current publishers. Nonetheless, we hope this emerging movement will solve presently unresolved problems, e.g., payment of incentives to reviewers, stability of reproducibility.16,19,20\n\nHere, we propose a system that integrates ethics reviews, peer reviews, and funding in a decentralized manner, based on Web3 technology. This autonomous, transparent, decentralized system would help shape cutting-edge scientific research and boost scientific transparency, efficiency, ethics, and reproducibility. We have already established a decentralized community called MinDAO to realize such a system as a host.\n\n\nABCDEF publishing\n\nFigure 1 illustrates the scheme of a system we call “Autonomous, bidding, credible, decentralized, ethical, and funded (ABCDEF) publishing.” based on MinDAO. See the original concept described in our published article and its supplementary (Mori et al. (2022),13 Supplementary (https://osf.io/rq5vb) for a detailed, phase-by-phase peer review scheme. After researchers write a research plan, there are five phases from reviewing to publishing. Here are how these phases would work.\n\nA. Scientific peer review and registered reports (RR)\n\nEach research proposal is peer-reviewed by multiple reviewers. In this process, peer reviewers evaluate the value of a research question, the rationale for the hypothesis, and the validity of methods for testing the hypothesis. RRs focus on the quality of methodology prior to data collection. Even in cases of exploratory research, peer reviewers evaluate scientific soundness, feasibility, and methodology of submitted proposals.21\n\nB. Ethics reviews\n\nSeveral reviewers specializing in ethical analyses are assigned to each protocol to review ethics of the research. If reviewers have ethical concerns about a submitted protocol, authors must revise it in compliance with reviewer comments and judgments of editors. In cases in which ethical considerations not covered by the protocol are required, e.g., clinical research, the protocol would be examined by author institutions.\n\nScientific reviewers assess the importance of research questions of a manuscript, the theoretical validity of proposed hypotheses, and whether experimental methods are appropriate for testing those hypotheses. Ethics reviewers assess the protocol for ethical issues. Scientific and ethics reviews are undertaken concurrently. Once the manuscript has successfully passed both reviews and is accepted in principle, authors can proceed to the funding review. If ethics reviewers determine that an institutional ethics review is necessary, an ethics review is conducted at author institutions. In this case, a funding review is possible only after passing institutional ethics reviews.\n\nOnce a protocol is accepted in Phase 1, voting for funding begins. The desired amount of funding is announced at the time of Phase 1 Peer Review. Voting on Phase 1 protocols occurs at this point, and funding is awarded from pooled funds. Community members evaluate Phase 1 protocols on their potential for scientific advancement and benefit to the public, and grants are made to protocols that meet these criteria. Voting is conducted primarily by community members possessing tokens. Although votes of individuals with more tokens have greater weight, they apply a voting system, such as quadratic funding, to minimize bias22 (see the below details). Even if members disagree with funding for the protocol, researchers can proceed to the next phase using their own grants if they have them. Alternatively, researchers can revise their protocols and resubmit them for Phase 1 scientific review to be voted on again (Figure 1). Also, DAO members who have the right to vote can require additional actions in both cases, i.e., agreeing or disagreeing with comments by DAO members. If members disagree, but ask authors to revise their proposals, researchers can modify their protocols to obtain a grant.\n\nIn the traditional system, funding based on popularity and performance assessed with indicators such as the h-index is not necessarily a problem. However, funds are biased toward a small subset of researchers, and funding allocation may be skewed away from early-career researchers. To solve this issue, we will apply “quadratic funding,” limiting the percentage of famous and accomplished researchers receiving funds by route (√).22 Quadratic Funding optimizes matching funds by prioritizing projects according to the number of voters. This ensures that funds are spent on projects that truly benefit the scientific community at large, not just a few prominent researchers.\n\nUnder this mechanism, the total amount of funding for a given issue is “the square root of each donation for that issue, i.e., the square of the total amount”. Even small donations are strongly encouraged and funding democratically balances funds for the public good. After a successful funding vote, researchers can be supported by pooled funding sources. Participation in voting is restricted to credibility gained via activities23 or Token holdings.\n\nThis is the phase in which actual research and writing proceed, following the same flow as typical funded research. As described below, methods, experiments, and analyses conducted here are tied to the Phase 1 protocol in the blockchain. Therefore, deviations from or additions to the RR protocol and ethical review are explicitly indicated. Researchers conduct their studies following procedures accepted in Phase 1. Procedures are linked to the Phase 2 article using the blockchain. Therefore, if researchers deviate from their original protocol, this is apparent to readers.\n\nThis is a review resulting from protocols proposed and accepted in principle in Phase 1. Reviewers evaluate the quality of modifications and protocol deviations or ethical violations. In the event of rejection, after consultation, researchers would be asked to return the funds. Of course, peer reviewers should attempt to improve manuscripts by providing constructive discussions, as in traditional scientific peer review. Authors resubmit a Phase 2 article after data collection and analysis that contains the “Introduction” and “Methods” from the initial submission together with the “Results and Discussion” section. After the Phase 2 scientific evaluation is finished, the final manuscript will be published.\n\nThe paper is published as a journal article. The community and the recommender make acceptance decisions as in Peer Community In (PCI) (https://peercommunityin.org/),24 and ABCDEF-friendly journals accept manuscripts selected, based on these recommendations.\n\nDetailed handling of tokens and funds is described in Table 1. Through these five phases, transparency is ensured as the research process proceeds. Scientific reviewers and ethics reviewers would be invited by the community based upon license tokens, guaranteeing the quality of reviewers. Possible incentives for reviewers arising at each phase could include the following. Each reviewer/author would have a track record in the form of non-fungible tokens, which could be presented as credit for acquiring funding.25 Incentives would be paid in tokens built on the blockchain. This incentive system is similar to that proposed in previous studies.17,19 Researchers could also pay open access fees with tokens or other funds. Those grants would be provided from pooled funds. Funds would be handled by utilizing multiple funding systems, including donations or investments as external funding, and pooling funds with support from funding DAOs with quadratic funding and retrospective public goods funding. There could also be a type of bounty for other community members via programmed, self-executing contracts, so-called smart contracts.\n\n\nAdvantages and opportunities\n\nThis section highlights advantages that this system would bring to the academic community. First, ABCDEF Publishing combines advantages of conventional review methods and blockchain-based techniques. It reduces the burden on researchers and provides incentives for all peer-review processes from the perspective of DeSci. Our past proposal integrated RRs, ethical reviews, and grant reviews. Also, as mentioned above, some previous articles have suggested incentivizing reviewers using blockchain-based tokens. ABCDEF Publishing would integrate all of these methods to improve efficiency, fairness, and transparency of the review process. Specifically, since a record of details of this review (who reviewed it and how, etc.) is kept on the blockchain or in decentralized storage, this authentication assurance is also important. This transparency enables funders to validate the security of their funding. Also, it maintains a record of how the budget was used. Use of funds can be documented. Furthermore, the blockchain would be able to link ethics statements and hypotheses that are registered in the RR system with methodologies and results. If that linkage is not made, it is possible to know that the method and analysis did not explicitly satisfy the registration.\n\nSecond, decentralized management would remove control from the hands of a few powerful administrators, leading to promotion of diverse research that contributes to science and more neutral evaluations of science and researchers. In addition, ABCDEF publishing would also benefit researchers whose institutions do not have ethics review boards and independent researchers who do not belong to specific institutions.26,27 This system would enable such researchers to review their protocols from an ethics perspective quickly and easily. Moreover, ABCDEF publishing would construct a reputational system based on activities of researchers/participants in a decentralized system of reviewers, independent of institutions and publishers (as in the Tenorio-Fornes proposal19). Such a reputation system would allow independent researchers to be reviewed and to expand the review process range by themselves. The system of DeSci would also improve efficiency of all publishing procedures by decreasing office work using smart contract techniques, as previously proposed.19\n\nThese advantages would allow ABCDEF-Publishing to achieve real distributed, citizen science. Nonetheless, ABCDEF Publishing does not seek to ignore or eliminate publishers, as has been claimed regarding the previously proposed DeSci system.17 On the contrary, the credibility and reputation of publishers are critical and need to be supported. The previous proposal also recommended a review method using a DeSci system that is organized and transparent, while working with publishers.19 We must respect the traditional scientific system that enables articles to be scientifically validated. Using ABCDEF Publishing, publishers could develop a more effective and efficient publishing system that would be mutually beneficial. Thus, it could help reform the complex systems of some journals, and indeed existing publishers are beginning to implement DeSci-based initiatives (e.g., https://twitter.com/ScisetsComm).\n\n\nPotential weaknesses, threats, and solutions\n\nThere are five potential pitfalls for ABCDEF Publishing.\n\n1) It is still possible that a WG and some members of the DAO will hold too much power. Therefore, establishing a more democratic method of DAO management, depending on the number of non-fungible tokens (NFTs) owned, is crucial. The ideal is to employ a managerial system that is genuinely autonomous and decentralized.\n\n2) As is often the case with token economics, tokens are unstable. Linking internal tokens ($MIN in our case) to current stablecoins is one option, e.g., USDC, USDT. Stablecoins are digital assets focused on price stability. Due to price volatility brought on by the lack of underlying assets, crypto assets have not yet been used as a form of payment. Stablecoins were created to spread and boost the utility of these assets.\n\n3) One concern is that fraudulent accounts, fabricated peer reviews, and fake contributions could appear. This issue is widely known as the Sybil attack, a type of attack on a computer service with many pseudonymous identities and enormous influence. Two types of defenses are proposed to thwart such abuses. One system is to evaluate risks of accounts using transaction data on the blockchain with machine learning. Another system uses non-exchangeable tokens linked to specific people, so-called soulbound tokens.28,29 These systems allow us to predict risks of accounts and subtract the influence of potentially risky accounts. However, such proposals are still under development.\n\n4) Another concern is about pairwise coordination of contributions in projects. For example, collaborators or unfriendly competitors work on the same project together in an attempt to control DAO decision-making. A similar idea in funding design is proposed to prevent such cases by controlling contributions based on social networks.30 Another technique to minimize the contribution level to the cap has recently been used when users assist one another based on their shared activity history.31\n\n5) There may be instances in which these approaches fail, having various impacts, even on specific fields or where RRs are unnecessary, as in the humanities. Thus, a flexible flow, such as skipping RRs, might be required to rescue projects in some circumstances.\n\n6) Increased transactions may impact “gas fees”, which are transaction costs in the public blockchain. DAOs often utilize a public blockchain like Ethereum, which requires gas fees for each transaction to maintain its services on the blockchain. The gas fee fluctuates according to the number of transactions within a certain time window, since the number of transaction times is limited, and the price incentivizes people to optimize timing of token trades. DAO activities can be hindered by such matters since they accrue high costs. Some off-chain solutions are proposed to mitigate such issues. In some solutions, including optimistic rollups and zero-knowledge rollups, security is derived directly from the public blockchain. Other solutions, such as sidechains and plasma chains, create new chains, and their security is distinct from the security of the public blockchain. In this manner, the number of transactions per second increases, and increased transactions do not hinder DAO activities due to a substantial reduction in gas fees.\n\n7) Compatibility of reviewer systems is also a matter of concern. Our proposed system envisions integrating a reputation system for reviewers using the blockchain. However, the reliability of the reputation system is undeveloped and uncertain. Instead of integrating this system, it should be possible to integrate existing reviewer communities, including Clarivate, with the ABCDEF publishing system. In so doing, our publishing system would be compatible to the conventional reviewer system.\n\n8) With ABCDEF publishing, which utilizes blockchain technology, there are limitations to how it can address environmental concerns, but there are also potential solutions to mitigate its impact. There are efforts to develop more energy-efficient blockchain algorithms and explore alternative energy sources, such as renewable energy, to power blockchain networks. Additionally, some decentralized publishing platforms are exploring using off-chain solutions to reduce the energy consumption required for transactions. While there are limitations to how ABCDEF publishing can address environmental concerns, there are potential solutions to mitigate its impact, such as developing more energy-efficient algorithms and promoting the reuse and recycling of electronic devices. It is important to continue exploring and implementing these solutions to ensure that the benefits of blockchain technology can be realized while minimizing its negative impact on the environment.\n\n9) Some scientists might insist there are strict regulations and accredited committees to review research with human subjects or animals in many countries. Such committees usually do not process applications before studies are granted. Also, they might think there are huge differences between grant and ethics applications and an introduction plus the method section of a research publication. These criticisms are not strange to researchers accustomed to the current process. However, as we have argued in our earlier paper,13 the process of applying for a grant and then conducting an ethical review may be one factor that has led to ethical deviations. Therefore, ABCDEF proposes the reversal of such a process. Moreover, as for grand and ethical considerations that require more than the background and methods section of the paper, those issues can be addressed by providing information as Supplementary information in the registered report.\n\n\nConclusion\n\nWe believe that ABCDEF publishing can effectively solve a panoply of problems facing the scientific community today. At the time of writing, we are just beginning to construct this system, which is community-based and developed on the blockchain. Most importantly, it will be realized as a large-scale movement involving various stakeholders, including scientists, publishers, and citizens.",
"appendix": "Data availability\n\nOSF: ABCDEF publishing. https://doi.org/10.17605/OSF.IO/NSVZD. 32\n\nThis project contains the following extended data:\n\n- Supplementary Information.pdf\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nMryglod O, Holovatch Y, Kenna R: Big fish and small ponds: why the departmental h-index should not be used to rank universities. Scientometrics. 2022 Jun; 127(6): 3279–3292. Publisher Full Text\n\nBarnes C: The emperor’s new clothes: theh-index as a guide to resource allocation in higher education. J. High. Educ. Policy Manag. 2014 Sep 3; 36(5): 456–470. Publisher Full Text\n\nLynch HF: Opening Closed Doors: Promoting IRB Transparency. J. Law Med. Ethics. 2018 Mar 1; 46(1): 145–158. Publisher Full Text\n\nPage SA, Nyeboer J: Improving the process of research ethics review. Res. Integr. Peer Rev. 2017 Aug 18; 2: 14. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAbbott L, Grady C: A systematic review of the empirical literature evaluating IRBs: what we know and what we still need to learn. J. Empir. Res. Hum. Res. Ethics. 2011 Mar; 6(1): 3–19. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNosek BA, Lakens D: Registered reports: A method to increase the credibility of published results. Soc. Psychol. 2014; 45(3): 137–141. Publisher Full Text\n\nChambers CD, Tzavella L: The past, present and future of Registered Reports. Nat. Hum. Behav. 2022 Jan; 6(1): 29–42. PubMed Abstract | Publisher Full Text\n\nParikh S, Malcom SM, Moran B: Public access is not equal access. Science. 2022 Sep 9; 377: 1361. Publisher Full Text\n\nLarivière V, Haustein S, Mongeon P: The oligopoly of academic publishers in the digital era. PLoS One. 2015; 10: e0127502. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLloyd J: How academic science gave its soul to the publishing industry. Issues Sci. Technol. 2020 [cited 2022 Sep 14]. Reference Source\n\nBerezin A: The perils of centralized research funding systems. Knowl. Technol. Policy. 1998 Sep 1; 11(3): 5–26. Publisher Full Text\n\nBol T, de Vaan M , van de Rijt A : The Matthew effect in science funding. Proc. Natl. Acad. Sci. U. S. A. 2018 May 8; 115(19): 4887–4890. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMori Y, Takashima K, Ueda K, et al.: Trinity review: integrating Registered Reports with research ethics and funding reviews. BMC. Res. Notes. 2022 May 19; 15(1): 184. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHamburg S: Call to join the decentralized science movement. Nature. 2021 Dec; 600(7888): 221. PubMed Abstract | Publisher Full Text\n\nSicard F: Can decentralized science help tackle the deterioration in working conditions in academia? Front. Blockchain. 2022; 5: 5. Publisher Full Text\n\nWang FY, Ding W, Wang X, et al.: The DAO to DeSci: AI for Free, Fair, and Responsibility Sensitive Sciences. IEEE Intell. Syst. 2022 Mar; 37(2): 16–22. Publisher Full Text\n\nTrovò B, Massari N: Ants-Review: A Privacy-Oriented Protocol for Incentivized Open Peer Reviews on Ethereum. European Conference on Parallel Processing.2020. Publisher Full Text\n\nResearchHub: ResearchHub.[cited 2022 Aug 28]. Reference Source\n\nTenorio-Fornés Á, Tirador EP, Sanchez-Ruiz AA: Decentralizing science: Towards an interoperable open peer review ecosystem using blockchain. Inf. Process. Manag. 2021 Nov 1; 58(6): 102724. Publisher Full Text\n\nCao L: Decentralized AI: Edge Intelligence and Smart Blockchain, Metaverse, Web3, and DeSci. IEEE Intell. Syst. 2022 May; 37(3): 6–19. Publisher Full Text\n\nDirnagl U: Preregistration of exploratory research: Learning from the golden age of discovery. PLoS Biol. 2020 Mar; 18(3): e3000690. PubMed Abstract | Publisher Full Text | Free Full Text\n\nButerin V, Hitzig Z, Weyl EG: Liberal Radicalism: A Flexible Design For Philanthropic Matching Funds. SSRN 3243656.2018 [cited 2022 Sep 27]. Reference Source\n\nAtwood J: Understanding Discourse trust levels. Discourse. 2018 [cited 2022 Oct 5]. Reference Source\n\nGuillemaud T, Facon B, Bourguet D: Peer Community In: A free process for the recommendation of unpublished scientific papers based on peer review. In: Revue Africaine de Recherche en Informatique et Mathématiques Appliquées. hal.science.2019. Reference Source\n\nHamburg S: A guide to DeSci, the latest Web3 movement. Future. 2022 [cited 2022 May 25]. Reference Source\n\nAlbagli S, Iwama AY: Citizen science and the right to research: building local knowledge of climate change impacts. Humanit. Soc. Sci. Commun. 2022 Feb 1; 9(1): 1–13. Publisher Full Text\n\nKenens, Van Oudheusden, Yoshizawa: Science by, with and for citizens: rethinking “citizen science”after the 2011 Fukushima disaster. Palgrave Commun. 2020; 6. Publisher Full Text Reference Source\n\nJain S, Erichsen L, Weyl G: A Plural Decentralized Identity Frontier: Abstraction v. Composability Tradeoffs in Web3. arXiv [cs.CR].2022. Reference Source\n\nWeyl EG, Ohlhaver P, Buterin V: Decentralized Society: Finding Web3’s Soul.2022 [cited 2022 Sep 15]. Reference Source\n\nPairwise coordination subsidies: a new quadratic funding design. Ethereum Research. 2020 [cited 2022 Oct 6]. Reference Source\n\nChou H, Lin D, Nakaguchi T, et al.: TMchain: A Blockchain-based Collaboration System for Teaching Materials. J. Inf. Process. 2022; 30: 343–351. Publisher Full Text Reference Source\n\nYamada Y: Information related to the ABCDEF publishing article. 2023. Publisher Full Text"
}
|
[
{
"id": "193287",
"date": "31 Aug 2023",
"name": "Timothy M. Errington",
"expertise": [],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript describes a vision of an alternative publishing process that would combine various emerging features being deployed to decrease bias and increase efficiency using a decentralized approach. Below is a list of recommendations for the author to consider.\nIn the introduction, why do the authors say “Accordingly, much research effort is wasted.”. This point is on ethical reviews. Are the authors suggesting there is waste because of having to review modified ethics protocols due to unforeseen changes? That doesn’t seem like waste per se, it’s important to revisit ethical protocols when deviations occur. And the unforeseen aspect doesn’t seem like waste because it was unknown during the initial protocol. I think the authors are trying to say there is research waste because those unforeseen changes by the authors might have been caught if methodological expertise was done alongside the ethical review in the first place. I’d suggest rewriting this to make that clearer. As a note, I also am unsure if I see that as waste – more inefficiency in a system.\nIn this model it assumes research progresses in single study/experimental settings, but most research papers currently are a collection of multiple studies/experiments. How will that work in this system? For example, Registered Reports can be submitted with pilot data – or the Registered Report study might be a replication of previous research. How does that work in this system?\nFor Phase 1, section B – this does not seem to align with how most research is done. The ethical reviews being independent of the institutional ethical review committees seems like it is adding an additional layer of review. In most journals that implement Registered Reports it is an expectation that the ethical review has already occurred, so approval is in place if the study is given IPA. Some research even requires initial ethical review at the grant review stage. I agree that having ethical and scientific review running in parallel is a good idea since these two areas are different and can influence each other, but if I’m understanding the diagram correctly, it seems like a lot of review might go into the process before it reaches the institutional review committee, which would only add additional revisions of the scientific peer review if ethical considerations need to change. Why not have the institutional ethics review running concurrently with the scientific review opposed to this institutional independent ethics review?\nRelated to this, in the ‘Advantages and opportunities’ section that this approach would help researchers who do not have institutional affiliations or institutional ethics committees. There already exists independent ethic review boards (e.g., BRANY) to help with this situation, which are similar to the institutional ethics reviews, how would this be integrated?\nFor Phase 2, funding – have the authors considered different workflows for having the funding and protocol peer review done? There are pilots experimenting with having a Registered Report reviewed by funders and journals. Here is a feasibility study of different models (https://doi.org/10.12688/wellcomeopenres.17028.1) and here is a journal consortium model being implemented (https://www.cos.io/consciousness).\nFinally, I think the article format is not appropriate for this article. This reads more like an opinion article (https://f1000research.com/for-authors/article-guidelines/opinion-articles) than a methods article (https://f1000research.com/for-authors/article-guidelines/method-articles). For example, the last sentence of the paper makes quite a strong statement (i.e., ‘it will be realized’) without any evidence – but the authors are of course open to having that opinion of what they believe could happen (e.g., ‘we believe it could be realized’).\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Partly\n\nAre sufficient details provided to allow replication of the method development and its use by others? No\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Partly",
"responses": [
{
"c_id": "10354",
"date": "06 Oct 2023",
"name": "Kaito Takashima",
"role": "Author Response",
"response": "1-1. This manuscript describes a vision of an alternative publishing process that would combine various emerging features being deployed to decrease bias and increase efficiency using a decentralized approach. Below is a list of recommendations for the author to consider. Reply: Thank you for the important insights. Below, we provide responses to each recommendation or question. 1-2. In the introduction, why do the authors say “Accordingly, much research effort is wasted.”. This point is on ethical reviews. Are the authors suggesting there is waste because of having to review modified ethics protocols due to unforeseen changes? That doesn’t seem like waste per se, it’s important to revisit ethical protocols when deviations occur. And the unforeseen aspect doesn’t seem like waste because it was unknown during the initial protocol. I think the authors are trying to say there is research waste because those unforeseen changes by the authors might have been caught if methodological expertise was done alongside the ethical review in the first place. I’d suggest rewriting this to make that clearer. As a note, I also am unsure if I see that as waste – more inefficiency in a system. Reply: As you pointed out, the explanation was misleading. We revised it as follows: ***Introduction \"Moreover, approved proposals must often be revised due to unforeseen changes in experimental methodology, necessitating reassessment by post hoc ethics or peer review.5 This rework could be prevented if methodological expertise review is done alongside the ethical review. \" 1-3. In this model it assumes research progresses in single study/experimental settings, but most research papers currently are a collection of multiple studies/experiments. How will that work in this system? For example, Registered Reports can be submitted with pilot data – or the Registered Report study might be a replication of previous research. How does that work in this system? Reply: Thank you for pointing this out. We apologize for the lack of explanation. We consider this system to be based on a Registered Report (RR) as we described in the manuscript. Therefore, the system naturally accepts such cases as you have suggested. We clearly explain in the manuscript that we accept such cases in the Advantages and opportunities as follows: Advantages and opportunities ***\"In addition, as seen in previous RRs, the ABCDEF system will accept submissions along with pilot data, replications of previous studies, and collections of various experiments and studies, allowing each content to be tied to the blockchain for reference.\" 1-4. For Phase 1, section B – this does not seem to align with how most research is done. The ethical reviews being independent of the institutional ethical review committees seems like it is adding an additional layer of review. In most journals that implement Registered Reports it is an expectation that the ethical review has already occurred, so approval is in place if the study is given IPA. Some research even requires initial ethical review at the grant review stage. I agree that having ethical and scientific review running in parallel is a good idea since these two areas are different and can influence each other, but if I’m understanding the diagram correctly, it seems like a lot of review might go into the process before it reaches the institutional review committee, which would only add additional revisions of the scientific peer review if ethical considerations need to change. Why not have the institutional ethics review running concurrently with the scientific review opposed to this institutional independent ethics review? Reply: We apologize the position of \"Ethical Review at the Institution\" in the figure is confusing. In our proposed framework, undergoing ethical review at the institution was considered a special case. This primarily occurs when an ethics review is conducted simultaneously with the initial scientific review, and it is recommended that reviewers cannot make a clear judgment, or it is recommended to undergo an institutional ethics review as well. Therefore, in line with the original concept, it is not in its current position but should be included within the Phase 1 Combined Review and the revision loop. We have modified Figure 1 to align with the original intention. 1-5. Related to this, in the ‘Advantages and opportunities’ section that this approach would help researchers who do not have institutional affiliations or institutional ethics committees. There already exists independent ethic review boards (e.g., BRANY) to help with this situation, which are similar to the institutional ethics reviews, how would this be integrated? Reply: Indeed, there is already an independent ethics review committee for those who do not have an ethics review committee within their affiliation. However, as pointed out in the background of our manuscript, the researchers must submit documents that are almost identical in content to those submitted for academic peer review in Stage 1 for even such institutions in their own format. When considering this structural and inefficient problem, our proposal system could exclude the barrier to undergoing an ethics review. Also, we’d appreciate it if you check our reply to Reviewer 2. We add the related sentence in the section as follows: ***Advantages and opportunities \"Although there is already an independent ethics review committee for such researchers, they must submit documents that are almost identical in content to those submitted for academic peer review in Stage 1 in their format. Our proposal system could exclude the barrier by integrating all stages.\" 1-6. For Phase 2, funding – have the authors considered different workflows for having the funding and protocol peer review done? There are pilots experimenting with having a Registered Report reviewed by funders and journals. Here is a feasibility study of different models (https://doi.org/10.12688/wellcomeopenres.17028.1) and here is a journal consortium model being implemented (https://www.cos.io/consciousness). Reply: Thank you for sharing this very innovative and important precedent! The direction that journals and funders, such as the ones you mentioned, are taking in setting up grant projects and having manuscripts submitted to them is a very compatible. For your question, we have not considered the sperate flows between funding and RR peer review because it might waste the time of researchers. This is one of our motivation to propose the system. However, the precedential funding system which you introduced can be applied in our case with necessary modification. We added the possibility of combination in the Phase 5 explanation as follows: “Another approach to grants involves journals of funding organizations initiating grant projects and allowing the submission of manuscript to them (Clark et al. 2021; Center for Open Science)” 1-7. Finally, I think the article format is not appropriate for this article. This reads more like an opinion article (https://f1000research.com/for-authors/article-guidelines/opinion-articles) than a methods article (https://f1000research.com/for-authors/article-guidelines/method-articles). For example, the last sentence of the paper makes quite a strong statement (i.e., ‘it will be realized’) without any evidence – but the authors are of course open to having that opinion of what they believe could happen (e.g., ‘we believe it could be realized’). Reply: We initially submitted the article as an Opinion article, but changed it to Methods article after consulting with the Editor on the submission. While we agree with your opinion, we would like to leave the final decision to the Editor. References Clark, R., Drax, K., Chambers, C. D., Munafò, M., & Thompson, J. (2021). Evaluating Registered Reports Funding Partnerships: a feasibility study. Wellcome Open Research, 6, 231. https://doi.org/10.12688/wellcomeopenres.17028.1"
}
]
},
{
"id": "199372",
"date": "19 Sep 2023",
"name": "David Mellor",
"expertise": [
"Reviewer Expertise Open science",
"meta-science",
"policy",
"ecology",
"citizen science"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn \"Autonomous, bidding, credible, decentralized, ethical, and funded (ABCDEF) publishing\" the authors provide a solution to current systems in scientific research that rely on slow, linear review processes for grants, publication, and ethical review by building on their previous work (\"Trinity Reviews\") to propose a system that incentivizes participation in the process through blockchain technology. While I believe there are a number of benefits to the proposed system, I also see a number of challenges to overcome that could be addressed in this manuscript.\n\nThe first, and most substantial shortcoming is the fact that the proposed workflow (Fig 1), will, for most researchers, still require a linear review process, with all of the shortcomings that that entails. In my experience, few researchers submit studies for ethical review unless they are required to do so. The \"Institutional ethics review (if necessary)\" box is functionally required, and changes by that process are likely to affect the study design, which would require an additional line in the author's figure from that box back up to editorial review after triage. Overcoming that inefficiency should be a more central purpose of this publishing model, and doing that would require working with the ethics review committees in individual universities. In the U.S., they are beholden to government guidelines, and so there could be substantial challenges to integrating them into this process.\n\nAnother limitation is that the funding review is still, in all cases, separate from the publishing and ethics review. As before, concerns that arise from the funding perspective cannot be addressed without editorial agreement if the \"in-principle acceptance\" is to be honored (in other words, any changes have to be approved by the editor, who may request additional reviewer insight).\n\nIf all three sections: editorial, ethics, and funding can be combined, then I would see substantial benefit to this system. Even if the funding section remains seperate (because in this model it is more distributed and focused less on review but rather on up and down votes of being worthy of funding), I still think there is need to integrate institutional ethics review with the scientific review.\n\nMy final set of comments are minor points that I think can be easily added to this manuscript:\nWhat type of funder is this model designed for? Are you proposing that a private research foundation support it, a government agency? It will be important to understand that funder perspective and motivation for participating in order for this model to work. Their considerations (such as funder intent for private foundations, or legal requirements and taxpayer oversight for government agencies) must be taken into account so that there is a chance for them to participate.\n\nIn item 7, you note that this is compatible with reviewer systems. Please describe how you would overcome compatibility issues with MULTIPLE systems. Currently, ethics reviews, funder reviews, and article reviews all use different systems, and that is a major barrier to a combined workflow such as you describe.\n\nIn item 3, you note a concern about fraudulent accounts. Would it be possible to use simpler verification systems, such as possessing an ORCID and a human reviewer verifying your identity and credentials?\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Partly\n\nAre sufficient details provided to allow replication of the method development and its use by others? Partly\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? No",
"responses": [
{
"c_id": "10328",
"date": "06 Oct 2023",
"name": "Kaito Takashima",
"role": "Author Response",
"response": "2-1. In \"Autonomous, bidding, credible, decentralized, ethical, and funded (ABCDEF) publishing\" the authors provide a solution to current systems in scientific research that rely on slow, linear review processes for grants, publication, and ethical review by building on their previous work (\"Trinity Reviews\") to propose a system that incentivizes participation in the process through blockchain technology. While I believe there are a number of benefits to the proposed system, I also see a number of challenges to overcome that could be addressed in this manuscript. Reply: Thank you for your compliments on our proposal. Below, we provide responses to each point that you point out. 2-2. The first, and most substantial shortcoming is the fact that the proposed workflow (Fig 1), will, for most researchers, still require a linear review process, with all of the shortcomings that that entails. In my experience, few researchers submit studies for ethical review unless they are required to do so. The \"Institutional ethics review (if necessary)\" box is functionally required, and changes by that process are likely to affect the study design, which would require an additional line in the author's figure from that box back up to editorial review after triage. Overcoming that inefficiency should be a more central purpose of this publishing model, and doing that would require working with the ethics review committees in individual universities. In the U.S., they are beholden to government guidelines, and so there could be substantial challenges to integrating them into this process. Reply: As you see in the reply to Reviewer 1, we proposed the system as a community for researchers for whom institutional ethics review is not possible in the first place, as we indicate in our previous (Mori et al., 2022) and present papers. As you pointed out, there would be situations where our system needs the cooperation of existing IRBs, and we need to be recognized by the committees. On the other hand, as the previous researchers indicated in the following paper, it is a stark fact that many researchers are unable to conduct research because they do not have their own ethics review board, or because the cost of asking an independent review board is impractical. Your point is important that we have added it as an issue in \"Potential weaknesses, threats, and solutions\". Simultaneously, we have added the point that proceeding on the premise of the current institutional ethics reviews are themselves an obstacle to broadening the scope of science in the Introduction section: https://psycnet.apa.org/doiLanding?doi=10.1037%2Fpst0000166 https://explore.bps.org.uk/content/report-guideline/bpsrep.2021.inf180/chapter/bpsrep.2021.inf180.12 ***Introduction \"Furthermore, proceeding on the assumption of the current institutional ethical reviews impede broadening the scope of science, considering that many researchers suffer from the lack of opportunities for institutional review.\" ***Potential weaknesses, threats, and solutions- item9 \"Of course, our proposed system may require the cooperation of existing IRBs in various situations. Additionally, this system must gain recognition from such institutions IRB and other relevant entities. The arrangement that enables cooperation with the respective institutional ethics review committees and publicity of our proposed system should be considered as issues to be addressed in the future.\" 2-3. Another limitation is that the funding review is still, in all cases, separate from the publishing and ethics review. As before, concerns that arise from the funding perspective cannot be addressed without editorial agreement if the \"in-principle acceptance\" is to be honored (in other words, any changes have to be approved by the editor, who may request additional reviewer insight). Reply: Basically, it is not envisioned that the funding phase will be reverted back to another previous phase after the IPA. If the (funding) voters feel that there are any problems with the research protocol/content at voting, they can simply not vote the project. If the researcher wants to modify the protocol and still receive funding from the system as a result of rejection, they can withdraw and resubmit the manuscript to our system. This part is not considered a limitation, but rather, the review of research funding is an evaluation and voting process, and asking for specific comments on the content and modifications would be very complicated; it may discourage anyone from joining the funding voting. 2-4. If all three sections: editorial, ethics, and funding can be combined, then I would see substantial benefit to this system. Even if the funding section remains separate (because in this model it is more distributed and focused less on review but rather on up and down votes of being worthy of funding), I still think there is need to integrate institutional ethics review with the scientific review. Reply: As we replied to your comment above, we do not require institutional review in our framework only, but at the same time we understand that some studies should actually be required. 2-5. My final set of comments are minor points that I think can be easily added to this manuscript: What type of funder is this model designed for? Are you proposing that a private research foundation support it, a government agency? It will be important to understand that funder perspective and motivation for participating in order for this model to work. Their considerations (such as funder intent for private foundations, or legal requirements and taxpayer oversight for government agencies) must be taken into account so that there is a chance for them to participate. Reply: Thank you for your important remark As for funders, we are assuming private research foundations, government agencies, or investors, as you have indicated. The format of the fund could be in the form of other DAOs, crowdfunding, or, as reviewer 1 gave us previous examples, the system launching a grant project with an open call for proposals. However, this model is not limited to these specific funders or formats, but aims to support research projects with a wide range of funders and diverse funding sources. 2-6. In item 7, you note that this is compatible with reviewer systems. Please describe how you would overcome compatibility issues with MULTIPLE systems. Currently, ethics reviews, funder reviews, and article reviews all use different systems, and that is a major barrier to a combined workflow such as you describe. Reply: We apologize for the misleading wording here. We don’t want to say that limitation 7 here is compatible with the traditional peer review system, but rather that we are advocating the creation of a reliable reviewer pool and making it as functional as the existing peer review system. As you pointed out, it is difficult to prepare reviewer pools for each of ethics and grant scientific review, but by working with the existing community and using a unified format for evaluation, we could bring the three types of reviews together. The sentences has been revised to be clear as follows: ***Potential weaknesses, threats, and solutions- item9 \"Compatibility of reviewer reputational systems is also a matter of concern. Our proposed system envisions integrating a reputation system for reviewers using the blockchain. However, the reliability of the reputation system is undeveloped and uncertain. Instead of integrating this system, we should create a trusted pool of reviewers and make it as functional as the traditional peer review system\" 2-7. In item 3, you note a concern about fraudulent accounts. Would it be possible to use simpler verification systems, such as possessing an ORCID and a human reviewer verifying your identity and credentials? Reply: We think it is possible. More to the point, it is possible to automatically create a non-exchangeable ID in the form of a combination of ORCID and soulbound tokens, not by human hands. However, the problem of fraudulent accounts has already been pointed out even with ORCID (Teixeira da Silva, 2021. .https://doi.org/10.1016/j.jemep.2021.100692), and tying them together may not solve the problem. Rather, we suggest that it would be more realistic to establish a more reliable ID by linking researcher information and research history with a decentralized token such as the one proposed in our manuscript. However, it might lower the overall risk if it can be tied to not only ORCID but also other accounts e.g., google accounts, github accounts, and so on. We add the combined method to prevent fraudulent accounts as follows: ***Potential weaknesses, threats, and solutions- item9 \"Moreover, it might lower the overall risk if it can be tied to other accounts (e.g., ORCID, google accounts, github accounts). \" References Teixeira da Silva, J. A. (2021). Non-compliance with ethical rules caused by misuse of ORCID accounts: Implications for medical publications in the COVID-19 era. Ethics, Medicine, and Public Health, 18, 100692."
}
]
}
] | 1
|
https://f1000research.com/articles/12-877
|
https://f1000research.com/articles/12-1271/v1
|
05 Oct 23
|
{
"type": "Study Protocol",
"title": "Comparative evaluation of gestosis score vs uterine artery pulsatility index in predicting gestational hypertension: A study protocol",
"authors": [
"Swati Dahiphale",
"Jyotsna Potdar",
"Neema Acharya",
"Jyotsna Garapati",
"Jyotsna Potdar",
"Neema Acharya",
"Jyotsna Garapati"
],
"abstract": "Background: Gestational hypertension and its consequences such as preeclampsia, eclampsia is a leading cause of maternal mortality in India. Multiple risk factors are already known to cause hypertension in pregnancy and with newer advances in the field of medicine, newer risk factors are also being detected which contribute to gestational hypertension. There is need to detect these risk factors so that women who are susceptible to developing hypertension in their pregnancy can be identified at the earliest and monitored and managed accordingly. This study includes two methods, gestosis score which is a newer method, and uterine artery Doppler pulsatility index which is commonly utilized in usually urban centers where ultrasonography facilities are available to look for these risk factors.\nObjective: The study intends to compare the results of both prediction approaches, the Gestosis score and the Uterine Artery Pulsatility Index in identifying women at risk for gestational hypertension so that these women can be monitored vigilantly for the development of hypertension during their pregnancies and contribute to better management and healthy outcomes of pregnancy.\nMethods: This study will include 140 pregnant women with gestational ages between 13 to 20 weeks. The gestosis score and mean uterine artery pulsatility index will be calculated. Women with a gestosis score of three or more are deemed at risk for gestational hypertension. Women with mean pulsatility index of 95th percentile or higher are labeled at risk of gestational hypertension. The outcomes of these two methods will be compared to assess which is more effective in predicting developing gestational hypertension.\nExpected outcome: The study aims to provide insights into the effectiveness of both the Gestosis Score and the Uterine Artery Pulsatility Index in predicting gestational hypertension. The results will contribute to employing better risk assessment in clinical practice and the management of high-risk pregnancies.",
"keywords": [
"Gestosis score",
"uterine artery pulsatility index",
"gestational hypertension",
"high-risk pregnancy"
],
"content": "Background\n\nAs outlined by the American College of Obstetrics and Gynaecology (ACOG), gestational hypertension is defined as systolic blood pressure of 140mmHg or more or diastolic blood pressure of 90mmHg or more on two instances of at least four hours apart after 20 weeks of gestation of pregnancy in previously normotensive women.1 When this high blood pressure is associated with proteinuria, it is known as preeclampsia.\n\nGestational hypertension is a major medical problem during pregnancy, with possible adverse implications on both mother's and fetal health.2–4 It is critical to predict and identify high-risk pregnancies early to provide proper monitoring and care. The pooled prevalence of Hypertensive disorders of pregnancy (HDOP) in India is 9% (95% CI, 8%–10%), which is significantly higher than the global prevalence, as reported in a study done in pregnant women of the Indian population.5\n\nMany initiatives have been carried out to anticipate and avert the onset of gestational hypertension and other pregnancy-related hypertensive disorders of pregnancy because of their epidemiological and clinical significance. In clinical settings, a variety of predictive multiparametric algorithms are employed. These algorithms utilize multiple maternal risk factors, radiological evaluations such as the uterine artery Doppler pulsatility index, and diverse plasma biomarkers to achieve their intended purpose.6–13 Despite the rising efficacy of these approaches, the actual predictive models for gestational hypertension are still a source of contention and hence not yet used in routine clinical practice.\n\nHence there is a need to analyze and promote newer predictive models which can help in predicting the occurrence of hypertensive disorders during pregnancy.\n\nThe purpose of this clinical study is to examine the effectiveness of two prediction approaches, the Gestosis Score and the Uterine Artery Pulsatility Index, in predicting the risk of developing gestational hypertension in pregnant women in the second trimester between the gestational age of 13 weeks to 20 weeks.\n\nGestosis score is a newly developed scoring system consisting of known and newly emerging risk factors for gestational hypertension developed by Dr. Gorakh Mandrupkar and modified by the FOGSI-ICOG committee (Table 1).14 The gestosis score is proposed to ensure accurate screening and prediction of gestational hypertension and hypertensive disorders of pregnancy.\n\n# Systemic Lupus Erythematosus.\n\n^ Anti-phospholipid Antibody Syndrome @ Rheumatoid Arthritis.\n\nThis scoring system takes into account both established and newly recognized factors that are linked to the causation of gestational hypertension. The score of 1, 2, or 3 for each clinical risk factor is determined based on its impact on the development of gestational hypertension. After conducting a thorough assessment and gathering detailed medical histories of the women, a cumulative score is determined for each participant. Women with a total score of 1 will be labeled low risk, a score of 2 will be labeled moderate risk and women with a total score of 3 or more will be labelled at high risk for development of gestational hypertension. As per one Indian study a gestosis score of 3 or more, appears to have promising diagnostic accuracy (95.35%) for predicting the development of preeclampsia (PE). It demonstrates good sensitivity (83.1%) and specificity (97.51%). The study showed the PPV of gestosis score in predicting preeclampsia is 85.51%, representing the likelihood of a positive result, while the NPV is 97.03%, indicating the probability of a negative result. This suggests it may be a useful early marker for identifying the risk of gestational hypertension and preeclampsia.15\n\nUterine artery Doppler velocimetry will be performed in the same women using a transabdominal probe. The pulsatility index will be measured in both uterine arteries and the mean will be calculated. Reference values for uterine artery pulsatility index are different for different gestational ages. Women with a mean pulsatility index more than the 95th percentile of the reference range for the given gestational age will be labeled as high risk and other women with a pulsatility index within the normal level that is below the 95th percentile will be labeled as mild risk for development of gestational hypertension.16\n\nAll these women will be routinely monitored during each ANC visit, blood pressure will be monitored regularly to detect de novo development of hypertension during their pregnancy.\n\n\n\n1. To evaluate the effectiveness of the Gestosis Score in predicting gestational hypertension.\n\n2. To assess the effectiveness of the Uterine Artery Pulsatility Index in predicting gestational hypertension.\n\n3. To compare the predictive ability of the Gestosis Score and Uterine Artery Pulsatility Index in identifying women at risk of developing gestational hypertension.\n\n\nProtocol\n\nRegistration: The trial has been registered with CTRI (REF/2023/04/065978).\n\nThis study will be a prospective observational study. The study will be conducted in the Department of Obstetrics and Gynaecology, Acharya Vinoba Bhave Rural Hospital, Sawangi, Wardha, India and will be conducted from 2023 to 2024 (two years).\n\nCriteria for inclusion:\n\n• Pregnant women who are 19 years of age or older.\n\n• Gestational age between 13 weeks to 20 weeks.\n\n• Pregnant women who provide informed consent to take part in the study.\n\nCriteria for exclusion:\n\n• Pregnant women who are not willing to be booked in this hospital for delivery.\n\n• Pregnant women with gestational age below 13 weeks or above 20 weeks.\n\n\nOutcomes\n\nAt the end of this study, we will know whether the gestosis score has better predictive values as compared to the uterine artery pulsatility index in predicting gestational hypertension.\n\n\n\na. Demographic data (age, weight, height, BMI).\n\nb. Medical history and obstetric history.\n\nc. Data needed to detect risk factors as per gestosis score (parity, utilization of assisted reproductive technology, family history of hypertension, history of psychiatric illness)\n\nd. Blood pressure measurements at regular intervals during antenatal visits.\n\ne. Gestosis Score assessment during the antenatal visit.\n\nf. Uterine Artery Pulsatility Index measurements through ultrasonography.\n\nPregnant women visiting antenatal clinic at Acharya Vinoba Bhave Rural Hospital, Sawangi, Wardha will be examined. After obtaining informed written consent, 140 pregnant women who meet the specific inclusion criteria will be included in the study. Their uterine artery pulsatility index and the presence of a notch will be assessed using ultrasound. Pregnant women with a mean pulsatility index higher than the 95th percentile will be classified as high-risk, while those with a mean pulsatility index lower than the 95th percentile will be categorized as low-risk. The same participants will be carefully assessed for risk factors as per the gestosis scoring system. All pertinent statistical data will be gathered during the study.14 The pregnant women will be categorized into three risk groups based on their gestosis scores: low risk (gestosis score of 1), moderate risk (gestosis score of 2), and high risk (gestosis score of 3 or higher). The participants will be followed up until six weeks after delivery. On every follow-up, blood pressure will be checked to look for hypertension.\n\nIn this study, the Daniel formula17 is employed to determine the required sample size using a prevalence rate of 9% for gestational hypertension.\n\n“n” represents the necessary sample size,\n\nZ is a statistical value to determine the level of confidence. In the case of a 95% confidence level, the Z-value is 1.96.\n\nP value is the Estimated prevalence of gestational hypertension (proportion of pregnant women with gestational hypertension), which is 9% or 0.09 in this case.\n\nAnd d is desired margin of error (precision), which is 5% or 0.05 in this case.\n\nCalculation of sample size:\n\nTherefore, the sample size required is 126 pregnant women for the study with a prevalence of 9%.\n\nBased on the prevalence of gestational hypertension (9%) and desired precision (5%), the calculated sample size is approximately 126 pregnant women. The target enrolment will be set at 140 participants to account for potential attrition and data loss.\n\nChi-square test and students paired t-test will be used to analyze the data.\n\nThe collected data will be organized in an Excel sheet and a master chart will be generated for further analysis. The statistical analysis will be conducted using SPSS version 27 software, considering a desired error margin and a confidence interval of 95%.\n\nAll collected data will be stored securely, and participant identities will be kept confidential.\n\nApproval from the Institutional Ethical Committee has been obtained before enrolling any participants in the study. Informed written consent will be obtained from each participant.\n\nEthical approval has been obtained for this study from the institutional ethical committee of Datta Meghe Institution of Higher Education and Research (approval: ECR/440/Inst/2013/RR-2019) on 21/07/2022.\n\nThe results of this study will be published in an indexed journal for wider dissemination and accessibility and presented at relevant scientific conferences to contribute to the existing body of knowledge on gestational hypertension prediction.\n\nData collection has started.\n\nA limitation of this study is the small sample size and the fact it is a single centre study.\n\nLarger sample size and multicentric studies will be needed to apply study results in wider population.\n\nThis research may lead to improved early detection and intervention strategies for gestational hypertension, potentially reducing adverse maternal and fetal outcomes.\n\nGestosis score14 (https://m.apkpure.com/hdp-gestosis-score/hdp.gestosis.score).\n\n\nDiscussion\n\nAs gestational hypertension has morbid consequences on the outcome of pregnancy, there is a need not only for diagnosis and management of gestational hypertension but also for methods that will help in identifying women who may develop gestational hypertension in pregnancy. This study evaluates the predictive abilities of two such methods, gestosis score with uterine artery pulsatility index with the expected outcome of gestosis score being better radiological evaluation in detecting at-risk pregnant women. This study will help in employing gestosis score as a screening method at health centers where ultrasonography or other expensive biochemical investigations cannot be done.\n\nHigh-risk pregnancies will be diagnosed earlier and managed accordingly to provide healthy outcomes and safe motherhood to women.",
"appendix": "Data availability\n\nNo underlying data are associated with this article.\n\n\nReferences\n\nGestational Hypertension and Preeclampsia. Accessed: July 31, 2023. Reference Source\n\nLiu C-M, Cheng P-J, Chang S-D: Maternal Complications and Perinatal Outcomes Associated with Gestational Hypertension and Severe Preeclampsia in Taiwanese Women. J. Formos. Med. Assoc. 2008; 107: 129–138. PubMed Abstract | Publisher Full Text\n\nWikström A-K, Haglund B, Olovsson M, et al.: The risk of maternal ischaemic heart disease after gestational hypertensive disease. BJOG Int. J. Obstet. Gynaecol. 2005; 112: 1486–1491. Publisher Full Text\n\nMaternal obesity, gestational hypertension, and preterm delivery. J. Matern. Fetal Neonatal Med. Vol 23(1); 82–88. Accessed: August 1, 2023. Publisher Full Text\n\nDhinwa: Prevalence of hypertensive disorders of pregnancy in India: A systematic review and meta-analysis. Accessed: July 31, 2023. Reference Source\n\nKumar N, Singh AK: Maternal serum uric acid and calcium as predictors of hypertensive disorder of pregnancy: A case control study. Taiwan. J. Obstet. Gynecol. 2019; 58: 244–250. PubMed Abstract | Publisher Full Text\n\nUriel M, Romero Infante XC, Rincón Franco S, et al.: Higher PAPP-A Values in Pregnant Women Complicated with Preeclampsia Than with Gestational Hypertension. Reprod. Sci. 2023; 30: 2503–2511. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBallegeer V, Spitz B, Kieckens L, et al.: Predictive value of increased plasma levels of fibronectin in gestational hypertension. Am. J. Obstet. Gynecol. 1989; 161: 432–436. PubMed Abstract | Publisher Full Text\n\nOkwudire EG, Atalabi OM, Ezenwugo UM: The use of Uterine Artery Doppler Indices for Prediction of Pre-eclampsia in Port-Harcourt, Nigeria. Niger. Postgrad. Med. J. 2019; 26: 223–229. PubMed Abstract | Publisher Full Text\n\nAudibert F, Boucoiran I, An N, et al.: Screening for preeclampsia using first-trimester serum markers and uterine artery Doppler in nulliparous women. Am. J. Obstet. Gynecol. 2010; 203: 383.e1–383.e8. PubMed Abstract | Publisher Full Text\n\nCampbell S: First-trimester screening for pre-eclampsia. Ultrasound Obstet. Gynecol. 2005; 26: 487–489. Publisher Full Text\n\nAdded Value of Angiogenic Factors for the Prediction of Early and Late Preeclampsia in the First Trimester of Pregnancy|Fetal Diagnosis and Therapy|Karger Publishers. Accessed: August 1, 2023. Reference Source\n\nO’Gorman N, Nicolaides KH, Poon LCY: The Use of Ultrasound and other Markers for Early Detection of Preeclampsia.2016. Accessed: August 1, 2023. Publisher Full Text\n\nAbout HDP-Gestosis Score.\n\nGupta M, Yadav P, Yaqoob F: A Prospective Study to Determine the Predictive Ability of HDP-Gestosis Score for the Development of Pre-eclampsia. J. Obstet. Gynecol. India. 2022; 72: 485–491. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source\n\nGómez O, Figueras F, Fernández S, et al.: Reference ranges for uterine artery mean pulsatility index at 11–41 weeks of gestation. Ultrasound Obstet. Gynecol. 2008; 32: 128–132. PubMed Abstract | Publisher Full Text\n\nMetcalfe C: Biostatistics: A Foundation for Analysis in the Health Sciences . 7th edn.Daniel WW, editor. Wiley; 1999; 20. : 324–6. No. of. pages: xiv+755+appendices. Price: £28.95. 0-471-16386-4. Stat. Med. 2001.Publisher Full Text"
}
|
[
{
"id": "242889",
"date": "12 Feb 2024",
"name": "Paolo Ivo Cavoretto",
"expertise": [
"Reviewer Expertise Maternal Fetal Medicine"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe protocol is sound and interesting. However, I have few major remarks to improve the study design: 1. outside the research design of RCT for such a study project it is mandatory to consider a multivariable model taking into account covariates with effects as confounders or moderators. 2. a major study showing uterine arteries distribution with a novel and robust method based upon fractional polinomials (as previously described by the Intergrowth model) was not considered. I strongly recommend to the authors to include these citations with related online material, and possibly to use this model (ref 1) and formula (ref 2) for their Z scores and centiles calculations.\nReferences (n1 includes the model, tables of centiles and the curves with charts of centiles, n2 includes the formula for calculating the Z-scores based on this model)\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1271
|
https://f1000research.com/articles/12-1270/v1
|
05 Oct 23
|
{
"type": "Case Report",
"title": "Case Report: Complete tomographic resolution of focal choroidal excavation complicated with choroidal neovascularization after anti-VEGF treatment",
"authors": [
"Imène Zhioua Braham",
"Selim Haddar",
"Mejdi Boukari",
"Manel Mokrani",
"Ilhem Mili",
"Raja Zhioua",
"Selim Haddar",
"Mejdi Boukari",
"Manel Mokrani",
"Ilhem Mili",
"Raja Zhioua"
],
"abstract": "Purpose: We report a case of focal choroidal excavation (FCE) that resolved after intravitreal injection of anti-vascular endothelial growth factor (VEGF) for choroidal neovascularization (CNV) and we describe its tomographic features. Case report: A 43-year-old female presented with blurred vision and metamorphopsia in her left eye (LE) evolving for 10 years. The best corrected visual acuity (BCVA) was 20/20 in the right eye and 20/32 in the LE. Fundus examination revealed the presence of a yellowish foveal lesion which corresponded to a conforming FCE associated to a pachychoroid on swept-source optical coherence tomography (OCT). The OCT-Angiography showed a foveal flow void in the choriocapillaris layer corresponding to the FCE area. Three years later, the patient complained of visual impairment, more metamorphopsia with a BCVA of 20/80 on her LE. The OCT showed intraretinal fluid with a foveal retinal pigment epithelium (RPE) detachment. The OCT-angiography confirmed the presence of CNV. Two months after one intravitreal bevacizumab injection, the OCT documented the complete resolution of macular edema, the regression of the CNV tissue and the restoration of a normal aspect of the fovea without any FCE. Her BCVA improved to 20/32 with resolution of the metamorphopsia. The OCT aspect remained stable during 3 years of follow-up. Conclusion: CNV can develop in FCE and anti-VEGF therapy is a good option treatment. After treatment, FCE pattern can change et may completely resolve.",
"keywords": [
"focal choroidal excavation",
"optical coherence tomography",
"choroidal neovascularization"
],
"content": "Background\n\nFocal choroidal excavation (FCE) is defined by a choroidal depression without evidence of posterior staphyloma or scleral ectasia, detected by swept-source optical coherence tomography (OCT) or by spectral-domain OCT using Enhanced Depth Imaging technology.1 It is mainly an idiopathic clinical entity, suggested to be congenital, but can be also be secondary to other diseases.2–5\n\nHereby, we report a case of foveal FCE complicated with choroidal neovascularization (CNV) which completely resolved after intravitreal injection of anti-VEGF.\n\n\nObjective\n\nTo describe the tomographic features of a case of FCE that resolved after intravitreal injection of anti-VEGF for CNV.\n\n\nCase report\n\nA 43-year-old female with no medical history presented with blurred vision and metamorphopsia in her left eye (LE) evolving for ten years. The best corrected visual acuity (BCVA) was 20/20 in the right eye and 20/32 in the LE (with a correction of -0,5 diopter). Anterior segment examination was unremarkable. Fundus examination revealed the presence of a yellowish foveal lesion (Figure 1). The swept-source OCT showed a foveal depression of the choroid, the Bruch’s membrane and the retinal pigment epithelium (RPE). A localized foveal RPE atrophy was noted with a choroidal hyper-transmission signal on OCT. The EZ was separated from the RPE by a hyperreflective material and a hyporeflective zone. The choroid appeared thinner in the area of the depression than the parafoveal choroid which was a pachychoroid with pachyvessels. The OCT-Angiography showed a foveal flow void in the choriocapillaris layer corresponding to the FCE area. This multimodal imaging confirmed the diagnosis of a conforming FCE (Figure 1). The right eye showed an isolated pachychoroid on OCT without FCE.\n\na. Color fundus photography of the left eye showing a yellow plaque-like foveal lesion. b. Fluorescein Angiography showing foveal hyperfluorescence without leakage c. Swept-source OCT in the macular region showing a foveal depression of the choroid and the complex Bruch’s membrane-RPE (blue arrow). A localized foveal RPE atrophy was noted with a hypertransmission signal (white asterisk). The EZ was separated from the RPE by a hyperreflective material (yellow arrow) and a hyporeflective zone. The choroid appeared thinner in the area of the RPE depression than the parafoveal choroid which was a pachychoroid with pachyvessels. d.e.f.g. OCT-angiography showing a normal retinal vasculature with a foveal choriocapillaris flow void, corresponding to the thinned choroid beneath the FCE.\n\nOCT: optical coherence tomography, RPE: retinal pigment epithelium, EZ: ellipsoid zone, SCP: superficial capillary plexus, DCP: deep capillary plexus.\n\nThree years later, the patient complained of visual impairment, more metamorphopsia with a BCVA of 20/80 on her LE. The OCT showed intraretinal fluid with a foveal retinal pigment epithelium (RPE) detachment within the excavation. The OCT-angiography confirmed the presence of CNV (Figure 2). Two months after one intravitreal bevacizumab injection, the OCT documented the complete resolution of macular edema, the regression of the CNV tissue and the restoration of a normal aspect of the fovea without any FCE. Her BCVA improved to 20/32 with resolution of the metamorphopsia. The OCT aspect remained stable during three years of follow-up.\n\na. Swept-source OCT showing intraretinal fluid with a foveal RPE detachment. b.c OCT-angiography at the level of the SCP (b) and the DCP (d) showing capillary disorganization and cystoid edema in the foveal region. d.e. OCT-angiography showing CNV at the level of the external retina (yellow arrow) and the choriocapillaris (blue arrow). f. Swept-source OCT two months after intravitreal injection of bevacizumab revealing normal aspect of the fovea with regular and intact RPE and resorption of the FCE. g.h. OCT-angiography at the level of the SCP (g) and the DCP (h) showing normalization of the retinal vasculature. i.j. Complete resorption of the CNV tissue on the external retina (i) and the choriocapillaris (j) on the OCT-angiography. The choriocapillaris showed persistence of the flow void in the foveal region corresponding to the localized choroidal thinning (white circle).\n\nVEGF: vascular endothelial growth factor, FCE: focal choroidal excavation, CNV: choroidal neovascularization, OCT: optical coherence tomography, RPE: retinal pigment epithelium, SCP: superficial capillary plexus, DCP: deep capillary plexus.\n\n\nDiscussion\n\nFCE is defined as an area of concavity in the choroid occurring in the absence of posterior staphyloma or scleral ectasia. Overlying retinal layers have usually a near-normal appearance.6\n\nThe disease was first described par Jampol et al. in 2006 and was designated by the term FCE later in 2011 by Margolis et al. who also distinguished two tomographic entities: “conforming FCE” and “non-conforming FCE”.7,8 OCT findings in “conforming FCE” show near-intact outer retinal layers laying against the excavated choroid without interruption and without any separation between photoreceptors and RPE. In “non-conforming FCE”, photoreceptors are separated from the underlying RPE within the excavated area with the presence of a hyporeflective space. Hyperreflective material may be visualized in this space indicating the presence of inflammatory material or degenerated outer segment residue. Additionally, Shinojima et al. described three patterns of the disease: the cone shaped, the bowl shaped and the mixed morphology.9 Although foveal location is described in most of cases, a few cases of extrafoveal involvement have been reported, including the peripapillary location.10\n\nThe exact pathogenesis of FCE remains to be understood. Usually, it is considered to be congenital, resulting from a focal defect of chorioretinal differentiation and found in asymptomatic eyes. Others may be acquired and secondary to an inflammatory or an ischemic process.11 In fact, FCE can be associated with other ocular findings such as pachychoroid spectrum diseases (central serous chorioretinopathy, pachychoroid aneurysmal type 1 choroidal neovascularization), age related macular degeneration, chorioretinal inflammation, retinal dystrophies, choroidal and retinal tumors.12–14 In our case, we noted a pachychoroid and pachyvessels on OCT in both eyes but without any sign of pachyhcoroid associated disease. In fact, choroidal vascular abnormalities have been described in association with FCE and included choroidal venous dilation (pachyvessels) and choroidal filling defects.15 These findings suggest that local choroidal ischemia may affects the underlying RPE and outer retinal layers, leading in some cases to the development of a CNV. CNV is usually located within the excavation, as seen in our patient, or adjacent to the excavation.16,17\n\nDue to its minimal to absent visual impairment, uncomplicated FCE alone does not require treatment. Coexistent ocular findings such as CSC, PVC and CNV should be treated accordingly. The use of anti-VEGF is indicated in the treatment of CNV associated FCE with a good response. In our case, only one intravitreal injection was required, but authors reported one to four needed injections.17 Following this treatment, conversion of non-conforming FCE with CNV to conforming pattern may be seen.18 However, to our knowledge, this is the first report showing complete resorption of the excavation which disappeared after CVN treatment. The aspect of the RPE was restored and continuous, however the vasculature of the choroid remained affected on OCT-Angiography within the previous site of the depression.\n\nIn conclusion, FCE is well detected by OCT, which could be idiopathic or associated with other ocular diseases. Its relationship with pachychoroid has been reported but its physiopathology remains unknown. FCE can be complicated with CNV that develops within or near the margin of the excavation. Anti-VEGF treatment is a good option in case of CNV complicating FCE, but does not follow a standard protocol. The shape of FCE can change after CNV treatment and can also completely resolve.\n\n\nConsent\n\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the patient/parent/guardian/relative of the patient.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nFigshare. CARE checklist and flowchart. DOI: https://doi.org/10.6084/m9.figshare.24117951.v1\n\n\nReferences\n\nMargolis R: The expanded spectrum of focal choroidal excavation. Arch. Ophthalmol. 2011; 129(10): 1320–1325. PubMed Abstract | Publisher Full Text\n\nLim FPM, Wong CW, Loh BK, et al.: Prevalence and clinical correlates of focal choroidal excavation in eyes with age-related macular degeneration, polypoidal choroidal vasculopathy and central serous chorioretinopathy. Br. J. Ophthalmol. 2016; 100(7): 918–923. PubMed Abstract | Publisher Full Text\n\nKim H, Woo SJ, Kim YK, et al.: Focal choroidal excavation in multifocal choroiditis and punctate inner choroidopathy. Ophthalmology. 2015; 122(7): 1534–1535. PubMed Abstract | Publisher Full Text\n\nOhki T, Sakai T, Tsuneoka H: Focal choroidal excavation associated with focal retinochoroiditis. Optom. Vis. Sci. 2015; 92(1): e12–e20. PubMed Abstract | Publisher Full Text\n\nHua R, Duan J, Zhang M: Pachychoroid Spectrum Disease: Underlying Pathology, Classification, and Phenotypes. Curr. Eye Res. 2021; 46(10): 1437–1448. PubMed Abstract | Publisher Full Text\n\nChung H, Byeon SH, Freund KB: Focal choroidal excavation and its association with pachychoroid spectrum disorders: a review of the literature and multimodal imaging findings. Retina. 2017; 37(2): 199–221. PubMed Abstract | Publisher Full Text\n\nJampol LM, Shankle J, Schroeder R, et al.: Diagnostic and therapeutic challenges. Retina. 2006; 26: 1072–1076. Publisher Full Text\n\nMargolis R, Mukkamala SK, Jampoll LM, et al.: The expanded spectrum of focal choroidal excavation. Arch. Ophthalmol. 2011; 129: 1320–1325. PubMed Abstract | Publisher Full Text\n\nShinojima A, Kawamura A, Mori R, et al.: Morphologic features of focal choroidal excavation on spectral domain optical coherence tomography with simultaneous angiography. Retina. 2014; 34: 1407–1414. PubMed Abstract | Publisher Full Text\n\nAgarwal P, Roy S, Azad SV, et al.: Juxtapapillary Focal Choroidal Excavation. Indian J. Ophthalmol. 2019; 67(3): 400–401. PubMed Abstract | Publisher Full Text\n\nEllabban AA, Tsujikawa A, Ooto S, et al.: Focal choroidal excavation in eyes with central serous chorioretinopathy. Am J. Ophthalmol. 2013; 156: 673–683.e1. Publisher Full Text\n\nLim FP, Wong CW, Loh BK, et al.: Prevalence and clinical correlates of focal choroidal excavation in eyes with age-related macular degeneration, polypoidal choroidal vasculopathie and central serous chorioretinopathy. Br. J. Ophthalmol. 2016; 100: 918–923. PubMed Abstract | Publisher Full Text\n\nAzimizadeh M, Hosseini SM, Babaei E: Focal choroidal excavation in a case of choroidal osteoma associated with choroidal neovascularization. J. Ophthalmic Vis. Res. 2020; 15(3): 419–423. PubMed Abstract | Publisher Full Text\n\nObata R, Takahashi H, Ueta T, et al.: Tomographic and angiographic characteristics of eyes with macular focal choroidal excavation. Retina. 2013; 33: 1201–1210. PubMed Abstract | Publisher Full Text\n\nSeo EJ, Moon TH, Kim DY, et al.: Choroidal inflammation and choriocapillaris ischemia in focal choroidal excavation in comparison to pachychoroid neovasculopathy. Retina. 2021; 41(5): 987–996. PubMed Abstract | Publisher Full Text\n\nGhadiali Q, Dansingani KK, Freund KB: Focal choroidal excavation and choroidal neovascularization with associated pachychoroid. Retin Cases Brief Rep. 2016; 10(4): 293–296. PubMed Abstract | Publisher Full Text\n\nTang WY, Zhang T, Shu QM, et al.: Focal choroidal excavation complicated with choroidal neovascularization in young and middle aged patients. Int. J. Ophthalmol. 2019; 12(6): 980–984. PubMed Abstract | Publisher Full Text\n\nXu H, Zeng F, Shi D, et al.: Focal choroidal excavation complicated by choroidal neovascularization. Ophthalmology. 2014; 121: 246–250. Publisher Full Text"
}
|
[
{
"id": "212716",
"date": "01 Nov 2023",
"name": "Imen Ksiaa",
"expertise": [
"Reviewer Expertise Medical retina",
"Surgical retina",
"Uveitis"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a nice and well-documented case of focal choroidal excavation associated with the late development of choroidal neovascularization (CNV). A single intravitreal Bevacizumab injection resulted in the regression of the CNV lesion and resolution of the choroidal excavation. The data provided by the authors may be of clinical relevance.\nAt the beginning of the discussion, authors should emphasize the originality of the case. Furthermore, the manuscript needs editing for typographical errors:\nIn the abstract section\n- “Case report: A 43-year-old female presented...evolving for 10 years” might be changed to “A 43-year-old female presented with a 10-year history of blurred vision and…”;\n- “option treatment” to “treatment option”.\n\nIn discussion section “…in 2006 and was designated by the term FCE” might be changed to “…was called FCE”.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
},
{
"id": "256520",
"date": "20 Mar 2024",
"name": "Niroj Kumar Sahoo",
"expertise": [
"Reviewer Expertise imaging",
"macular disorders"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors provide an interesting article on the response of FCE with CNVM to anti-VEGF. A few modifications are needed: Case report section, Paragraph 1: The initial presentation looks like a \"non-conforming\" variant of FCE. This term can be included in the text.\nFigure 2: The presenting OCTA is a zoomed-in image/ 3 mm scan, while the follow-up image is a zoomed-out image/ 6 mm scan. It would be better to provide a zoomed-in OCTA image for the follow up too, for a better comparison of the retinal vasculature.\nDiscussion: \"However, to our knowledge, this is the first report showing complete resorption of the excavation which disappeared after CVN treatment. \" We can still see the excavation on follow-up, although it has reduced in depth. This can be rephrased.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1270
|
https://f1000research.com/articles/12-1267/v1
|
05 Oct 23
|
{
"type": "Case Report",
"title": "Case Report: Duodenal perforation complicated by psoas muscle collection and spondylodiscitis successfully managed without surgery - An unusual case of a toothpick ingestion",
"authors": [
"Anis Belhadj",
"Med Dheker Touati",
"Fahd Khefacha",
"Sahar HAMZA",
"Ahmed OMRY",
"Mohamed Raouf BEN OTHMENE",
"Leila BELHAJ AMMAR",
"Ahmed Saidani",
"Lamia KALLEL",
"Faouzi Chebbi",
"Anis Belhadj",
"Fahd Khefacha",
"Sahar HAMZA",
"Ahmed OMRY",
"Mohamed Raouf BEN OTHMENE",
"Leila BELHAJ AMMAR",
"Ahmed Saidani",
"Lamia KALLEL",
"Faouzi Chebbi"
],
"abstract": "Perforation of the intestine caused by an ingested foreign object remains a complex challenge in terms of clinical presentation, diagnosis, and treatment. A 55-year-old man presented with complaints of right-sided abdominal pain and functional impairment of the lower limbs. Physical examination revealed an afebrile status and tenderness in the right upper quadrant of the abdomen. Abdominal computed tomography (CT) and magnetic resonance imaging (MRI) revealed a duodenal perforation caused by a densely linear foreign body. Additionally, a collection in the psoas muscle and contiguous spondylodiscitis were identified. To address this condition, an endoscopic procedure was performed to extract the toothpick successfully, and a CT-guided fine-needle aspiration was conducted to collect the fluid. Spondylodiscitis was managed with antibiotic therapy and immobilization. Remarkably, significant clinical and radiological improvement was observed within a span of three weeks. This case emphasizes the importance of multidisciplinary care involving interventional treatments as a viable and safe alternative to surgical intervention.",
"keywords": [
"Emergency",
"Gastroenterology",
"Spondylodiscitis",
"Duodenal Perforation",
"Foreign Bodies",
"Psoas Abscess"
],
"content": "Introduction\n\nThe ingestion of foreign bodies is a medical emergency; however, the majority of cases resolve spontaneously without causing damage to the gastrointestinal tract. Approximately 20% of cases require endoscopic extraction, and in 1% of cases, surgical intervention becomes necessary, especially when complications arise such as acute peritonitis.1,2 While fish bones are the most commonly implicated foreign bodies, occurrences involving toothpicks are much more rare.3 In this report, we present an unusual case of duodenal perforation caused by an ingested toothpick, which led to the formation of a collection in the psoas muscle and contiguous spondylodiscitis. Diagnosis and treatment were achieved through the utilization of endoscopy, radiology, and antibiotic therapy, without the need for surgical intervention.\n\n\nCase report\n\nA 55-year-old north-African greengrocer man presented with a five-day history of right upper quadrant abdominal pain and functional impairment of the lower limbs. He had no significant medical history and was taking no medication. His symptoms were not accompanied by nausea or vomiting. Physical examination revealed an afebrile patient with tenderness in the right upper quadrant of the abdomen. Blood tests showed normal results. An abdominal computed tomography (CT) scan revealed the presence of a spontaneously dense linear foreign body measuring 6 cm in length. It was located retroperitoneally, with one end at the level of the superior duodenal flexure and the second portion of the duodenum, perforating the posterior wall of the second duodenum. The other end of the foreign body was situated at the level of the right psoas muscle, surrounded by a collection measuring 26 × 11 mm on the axial plane and extending over 47 mm in height. There was regular and circumferential thickening of the first and the second duodenum portions with an inflammatory appearance (Figure 1). No vessel injury was observed.\n\nUpper gastrointestinal endoscopy revealed a wooden toothpick deeply embedded in the duodenal wall (Figure 2), which was successfully removed using biopsy forceps (Figures 2 and 3) without complications such as bleeding or purulent discharge.\n\nNo clinical improvement was noted after seven days of empirical antibiotic. A follow-up abdominal scan was conducted, which showed the collection size to be stable. Due to the persistent functional impairment, an MRI of the lumbar spine was performed, leading to a diagnosis of contiguous spondylodiscitis at the L4-L5 level (Figure 4).\n\nA CT-guided fine-needle aspiration of the collection was carried out, and the puncture fluid was found to be purulent. A sample was sent for bacteriological examination, which revealed Escherichia coli as the causative agent. Subsequently, an eight-week antibiotic therapy regimen was initiated, adjusted based on the antibiogram results (Cefotaxime: 2 grams × 4/day, Ciprofloxacin 200 mg × 2/day. Immobilization of the lumbar spine was achieved using a corset.\n\nThe clinical and radiological progression showed improvement, with the functional impotence resolving and the psoas collection regressing on the follow-up CT scan. On the 13th day of hospitalization, the patient was discharged without further active treatment for spondylodiscitis. During the subsequent follow-up, one year after discharge, the patient remained asymptomatic.\n\n\nDiscussion\n\nThe majority of ingested foreign bodies pass through the gastrointestinal (GI) tract without complications, symptoms, or requiring further intervention.1,2 GI perforation occurs in approximately 1% of cases, and the risk of perforation increases to 15–35% with thin and pointed objects such as toothpicks, needles, fish and chicken bones.2–4\n\nBatteries can also cause chemical and electrical damage to the mucosal tissues.5,6 Other complications that may occur include obstruction, peritonitis, abscess, or perforation into adjacent organs.7\n\nTo the best of our knowledge, this is the second reported case of spondylodiscitis caused by toothpick ingestion in the literature. Toothpicks account for approximately 9% of ingested foreign bodies.7–9 Risk factors for toothpick ingestion include alcohol abuse, mental disorders, rapid eating, and consumption of foods containing toothpicks.7,10,11 Many patients are unaware of the ingestion, making the diagnosis of toothpick ingestion challenging.1 The clinical presentation varies widely depending on the site of perforation, with abdominal pain being the most prominent symptom.12 In the differential diagnosis, peptic ulcer perforation, acute appendicitis, and acute diverticulitis should be considered.13\n\nStudies have shown that GI perforation most commonly occurs in the colon and ileocecal region, particularly in the appendix and Meckel’s diverticulum.2 Perforations in the gastric and duodenal regions are less frequent, and their presentations tend to be more chronic and less severe in nature.2,12,14 The occurrence of duodenal perforation is likely related to its anatomical morphology, characterized by an angulation and a C-loop shape.7\n\nPlain radiographs are a simple and useful diagnostic tool for ingested foreign bodies; however, they may not detect radiolucent objects such as animal bones, glass, plastics, medications, and small metal objects.2,3,15,16 Radiographs can be sufficient to rule out free abdominal gas and determine the size, shape, location, and number of foreign bodies.11,17 However, identifying the localization of a toothpick using plain X-rays is challenging.11 In such cases, CT scanning and diagnostic endoscopy are generally preferred modalities.2\n\nIt is important to note that barium swallow studies are contraindicated in these cases due to the risk of GI perforation. Additionally, contrast agents used in these studies may interfere with endoscopic evaluation.2 The sensitivity of CT scans can be improved with 3D reconstruction.18 After performing a CT scan, endoscopic intervention can be carried out, allowing for both diagnosis and therapeutic removal of the foreign body to be done simultaneously.19\n\nIn our case, CT images were invaluable in detecting the foreign body in the duodenum, which appeared as a high-density linear object, but its exact nature could not be identified. The CT scan accurately determined the location of both ends of the toothpick and the depth of duodenal penetration. Furthermore, it confirmed the absence of vessel injury before endoscopic removal of the toothpick. Upper GI endoscopy is contraindicated when peritonitis or vascular penetration is suspected.7 Endoscopy confirmed the presence of a wooden toothpick, and our patient recalled possibly swallowing the object while he was asleep, intoxicated, with a toothpick in his mouth after consuming tapas containing toothpicks, one week prior.\n\nTreatment modalities for foreign bodies in the GI tract are chosen based on the type and location of the object. Endoscopy is the recommended first-line management for duodenal or lower rectal perforation.11 Flexible endoscopic techniques are preferred over rigid endoscopes due to a lower risk of perforation.20,21 Commonly used tools include crocodile teeth forceps, polypectomy snares, magnetic probes, retrieval snare nets, Dormia panniers, and transparent cap-fitting devices.17,22,23 Endoscopists should be familiar with these tools and comfortable using them. In our case, a biopsy forceps easily grasped the toothpick. However, it is important to note that if there is suspected frank perforation or peritonitis, surgical treatment should not be delayed.\n\nIn our case, the duodenal perforation was associated with a collection in the psoas muscle, without signs of sepsis. Radiological drainage was preferred over surgery. Percutaneous drainage is the preferred method for treating retroperitoneal abscesses as it is better tolerated by patients, eliminates the need for general anesthesia, and is associated with shorter hospital stays.2,4,14,15 The mortality rate after surgical drainage of retroperitoneal abscesses is reported to be 39%–50%, whereas it is around 1.5%–10% for percutaneous drainage.2,14–16\n\nFortunately, the diagnosis of spondylodiscitis was quickly suspected and confirmed by an MRI of the lumbar spine. This allowed for the appropriate treatment of spondylodiscitis and halted its progression.\n\n\nConclusions\n\nTo the best of our knowledge, this is the first documented case of duodenal perforation complicated by a psoas muscle collection and spondylodiscitis. In summary, the overall disease course of this patient was unusual, primarily due to the delayed diagnosis and the patient’s lack of awareness regarding the ingestion of the toothpick. It is important to consider the possibility of foreign body ingestion and gastrointestinal perforation in patients presenting with abdominal pain. Thorough questioning and clinical suspicion can help avoid unnecessary surgical interventions.\n\n\nConsent\n\nWritten informed consent to publish this case and associated images was obtained from the patient.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReferences\n\nVelitchkov NG, Grigorov GI, Losanoff JE, et al.: Ingested foreign bodies of the gastrointestinal tract: retrospective analysis of 542 cases. World J. Surg. 1996; 20(8): 1001–1005. PubMed Abstract | Publisher Full Text\n\nBekkerman M, Sachdev AH, Andrade J, et al.: Endoscopic Management of Foreign Bodies in the Gastrointestinal Tract: A Review of the Literature. Gastroenterol. Res. Pract. 2016; 2016: 8520766–8520767. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen CK, Su YJ, Lai YC, et al.: Fish bone-related intra-abdominal abscess in an elderly patient. Int. J. Infect. Dis. 2010; 14(2): e171–e172. PubMed Abstract | Publisher Full Text\n\nWilliams C, McHenry CR: Unrecognized foreign body ingestion: an unusual cause for abdominal pain in a healthy adult. Am. Surg. 2004; 70(11): 982–984. PubMed Abstract | Publisher Full Text\n\nMarom T, Goldfarb A, Russo E, et al.: Battery ingestion in children. Int. J. Pediatr. Otorhinolaryngol. 2010; 74(8): 849–854. Publisher Full Text\n\nSzaflarska-Popławska A, Popławski C, Romańczuk B, et al.: Endoscopic removal of a battery that was lodged in the oesophagus of a two-year-old boy for an extremely long time. Prz Gastroenterol. 2015; 10(2): 122–126. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRobert B, Bartoli E, Fumery M, et al.: Duodenal perforation due to toothpick perforation, an uncommon cause of chronic abdominal pain. Endoscopy. 2012; 44: E27–E28. PubMed Abstract | Publisher Full Text\n\nNigri GR, Di Giulio E, Di Nardo R, et al.: Duodenal perforation and right hydronephrosis due to toothpick ingestion. J. Emerg. Med. 2008; 34(1): 55–57. PubMed Abstract | Publisher Full Text\n\nGastric penetration by an ingested toothpick successfully managed with computed tomography and endoscopy - PubMed. Accessed October 8, 2022. Reference Source\n\nSteenvoorde P, Moues CM, Viersma JH: Gastric perforation due to the ingestion of a hollow toothpick: report of a case. Surg. Today. 2002; 32(8): 731–733. PubMed Abstract | Publisher Full Text\n\nSteinbach C, Stockmann M, Jara M, et al.: Accidentally ingested toothpicks causing severe gastrointestinal injury: a practical guideline for diagnosis and therapy based on 136 case reports. World J. Surg. 2014; 38(2): 371–377. PubMed Abstract | Publisher Full Text\n\nTumay V, Guner OS, Meric M, et al.: Endoscopic Removal of Duodenal Perforating Fishbone - A Case Report. Chirurgia (Bucur). 2015; 110(5): 471–473. PubMed Abstract\n\nLaw WL, Lo CY: Fishbone perforation of the small bowel: laparoscopic diagnosis and laparoscopically assisted management. Surg. Laparosc. Endosc. Percutan. Tech. 2003; 13(6): 392–393. Publisher Full Text\n\nGoh BKP, Chow PKH, Quah HM, et al.: Perforation of the gastrointestinal tract secondary to ingestion of foreign bodies. World J. Surg. 2006; 30(3): 372–377. Publisher Full Text\n\nForeign Bodies|RadioGraphics. Accessed October 8, 2022. Publisher Full Text\n\nA review of gastrointestinal foreign bodies - PubMed. Accessed October 8, 2022. Reference Source\n\nManagement of ingested foreign bodies and food impactions - PubMed. Accessed October 8, 2022. Reference Source\n\nTakada M, Kashiwagi R, Sakane M, et al.: 3D-CT diagnosis for ingested foreign bodies. Am. J. Emerg. Med. 2000; 18(2): 192–193. Publisher Full Text\n\nSugawa C, Ono H, Taleb M, et al.: Endoscopic management of foreign bodies in the upper gastrointestinal tract: A review. World J. Gastrointest. Endosc. 2014; 6(10): 475–481. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGmeiner D, von Rahden BHA , Meco C, et al.: Flexible versus rigid endoscopy for treatment of foreign body impaction in the esophagus. Surg. Endosc. 2007; 21(11): 2026–2029. PubMed Abstract | Publisher Full Text\n\nBounds BC: Endoscopic Retrieval Devices. Tech. Gastrointest. Endosc. 2006; 8(1): 16–21. Publisher Full Text\n\nFaigel DO, Stotland BR, Kochman ML, et al.: Device choice and experience level in endoscopic foreign object retrieval: An in vivo study. Gastrointest. Endosc. 1997; 45(6): 490–492. PubMed Abstract | Publisher Full Text\n\nNelson DB, Bosco JJ, Curtis WD, et al.: ASGE technology status evaluation report. Endoscopic retrieval devices. February 1999. American Society for Gastrointestinal Endoscopy. Gastrointest. Endosc. 1999; 50(6): 932–934. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "277185",
"date": "04 Jun 2024",
"name": "Faming Zhang",
"expertise": [
"Reviewer Expertise Innovative microbiome and gastrointestinal intervention therapy."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nComments to Author: This article presents an intriguing case of a duodenal perforation caused by a toothpick, further complicated by a psoas muscle abscess and spondylodiscitis. The authors accurately diagnosed and successfully managed the condition through a comprehensive examination utilizing imaging and endoscopy techniques. Besides, the authors provided clear explanations of the patient's symptoms and signs, offering thorough consideration of potential differential diagnoses and incorporating insights from recent advancements in the field. However, some minor aspects could benefit from improvement. Minor Points: 1.\n\nLogic of writing: Please revise the third sentence in the \"Introduction\" and the third sentence of paragraph seven in the \"Discussion\". 2.\n\nConciseness of writing: Please avoid redundancy in the first paragraphs of both the \"Introduction\" and \"Discussion\". 3.\n\nScientific writing: Please delete the sentences \"the second reported case of spondylodiscitis caused by toothpick ingestion\" and \"the first documented case of duodenal perforation complicated by a psoas muscle\". 4.\n\nPlease replace some unusual expressions, such as \"collection,\" with more common terms like \"fluid accumulation\".\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1267
|
https://f1000research.com/articles/12-1266/v1
|
04 Oct 23
|
{
"type": "Case Report",
"title": "Case Report: Bilateral optic disc swelling in a patient with tuberculoma",
"authors": [
"Ayushi Tayal",
"Sachin Daigavane",
"Sachin Daigavane"
],
"abstract": "BACKGROUND: In children, tuberculosis of the central nervous system most usually manifests as tubercular meningitis, hydrocephalus post-tubercular meningitis, and, in rare cases, space-occupying lesions known as tuberculoma. We address the diagnostic difficulty in an adult patient with mainly ocular symptoms who was diagnosed with tuberculoma. A 19-year-old young man came with painless bilateral blurring of vision. Bilateral optic disc swelling and bilateral sixth cranial nerve palsy were present. METHODS: Brain imaging revealed ring-enhancing lesions in the cerebellar vermis, left cerebellar hemisphere and left middle cerebral peduncle with surrounding extensive perilesional edema causing effacement of fourth ventricle leading to obstructive hydrocephalus suggestive of tuberculoma. RESULTS: He had a high erythrocyte sedimentation rate and a positive Mantoux test. His Quantiferon-TB Gold test result was positive. The examination of cerebrospinal fluid suggested a high opening pressure. Following anti-tubercular medication along with systemic steroids, his vision improved due to decreased optic disc swelling. CONCLUSION: We wish to highlight that visual loss and grave consequences of tuberculoma can be averted with early recognition and treatment.",
"keywords": [
"Optic disc swelling",
"obstructive hydrocephalus",
"tuberculoma"
],
"content": "Introduction\n\nA rare but unquestionably deadly form of tuberculosis is the central nervous system (CNS) disease brought on by Mycobacterium tuberculosis. Only 10% of tuberculosis patients are CNS cases, which have a significant mortality rate and distressingly severe neurological morbidity.1 Tuberculous meningitis (TBM) is a potentially fatal form of CNS infection causing death and severe disability up to 50%–60% of affected patients.1 Although there has been a recent come back of the disease in both developed and developing countries, the burden of CNS tuberculosis is primarily found in resource-poor regions of the world.2 The original Rich description2 suggested that CNS tuberculosis develops in two stages: first, tuberculous lesions (Rich’s focus) form in the brain during the bacteraemia stage or shortly thereafter, and later, CNS tuberculosis develops when one or more of these lesions burst or enlarge. This case demonstrates how disc edema and blurred vision might be tuberculoma’s early presenting symptoms. However, it can be difficult to detect and treat its morbidity. Early recognition and treatment improve the outcome.\n\n\nCase presentation\n\nA 19-year-old male Hindu by religion, student by occupation and no relevant family history presented with subacute onset of painless blurring of vision in both eyes for a two-week duration. This was associated with diplopia which later resolved spontaneously. Otherwise, there were no other complaints such as fever, headache, vomiting, cough, stiff neck, or any neurological symptoms. His best corrected visual acuity (BCVA) in both of his eyes was 6/12 upon evaluation. His dilated fundus examination revealed bilateral swelling of the optic disc, with few peripapillary shaped haemorrhages, tortuous vessels and multiple hard exudates confined to temporal to the disc suggestive of macular fan (Figure 1A and B). There were no other signs of uveitis such as vitritis, retinitis or choroiditis. Optic nerve function tests which included visual fields, pupillary light reflexes and colour vision were normal in both eyes. There was no relative afferent pupillary defect. Otherwise, his vital parameters were normal. There were no signs of meningeal irritation, such as neck rigidity or the Kernig’s sign. Higher mental functions were normal. The patient was oriented to time, place and person.\n\nFundus photograph was taken through Zeiss Visucam 524.\n\nAfter obtaining written informed consent from the patient further intervention was started.\n\nAn evaluation of the cranial nerves indicated left sixth cranial nerve palsy that later spread to the right side. Treatment for tuberculosis was started. During the initial phase, he received isoniazid, rifampicin, pyrazinamide, and ethambutol for two months. Systemic steroids were also started. The continuation phase, which consisted of isoniazid and rifampicin, lasted for seven months after that.\n\nLaboratory investigations showed a raised erythrocyte sedimentation rate (ESR) of 109 mm with positive Mantoux reading of 20 mm at 72 hours. The Quantiferon-TB Gold in-tube test was positive. cerebrospinal fluid examination revealed an opening pressure of 12-20 cmH20, turbid in appearance; a lymphocytic predominant pleiocytosis. Total white blood cell counts ranged 60-500 cells/μL, with raised protein levels greater than 2.2 g/L and low glucose levels lower than 40 mg/dL. MRI imaging showed ring enhancing lesions noted in the cerebellar vermis, left cerebellar hemisphere and left middle cerebral peduncle with surrounding extensive perilesional edema appearing hyperintense on T2WI/FLAIR, hypointense on T1W1, showing central restriction on DWI with no blooming on SWI causing effacement of fourth ventricle leading to obstructive hydrocephalus suggestive of tuberculoma (Figure 2A and B).\n\n\nDiscussion\n\nThe clinical characteristics, laboratory results, CSF findings, and radiographic imaging are used to make the diagnosis of tuberculoma. However, if there are no signs of the typical clinical characteristics, the condition may prove difficult to diagnose. Tuberculomas are spherical, firm, avascular masses that range in size from 2 to 10 cm in diameter. They are well defined, and the gliosis and edema in the compressed brain tissue around them are visible.3 In our patient, the presentation of tuberculoma was associated with bilateral optic disc swelling. He presented with ocular signs of visual impairment, bilateral disc edema and sixth cranial nerve palsy. Our patient’s positive Mantoux test and positive TB-gold, elevated ESR indicated tuberculosis infection. After two months of anti-tubercular medications with steroids on tapering dose patient had marked reduced optic disc swelling and exudates with visual gain of 6/9 in both eyes (Figure 3A and B).\n\nOn follow-up visit liver function test was within normal limits (Table 1).\n\nThe majority of patients (80%) with TBM manifest in late stages (stages II and III), according to a review of 101 cases by Sinha et al.2 Late-stage TBM patients had papilloedema and cranial nerve palsy in 52% and 31% of cases, respectively,4 and 27% of patients had visual impairment. At the time of initial TBM presentation, visual impairment of less than 6/18, papilloedema, and cranial nerve palsy were found to be predictors of blindness and severe disability at 6 months. Kumar et al. have proposed that basal meningeal enhancement or tuberculoma or both were 89% sensitive and 100% specific for TBM.5 Commercial nucleic acid amplification assays for the diagnosis of TBM have shown a 98% specificity and 56% sensitivity, according to a recent meta-analysis.6 Our patient’s BCVA increased to 6/6, and the edema of his optic disc significantly decreased (Figure 3). Due to early initiation of anti-tubercular medication, adverse outcomes including blindness and impairment at 6 months were not observed in our patient. When left untreated, 30–50% of tuberculomas enter and continue to progress in a stationary course, according to reports published prior to the development of efficient anti-tuberculosis therapy.7\n\nThe majority of tuberculomas disappear after 12 to 24 months, while continued treatment lasting longer than two years may be necessary in patients with multiple or larger lesions. Anti-inflammatory drugs are administered in addition to the normal anti-tuberculosis regimen in some patients whose symptoms paradoxically deteriorate after therapy due to the release of inflammatory mediators.8 Surgery is necessary to remove particularly large tuberculomas, those that have a mass effect on the brain, and those that do not respond to medical treatment. In some cases, surgical excision is necessary for diagnosis as well as treatment.9\n\nFor individuals with clinically suspected TBM, the quantitative real-time PCR approach has been shown to have higher specificity (100%) and sensitivity (95.8%) than the traditional conventional PCR.10\n\n\nConclusions\n\nWe conclude that ocular symptoms can be the only presenting feature of tuberculoma even though uncommon. We wish to highlight that visual loss and grave consequences of tuberculoma can be averted with early recognition and treatment.\n\nPatient was informed of all the procedures and verbal and written consent were obtained.",
"appendix": "Data availability\n\nAll data are included in the article and no additional source data are required.\n\n\nReferences\n\nLee HG, William T, Menon J, et al.: Tuberculous meningitis is a major cause of mortality and morbidity in adults with central nervous system infections in Kota Kinabalu, Sabah, Malaysia: an observational study. BMC Infect. Dis. 2016; 16: 296. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRich AR, McCordock HA: The pathogenesis of tuberculous meningitis. Bull. Johns Hopkins Hosp. 1933; 52: 5–37.\n\nBrain tuberculomas, tubercular meningitis, and post-tubercular hydrocephalus in children. J. Pediatr. Neurosci. 2011 Oct; 6(Suppl1): S96–S100. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSinha MK, Garg RK, Hk A, et al.: Vision impairment in tuberculous meningitis: predictors and prognosis. J. Neurol. Sci. 2010; 290(1-2): 27–32. PubMed Abstract | Publisher Full Text\n\nKumar R, Kohli N, Thaynani A, et al.: Value of CT scan in the diagnosis of meningitis. Indian Pediatr. 1996; 33: 465–468. PubMed Abstract\n\nThwaites G, Fisher M, Hemingway C, et al.: British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J. Infect. 2009; 59: 167–187. PubMed Abstract | Publisher Full Text\n\nLee HS, Oh JY, Lee JH, et al.: Response of pulmonary tuberculomas to anti-tuberculous treatment. Eur. Respir. J. March 2004; 23(3): 452–455. PubMed Abstract | Publisher Full Text\n\nPerez-Malagon CD, Barrera-Rodriguez R, Lopez-Gonzalez MA, et al.: Diagnostic and Neurological Overview of Brain Tuberculomas: A Review of Literature. Cureus. December 2021; 13(12): e20133. PubMed Abstract | Publisher Full Text\n\nFriedman LN, Dedicoat M, Davies PDO: Clinical tuberculosis. 6th ed.Boca Raton, FL; 2020. 978-1-351-24998-0.\n\nTakahashi T, Tamura M, Asami Y, et al.: Novel wide-range quantitative nested real-time PCR assay forMycobacterium tuberculosis DNA: clinical application for diagnosis of tuberculous meningitis. J. Clin. Microbiol. 2008; 46: 1698–1707. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "274840",
"date": "21 May 2024",
"name": "Ikhwanuliman Putera",
"expertise": [
"Reviewer Expertise Ophthalmology",
"tuberculosis"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear authors,\nThe presented case is interesting and raises awareness among readers about the possibility of papilledema as an initial manifestation leading a brain tuberculoma patient to seek medical help. There are some areas that need improvement:\nThe Title: The title needs clarity as \"tuberculoma\" is a general term that can manifest in various organs. As an ophthalmologist, I initially assumed it was a tuberculoma in the eye, but it was not. I recommend revising it to: \"Brain or CNS Tuberculoma.\" Abstract: The first sentence of the background section of the abstract discusses TB CNS in children. I recommend revising it since this is not relevant to the patient described, who is an adult, and not even in the \"nearly adult\" age range (such as between 15-18 years old). Case Presentation and Discussion: Bilateral, symmetrical disc swelling (papilledema) and impaired CN.VI are suggestive of a space-occupying lesion in the brain and are not specific for brain tuberculoma. Please clarify this in the discussion. Additionally, I recommend mentioning \"restricted eye abduction suggestive of CN.VI palsy\" rather than just directly \"CN.VI palsy. What kind of visual field test being used (Humphrey?)? Patients with papilledema often present with enlarged blind spots. For color vision testing, what test did the authors refer to? Please provide details, such as Ishihara (number of correct responses), as patients with papilledema often have declined color vision. I do recommend removing the religion part in the beginning of the case presentation. Fundus Images (Fig 1 and 3): It is uncommon to present the position of right retinal image as shown. The retinal image of the right eye should be positioned on the left. Figure A in Fig 1 and 3 corresponds to the left eye (please also correct the figure legend). Chest Radiography: The authors mentioned Mantoux and QFT tests but did not include chest radiography investigation results. I recommend adding this to determine whether TB lesions are present. Also, what are the other immunological parameters of this patient, such as HIV testing and CD4/CD8 counts? Is there any other TB foci in other organs? Treatment Details: The authors repeatedly mention \"early initiation.\" How early did the treatment begin in this case? Also, please mention the dose of the steroid that was given. Follow up details: Are there any follow-up data at the completion of treatment? How does the MRI image of the brain look at the end of the treatment?\nThank you.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": []
},
{
"id": "213292",
"date": "30 May 2024",
"name": "Aditya Verma",
"expertise": [
"Reviewer Expertise Diabetic retinopathy",
"age related macular degeneration",
"optical coherence tomography angiography",
"ultrawide field imaging"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbstract: Background: It needs rephrasing. The manuscript talks about the imaging/ labs and treatment concerning an adult with CNS Tuberculosis. Further, the second line needs rephrasing as there does not appear a diagnostic difficulty in this case. Any patient with bilateral disc swelling will undergo a certain panel of CNS investigations including investigations for TB, especially when from Indian (or other high risk regions) origin. It can be rephrased to something like \"this article highlights the importance of appropriate investigations including imaging and early treatment in a young adult presenting with bilateral optic disc swelling as a sole manifestation of CNS tuberculosis\" Methods: It needs extensive re-phrasing. The exact methodology should highlight the patient details and the investigations/ labs/ treatment, which has been distributed in the last part of background, methods and first part of results. It should also mention the follow up period and if any further investigations were done at the end of treatment. Results should mention the treatment outcomes, change in labs/ imaging/ vision/ patient symptoms after treatment etc. Conclusions: Please rephrase. The content in the article details a thorough investigation/lab imaging/treatment for CNS tuberculoma/TB meningitis. highlighting the importance of extensive search for a potentially blinding and lethal disease with appropriate investigations, early recognition and proper treatment. Case presentation: The authors mention that there were no other positive ophthalmic signs, with no mention of the extraocular movements as this is an important part of evaluation in a patient who has left sided cranial nerve 6th palsy. What do authors mean by \"which later spread to the right side\"? Were these cranial nerve evaluations done over a period of time? The patient had a history of diplopia (there is no mention which type/ duration/ direction) which later resolved spontaneously. With the patient having Left 6th cranial nerve palsy, absent diplopia or any abnormality of extraocular movements is unlikely. Authors are requested to re-phrase the whole content in this regard. Further, the case presentation section is not arranged sequentially. It can be rephrased to include the investigations/ labs/ imaging first followed by treatment. The treatment needs to be explained in detail. Did the patient have both TB meningitis and CNS tuberculoma? If that is the case, was the patient admitted? With signs of meningitis (high opening pressure), it is hard to believe that the patient did not have any neurological symptoms in the beginning. Can the authors explain this aspect in detail?\nThe table showing the liver function tests has no relevance in this study unless the effect of anti-TB drugs on liver function tests is being studied.\nLastly, the legends for all the images need to be explained in detail. The hard exudates are distributed nasal to the macula, and are more in the left eye as compared to the right eye. The authors are encouraged to use arrows to illustrate the disc margins and hard exudates respectively and mention the same in the legends. For example, a typical figure legend may be expressed as \"Color fundus images of the right (fig 1A) and the left (fig 1B) respectively showing the optic disc swelling, blurred disc margins (red arrows), and hard exudates scattered at the nasal margins of macula (yellow arrows), more in the left as compared to the right eye\". The legends in MRI scans need further detailing. The legends also need to mention what the arrows are pointing at. Was the follow up evaluation done only at 2 months? If that is the case, were any labs/imaging/ investigations done at this stage?\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1266
|
https://f1000research.com/articles/11-424/v1
|
14 Apr 22
|
{
"type": "Case Report",
"title": "Case Report: Malignant melanoma in a patient with Crohn’s disease treated with ustekinumab",
"authors": [
"Georgios Axiaris",
"Alexandros Ioannou",
"Marina Papoutsaki",
"Leonidas Marinos",
"Michael Liontos",
"Spyridon Michopoulos",
"Evanthia Zampeli",
"Georgios Axiaris",
"Alexandros Ioannou",
"Marina Papoutsaki",
"Leonidas Marinos",
"Michael Liontos",
"Spyridon Michopoulos"
],
"abstract": "The cornerstone of inflammatory bowel disease (IBD) treatment is immunomodulators. IBD patients are at increased risk of intestinal and extraintestinal malignancy. Ustekinumab is a fully humanized monoclonal anti-IL12/23 antibody with a good safety profile. Malignancies of breast, colon, head and neck, kidney, prostate, thyroid, and non-melanoma skin cancer have been reported among patients who received ustekinumab. We report the case of a 42-year-old Crohn’s patient on long-term treatment with ustekinumab, who developed achromatic malignant melanoma. Crohn’s was diagnosed at the age of 15, with upper and lower gastrointestinal involvement and was initially treated with azathioprine (2mg/kg for 4 years) and infliximab (5mg/kg for 6 weeks). Due to ileal obstruction, the patient underwent stricturoplasty and received adalimumab (40mg every other week) for two years. He then discontinued therapy and a year later underwent right hemicolectomy. Adalimumab was reinstituted (40mg every other week) and the patient remained in clinical remission for two years. His overall exposure to adalimumab was four years. Ustekinumab was initiated due to a relapse and after 3 years, an incident of scalp itching led to the diagnosis metastatic achromatic malignant melanoma bearing BRAF V600E mutation. He received targeted therapy with an initial good response. We aim to point out the risk of dermatologic malignancy in IBD patients on long-term immunosuppression and the lifelong and meticulous evaluation that is required.",
"keywords": [
"Melanoma",
"IBD",
"Crohn’s disease",
"Ustekinumab"
],
"content": "Introduction\n\nCrohn’s disease is a chronic inflammatory disorder of unknown etiology. Patients with inflammatory bowel disease (IBD) are at a higher risk of developing colorectal cancer as well as extraintestinal malignancies, probably related to chronic inflammation as well as immunosuppression.1–4 Malignancies associated with long-term suppression of the immune system in the IBD setting, include skin cancers, myelodysplastic syndromes, lymphomas, acute myeloid leukemia, and urinary tract cancers.5 Melanoma is potentially aggressive, highly immunogenic, and strongly related to UV radiation exposure. An increased risk of melanoma has been observed in IBD patients, especially those exposed to tumor necrosis factor (TNF)-α antagonists in contrast to those receiving thiopurines who have an increased risk of non-melanotic skin cancers.6–8 The risk for melanoma increases 1.5 to 2 times for those exposed to TNF-α antagonists.9 Ustekinumab, a fully humanized interleukin (IL)-12/23 monoclonal antibody, targets the common p40 subunit shared by IL-12 and IL-23. The incidence of malignancies was comparable between ustekinumab-exposed psoriatic patients and the general population according to a study with three years follow up.10 The reported malignancies share no particular pattern (colon, breast, kidney, thyroid, head and neck, prostate, and non-melanoma skin cancer). Achromatic malignant melanoma has not been reported so far. Data regarding ustekinumab and development of melanoma are scarce.11 We report the case of a 42-year-old Crohn’s patient on long-term treatment with ustekinumab, who developed achromatic malignant melanoma.\n\n\nCase presentation\n\nΑ 42-year-old male patient with Crohn’s disease who was under treatment with ustekinumab developed achromatic malignant melanoma. The patient’s family history was negative both for malignancy and IBD. The patient is a current smoker with alcohol consumption of less than 10 units per week.\n\nCrohn’s was diagnosed at the age of 15, with upper and lower gastrointestinal involvement (Montreal classification A1L3L4B2p). The patient was initially treated with azathioprine (100 mg/day for 4 years) and infliximab (5 mg/kg every 8 weeks). Infliximab was discontinued due to an allergic reaction during the third infusion. Whilst on azathioprine for four years, the patient was admitted to hospital due to ileal obstruction and was effectively treated with multiple stricturoplasties.\n\nPostoperatively, the patient received adalimumab (40 mg every other week) for two years; he discontinued the treatment on his own accord. A year later the patient underwent right hemicolectomy due to obstruction; an anastomotic leak led to a temporary ileostomy. Adalimumab was reinstituted and the patient remained well for two years when peripheral polyneuropathy occurred. This was attributed to adalimumab, once other possible causes were excluded, leading to its discontinuation after an approximate overall exposure of four years. Moreover, endoscopy revealed a sigmoid stenosis and a third operation was performed for excision of colonic stenosis and restoration of bowel continuity. Six months after surgery, the patient presented with elevated inflammatory markers [calprotectin 676 mcg/g (normal value <50), C-reactive protein (CRP) 45 mg/L (normal value <5)]. Endoscopy revealed multiple large ulcers in the ileocolonic anastomosis and ileum corresponding to an endoscopic Rutgeerts score of i2b. Ustekinumab was initiated in January 2018 (initial dose of 390 mg intravenously according to patient’s weight and 90 mg subcutaneously every eight weeks thereafter).\n\nThree years after initiation of ustekinumab, the patient complained about scalp itching. Clinical examination revealed a scratched bleeding mole on the scalp. Dermatologic assessment, which included full body inspection, was initially reassuring. One month later the patient complained about intense fatigue and presented with multiple, hard, subcutaneous nodules initially on the scalp and rapidly expanding on the trunk and arms (Figure 1). A surgical biopsy was performed, and while awaiting histology, the patient presented to the emergency department with severe dyspnea. Computed tomography (CT) scans showed multiple, large, nodular lesions in the brain, lung, liver, pericardium, adrenal glands, kidneys and abdominal muscles, as well as multiple osteolytic lesions. Histology showed an extensive infiltration of the dermis with sparing of the epidermis, by large aggregates of neoplastic cells with variable amount of eosinophilic cytoplasm and mostly round nuclei with uneven chromatin distribution (Figure 2a-c). Despite a thorough examination of all available sections and fields, no melanin pigment was found. Immunohistochemistry revealed strong and uniform staining for S-100 and BRAF V600E (VE1) and focal staining for HMB45 (Figure 2d-f). The intensity of staining with the monoclonal BRAF V600E (VE1) antibody was graded as 3.11\n\nThe patient was diagnosed with metastatic cutaneous melanoma bearing the BRAF V600E mutation according to immunohistochemical testing. The clinical status of the patient rapidly deteriorated with acute respiratory failure and acute kidney injury. He was therefore started on treatment with combined BRAF/MEK inhibition with dabrafenib (150 mg twice a day) and trametinib (2 mg daily) under the provisional approval of the regulatory authorities. Since day 3 of treatment, clinical improvement has been noted with improvement of dyspnea, renal function and mental status.\n\nThe patient tolerated treatment without any severe adverse events. Most of the nodular lesions started shrinking by day 5 of treatment and the patient was discharged from the hospital on day 20. At discharge, almost all nodular lesions on the skin and tongue disappeared and renal and lung function returned to normal. The patient continued combined BRAF/MEK inhibition. However, he gradually presented cognitive impairment and developed psychiatric symptomatology, which were attributed to persistent brain metastases.\n\n\nDiscussion\n\nWe present a case of a patient with complicated Crohn’s disease, who underwent repeated surgeries and received prolonged immunosuppression with azathioprine, TNF-α antagonists and ustekinumab. The patient ultimately developed melanoma.\n\nUstekinumab (Stelara®) is a fully human monoclonal antibody against the common p40 subunit of IL-12 and IL-23. According to existing evidence, IL-12 and IL-23 influence the development and behavior of melanoma. In particular, murine models show that IL-23 influences the growth and progression of melanomas. Since human melanocytes and melanoma cells express IL-23 receptors, the neutralization of IL-23 may potentially increase the susceptibility of melanoma development.12 IL-12 deficiency promotes photo-carcinogenesis and angiogenesis in UV radiation-induced skin cancers,13,14 thus providing a possible explanation of how anti-IL-12/IL-23 therapy may exacerbate the risk for UV radiation-induced skin malignancies.15 IL-12 has demonstrated anti-tumor activity via induction of interferon (IFN) γ production from natural killer cells, CD4+ and CD8+ T cells, thus modifying the tumor microenvironment.16 Data from the pivotal UNITI studies and real-world data are reassuring regarding the safety of ustekinumab.17 The data for 2574 patients included in six phase 2/3 studies corroborated the favorable safety profile of ustekinumab.18\n\nTo date, no clear link between ustekinumab and cutaneous carcinogenesis has been demonstrated. Regarding squamous cell carcinoma and ustekinumab, a few case reports in patients with psoriasis have been published.19 A case of a patient with psoriasis vulgaris and a history of melanoma, who received ustekinumab for seven consecutive years without relapse of melanoma, was reported.20 A 53-year-old female with severe psoriatic arthritis and a history of metastatic melanoma received sequential therapy with secukinumab and ustekinumab (for nearly two years) and no melanoma relapse or progression was recorded.21\n\nThere is insufficient evidence regarding the oncogenic potential of ustekinumab. It is difficult to establish an association between treatment with ustekinumab and melanoma in our patient since, on one hand, Crohn’s increases the risk for malignancy and on the other, our patient was exposed to multiple immunosuppressive treatments over the years. Although a strong association cannot be established, this case is worth reporting as the prolonged exposure to ustekinumab justifies the hypothesis of a possible connection. The management of patients who develop malignancy while on immunosuppressives is quite demanding as immune suppression is associated with worse survival.22 By means of this case, we would like to point out the risk of malignancy for IBD patients on long-term immunosuppression and the strict and meticulous follow-up that is required. Emphatically, a prophylactic total body dermatologic assessment should not be neglected in IBD patients.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nConsent\n\nWritten informed consent for publication of the patient’s clinical details and clinical images was obtained from the relative and guardian of the patient. The patient was cognitively and psychiatrically unstable meaning he was unable to give consent to publish.",
"appendix": "References\n\nRutter MD, Saunders BP, Wilkinson KH, et al.: Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology. 2006; 130: 1030–1038. Publisher Full Text\n\nEaden JA, Abrams KR, Mayberry JF: The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001; 48: 526–535. PubMed Abstract | Publisher Full Text | Free Full Text\n\nUllman TA, Itzkowitz SH: Intestinal inflammation and cancer. Gastroenterology. 2011; 140: 1807–1816.e1. Publisher Full Text\n\nPedersen N, Duricova D, Elkjaer M, et al.: Risk of extra-intestinal cancer in inflammatory bowel disease: meta-analysis of population-based cohort studies. Am. J. Gastroenterol. 2010; 105: 1480–1487. PubMed Abstract | Publisher Full Text\n\nGreuter T, Vavricka S, König A, et al.: Malignancies in Inflammatory Bowel Disease. Digestion. 2020; 101(suppl 1): 136–145. Publisher Full Text\n\nPeyrin-Biroulet L, Khosrotehrani K, Carrat F, et al.: Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 2011; 141: 1621–1628.e5. PubMed Abstract | Publisher Full Text\n\nSingh S, Nagpal SJ, Murad MH, et al.: Inflammatory bowel disease is associated with an increased risk of melanoma: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 2014; 12: 210–218. PubMed Abstract | Publisher Full Text\n\nNyboe Andersen N, Pasternak B, Basit S, et al.: Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease. JAMA. 2014; 311: 2406–2413. PubMed Abstract | Publisher Full Text\n\nEsse S, Mason KJ, Green AC, et al.: Melanoma Risk in Patients Treated With Biologic Therapy for Common Inflammatory Diseases: A Systematic Review and Meta-analysis. JAMA Dermatol. 2020 Jul 1; 156(7): 787–794. PubMed Abstract | Publisher Full Text\n\nScherl EJ, Kumar S, Warren RU: Review of the safety and efficacy of ustekinumab. Ther. Adv. Gastroenterol. 2010 Sep; 3(5): 321–328. PubMed Abstract | Publisher Full Text\n\nPearlstein MV, Zedek DC, Ollila DW, et al.: Validation of the VE1 immunostain for the BRAF V600E mutation in melanoma. J. Cutan. Pathol. 2014; 41(9): 724–732. PubMed Abstract | Publisher Full Text\n\nJani M, Dixon WG, Chinoy H: Drug safety and immunogenicity of tumour necrosis factor inhibitors: the story so far. Rheumatology (Oxford). 2018 Nov 1; 57(11): 1896–1907. PubMed Abstract | Publisher Full Text\n\nMeeran SM, Katiyar S, Elmets CA, et al.: Interleukin-12 deficiency is permissive for angiogenesis in UV radiation-induced skin tumors. Cancer Res. 2007 Apr 15; 67(8): 3785–3793. Retraction in: Cancer Res. 2018 Dec 1; 78(23): 6708. Publisher Full Text\n\nEhmann LM, Tillack-Schreiber C, Brand S, et al.: Malignant Melanoma During Ustekinumab Therapy of Crohn's Disease. Inflamm. Bowel Dis. 1 January 2012; 18(1): E199–E200. PubMed Abstract | Publisher Full Text\n\nChen Y, Friedman M, Liu G, et al.: Do Tumor Necrosis Factor Inhibitors Increase Cancer Risk in Patients With Chronic Immune-Mediated Inflammatory Disorders?. Cytokine. 2018; 101: 78–88. Publisher Full Text\n\nBerraondo P, Sanmamed MF, Ochoa MC, et al.: Cytokines in clinical cancer immunotherapy. Br. J. Cancer. 2019 Jan; 120(1): 6–15. PubMed Abstract | Publisher Full Text\n\nGhosh S, Gensler LS, Yang Z, et al.: Ustekinumab Safety in Psoriasis, Psoriatic Arthritis, and Crohn's Disease: An Integrated Analysis of Phase II/III Clinical Development Programs. Drug Saf. 2019 Jun; 42(6): 751–768. PubMed Abstract | Publisher Full Text\n\nLamb YN, Duggan ST: Ustekinumab: A Review in Moderate to Severe Crohn's Disease. Drugs. 2017 Jul; 77(10): 1105–1114. Publisher Full Text\n\nYoung L, Czarnecki D: The rapid onset of multiple squamous cell carcinomas in two patients commenced on ustekinumab as treatment of psoriasis. Australas. J. Dermatol. 2012 Feb; 53(1): 57–60. PubMed Abstract | Publisher Full Text\n\nGkalpakiotis S, Arenberger P, Fridman M, et al.: Long-term therapy with ustekinumab for psoriasis in a patient with a history of malignant melanoma. Dermatol. Ther. 2017 Nov; 30(6). Publisher Full Text\n\nGhazanfar MN, Karlsmark T, Danielsen PL, et al.: Sequential treatment with secukinumab and ustekinumab in a patient with severe psoriasis and recent history of cerebral malignant melanoma metastasis. Clin. Case Rep. 2019; 7(7): 1350–1351. Published 2019 Jun 3. PubMed Abstract | Publisher Full Text\n\nBogach J, Pond G, Eskicioglu C, et al.: Extent of Surgical Resection in Inflammatory Bowel Disease Associated Colorectal Cancer: a Population-Based Study. J. Gastrointest. Surg. 2021 Oct; 25(10): 2610–2618. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "148374",
"date": "05 Sep 2022",
"name": "Giovanni Marasco",
"expertise": [
"Reviewer Expertise Microbiota",
"GI Immunology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe report is well-written and exhaustive. The case reports on a new connection between ustekinumab, crohn's disease and melanoma. It can be useful for clinicians to increase the awareness of this possible complication. Well done. My only suggestion is to add aa table summarizing the updated effect of ustekinumab regarding cancer development\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
},
{
"id": "188078",
"date": "03 Aug 2023",
"name": "Sophie Vieujean",
"expertise": [
"Reviewer Expertise Inflammatory bowel diseases"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nPerianal status not clear\n\nThe presence of brain metastases should be explained earlier\n\n\"According to existing evidence, IL-12 and IL-23 influence the development and behavior of melanoma.\" This statement should be formulated with more caution because, as mentioned by authors a bit latter \"no clear link between ustekinumab and cutaneous carcinogenesis has been demonstrated\"\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": [
{
"c_id": "10322",
"date": "06 Oct 2023",
"name": "ALEXANDROS IOANNOU",
"role": "Author Response",
"response": "Dear Dr. Vieujean We would like to thank you for reviewing our manuscript. Here are the answers to your valuable comments: Regarding the perianal status of the patient: “Specifically, the patient was diagnosed with a perianal abscess a few years after Crohn’s diagnosis and was managed with antibiotics. The perianal lesions responded well to Crohn’s treatment and remained inactive over the years.” The brain metastases were diagnosed once the patient was admitted to the hospital due to dyspnea and deranged mental status. Before that, the evaluation only regarded the skin manifestations, as there were no other symptoms. Whist awaiting for the histology results, the patient developed acute respiratory distress and it was then that he underwent CT scans that revealed the lesions in other organs. We revised the relevant sentence following your kind suggestion: “According to existing evidence, IL-12 and IL-23 may influence the development and behavior of melanoma”"
}
]
}
] | 1
|
https://f1000research.com/articles/11-424
|
https://f1000research.com/articles/11-183/v1
|
14 Feb 22
|
{
"type": "Research Article",
"title": "Performance and preference of problem-based learning (PBL) and lecture-based classes among medical students of Nepal",
"authors": [
"Saroj Adhikari Yadav",
"Sangeeta Poudel",
"Oshna Pandey",
"Dhiraj Prasad Jaiswal",
"Bhupendra Prakash Malla",
"Brajesh Kumar Thakur",
"Swotantra Gautam",
"Sirish Raj Pandey",
"Sangeeta Poudel",
"Oshna Pandey",
"Dhiraj Prasad Jaiswal",
"Bhupendra Prakash Malla",
"Brajesh Kumar Thakur",
"Swotantra Gautam",
"Sirish Raj Pandey"
],
"abstract": "Background: PBL (problem based learning) is new active learning educational strategy that has been extensively tested and used in recent years. This study aims to compare students' understanding and knowledge retention when taught through PBL and lecture-based classes and compare PAHS students' perceptions of PBL and lectures in medical education. Methods: This is a cross-sectional study of medical students of a PBL based medical school in Nepal, a non-Western low-income country. Ethical approval was given by the institutional research committee of the Patan Academy of Health Sciences. Understanding and knowledge retention was assessed with 50 vignette-based multiple-choice questions, half of which were taught through PBL sessions, and the remaining half were taught in didactic lectures during basic science years of medical school. A separate pre-validated perception questionnaire was used to assess students' preferences regarding PBL and lectures. Results: Out of 107 students, 99 participated in the understanding and knowledge retention questionnaires and 107 completed perception questionnaires. Understanding and knowledge retention of students was found to be the same for topics taught by PBL and lectures, with median scores of 17 and s16, respectively. PBL were mostly preferred for the physiology (59.81%), pathology (51.40%) and pharmacology (53.27%) concepts, and lectures were mostly preferred for the anatomy (78.50%), biochemistry (45.79%), and microbiology (42.99%) topics. Students wanted the same concepts to be taught through both PBL and lectures, especially for anatomy. Conclusions: Understanding and knowledge retention is the same for topics taught by either PBL or lectures during the basic science years of undergraduate medical education. Students prefer PBL for physiology, pathology, and pharmacology-related concepts, conventional didactic lecture for physiology and microbiology, and a combination of lecture and PBL sessions for anatomy.",
"keywords": [
"medical education",
"undergraduate medical education",
"medical school",
"lecture-based classes",
"problem-based learning",
"PBL"
],
"content": "Introduction\n\nSir William Osler, referred to as the father of modern medicine, emphasized the role of teachers in helping students to observe and reason. He recommended for teachers to abolish the traditional lecture method of instruction.1 PBL (problem-based learning) is a newer active learning educational strategy that has been extensively tested and used in recent years.2 PBL is an integral part of teaching in the undergraduate medical education of several medical schools around the globe, including Patan Academy of Health Sciences (PAHS), a government medical school of a non-Western LIC (low-income country), Nepal.2 The PBL process was pioneered by Barrows and Tamblyn at the medical school of McMaster University in Canada in the 1960s.3 Students like PBL because it is student-focused, allows active learning, and leads to better understanding and retention of knowledge.4,5\n\nStudents take more interest and responsibility for learning, look for resources like research articles, journals, internet, textbooks, etc. and themselves resolve the contextual problems given in PBL.6 PBL enhances content knowledge and simultaneously fosters the development of communication, collaboration, problem-solving, critical thinking, and self-directed learning.7,8 PBL emphasizes lifelong learning by developing the potential to determine goals, locate appropriate resources, and assume responsibility for what one needs to know.9 It helps students for long-term knowledge retention and improves competency as physicians after graduation.10,11 PBL has gradually been adopted by several medical schools around the globe for undergraduate education.12–14\n\nPBL encourages students to ask questions, search references, and think of logical answers. On the other hand, PBL is resource-intensive and requires more physical space, computer resources, and more staff to facilitate PBL sessions.15 Students also report uncertainty, information overload, and inability to determine the required depth and relevance of information available.15 This study aims to compare students’ understanding and knowledge retention of topics taught through PBL and lectures, and also compare students’ perception of PBL and traditional lectures, among the first two batches of medical students of PAHS who passed in 2016 and 2017.\n\n\nMethods\n\nThis study is a cross-sectional study performed in Nepal, a non-Western low-income country, among medical students of PAHS, where the hybrid PBL method is used during basic science years. All of the selected two batches of PAHS medical students were included in this study with their written informed consent. Students who did not give consent, students among the researcher team of this study, and students who participated in the pilot survey of questionnaires developed for this research were excluded from the study. The developed questionnaires were administered to 15 students who were randomly selected in the pilot study, to establish the validity and feasibility of these. They were asked in detail about the questionnaire and any suggestions for revisions or editing needed. The pilot survey did not undergo any statistical comparisons. Only a few grammatical corrections were made after review and feedback from the pilot study. Subsequently, the final study was conducted. Ethical approval was given by the Institutional Research Committee (IRC) of PAHS (IRC-PAHS) and research was carried out per relevant guidelines and regulations.16\n\nMultiple-choice questions (MCQ) were used to assess understanding and knowledge retention, whereas a separate questionnaire was used to assess the preference for PBL and lectures.25 The MCQ questionnaire for the assessment of understanding and knowledge retention had a total of 50 vignette-based MCQs, half of which were from topics taught through PBL, and the remaining half were from topics taught through lectures. These MCQs were developed and validated by the students with the help of research advisors. The MCQ scores were converted into percentages and interpreted in terms of percentage: <60% = very low, 60-70% = low, 70-80% = moderate, 80-90% = high and 90-100% = very high. The perception questionnaire was compiled and discussed in the student research group and reviewed by the research advisors to establish content validity. It was administered to the 15 students to establish the face validity and feasibility. The perception questionnaire had 30 questions to be answered on a forced Likert scale, ranging from one (strongly agree) to four (strongly disagree). Students were allowed to explain or give opinions qualitatively in some questions of the perception questionnaire. Data entry and editing were done in a MS Excel spreadsheet and analyzed in the SPSS 13.0 software for Windows. Descriptive statistics (mean and percentage) and inferential statistics were used to compare perception. A p-value less than 0.05 was taken as a statistically significant result.\n\n\nResults\n\nOut of 107 students, 99 completed the understanding and knowledge retention questionnaires.25 The mean age of the participants was 22 years. In total 59.6% of respondents were male and 40 (40.4%) were female. The majority (67/99 i.e., 67.7%) of respondents have completed their schooling at a private school and 32 (32.3%) completed their schooling at a public school. About half (49.5%) were living in urban areas while 24 (24.2%) and 26 (26.3%) were from semi-urban and rural areas, respectively. The majority (91 i.e., 91.9%) of the respondents were from a 10 + 2 high school science background, while only 8 (8.1%) were from 10 + 3 health sciences background.\n\nThe normality test showed that the marks obtained by participants on topics taught via PBL and topics taught via lecture were not normally distributed (Shapiro-Wilk p-value = 0.015 for lectures and 0.024 for PBL). Thus, the median score was computed, which was 16 for lectures and 17 for PBL, as shown in Table 1.\n\nThe perception scale was found to be internally consistent as the coefficient alpha of the perception questionnaire was 0.893. Students mostly preferred physiology, pathology, and pharmacology-related concepts through PBL whereas they preferred anatomy, biochemistry, and microbiology-related topics through lectures. Some students wanted to be taught via both PBL and lectures, especially for anatomy subjects (Table 2).\n\nNeither PBL nor lectures were preferred for Community Health Science (CHS) and Introduction to Clinical Medicine (ICM) where many opted not to respond. Regarding CHS, students mentioned they learn public/community health better in community postings and lecture sessions with a group of faculty members as a part of Community-Based Learning Education (CBLE). Regarding ICM they prefer it on hospital wards and bedside teaching.\n\n\nDiscussion\n\nThis study showed that students mostly liked being taught by both PBL and lectures. PBL was preferred for physiology, pathology, and pharmacology-related concepts, lectures were preferred for biochemistry and microbiology-related topics, and a combination of both for anatomy. Overall, the respondents wanted to be taught the same concepts via both PBL and lectures for anatomy. A meta-analysis by Nandi et al. compared the newer PBL curriculum and the conventional lecture-based mode of teaching undergraduate medical students. They concluded that a combination of both the conventional lecture-based and newer PBL curricula would provide the most effective training for undergraduate medical students.17 However, their findings were not subject-specific.\n\nThis study showed understanding and knowledge retention of students remained the same for topics taught by PBL compared to topics taught by lecture. There was no statistical difference in the median score obtained for PBL and lectures for the understanding and knowledge retention questionnaire (17 and 16, respectively). However, most other studies show better understanding and knowledge retention with PBL than lectures. A study by Albanese et al. showed that the PBL students score higher than the students in traditional courses. They also concluded that the reason for higher scores in PBL are the learning competencies, problem-solving, self-assessment techniques, data gathering, behavioral science, etc. of PBL students.18 Similarly, a study from Pakistan showed the mean score in the group exposed to PBL was 3.2 ± 0.8 while those attending lecture based classes was 2.7 ± 0.8 (p = 0.0001).19 Another study on students of mathematics from Slovenia found that students exposed to PBL were better at solving more difficult problems.20\n\nThis study involved students taught through PBL in the first and second year of medical school i.e. basic science years and showed equivalent results compared to lectures. However, another study on PAHS students showed that PBL imparts long-term knowledge retention through students’ active participation.21 Wun et al. have also found that PBL which is started in the initial years of medical school is associated with more active participation, interaction, and collaboration among students, and PBL students score higher too.22 Another study on nursing students found that all students with higher or lower grades showed a significant increase in scores among students in the PBL group, but only students with higher grades showed a notable increase in scores among students in the lecture group. Learning motivation was also found to be significantly higher in the PBL group (t = 2.608, p = 0.012).23\n\nA few of the respondents qualitatively reported in this study that some students in the PBL group worked harder than other members of the same group to prepare and participate in discussions. They also found the time allocated for each topic was not sufficient at times. Silva et al. reported that teamwork and the time involved are factors which can limit PBL learning.24 According to Wood, major disadvantages to this process involve the tutor facilitation and utilization of excessive resources.15\n\n\nConclusion\n\nThe understanding and knowledge retention of students is the same for topics taught by PBL compared to topics taught by conventional didactic lecture. PBL is preferred for physiology, pathology, and pharmacology-related concepts, whereas conventional didactic lectures were preferred for biochemistry and microbiology-related topics, and a combination of lecture and PBL sessions were preferred for anatomy during the basic science years of undergraduate medical education. Students prefer community-based programs and lecture sessions delivered by a group of faculty members for CHS. In contrast, they prefer a bedside teaching and hospital ward-based teaching methodology for ICM rather than lectures and PBL.\n\n\nData availability\n\nFigshare: Raw data and Questionnaire of research “Performance and Preference of Problem-Based Learning (PBL) and Lecture-Based Classes Among Medical Students of Nepal.” https://doi.org/10.6084/m9.figshare.17286902.v1.23\n\nThis project contains the following underlying data:\n\n• Raw Data of PBL Research.xls\n\n• Descriptive Analysis of PBL Research.doc\n\nFigshare: Raw data and Questionnaire of research “Performance and Preference of Problem-Based Learning (PBL) and Lecture-Based Classes Among Medical Students of Nepal.” https://doi.org/10.6084/m9.figshare.17286902.v1.23\n\nThis project contains the following extended data:\n\n• Preference questionaire of PBL Research.doc\n\n• Understanding questionnaire by MCQ of PBL Research.docx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nWe thank Prof. (Associate) Shital Bhandary and Prof. Dr. Kedar Prasad Baral for immense help during conduct of this research. We would like to acknowledge respondent medical students of PAHS-SOM.\n\n\nReferences\n\nOsler W: An introductory address on examinations, examiners, and examinees. Lancet. 1913; 182: 1047–1050. Publisher Full Text\n\nCurriculum for MBBS program of PAHS 2010: Accessed from pahs.edu.np on January 14, 2021. Reference Source\n\nBarrows HS: Problem-based learning in medicine and beyond: A brief overview. New Dir. Teach. Learn. 1996; 1996: 3–12. Publisher Full Text\n\nAntepohl W, Herzig S: Problem-based learning versus Lecture-based learning in a course of basic pharmacology: a controlled, randomized study. Med. Educ. 1999; 33(2): 106–113. PubMed Abstract | Publisher Full Text\n\nWood D; ABC of learning and teaching in medicine. Br. Med. J. 2003; 326(7384): 328–330. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVernon DT, Blake RL: Does problem-based learning work? A meta-analysis of evaluative research. Acad. Med. 1993; 68(7): 550–563. PubMed Abstract | Publisher Full Text\n\nBarrett T: The problem-based learning process as finding and being in flow. Innov. Educ. Teach. Int. 2010; 47(2): 165–174. Publisher Full Text\n\nWells SH, Warelow PJ, Jackson KL: Problem based learning (PBL): A conundrum. Contemp. Nurse. 2009; 33(2): 191–201. PubMed Abstract | Publisher Full Text\n\nCandy PC: Self-direction for lifelong learning: a comprehensive guide to theory and practice. San Francisco: Jossey-Bass; 1991.\n\nNorman G, Schmidt H: The psychological basis of problem-based learning: A review of the evidence. Acad. Med. 1992; 67(9): 557–565. PubMed Abstract | Publisher Full Text\n\nKoh GC-H, Khoo HE, Wong ML, et al.: The effects of problem-based learning during medical school on physician competency: A systematic review. Can. Med. Assoc. J. 2008; 178(1): 34–41. PubMed Abstract | Publisher Full Text | Free Full Text\n\nArmstrong EG: A Hybrid Model of Problem-based Learning. Boud D, Feletti G, editors. The challenge of problem-based learning. London: Routledge; 2008. 978-0-7494-2560-9.\n\nDuch BJ, Groh S, Allen DE: The power of problem-based learning: a practical “how to” for teaching undergraduate courses in any discipline. 1st ed.Sterling, VA: Stylus Pub.; 2001. 978-1579220372.\n\nPeters JAA, Libby Miles CB: The practice of problem-based learning: a guide to implementing PBL in the college classroom. Bolton, Mass: Anker Pub. Co.; 2006. 978-1933371078.\n\nWood D: ABC of learning and teaching in medicine: Problem based learning. Br. Med. J. 2003; 326(7384): 328–330. PubMed Abstract | Publisher Full Text | Free Full Text\n\nInstitutional Review Committee (IRC) of Patan Academy of Health Sciences (PAHS). Reference Source\n\nNandi PL, et al.: Undergraduate medical education: comparison of problem-based learning and conventional teaching. HKMJ. 2000; 2000(6): 301–306.\n\nAlbanese MA, Mitchell S: Problem-based learning: a review of literature on its outcomes and implementation issues. Acad. Med. 1993; 68(1): 52–81. PubMed Abstract | Publisher Full Text\n\nFaisal R, Khalil-ur-Rehman, Bahadur S, Shinwari L: Problem-based learning in comparison with Lecture-based learning among medical students. J. Pak. Med. Assoc. 2016 Jun; 66(6): 650–653. PubMed Abstract Reference SourceReference Source\n\nCotič M, Zuljan MV: Problem-based instruction in mathematics and its impact on the cognitive results of the students and on affective-motivational aspects. Educ. Stud. 2009; 35(3): 297–310. Publisher Full Text\n\nGhimire S, Bhandary S: Students’ Perception and Preference of Problem Based Learning During Introductory Course of a Nepalese Medical School. Journal of Patan Academy of Health Sciences. 2015; 1(1): 64–68. Publisher Full Text\n\nWun YT, Tse EY, Lam TP, et al.: PBL curriculum improves medical students' participation in small-group tutorials. Med. Teach. 2007 Sep; 29(6): e198–e203. PubMed Abstract | Publisher Full Text\n\nHwang SY, Kim MJ: A comparison of problem-based learning and Lecture-based learning in an adult health nursing course. Nurse Educ. Today. 2006; 26: 315–321.\n\nSilva ABD, Bispo ACKA, Rodriguez DG, et al.: Problem-based learning: A proposal for structuring PBL and its implications for learning among students in an undergraduate management degree program. Revista de Gestão. 2018; 25(2): 160–177. Publisher Full Text\n\nAdhikari Yadav S: Raw data and Questionnaire of research “Performance and Preference of Problem-Based Learning (PBL) and Lecture-Based Classes Among Medical Students of Nepal.”. figshare. Collections. 2021. Publisher Full Text"
}
|
[
{
"id": "126411",
"date": "01 Apr 2022",
"name": "Mamata Chimmalgi",
"expertise": [
"Reviewer Expertise Anatomy",
"Histology and Medical education"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSaroj Adhikari Yadav et al. in their article ‘Performance and preference of problem-based learning (PBL) and lecture-based classes among medical students of Nepal’ have compared the learning outcome following PBL and didactic lecture and assessed preference of the students regarding the two methods. The article is written adhering to IMRAD structure and elaborates the findings of a cross sectional study conducted in PAHS in Nepal.\nAbstract is structured and draws attention to the aims of the study and the correctly drawn conclusions.\n\nIntroduction segment enumerates the merits and challenges of PBL and proceeds to list the aims of this study in that context.\n\nMethods segment elaborates on inclusion and exclusion criteria; developing MCQ questionnaire and perception questionnaire; establishing validation of the questionnaire; implementation and analysis. However, time intervals between the T/L methods and the administration of the questionnaire may be added to understand whether immediate learning or long-term retention were being studied - although the discussion segment mentions another study at PAHS addressing the long term retention, the method followed in the current study is missing.\n\nIn the Results segment, inference drawn regarding the performance may be included under ‘understanding and knowledge retention of students’ before proceeding to the results - e.g. ‘learning outcome following PBL was similar to lecture’ or ‘students performance following PBL was comparable to performance following didactic lecture’….…\n\nRegarding perception of students - both in results and in discussion segments, other parameters assessed by the perception questionnaire - unless deliberately omitted - may be included.\n\nConclusion segment effectively and correctly sums up the findings.\n\nUnder References, is there a need to add the last reference by the authors (no. 25), when the same are shared under data availability?\nOverall, a well-written, clear and concise article.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8141",
"date": "27 Apr 2022",
"name": "Saroj Adhikari Yadav",
"role": "Author Response",
"response": "Dear Dr. Chimmalgi, Thank you for your comments and suggestion. I am including your feedback and uploading a new version of the manuscript. Thank you once again."
}
]
},
{
"id": "134523",
"date": "20 Apr 2022",
"name": "Babu Raja Maharjan",
"expertise": [
"Reviewer Expertise Health Professions Education",
"Obesity",
"Adipocyte Biology",
"Insulin resistance",
"Diabetes"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper follows the IMRAD guidelines. Abstract and introduction is well written. But the limitations of the study need to be stated and following comments need to be addressed before indexing.\nPerception questionnaire was mentioned in the research method, but its finding was not described in the result section. Please provide a reason for this inconsistency.\nIt is not stated when the questionnaire and MCQ test was administered. Recall bias will be there if it is administered a long time after the completion of basic science years where PBL is being implemented. This in turn will affect the measurement of performance by MCQ score and preference of PBL/Lecture for various subjects. Therefore, it should be clearly mentioned as the limitation of the study and current finding is based on students preference and performance of PBL measured after ?? time period.\nFurthermore, the drawing of comparative inference on the preference of subjects for either PBL or Lecture is inappropriate. Questionnaire that was used in the study independently asked the preference of subjects for PBL and Lecture to the participants hence inference cannot be drawn if a certain subject has been preferred more or less for PBL over lecture. With the given study design, valid inference that can be drawn will be just the preference of various subjects to PBL and the preference of different subjects to Lecture but not comparison between PBL and lecture for a subject as mentioned in discussion and conclusion.\nIn discussion section, all of a sudden there is presentation of qualitative findings while it was neither mentioned in method section or result section. This needs to be consistent.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8142",
"date": "27 Apr 2022",
"name": "Saroj Adhikari Yadav",
"role": "Author Response",
"response": "Dear Dr. Maharjan, Thank you for your comments and suggestion. Regarding your comments and reservation- 1. I am including your feedback and uploading a new version of the manuscript. 2. Preference data is included in the 3rd and 4th paragraphs of the results. 3. Data were collected before the 1st and 2nd batch graduated in 2016 and 2017. So, I assume, recall bias should not be that significant. I am including this in the updated version of the manuscript. 4. We have mentioned in the 2nd paragraph of the method section that \"Students were allowed to explain or give opinions qualitatively in the perception questionnaire.\" Thank you once again."
}
]
}
] | 1
|
https://f1000research.com/articles/11-183
|
https://f1000research.com/articles/12-417/v1
|
18 Apr 23
|
{
"type": "Brief Report",
"title": "Multiomic sequencing of paired primary and metastatic small bowel carcinoids",
"authors": [
"Mackenzie D. Postel",
"Sourat Darabi",
"James R. Howe",
"Winnie S. Liang",
"David W. Craig",
"Michael J. Demeure",
"Mackenzie D. Postel",
"Sourat Darabi",
"James R. Howe",
"Winnie S. Liang",
"David W. Craig"
],
"abstract": "Background: Small bowel carcinoids are insidious tumors that are often metastatic when diagnosed. Limited mutation landscape studies of carcinoids indicate that these tumors have a relatively low mutational burden. The development of targeted therapies will depend upon the identification of mutations that drive the pathogenesis and metastasis of carcinoid tumors. Methods: Whole exome and RNA sequencing of 5 matched sets of normal tissue, primary small intestine carcinoid tumors, and liver metastases were investigated. Germline and somatic variants included: single nucleotide variants (SNVs), insertions/deletions (indels), structural variants, and copy number alterations (CNAs). The functional impact of mutations was predicted using Ensembl Variant Effect Predictor. Results: Large-scale CNAs were observed including the loss of chromosome 18 in all 5 metastases and 3/5 primary tumors. Certain somatic SNVs were metastasis-specific; including mutations in ATRX, CDKN1B, MXRA5 (leading to the activation of a cryptic splice site and loss of mRNA), SMARCA2, and the loss of UBE4B. Additional mutations in ATRX, and splice site loss of PYGL, leading to intron retention observed in primary and metastatic tumors. Conclusions: We observed novel mutations in primary/metastatic carcinoid tumor pairs, and some have been observed in other types of neuroendocrine tumors. We confirmed a previously observed loss of chromosome 18 and CDKN1B. Transcriptome sequencing added relevant information that would not have been appreciated with DNA sequencing alone. The detection of several splicing mutations on the DNA level and their consequences at the RNA level suggests that RNA splicing aberrations may be an important mechanism underlying carcinoid tumors.",
"keywords": [
"Carcinoids",
"whole exome sequencing",
"Whole transcriptome",
"Splicing variants",
"Small bowel carcinoids",
"Metastatic carcinoids"
],
"content": "Introduction\n\nSmall intestine neuroendocrine tumors (SI-NETs), or carcinoid tumors, are the most common malignancy of the small bowel (Bilimoria et al. 2009). These tumors are characterized by their secretion of biogenic amines (such as serotonin and histamine), peptides (such as somatostatin and chromogranins), tachykinins, and/or prostaglandins (Pinchot et al. 2008; de Mestier et al. 2021). Secretion of these substances can lead to carcinoid syndrome, which is characterized by diarrhea, abdominal pain, bronchoconstriction, skin flushing, and valvular heart disease (Eltawil et al. 2022; Tran, Sherman, and Howe 2021; Moertel 1987).\n\nIt has been postulated that carcinoid tumors are derived from enterochromaffin cells within intestinal crypts (Pinchot et al. 2008). Anatomically, small bowel carcinoids most frequently occur in the terminal ileum (Keck et al. 2018). Although these tumors tend to be indolent and insidious, they are often already metastatic at the time of diagnosis (Yao et al. 2008; Shah et al. 2019). The median age of diagnosis for small bowel carcinoid tumors is 61 years (Shah et al. 2019). Carcinoids are generally well-differentiated and slow-growing (Cunningham et al. 2011; 'StatPearls' 2022). These tumors most often spread to regional lymph nodes, adjacent mesentery, and the liver (Pinchot et al. 2008). Improved imaging modalities, including the intravenous use of radiopharmaceutical gallium 68Ga-or copper 64Cu-dotatate paired with positron emission tomography (PET), may demonstrate metastases that are not appreciated with other, less sensitive imaging studies (Sanli et al. 2018).\n\nSurgical removal of a localized, primary carcinoids (along with adjacent mesentery and lymph nodes) can be curative (Quinones et al. 2022). Treatment of metastatic carcinoid tumors, however, requires selection from a repertoire of therapeutic options, including surgical resection, administration of somatostatin analogues, peptide receptor radiotherapy with 177Lu-dotatate, hepatic arterial embolization, hepatic radiofrequency ablation, external beam radiotherapy of selected isolated metastases, and administration of targeted therapies (Howe et al. 2017).\n\nAs the incidence of carcinoid tumors is increasing at an annual rate of 6.3%, the development and adoption of more effective targeted therapies is imperative (Ahmed 2020; Dasari et al. 2017; Maggard, O'Connell, and Ko 2004). Better elucidation of molecular drivers of carcinogenesis and metastasis underlying carcinoid tumors will help foster the development of new treatments. Knowledge of the full genomic landscape of carcinoid tumors is limited, as prior studies have deemed carcinoids to be relatively “mutationally silent” compared to other malignancies (Lim and Pommier 2021). Loss of chromosome 18 as well as various loss of function mutations in cyclin-dependent kinase inhibitor 1B (CDKN1B, which encodes the cell cycle regulatory protein p27) have been reported in a minority of patients (i.e. 9%) (Crona et al. 2015; Crona and Skogseid 2016; Cunningham et al. 2011; Francis et al. 2013; Kulke et al. 2008; Kytölä et al. 2001; Lim and Pommier 2021; Löllgen et al. 2001; Banck et al. 2013).\n\nReported aberrations include germline mutations in CDKN1B, which are known to cause Multiple Endocrine Neoplasia type IV (MEN4) (Seabrook et al. 2022). It has been suggested that loss of chromosome 18q may be an early event in the evolution of carcinoids, whereas loss of CDKN1B and, therein, loss of tumor suppressor p27, occur later in malignant progression (Crona and Skogseid 2016; Di Domenico et al. 2017).\n\nRecent studies have demonstrated that analysis of RNA may reveal the presence of causative molecular drivers of disease when DNA-level analysis has failed to do so (McCullough et al. 2020). Therefore, the integration of genomic data with transcriptomic data is the next logical step toward characterizing the molecular alterations underlying carcinoid tumors and, in doing so, identifying biomarkers for precision diagnosis, prognosis, and treatment. In this study, we investigated the genomic and transcriptomic landscapes of trio sets of germline, primary tumor, and metastatic tumor samples derived from 5 patients. We observed consistent loss of chromosome 18, as well as loss of function (LOF) mutations in CDKN1B. We identified metastasis-specific mutations in primary and metastatic carcinoid tumor pairs, several of which have been reported as driver mutations in other neuroendocrine tumor types. Transcriptome sequencing added relevant information that would not have been appreciated from DNA data alone. The detection of several splicing mutations on the DNA level, and of their consequences at the RNA level, suggest that RNA splicing aberrations may be an important mechanism underlying the development of carcinoid tumors.\n\n\nMethods\n\nFive patients (here referred to as 0006, 0007, 0008, 0009, 0018) undergoing surgical resection of their carcinoid tumors at Hoag Hospital (Newport Beach CA) or the University of Iowa Neuroendocrine Tumor Clinic consented to this study (written consent), which received IRB approval from the participating institutions (Hoag IRB number: 20180303; Iowa IRB number: 199911057). These patients had tissue available from normal tissue, primary tumors, and liver metastases. Deidentified tissue samples were sent for DNA/RNA extraction and sequencing as detailed below at the Translational Genomics Research Institute (TGen) (Phoenix AZ).\n\nTumor or constitutional DNA was extracted using the Qiagen AllPrep Kit or GeneRead FFPE DNA Kit (Cat. No. 80234, 180134), and tumor RNA was extracted using the Qiagen AllPrep Kit or RNeasy Mini Kit (Cat. No. 74104). Using 200 ng of input DNA, whole exomes were constructed for each sample using the Kapa Hyper Prep Kit (Cat. No. 07962363001) using Agilent SureSelect Human All Exon V7 baits. RNA libraries were constructed using 500ng of input RNA per sample and using the Illumina TruSeq Stranded Total RNA Kit with Ribo-zero (Cat. No. RS-122-2201). Paired-end sequencing of libraries was performed on the Illumina NovaSeq 6000 using S1 and SP flowcells for 100bp reads. Approximate sequencing targets were 200× for tumor exomes, 100× for constitutional exomes, and 150 million total reads for each RNA library.\n\nPaired DNA and RNA data (for germline, primary, and metastatic tissue samples) were input into two pipelines: TGen’s Phoenix pipeline, and the Keck School of Medicine of USC’s Genomics Platform (KGP) “Echo” pipeline.\n\nThis pipeline utilizes SAMtools (v1.10) and Burrows-Wheeler Aligner (bwa v0.7.17) for alignment of whole exome sequencing (WES) data; STAR (v2.7.5a) for RNA sequencing (RNAseq) alignment; DeepVariant (0.10.0-gpu) to call germline SNVs and small indels; lancet (v1.1.x) for somatic variant calling; Manta (v1.6) for detection of somatic structural variants and indels; Octopus (v0.6.3-beta) for haplotype-based variant calling; Strelka2 (v2.9.10) to call small somatic variants; Vardict (Java v1.7.0), which calls somatic SNVs, multi-nucleotide variants, indels, structural variants, and loss of heterozygosity; SnpEff (v4.3T) for SNP annotations; and vcfMerger2 (v0.8.7).\n\nWhole exome FASTQs (tumor/normal pairs, for both primary and metastatic tumors) were aligned to human genome build GRCh38 (Gencode v29 primary assembly) using bwa mem (v0.7.17). Base quality score recalibration was performed using GATK’s BaseRecalibrator (v4.0.10.1) and ApplyBQSR. SAM files were merged, and duplicate reads were marked using GATK’s MergeSamFiles and MarkDuplicates, respectively. Quality control metrics for the resulting sorted, indexed BAMs were retrieved using Samtools Stats, Picard HSMetrics, Picard GCBias Metrics, and Picard MultiMetrics. Variants and mutations were called using a dbSNP reference variant call format (VCF) file (v146 hg38) and GATK HaplotypeCaller. Resulting VCFs were annotated with GATK’s Mutect2 (for detection of somatic point mutations), Manta (v1.5.0, for detection of structural variants and indels), Strelka (v2.9.0, for detection of somatic SNVs and small indels), TGen’s Seurat (v2.5, for detection of somatic point mutations), TGen’s tCoNuT (v1.0, for copy number analysis), TGen’s translocation tool, Freebayes (v1.2.0, a Bayesian small SNV/indel detector), and SnpEff (predictor of variant effects). The final variant candidate set was annotated with Ensembl Variant Effect Predictor (VEP).\n\nRNAseq FASTQs (tumors only) were aligned to human genome build GRCh38 using STAR (v2.6.1d). Duplicates were marked using GATK’s MarkDuplicates. Gene fusion predictions were made using STAR-Fusion (v2.6.1d). Quality control metrics for the resulting sorted, indexed BAMs were retrieved using Samtools Stats, Picard RNA Metrics, and Picard MultiMetrics. Variants and mutations were called using a dbSNP reference VCF (v146 hg38) and GATK’s RNA HaplotypeCaller. Salmon, featureCounts, HTSeq Counts, and Cufflinks were used for gene quantification. The final variant candidate set was annotated with VEP. We utilized MultiQC to compile analysis logs and create a comprehensive quality control report. Differential expression and pathway analyses were run using iDEP with GAGE analysis, KEGG gene sets, and Pathview for visualization (Ge, Son, and Yao 2018; Luo and Brouwer 2013; Kanehisa et al. 2021).\n\n\nResults\n\nTumor samples had, on average, a 45-fold gene enrichment, a coverage ≥30× for 95% of target bases, 87% aligned reads, and 96% RNAseq correct strand mapping. Constitutional samples had, on average, a 43-fold gene enrichment, a coverage of ≥30× for 91% of target bases, and 99.8% aligned reads.\n\nPatient 0006 is a 66-year-old male with grade 1 disease, treated with Octreotide (Table 1). He had large-scale copy number loss of chromosome 18 (Table 2). He also had a PYGL mutation (rs74464749) in both his primary and metastatic tumors (Table 3). He had a metastasis-specific mutation in MXRA5 (chrX:3,317,443:G:C).\n\nPatient 0007 was a 62-year-old female with grade 2 disease, treated with 177Lu-dotatate (Table 1). She succumbed to her disease. She had large-scale copy number changes in both her primary and metastatic tumors; these included: gain of chromosomes 5, 7, 10, 14q, 15q, and 20, and loss of chromosomes 18 and 11q (Table 2). She did not have any apparent pathogenic point mutations.\n\nPatient 0008 was a 67-year-old male with grade 1 disease, treated with surgical resection, everolimus, then temozolomide (Table 1). He succumbed to his disease. He had one copy number alteration observed in both his primary and metastatic tumors, gain of chromosome 5 (Table 2). He also had metastasis-specific copy number changes including gain of chromosomes 7 and 10, and loss of chromosomes 9 and 18. He had metastasis-specific CDKN1B (rs797044482) and a UBE4B (chr1:10,105,515:G:A) mutations (Table 3).\n\nPatient 0009 is a 52-year-old female with grade 2 disease, treated by surgical resection (Table 1). The only copy number alteration observed in her tumors was loss of chromosome 18 in the primary/metastatic pair (Table 2). An ATRX point mutation (chrX:77,683,393:G:T) was identified in both her primary and metastatic tumors resulting in loss of heterozygosity (LOH) and allele-specific expression (ASE) in the mRNA (monoallelic expression of the wild-type allele in mRNA) (Table 3). She had a metastasis-specific mutation in SMARCA2 (rs752254994).\n\nPatient 0018 is a 71-year-old female with grade 2 disease, treated with surgical resection then monthly lanreotide (Table 1). She had copy number loss of chromosome 18 in both her primary and metastatic tumors (Table 2). She had metastasis-specific, large-scale copy number loss of chromosome 16q. She had a metastasis-specific ATRX mutation (chrX:77,684,450:T:A) with monoallelic expression of the wild-type allele in mRNA (Table 3).\n\nUsing iDEP’s GAGE analysis tool with KEGG gene sets, it was determined that the top 20 pathways with differentially expressed genes between metastatic vs. primary carcinoids included: “pathways in cancer,” “chemical carcinogenesis,” and “viral carcinogenesis” (Figure 5; Tables 4 & 5). The pathways within the “pathways in cancer” framework that appear to have the most significant changes in expression between metastases vs. primary tumors include: cytokine-cytokine receptor interaction, p53 signaling, extracellular membrane receptor and focal adhesion interactions, Wnt signaling, PI3K-Akt signaling, MAPK signaling, calcium signaling, TGF-b signaling, HIF-1 signaling, Notch and Hedgehog signaling, estrogen and androgen signaling, cell cycle, and block of differentiation (Figure 5).\n\n\nDiscussion\n\nPrevious genomic analyses have failed to identify a consistent, putative driver mutation in small bowel neuroendocrine tumors. We endeavored to dive deeper into the molecular landscape of carcinoids by supplementing exome analysis with transcriptomic analysis in paired primary small bowel tumors and liver metastases from the same patients. We were particularly interested in discovering drivers of metastatic potential, as metastatic carcinoids pose the greatest morbidity and mortality risks. We intended to probe RNA for potential culprits that were, perhaps, not immediately evident from DNA analysis alone. RNAseq data enabled us to confirm the consequences of alterations found on the DNA level while also observing phenomena (like intron retention and ASE) that would not otherwise be apparent.\n\nTumor cells gain oncogenic and lose tumor-suppressive functions via various mechanisms, including point mutations, CNAs, and structural variants. In this study, we observed various CNAs, the most frequent being loss of chromosome 18. Loss of 18q has been previously reported as a potential mechanism of early oncogenesis in carcinoid tumors (Crona and Skogseid 2016). The long arm of chromosome 18 spans several confirmed and putative tumor suppressors, including Retinoblastoma-Binding Protein 8 (RBBP8), SMAD family members 2 and 4 (SMAD2/4), and deleted in colorectal cancer (DCC) (Cunningham et al. 2011; Lim and Pommier 2021). Though several studies have suggested that DCC may be the key tumor suppressor lost, this has not been rigorously confirmed (Löllgen et al. 2001; Nieser et al. 2017). Other CNAs – which were less consistent across our samples, but which reflect previously reported evidence – included loss of chromosomes 9p, 11q, and 16q, and gain of chromosome 14 (Table 2) (Cunningham et al. 2011).\n\nLoss of CDKN1B function is another previously reported characteristic of small bowel carcinoid tumors (though it has only ever been reported in a minority, i.e. 9% of tumors in larger studies) (Crona and Skogseid 2016; Crona et al. 2015; Maxwell et al. 2015). An insertion in CDKN1B (rs797044482, reported as “likely pathogenic” for neuroendocrine neoplasms in ClinVar) was identified in patient 0008’s metastasis (Figure 1). Indel presence was confirmed in mRNA. Interestingly, this patient had a “second hit” to CDKN1B: uniparental disomy (and resulting LOH). B-allele frequency (BAF) is a measure of allelic balance, whereby a heterozygous SNP would have a BAF of 0.5 and a homozygous SNP – or LOH event – would result in a BAF that deviates from 0.5 (to 0 or 1). Patient 0008’s uniparental disomy event was identified via CNA, as B-allele frequency deviated from 0.5 despite the fact that there was no copy number change at that location. This example exemplifies the ability of cancer cells to “mix and match” mechanisms to gain and lose gene products.\n\nA loss-of-function frameshift mutation resulting in intron inclusion is observed in the metastatic tumor alone. This is perceptible as the orange signal that reads through intronic regions (i.e., the thin blue lines in the gene track). Sashimi plots were generated using the Broad Institute’s Integrative Genomics Viewer (IGV).\n\nThe tumor suppressor gene ATRX encodes a chromatin-remodeler that is a member of the SWI-SNF family of proteins; it is involved in transcriptional regulation, DNA recombination, nucleosome remodeling, and DNA repair (Bradley et al. 2019; Valenzuela et al. 2021). Somatic mutations in this gene have frequently been reported in gliomas, gastro/pancreatic neuroendocrine tumors, pheochromocytomas, and paragangliomas (Crona and Skogseid 2016; Jiao et al. 2011). ATRX has also been found to be mutated in gliomas and acute lymphoblastic leukemia (ALL) (Bradley et al. 2019). ATRX plays an essential role in brain development and is ubiquitously expressed at high levels in brain tissue (Valenzuela et al. 2021).\n\nThough conflicting evidence exists, it has been reported that ATRX escapes X-inactivation, perhaps in a developmental stage and/or tissue-specific manner, with ATRX showing biallelic expression in XX-females and monoallelic expression in XY-males (Valenzuela et al. 2021). ATRX deficiency results in impaired nonhomologous end-joining and genomic instability (Bradley et al. 2019). Notably, ATRX mutations are frequently observed in female gastric cancer patients with high microsatellite instability (MSI), tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) expression; these characteristics are purported to be predictive biomarkers for immunotherapy response (Ge et al. 2021).\n\nTwo of our patients (0009, 0018) had ATRX mutations. Patient 0009, an XX-female, had LOF mutations in ATRX in both her primary and metastatic tumors. Patient 0018, another XX-female, harbored a metastasis-specific ATRX mutation. Curiously, both mutations were predicted to be “tolerated” by VEP and showed ASE/monoallelic expression of the wild-type allele in RNA.\n\nAs mentioned above, one metastasis-specific finding was patient 0008’s CDKN1B mutation (rs797044482) (Figure 1). A metastasis-specific missense mutation in the gene Matrix Remodeling Associated 5 (MXRA5, chrX:3,317,443:G:C) was seen in patient 0006 (Figure 2). MXRA5 is a purported tumor suppressor gene (Tegally et al. 2020; Xiong et al. 2012; Cheng et al. 2017). It also plays a role in normal matrix remodeling and anti-inflammatory responses, the disruption of which is essential to metastatic progression (Poveda et al. 2017). This deleterious MXRA5 mutation resulted in the activation of a cryptic splice site and loss of mRNA transcripts. As patient 0006 is male, there was no dosage compensation for MXRA5. Patient 0006’s primary and metastatic tumors had a splicing mutation in liver glycogen phosphorylase (PYGL, rs74464749), resulting in intron retention and expression of alternative splice variants in mRNA. A metastasis-specific missense mutation in SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A, Member 2 (SMARCA2, rs752254994) was called for patient 0009 (confirmed in mRNA, Figure 3). SMARCA2 is part of a chromatin-remodeling complex, and mutations in this gene have been reported in neuroendocrine tumors of the lung and thymus (Fernandez-Cuesta et al. 2014). A metastasis-specific mutation in Ubiquitination Factor E4B (UBE4B, chr1:10105515:G:A) was called for patient 0008, which resulted in intron retention in the mRNA (Figure 4); this was paired with a “second hit” of large-scale copy loss of chromosome 1. Mutations in UBE4B have previously been associated with neuroblastoma, another type of neuroendocrine tumor (Byron et al. 2016).\n\nThis is appreciable as a lack of mRNA reads corresponding to the downstream portion of the depicted exon (i.e., the thick blue line in the gene track) in the metastatic tumor (brown trace). This phenomenon is not observed in the primary tumor. Sashimi plots were generated in IGV.\n\nSashimi plots were generated in IGV.\n\nIntron retention is apparent as the presence of mRNA (i.e., the orange signal/bars) corresponding to intronic material (i.e., the thin blue lines in the gene track). Sashimi plots were generated in IGV.\n\nGenes colored bright red are most upregulated, and those colored bright green are most downregulated. The most significant sub-pathways within this framework appear to be: cytokine-cytokine receptor interaction, p53 signaling, extracellular membrane receptor and focal adhesion interactions, Wnt signaling, PI3K-Akt signaling, MAPK signaling, calcium signaling, cell cycle, TGF-b signaling, HIF-1 signaling, Notch and Hedgehog signaling, estrogen and androgen signaling, and block of differentiation. These pathways may provide clues regarding which molecular events confer carcinoid tumor metastatic potential.\n\nAs mentioned in the section above, patient 0008 had several metastasis-specific splicing mutations illuminated by RNA analysis. This included a mutation in UBE4B resulting in intron retention (Figure 4), and a mutation in MXRA5 leading to activation of a cryptic splice site and loss of mRNA.\n\nSplicing mutations were also observed in the tumors of patient 0006. He had a splice-acceptor SNV in PYGL, which encodes liver glycogen phosphorylase, in both the primary and metastatic tumor in the liver. The splicing mutation resulted in intron retention. PYGL was listed as a mutated gene in carcinoid tumors in a previous study (Francis et al. 2013).\n\nLimitations of this study include its relatively small sample size, albeit for a rare tumor type, and the fact that we utilized whole exome data (thereby ignoring introns). It is possible that the molecular drivers of carcinoid tumorigenesis and progression/metastasis are in noncoding regions. Noncoding RNAs – including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), small interfering RNAs (siRNAs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), and PIWI-interacting RNAs (piRNAs) – have been shown to play a role in the pathogenesis of various tumor types (Byron et al. 2016; Zeuschner, Linxweiler, and Junker 2020). Additionally, given the fact that two of the mutations identified in this study were in genes involved in chromatin remodeling (i.e. ATRX and SMARCA2), it will be important to study the epigenomic landscape of carcinoid tumors in the future (Kidd et al. 2021). Lastly – as disparities exist in terms of carcinoid incidence, treatment, and survival – evaluation of the associations between race, ethnicity, and genetic ancestry with carcinoid genetic aberrations may be informative in a larger sample dataset (Takayanagi et al. 2022; Kessel et al. 2021).\n\nIn conclusion, we identified several candidate mutations potentially involved in the pathogenesis and metastatic cascade of carcinoid tumors. Mutations that were identified as metastasis-specific may provide insight into intermediate steps between initial tumorigenesis and metastasis (i.e., drivers of metastatic potential). We confirmed the presence of previously reported molecular aberrations (i.e., loss of chromosome 18 and LOF mutations in CDKN1B). It remains unclear whether there is a key tumor suppressor or set of tumor suppressors on chromosome 18, the loss of which is important to the etiology of small bowel carcinoids. Gene knock-outs could be performed to determine which regions on chromosome 18 are necessary and/or sufficient to drive the formation of carcinoid tumors. Additionally, it is worth noting that one potential explanation that could account for the fact that previous studies identified mutations in CDKN1B in a minority of carcinoid tumors is the possibility that distinct molecular subtypes of small bowel carcinoids exist. The significant utility of considering transcriptomic data in addition to genomic data was exemplified by our detection of phenomena such as intron retention, splicing variants, and ASE. The addition of RNAseq data also enabled us to confirm the consequences of mutations called on the DNA level in mRNA, and perform differential expression and pathway analyses to identify several pathways potentially involved in conferring metastatic potential to carcinoid tumors.",
"appendix": "Data availability\n\nEuropean Genome-Phenome Archive: EGAS00001006988, Multiomic Sequencing of Paired Primary and Metastatic Small Bowel Carcinoids, https://ega-archive.org/studies/EGAS00001006988 (Postel et al. 2023).\n\nFurther information regarding TGen’s Phoenix and USC’s KGP Echo pipelines can be accessed online at https://github.com/tgen/phoenix and https://kgp.usc.edu, respectively.\n\n\nReferences\n\nAhmed M: Gastrointestinal neuroendocrine tumors in 2020. World J. Gastrointest. Oncol. 2020; 12: 791–807. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBanck MS, Kanwar R, Kulkarni AA, et al.: The genomic landscape of small intestine neuroendocrine tumors. J. Clin. Invest. 2013; 123: 2502–2508. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBilimoria KY, Bentrem DJ, Wayne JD, et al.: Small bowel cancer in the United States: changes in epidemiology, treatment, and survival over the last 20 years. Ann. Surg. 2009; 249: 63–71. 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PubMed Abstract | Publisher Full Text\n\nZeuschner P, Linxweiler J, Junker K: Non-coding RNAs as biomarkers in liquid biopsies with a special emphasis on extracellular vesicles in urological malignancies. Expert. Rev. Mol. Diagn. 2020; 20: 151–167. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "178411",
"date": "10 Jul 2023",
"name": "Phillip Stafford",
"expertise": [
"Reviewer Expertise WTS/WES NGS bioinformatics",
"cancer biology",
"immunology."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nPostel et al. investigate small bowel carcinoids using whole exome/whole transcriptome NGS. The methods the group used to asses metastatic vs. non-metastatic conditions are typical of an NGS study of this kind, but with the benefit of using WES/WTS. The cohort is small, but this is a rare condition and the results should bolster further development in this important area.\n\nMethods: Pindel and grids are superior methods for finding SV's than MANTA, but the difference would be minor in this type of study. Other methods are acceptable. Since this is a small study, the definition of differential expression is between the two different conditions, this is a limitation of the study - more accurate assessment of expression would be a non-parametric ranking of gene expression- how unlikely either very high or very low expression is across a cohort of similar tumors. This would be a meta-analysis, likely using public data in cBioPortal or data from TGen or USC biobanks, and while useful would likely exceed the scope of the present project. This limitation is also acceptable. This reviewer would like a separate section or note near the methods section describing the statistical limitations of the cohort, the study, and the statistical design. While mentioned in the discussion (small sample size, non-coding RNA's are assigned slightly more importance than may be warranted) this reviewer suggests the methods section should note that this study is not a meta-analysis, the differential expression is highly limited, non-parametric analyses have limited utility, and the pathway analysis and other interpretations should be presented in the context of the study limitations, rather than a sentence in the discussion. Minor additions to the data addressing these limitations would provide readers a way to understand that extending the results to a biological cause or even to a pathway is pure speculation. I would much prefer the authors use phrases like \"evidence suggests genes X, Y, Z that were found through our analysis are implicated in the functions shown in our genetic pathway figures.\" The way it's written, there is more confidence in the interpretation of the biological role of the detected gene expression than may be warranted. It would be beneficial to highlight similar findings in published journals concerning similar tumor types, similar benign vs. metastatic cases, and perhaps making a case for a set of commonly activated genes or types of genes that appear in published/public studies of metastasis/benign tumors.\nOverall the study brings up good points, the NGS analysis is fine, the WTS and WES are an important combination, and releasing these data into the public domain will spur further studies from these important data. The biological analysis is extensive but may be a little overstated. The conclusions are warranted. The text and writing style are acceptable, the references are well-chosen but could be bolstered by finding any studies between met/benign tumors in similar tissues that might have found similar over/underexpressed genes.\nRecommend publish with minor revisions.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Yes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10339",
"date": "06 Oct 2023",
"name": "Mackenzie Postel",
"role": "Author Response",
"response": "REVIEWER: “This reviewer would like a separate section or note near the methods section describing the statistical limitations of the cohort, the study, and the statistical design. While mentioned in the discussion (small sample size, non-coding RNA's are assigned slightly more importance than may be warranted) this reviewer suggests the methods section should note that this study is not a meta-analysis, the differential expression is highly limited, non-parametric analyses have limited utility, and the pathway analysis and other interpretations should be presented in the context of the study limitations, rather than a sentence in the discussion… I would much prefer the authors use phrases like \"evidence suggests genes X, Y, Z that were found through our analysis are implicated in the functions shown in our genetic pathway figures.\" AUTHOR RESPONSE: Thank you for your feedback. In our updated manuscript, we have added an explicit “limitations” section, as well as specified the parametric and semi-parametric differential expression packages utilized by the iDEP tool. We have also endeavored to qualify results such that readers interpret them within the context of study limitations. Note: we also cited 11 new papers, related to reviewers’ suggestions, 3 of which were published after we had written our original manuscript."
}
]
},
{
"id": "191552",
"date": "17 Aug 2023",
"name": "Anela Blažević",
"expertise": [
"Reviewer Expertise Neuro-endocrine tumors",
"proteomics",
"radiomics",
"cell culture."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nPostel et al. investigate small intestinal neuro-endocrine tumors using whole exome and RNA sequencing in a small cohort. Sequencing is done on normal tissue, primary tumor and liver metastases. The study assessed differential expression only on metastatic vs. non-metastatic primary tumors and observed known and novel mutations.\nI do have a few points I would like to have clarified.\nSamples:\nWhat was the timing between the surgical resection and other treatments as these could affect mutational load. In the result section, patient-specific molecular finding paragraph it is not clearly enough stated.\n\nGrading. Was the tumor grade determined in the included tissue in the study or on initial biopsy? Was there a discrepancy between the primary tumor and liver metastases?\n\nWhat was the origin of the normal tissue? Intestine or healthy liver tissue?\n\nWas the collection of primary tumor and liver metastases synchronous or metachronous?\nResults:\nNo mentioning of analysis on normal tissue. If this was deemed not relevant, it should be clarified why the was no differential analysis between normal and primary tumor tissue as this is theoretically also interesting. If there was no significant differential expression, it is also an important observation.\n\nTable 5 does not add relevant information and the findings are not further discussed, so I would recommend removing it to increase readability and focus on relevant information.\nDiscussion\nIt would be beneficial to discuss the similarities and discrepancies between the finding in this study and published literature in greater details. For example, the statement: Additionally, it is worth noting that one potential explanation that could account for the fact that previous studies identified mutations in CDKN1B in a minority of carcinoid tumors is the possibility that distinct molecular subtypes of small bowel carcinoids exist. What is already know about distinct molecular subtypes? Is there another explanation such as a difference in patient selection or pretreatment? These discrepancy deserve more discussion in order to embed this study properly in the known literature.\n\nIt would also be insightful to discuss the relation between epigenetic modification and the found RNA splicing results, as small intestinal neuroendocrine tumors are known to have epigenetic dysregulation.\nFinally, Postel et. Al. should consider using the term small intestinal neuroendocrine tumor as this is more in line with current guidelines.\nOverall, the study is interesting as it combines whole exome/whole transcriptome NGS and reveals interesting novel data. However, I have significant reservations, as outlines above.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10340",
"date": "06 Oct 2023",
"name": "Mackenzie Postel",
"role": "Author Response",
"response": "REVIEWER: “What was the timing between the surgical resection and other treatments as these could affect mutational load. In the result section, patient-specific molecular finding paragraph it is not clearly enough stated.”
AUTHOR RESPONSE: For each patient, surgical resection was the first intervention performed (i.e., sequence was: surgery, medication). Molecular findings, therefore, represent tissues before use of chemotherapeutics/other medications. In the Results section, for each patient, we have used the phrasing: “treated with surgical resection then ___” to give a sense of the chronology of treatment. — REVIEWER: “Grading. Was the tumor grade determined in the included tissue in the study or on initial biopsy? Was there a discrepancy between the primary tumor and liver metastases?”
AUTHOR RESPONSE: We are happy to clarify. WHO grading by mitotic count and/or Ki-67 labeling index was performed at the time of surgical resection of the tissues used in this study. Primary/met grading was consistent for each pair (no discrepancy between tumors in any given patient). All this to say, in our manuscript, “grade” can be taken to refer to the grade of a given patient’s primary tumor as well as their met. We have endeavoured to make this more clear in the text. — REVIEWER: “What was the origin of the normal tissue? Intestine or healthy liver tissue?” AUTHOR RESPONSE: Thank you for your question. The “normal” or constitutional samples were used mainly to differentiate germline from somatic alterations in DNA. We did not have RNA data available for constitutional samples, therefore we did not perform differential expression analysis, eQTLs, or any other transcriptomic comparison between normal and tumor (which would, as I believe you are suggesting, require matched healthy liver or intestine). We simply wanted to establish the patients’ germline variants to distinguish them from somatic mutations. Constitutional samples were derived from: gallbladder for patients 0006 and 0007, healthy bowel for patients 0008 and 0009, and peripheral blood for patient 0018. We have added a statement to the Methods section clarifying the sources of constitutional samples. — REVIEWER: “Was the collection of primary tumor and liver metastases synchronous or metachronous?” AUTHOR RESPONSE: Thank you for your comment. If you mean metachronous as in two sites with independent primary malignancies, then no — the liver tumors represented metastases from primary small bowel tumors. If you are asking whether primary/metastatic tumors were collected at the same time vs. in sequential surgeries, they were collected at the same time (patients were metastatic at time of presentation/there was no lag time in terms of diagnosis of primary and met as they were diagnosed simultaneously). In this study, one primary tumor and one metastatic tumor were analyzed for each patient (no multiple, synchronous primary tumors for a given patient). I hope this answers your question. — REVIEWER: “No mentioning of analysis on normal tissue. If this was deemed not relevant, it should be clarified why the was no differential analysis between normal and primary tumor tissue as this is theoretically also interesting. If there was no significant differential expression, it is also an important observation.” AUTHOR RESPONSE: Thank you for your comment. We did not have RNAseq data available for normal tissue. Should we have the opportunity to gather constitutional transcriptomic data for these patients in the future, it would certainly allow us to investigate the interesting comparison you suggest. We have clarified in the Methods section that differential expression analysis focused on primary/met tumor pairs (and excluded normal tissue) because we only had RNA for tumors. — REVIEWER: “Table 5 does not add relevant information and the findings are not further discussed, so I would recommend removing it to increase readability and focus on relevant information.” AUTHOR RESPONSE: Table 5 has been removed per the reviewer’s helpful suggestion. — REVIEWER: “It would be beneficial to discuss the similarities and discrepancies between the finding in this study and published literature in greater details.“ AUTHOR RESPONSE: Thank you for this consideration. This manuscript was submitted several months ago but had not been assigned reviewers until relatively recently. In this time gap, more multi-omicliterature has been published re: SI-NETs. We have incorporated several of these new studies, including a recent paper by the reviewer. — REVIEWER: “It would also be insightful to discuss the relation between epigenetic modification and the found RNA splicing results, as small intestinal neuroendocrine tumors are known to have epigenetic dysregulation.” AUTHOR RESPONSE: This would be a fascinating future direction. However, currently, we do not have epigenetic data available for these patients. — REVIEWER: “Finally, Postel et. Al. should consider using the term small intestinal neuroendocrine tumor as this is more in line with current guidelines.” AUTHOR RESPONSE: Thank you for this feedback. The first sentence of our Introduction section touches on this (defines small bowel “carcinoids” as small intestine neuroendocrine tumors/SI-NETs). We have updated our text to more frequently use the latest terminology “SI-NETs.” We also added this terminology to the manuscript’s “keywords” list. — Note: we also cited 11 new papers, related to reviewers’ suggestions, 3 of which were published after we had written our original manuscript."
}
]
}
] | 1
|
https://f1000research.com/articles/12-417
|
https://f1000research.com/articles/12-58/v1
|
13 Jan 23
|
{
"type": "Review",
"title": "Emerging implications of exosomes as mediators of cellular communication in potentially malignant oral lesions and head and neck cancers",
"authors": [
"Monica Charlotte Solomon",
"Chetana Chandrashekar",
"Spoorti Kulkarni",
"Nisha Shetty",
"Aditi Pandey",
"Chetana Chandrashekar",
"Spoorti Kulkarni",
"Nisha Shetty",
"Aditi Pandey"
],
"abstract": "Exosomes are a unique type of extracellular vesicles that contain a plethora of biological cargo such as miRNA, mRNA, long non-coding RNA, DNA, proteins and lipids. Exosomes serve as very effective means of intercellular communication. Due the presence of a lipid bilayer membrane, exosomes are resistant to degradation and are highly stable. This makes them easily identifiable in blood and other bodily fluids such as saliva. The exosomes that are secreted from a parent cell directly release their contents into the cytoplasm of a recipient cell and influence their cellular activity and function. Exosomes can also transfer their content between cancer cells and normal cells and regulate the tumor microenvironment. Exosomes play a vital role in tumor growth, tumor invasion and metastasis. Exosomes provide a multitude of molecular and genetic information and have become valuable indicators of disease activity at the cellular level. This review explores the molecular characteristics of exosomes and the role that exosomes play in the tumorigenesis pathway of potentially malignant oral lesions and head and neck cancers The application of exosomes in the treatment of oral cancers is also envisioned. Exosomes are very small and can easily pass through various biological barriers, making them very good delivery vectors for therapeutic drugs as well as to selectively induce DNA’s mRNA and miRNAs into targeted cancer cells.",
"keywords": [
"Exosomes",
"miRNA",
"intercellular communication",
"tumor microenvironment",
"invasion and metastasis"
],
"content": "Introduction\n\nExosomes are a form of extracellular vesicles (EVs) that were first described by Colombo et al. in 2014.1 Exosomes are formed intracellularly, and the size of exosomes ranges from 30nm-150nm. The exosomes contain a plethora of biological entities such as proteins, lipids, DNA, microRNA, messenger RNA and long noncoding RNA enclosed in a lipid bilayer.2–5\n\nExosomes originally form as intraluminal vesicles within the endosome and are released to the environment by fusion with the plasma membrane.1 Exosomes are formed by the invagination of the endosomal plasma membrane during the transformation of an early endosome into a late endosome. The late endosomes, also known as microvesicular bodies, fuse with the cell membrane and release their contents into the extracellular environment and are now called exosomes.6 The formation of exosomes depends on two different pathways; the first an endosomal sorting complex required for transport (ESCRT)-dependent mechanism, and an ESCRT- independent mechanism.7 Several factors influence the release of exosomes into the extracellular environment, such as oxidative stress and hypoxia. In addition, drugs such as sitafloxacin, pentatrezole and fenoterol activate the production of exosomes.8\n\nExosomes are an unique mode of intercellular communication for transferring bioactive cargo to recipient cells.9 As exosomes are released into the extracellular compartment, they are richly available in most of the body’s fluids including saliva. The lipid bilayer membrane that forms around the exosome capsule protects their cargo from degradation and RNAse damage, thus allowing exosomes to be highly stable in circulation.10\n\nExosomes play a vital role in transferring molecular mediators and promote cell-to-cell communication both locally and to distant sites.11 When exosomes release the protein, signaling molecules, mRNA and miRNA into the cytoplasm of the target cells, this modifies the cell biology of that target cell.12\n\nThe mRNA and the miRNA that are present in exosomes can be translated into proteins in the target cells that they enter, thereby transferring genetic information from one cell to another cell.13\n\nThis review elucidates the molecular characteristic of exosomes and their implication in the biology of potentially malignant oral disorders and head and neck cancers.\n\n\nCharacteristic features of exosomes\n\nZlotogorski et al.14 elucidated the molecular characteristics of exosomes through several molecular techniques such as transmission electron microscopy, nanoparticle tracking, atomic force microscopy, ELISA and Western blot. In his experimental analysis he compared the morphological features and molecular characteristic of exosomes in oral fluids of healthy individual and oral cancer patients.\n\n\nTransmission electron microscopy\n\nThe ultrastructural features of the pellets that were obtained from saliva of healthy individuals and oral cancer patients are similar. They appear as round-shaped vesicles surrounded by bilayered membranes.\n\n\nNanoparticle tracking analysis\n\nThe number of exosomes in saliva as determined by nanoparticle tracking analysis was 17.9 ±12.45E8 particles/ml in healthy individuals, while that in oral cancer patients was 36.0± 7.5E8 particles/ml. The average size of the nanoparticles in healthy individuals was 49.05 ± 32.87 nm and that of exosomes in oral cancer patients was 95.36±36.76 nm, which is much larger than that of healthy Individuals.\n\n\nAtomic force microscopy\n\nThe 3D topographical images of the nanoparticle in the Oral fluids of both healthy individuals and oral cancer patients appeared as circular bulging structures, but the height of the particles in oral cancer patients was larger than the height of those in healthy individuals.\n\n\nEnzyme linked immunosorbent analysis (ELISA)\n\nThe concentration of CD63 in the exosomes in the oral fluids was higher in oral cancer patients (234±79 pg/ml) compared with that of normal individuals (176±42.3pg/ml). The concentration of CD81 in exosomes was lower in OSCC (61.1±37 pg/ml) compared to that of healthy individuals (201±pg/ml). The concentration of CD9 in the exosomes of oral cancer was less (104.1±18 pg/ml) than that of healthy individuals (152.9±24.4pg/ml).\n\n\nWestern blot\n\nIn oral cancer patients the exosomal pellets obtained from the oral fluids showed the presence of the glycosylated form of CD63 as a prominent band at 53Kd. With regard to CD81, the exosomes obtained from the oral fluids of oral cancer patients and healthy individuals showed a band at the expected 26 kDa area of the protein. The exosomes obtained from the oral fluid of both oral cancer patients and healthy individuals showed a specific band at 28kDa area to represent CD9. However, in oral cancer patients the intensity of the band was lower than that in healthy individuals.\n\nMathivanan et al also found a significant increase in the expression of CD63 and a decrease in the expression of CD9 and CD81 in exosomes present in the saliva of oral cancer patients compared to that of the exosomes in the saliva of healthy individuals.6 Exosomes are recognized by the molecular biomarkers that they express; namely, CD63, CD9, CD81, Alix, TSG101 and hsp70.15\n\nProteins that are encapsulated and transported by exosomes are responsible for regulating the fusion, migration, and adhesion to the target cells. These proteins are transmembrane proteins such as CD9, CD63, CD81 and CD82 molecular chaperones Hsp70 and Hsp90, and multi-capsule synthesis proteins TSG101 and ALIX.16–20 The miRNAs in the exosomes are of higher concentration and greater stability while they are in circulation as they are within encapsulated vesicles.11,21,22 The proteases and RNAases in circulation cannot act on the exosomal proteins; hence they have a longer half-life than the free molecules.19 Exosomes are enriched in cholesterol, diglycerides, glycerophospholipids, phospholipids and sphinolipids or glyceromides23\n\n\nExosomes in oral potentially malignant disorders\n\nLi et al. isolated mesenchymal stem cells from the clinical tissue samples of normal oral mucosal tissues, dysplastic oral lesions and oral squamous cell carcinoma tissue. The exosomes were isolated from the Mesenchymal stem cells and a microarray analysis of the exosomes showed that miR 8485 was differentially expressed in the three groups. The miRNA-8485, when transfected into dysplastic oral mucosal cell lines (DOK) as well as tongue squamous cell carcinoma cell line SCC15, caused rapid growth, promoted migration and invasion of the cells.24\n\nWang et al. found that when MSC-EV-miR-185 was pasted onto buccal lesions in dimethylbenzanthracene (DMBA) induced Oral Potentially Malignant disorders (OPMD) model it remarkably attenuated the severity of inflammation and significantly decreased the incidence and the number of dysplastic characteristics in the OPMD tissue. Also, these cells showed a low immunohistochemical expression of PCNA and CD 31. By activating caspase 3 and 9 of the apoptotic pathway, the miR-185 targeted the Akt pathway.25\n\n\nExosomes in oral submucous fibrosis\n\nOral submucous fibrosis is a multifactorial precancer disorder that is caused by chewing areca nuts. Liu et al. isolated adipose-derived mesenchymal stem cell exosomes from the fibroblasts of oral submucous fibrosis patients and normal individuals. These ADSC-Exos were found to be positive for CD63. The mRNA expression levels of COLIA 1 and COLIA III were down regulated in fibroblasts that were stimulated with both TGF- Beta and ADSC-Exos in the culture media. Similarly, the expression of Collagen I and Collagen III was downregulated in fibroblasts that were treated with both TGF Beta and ADSC-exosomes. The ADSC-exosomes inhibited the p38 MAPK signalling pathway and reduced the expression of collagen I and Collagen III.\n\nHowever, the expression levels of matrix metalloproteinase (MMP)1 and MMP3 were significantly upregulated in fibroblasts when they were stimulated with both TGF beta and ADSC-Exosomes in the culture media. With the ability of ADSC-Exos to inhibit the P38 MAPK signaling pathway, this biomarker can serve as remarkable treatment option for Oral submucous fibrosis.26\n\nIn another study, Zhou et al. isolated exosomal long non-coding RNA ADAMTS9-AS2 from tissue samples of oral submucous fibrosis and oral squamous cell carcinomas. miRNAs regulated by lncRNA ADAMTS9-AS2 enriched the metabolic pathway, epithelial mesenchymal transition, p13K-Akt pathway and pathways of cancer and enhanced the malignant potential of OSF. ADAMTS9-AS2 plays a crucial role in altering the cell microenvironment during the carcinogenesis process of oral submucous fibrosis and, thus is an ideal marker for early diagnosis of OSCC in oral submucous fibrosis.27\n\n\nExosomes in oral lichen planus\n\nOral lichen planus is a chronic inflammatory disease of the oral mucosa with an unknown etiology which is characterized by abnormal activity in the T-cell mediated immune response and is also regarded as a “potentially precancerous disorder”.28,29\n\nByun et al.30 isolated exosomes from the lesions of oral lichen planus and from saliva of 16 patients and eight age-matched normal individuals. The miRNA microarray analysis showed that there were 21 miRNAs that showed a 2-fold increase in the saliva samples of oral lichen planus compared to that in normal individuals. Among all the miRNAs that were identified, hsa-miR4484, hsa-miR1246 and hsa-miR1290 were found to be upregulated in the salivary exosomes of oral lichen planus patients. The miRNA 4484 can target a multitude of genes and initiate their translation into proteins that alter the cellular mechanisms.\n\n\nExosomes in oral cancer\n\nExosomes derived from oral cancer are saucer-like in shape with a membranous structure. The size of the exosomes in the saliva of oral cancer patients are also larger compared to that of healthy individuals and range from 20-400nm in diameter14 Western blot can detect proteins CD63, Rab 5, CD9 and Alix in the exosomes derived from oral cancer patients. Exosomes derived from oral cancer cell lines contain close to 267 proteins.31\n\nExosomes are involved in several cellular mechanisms of oral cancers such as tumor growth, invasion, metastasis and chemoresistance.9,32 Exosomes secreted by neoplastic cells into the tumor microenvironment (TME) play a vital role in tumor growth, invasion and metastasis.33 Exosomes are also found to promote epithelial-mesenchymal transition during the progression of squamous cell carcinomas of the tongue.34,35 Early-stage tumors release exosomes that contain several tumor markers into saliva and hence they can serve as non-invasive, efficient diagnostic tools.5\n\nWang et al. found that in oral cancer patients with lymphatic metastasis, exosomal laminin 332 was highly expressed.36 Theodoraki et al.37 found that exosomal PD-L 1 was associated with the clinical stage of oral cancer. Rabinowitz also found exosomes enriched with miRNA in the tissue samples of tongue oral squamous cell carcinomas.38 The exosomes in saliva from oral cancer patients are larger compared to that of normal exosomes. The density of CD63 in the exosomes of oral cancer patients is markedly increased when compared with normal exosomes.39 Yet the density of the other surface markers of exosomes CD9 and CD81 is significantly reduced in saliva of oral cancer patients when compared with that of normal individuals.14\n\nExosomes from hypoxic oral squamous cell carcinoma cells are found to deliver the miR-21 to normal OSCC cells. This promotes prometastatic behaviour among tumor cells.40 Exosomes can also spread the invasive potential to non-invasive cells by transferring oncogenic miRNAs. Highly invasive tongue cancer cells can release exosomes containing miR-200-3p that will prevent the expression of CHD 9 and WRN in non-invasive cells and confer a invasive potential to these cells as well.41 Qadir et al. found that CEP55 (a centrosomal protein) was present in all the exosomes released from cell lines of Head and Neck Carcinoma cells and absent in the exosomes released from normal oral keratinocytes.42\n\nLiu et al. found that oral squamous cell carcinoma cells released chemo resistant exosomes which induce cisplatin resistance in OSCC. These exosomes can upregulate miR-21 and downregulate the expression of phosphate and tensin homolog and programmed cell death.43 Langevi et al. found that salivary exosomes expressed elevated levels of miRNA 486-5p in oropharyngeal squamous cell carcinomas compared to controls.44 He et al. isolated salivary exosomes from oral squamous cell carcinoma patients and quantified them by NTA and characterized them by TEM and found that salivary exosomes had higher level of miR24-3p in oral squamous cell carcinoma patients.45\n\nFaur et al. found that miR-10b-5p, miR-486-5p, miR-24-3p and miR-200a in the exosomes of saliva are the most apparently useful salivary biomarkers of head and neck cancer.46\n\nExosomal miR-29a-3p derived from OSCC cells can promote proliferation and invasion of OSCC cells by enhancing the polarization of M2-subtype of macrophages, the tumor associated macrophages (TAMs).47 When OSCC cells release exosomes that contain THBS1, they communicate with M1 subtype of macrophages and transform them into TAMs. These TAMs can now promote migration of OSCC cells.48\n\nZhu et al. found that oral cancer cells released exosomes that contained TGF-beta. these exosomes are internalized by natural killer cells in the microenvironment. During the early stages, the proteins in the exosomes enhanced the function of the NK cells. Yet, with a longer incubation time, the TGF-beta gradually inhibited the cellular cytotoxicity of NK cells. The killer function of natural killer cells also decreased. A PANTHER protein class analysis showed that there is salient enrichment of proteins related to localization and adhesion of exosomes to their recipient cells. Then the exosomes fuse with the cell membrane of the recipient cell and transfer their contents in the recipient cell.49\n\nExosomes derived from oral cancer cell contain NAP1 that enhanced the cytotoxicity of NK cells.50 Exosomes derived from oral squamous cell carcinomas also contain EGFR.51 The EGFR and CD 9 are usually in the same exosome.52 The EGFR secreted by OSCC cells play a vital role in the EMT of epithelial cells. Exosomal EGFR secreted from transformed OSCC play an important role in EMT of normal epithelial cells. Cetuximab is not able to inhibit the EGFR mediated EMT transition of the transformed OSCC cells.53 Metastatic OSCC cells actively secrete chaperone-rich exosomes that are rich in stress resistant protein HSP.54\n\n\nCancer associated fibroblasts\n\nCancer associated fibroblasts promote tumor progression mainly through actively communicating with cancer cells. CAFs-associated exosomes mediate migration and invasion of OSCC cells. CAF’s derived exosomes exert a stronger effect on upregulation of MMP-3, MMP-9, N-Cadherin and Beta catenin. miR-382-5p are transferred from CAFs to OSCC cells through exosomes. The expression of miR-382-5p in CAFs is elevated by ~3.83 fold compared to that of normal fibroblasts.55 Languino et al. showed that exosomes released from cancer-associated fibroblasts transferred TBRII to malignant keratinocyte and activates them to be responsive to the TGF B ligand.56\n\n\nExosomes in salivary gland malignancies\n\nYang et al. in their study found that exosomes loaded with epiregulin from salivary adenoid cystic carcinoma induced epithelial-mesenchymal transition by down regulating the expression of E cadherin.57 Epilegrin-enriched exosomes derived from salivary adenoid cystic carcinoma can also enhance invasion and metastasis of this tumor.\n\nHou et al. found that exosomes-derived salivary adenoid cystic carcinoma 833 cells target the tight junction proteins claudin -1, Zo-1 and beta catenin and enhance migration and invasion of the tumor cells.58\n\nExosomes are a unique biological entity that play an important role in pathogenesis of potentially malignant oral disorders and head and neck cancers (Tables 1 and 2).\n\n\n\n• Reversed the upregulation of Collagen I and Collagen III that is induced by TGF- β1.\n\n• Downregulation of COLIA 1 and COL3A I mRNA.\n\n• Upregulation of MMP1 and MMP3.\n\n• Reversed the upregulation of phosphorylation of p38 that is induced by TGF-.\n\n\n\n• Suppresses the malignant transformation of oral submucous fibrosis\n\n• Can also inhibit the cell growth, migration and invasion of oral squamous cell carcinoma cells.\n\n\n\n• Screening and diagnosis of oral cancers.\n\n\n\n• Proliferation of Oral Squamous cell carcinoma cells\n\n\n\n• Promotes proliferation and invasion of Oral Squamous cell carcinoma\n\n• Promotes angiogenesis, cancer growth and metastasis.\n\n\n\n• Transform macrophages into tumor associated macrophages\n\n• Regulates the migration of tumor cells.\n\n\n\n• Inhibits the cellular cytotoxicity of natural killer lymphocytes.\n\n\n\n• Enhanced the cytotoxicity of natural killer cells.\n\n\n\n• Inhibited by anti-EGFR cetuximab\n\n\n\n• Lymph node metastatic oral squamous cell carcinomas.\n\n\n\n• Migration and invasion of CAL 27 lines.\n\n\n\n• Migration and invasion of tumor cells.\n\n\n\n• Induces epithelial-mesenchymal transition\n\n• Enhances invasion and metastasis\n\n• Generates a premetastatic niche at the site of future metastasis.\n\n\n\n• Promotes tumor cell migration and invasion.\n\n\nExosomes in oral cancer treatment – drug delivery\n\nPrecise targeted delivery of chemotherapeutic drugs is one of the best methods to reduce the toxic side effects of chemotherapy. Exosomes have superior drug delivery properties, such as good stability, allowing them to travel to distant target organs. The hydrophilic core encapsulates water soluble drug molecules. Exosomes are highly biosafe and do not induce an immune response in the body.59,60 Exosomes can track and monitor tumor progression and drug resistance in real-time giving information on drug heterogeneity.61 A proteome map of human parotid exosomes has also been developed using multi-dimensional protein identification technology, which helps in discovering exosome protein markers related to oral cancer.62\n\nExosomes can be used as natural drug delivery vehicles for oral cancer. Exosomes can deliver their contents to the target cell by binding to the cell membranes and the receptors present on the surface membrane and then by cytocytosis.63 Exosomal drug loading can either be through three types of a passive methods and four types of active methods.64–70\n\nOne of the passive forms of exosomal drug loading is to transfect the drugs to be loaded into the donor cells and then encapsulate the drugs into the exosomes inside the donor cells. Although the drugs might have a toxic effect on the donor cell, this method is safe and is used in immunotherapeutic treatment for cancer.65 Another method of passive drug loading is to separate and purify the exosomes from the donor cell and mix them with the drug to be loaded. Although the drug loading is slow, the integrity of the exosomal membrane is maintained.64\n\nOne of the active methods of loading exosomes with drugs is to prepare a pore in the exosomal membrane by an electrical field and then to allow the therapeutic drug to penetrate the exosomes. By this method, hydrophilic molecules are transported into the hydrophilic core of the exosomes.67 In another active method the exosomes and the drugs are first frozen and then thawed.70\n\nExosomes can also serve as carriers of therapeutic small molecules, proteins and nuclei acids for therapeutic application in diseases. Exosomes have an amazing advantage of good biocompatibility, almost non-toxic side effects and can be used as a sound drug delivery system. The lipid bilayer membrane of exosomes protects their contents from degradation and destruction, and they are highly stable in circulation. The small size of exosomes gives them the ability to cross various biological barriers such as the blood – brain barrier and reach the target cell or organ.63\n\nExosomes carry hydrophilic molecules such as miRNAs. An effective way of cancer treatment would be load the exosomes with miRNAs that can inhibit OSCC progress such as miR-1294, miR- 6887-5p or miR-101-3p. It is revealed that Fe3O4 nanoparticles and a constant magnetic field can induce exosomal miR-21-5p upregulation. This method of a combination of nanomaterials and a magnetic field improves the precise localization of drug, drug retention and the drug half-life and reduces the drug dose that is needed and improves drug efficacy.71,72\n\nThe saliva of patients with oral cancer is loaded with proteins related to cancer development and progression. The exosomes of cancer cells express carcinogenic and tumour suppressor miRNAs that are different from that of normal cells. Identification of a combination of exosomal DNA, RNA and proteins can improve the accuracy of exosomal based diagnosis of oral cancer.63 The presence of CD47 on exosomes produces a signal that protects them from phagocytosis.73 Delivering specific DNA, RNA or proteins via exosomes can be an interesting method of treating oral cancers.\n\nA few challenges of employing exosomes in oral cancer diagnosis are that purity and the quality of the exosomes obtained is not high and its time consuming, laborious, costly and at times inefficient.72 Although exosomes are heterogenous in origin and exhibit differential effect on oral cancer progression, it is challenging for vaccine development, and exosomes-based vaccines for oral cancer are in the making.74\n\n\nConclusion\n\nExosomes are extracellular messengers that transport and exchange valuable molecules across cells and this has a huge influence on the cellular activity of the recipient cell as well as their microenvironment. An astute evaluation of the components of exosomes will provide a greater insight into the underlying molecular mechanism of the disease process. Exosomes are found in abundance in biofluids such as saliva, which can be readily and easily obtained through non-invasive methods. Salivary exosomes are more stable and can be widely used for the diagnosis and early detection of oral cancers. miRNAs in the exosomes provide molecular and genetic information that can assist in the prognosis and for disease monitoring of oral cancer patients. Further investigation in the area of salivary exosomes, will unravel the biological mechanism of exosomes in the tumorigenesis pathway of oral precancers and cancers. Exosomes are very small and can easily pass through various biological barriers, making them very good delivery vectors for therapeutic drugs as well as to selectively induce DNA’s mRNA and miRNAs into targeted cancer cells.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nRani S, Ritter T: The Exosome - A Naturally Secreted Nanoparticle and its Application to Wound Healing. Adv. Mater. 2016 Jul; 28(27): 5542–5552. PubMed Abstract | Publisher Full Text\n\nKourembanas S: Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu. Rev. Physiol. 2015; 77: 13–27. Publisher Full Text\n\nTkach M, Théry C: Communication by Extracellular Vesicles: Where We Are and Where We Need to Go. Cell. 2016 Mar 10; 164(6): 1226–1232. PubMed Abstract | Publisher Full Text\n\nMeng Y, Sun J, Wang X, et al.: Exosomes: A Promising Avenue for the Diagnosis of Breast Cancer. Technol. Cancer Res. Treat. 2019 Jan 1; 18: 1533033818821421. PubMed Abstract | Publisher Full Text | Free Full Text\n\nColombo M, Raposo G, Théry C: Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 2014; 30: 255–289. PubMed Abstract | Publisher Full Text\n\nMathivanan S, Ji H, Simpson RJ: Exosomes: extracellular organelles important in intercellular communication. J. Proteome. 2010 Sep 10; 73(10): 1907–1920. Publisher Full Text\n\nDoyle LM, Wang MZ: Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells. 2019 Jul 15; 8(7): 727. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJohny J, Sreedhar S, Jaseela CR, et al.: Role of exosomes in oral cancer- A review. Int J Dent Sci. 2022; 4(1): 13–16.\n\nZhan C, Yang X, Yin X, et al.: Exosomes and other extracellular vesicles in oral and salivary gland cancers. Oral Dis. 2020 Jul; 26(5): 865–875. PubMed Abstract | Publisher Full Text\n\nTschuschke M, Kocherova I, Bryja A, et al.: Inclusion Biogenesis, Methods of Isolation and Clinical Application of Human Cellular Exosomes. J. Clin. Med. 2020 Feb 6; 9(2): 436. 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Med. 2021 Feb; 25(4): 2262–2273. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLodi G, Scully C, Carrozzo M, et al.: Current controversies in oral lichen planus: report of an international consensus meeting. Part 2. Clinical management and malignant transformation. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2005 Aug; 100(2): 164–178. PubMed Abstract | Publisher Full Text\n\nWarnakulasuriya S, Johnson NW, van der Waal I : Nomenclature and classification of potentially malignant disorders of the oral mucosa. J. Oral Pathol. Med. 2007 Nov; 36(10): 575–580. PubMed Abstract | Publisher Full Text\n\nByun JS, Hong SH, Choi JK, et al.: Diagnostic profiling of salivary exosomal microRNAs in oral lichen planus patients. Oral Dis. 2015 Nov; 21(8): 987–993. PubMed Abstract | Publisher Full Text\n\nZhu X, Qin X, Wang X, et al.: Oral cancer cell-derived exosomes modulate natural killer cell activity by regulating the receptors on these cells. Int. J. Mol. Med. 2020 Dec; 46(6): 2115–2125. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRen J, Ding L, Zhang D, et al.: Carcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19. Theranostics. 2018 Jun 24; 8(14): 3932–3948. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang HG, Grizzle WE: Exosomes: a novel pathway of local and distant intercellular communication that facilitates the growth and metastasis of neoplastic lesions. Am. J. Pathol. 2014 Jan; 184(1): 28–41. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVered M, Lehtonen M, Hotakainen L, et al.: Caveolin-1 accumulation in the tongue cancer tumor microenvironment is significantly associated with poor prognosis: an in-vivo and in-vitro study. BMC Cancer. 2015 Jan 30; 15: 25. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDayan D, Salo T, Salo S, et al.: Molecular crosstalk between cancer cells and tumor microenvironment components suggests potential targets for new therapeutic approaches in mobile tongue cancer. Cancer Med. 2012 Oct; 1(2): 128–140. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang SH, Liou GG, Liu SH, et al.: Laminin γ2-enriched extracellular vesicles of oral squamous cell carcinoma cells enhance in vitro lymphangiogenesis via integrin α3-dependent uptake by lymphatic endothelial cells. Int. J. Cancer. 2019 Jun 1; 144(11): 2795–2810. Publisher Full Text\n\nTheodoraki MN, Yerneni SS, Hoffmann TK, et al.: Clinical Significance of PD-L1+ Exosomes in Plasma of Head and Neck Cancer Patients. Clin. Cancer Res. 2018 Feb 15; 24(4): 896–905. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRabinowits G, Bowden M, Flores LM, et al.: Comparative Analysis of MicroRNA Expression among Benign and Malignant Tongue Tissue and Plasma of Patients with Tongue Cancer. Front. Oncol. 2017 Aug 29; 7: 191. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSharma S, Gillespie BM, Palanisamy V, et al.: Quantitative nanostructural and single-molecule force spectroscopy biomolecular analysis of human-saliva-derived exosomes. Langmuir. 2011 Dec 6; 27(23): 14394–14400. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSakha S, Muramatsu T, Ueda K, et al.: Exosomal microRNA miR-1246 induces cell motility and invasion through the regulation of DENND2D in oral squamous cell carcinoma. Sci. Rep. 2016 Dec 8; 6: 38750. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKawakubo-Yasukochi T, Morioka M, Hazekawa M, et al.: miR-200c-3p spreads invasive capacity in human oral squamous cell carcinoma microenvironment. Mol. Carcinog. 2018 Feb; 57(2): 295–302. PubMed Abstract | Publisher Full Text\n\nQadir F, Aziz MA, Sari CP, et al.: Transcriptome reprogramming by cancer exosomes: identification of novel molecular targets in matrix and immune modulation. Mol. Cancer. 2018 Jul 16; 17(1): 97. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLiu T, Chen G, Sun D, et al.: Exosomes containing miR-21 transfer the characteristic of cisplatin resistance by targeting PTEN and PDCD4 in oral squamous cell carcinoma. Acta Biochim. Biophys. Sin. Shanghai. 2017 Sep 1; 49(9): 808–816. PubMed Abstract | Publisher Full Text\n\nLangevin S, Kuhnell D, Parry T, et al.: Comprehensive microRNA-sequencing of exosomes derived from head and neck carcinoma cells in vitro reveals common secretion profiles and potential utility as salivary biomarkers. Oncotarget. 2017 Jul 27; 8(47): 82459–82474. Publisher Full Text\n\nHe L, Ping F, Fan Z, et al.: Salivary exosomal miR-24-3p serves as a potential detective biomarker for oral squamous cell carcinoma screening. Biomed. Pharmacother. 2020 Jan; 121: 109553. PubMed Abstract | Publisher Full Text\n\nFaur CI, Rotaru H, Osan C, et al.: Salivary exosomal microRNAs as biomarkers for head and neck cancer detection-a literature review. Maxillofac Plast Reconstr Surg. 2021 Jun 30; 43(1): 19. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCai J, Qiao B, Gao N, et al.: Oral squamous cell carcinoma-derived exosomes promote M2 subtype macrophage polarization mediated by exosome-enclosed miR-29a-3p. Am. J. Physiol. Cell Physiol. 2019 May 1; 316(5): C731–C740. PubMed Abstract | Publisher Full Text\n\nXiao M, Zhang J, Chen W, et al.: M1-like tumor-associated macrophages activated by exosome-transferred THBS1 promote malignant migration in oral squamous cell carcinoma. J. Exp. Clin. Cancer Res. 2018 Jul 9; 37(1): 143. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhu X, Qin X, Wang X, et al.: Oral cancer cell-derived exosomes modulate natural killer cell activity by regulating the receptors on these cells. Int. J. Mol. Med. 2020 Dec; 46(6): 2115–2125. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang Y, Qin X, Zhu X, et al.: Oral cancer-derived exosomal NAP1 enhances cytotoxicity of natural killer cells via the IRF-3 pathway. Oral Oncol. 2018 Jan; 76: 34–41. PubMed Abstract | Publisher Full Text\n\nHuang SH, Li Y, Zhang J, et al.: Epidermal growth factor receptor-containing exosomes induce tumor-specific regulatory T cells. Cancer Investig. 2013 Jun; 31(5): 330–335. PubMed Abstract | Publisher Full Text\n\nFujiwara T, Eguchi T, Sogawa C, et al.: Carcinogenic epithelial-mesenchymal transition initiated by oral cancer exosomes is inhibited by anti-EGFR antibody cetuximab. Oral Oncol. 2018 Nov; 86: 251–257. PubMed Abstract | Publisher Full Text\n\nFujiwara T, Eguchi T, Sogawa C, et al.: Anti-EGFR antibody cetuximab is secreted by oral squamous cell carcinoma and alters EGF-driven mesenchymal transition. Biochem. Biophys. Res. Commun. 2018 Sep 10; 503(3): 1267–1272. PubMed Abstract | Publisher Full Text\n\nOno K, Eguchi T, Sogawa C, et al.: HSP-enriched properties of extracellular vesicles involve survival of metastatic oral cancer cells. J. Cell. Biochem. 2018 Sep; 119(9): 7350–7362. PubMed Abstract | Publisher Full Text\n\nSun LP, Xu K, Cui J, et al.: Cancer-associated fibroblast-derived exosomal miR-382-5p promotes the migration and invasion of oral squamous cell carcinoma. Oncol. Rep. 2019 Oct; 42(4): 1319–1328. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLanguino LR, Singh A, Prisco M, et al.: Exosome-mediated transfer from the tumor microenvironment increases TGFβ signaling in squamous cell carcinoma. Am. J. Transl. Res. 2016 May 15; 8(5): 2432–2437. PubMed Abstract\n\nYang WW, Yang LQ, Zhao F, et al.: Epiregulin Promotes Lung Metastasis of Salivary Adenoid Cystic Carcinoma. Theranostics. 2017 Aug 23; 7(15): 3700–3714. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHou J, Wang F, Liu X, et al.: Tumor-derived exosomes enhance invasion and metastasis of salivary adenoid cystic carcinoma cells. J. Oral Pathol. Med. 2018 Feb; 47(2): 144–151. PubMed Abstract | Publisher Full Text\n\nHa D, Yang N, Nadithe V: Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharm. Sin. B. 2016 Jul; 6(4): 287–296. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJiang XC, Gao JQ: Exosomes as novel bio-carriers for gene and drug delivery. Int. J. Pharm. 2017 Apr 15; 521(1-2): 167–175. PubMed Abstract | Publisher Full Text\n\nBalasaheb Mali S, Dahivelkar S: Liquid biopsy = Individualized cancer management: Diagnosis, monitoring treatment and checking recurrence and metastasis. Oral Oncol. 2021 Dec; 123: 105588. PubMed Abstract | Publisher Full Text\n\nPrincipe S, Hui AB, Bruce J, et al.: Tumor-derived exosomes and microvesicles in head and neck cancer: implications for tumor biology and biomarker discovery. Proteomics. 2013 May; 13(10-11): 1608–1623. PubMed Abstract | Publisher Full Text\n\nLiu H, Huang Y, Huang M, et al.: Current Status, Opportunities, and Challenges of Exosomes in Oral Cancer Diagnosis and Treatment. Int. J. Nanomedicine. 2022 Jun 16; 17: 2679–2705. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSun D, Zhuang X, Xiang X, et al.: A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol. Ther. 2010 Sep; 18(9): 1606–1614. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPascucci L, Coccè V, Bonomi A, et al.: Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery. J. Control. Release. 2014 Oct 28; 192: 262–270. PubMed Abstract | Publisher Full Text\n\nZeelenberg IS, Ostrowski M, Krumeich S, et al.: Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses. Cancer Res. 2008 Feb 15; 68(4): 1228–1235. PubMed Abstract | Publisher Full Text\n\nJohnsen KB, Gudbergsson JM, Skov MN, et al.: Evaluation of electroporation-induced adverse effects on adipose-derived stem cell exosomes. Cytotechnology. 2016 Oct; 68(5): 2125–2138. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFuhrmann G, Serio A, Mazo M, et al.: Active loading into extracellular vesicles significantly improves the cellular uptake and photodynamic effect of porphyrins. J. Control. Release. 2015; 205: 35–44. PubMed Abstract | Publisher Full Text\n\nKim MS, Haney MJ, Zhao Y, et al.: Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine. 2016 Apr; 12(3): 655–664. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSato YT, Umezaki K, Sawada S, et al.: Engineering hybrid exosomes by membrane fusion with liposomes. Sci. Rep. 2016 Feb 25; 6: 21933. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWu D, Kang L, Tian J, et al.: Exosomes Derived from Bone Mesenchymal Stem Cells with the Stimulation of Fe3O4 Nanoparticles and Static Magnetic Field Enhance Wound Healing Through Upregulated miR-21-5p. Int. J. Nanomedicine. 2020 Oct 19; 15: 7979–7993. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen Y, Hou S: Application of magnetic nanoparticles in cell therapy. Stem Cell Res Ther. 2022; 13: 135. 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}
|
[
{
"id": "177869",
"date": "26 Jun 2023",
"name": "John W Barrett",
"expertise": [
"Reviewer Expertise Translational head and neck cancer biology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors review the literature surrounding exosomes generally and more specifically the role of exosomes in oral cancer. Although this manuscript is presented as a Review it reads more like a list of observations or facts. The authors provide two organized tables outlining the exosomal components in the biology of malignant disorders (table 1) or head and neck cancers (table 2) but there is overlap. For example, the first example in Table 1 (Oral Disorders) is dysplastic oral mucosal cell line and human tongue squamous cell carcinoma cell line which should properly be in Table 2 (head and neck cancers).\nMinor issues:\nThe first sentence of the Introduction is clearly untrue. I am not sure what the authors meant to say but to state that exosomes were first described in 2014 is incorrect by about 40 years. Exosomes were first described in the 1970s.\n\nPage 3 TEM section. This section contains a single sentence, and it requires a reference. And in the same section what are the pellets that the authors are referring to?\n\nPage 3 ELISA section. The authors report the levels of CD63 observed in exosomes from the oral fluids from oral cancer patients compared to normal individuals; however, there is no mention as to whether the differences are statistically significant or how many patients were sampled. Looking at the numbers I would predict that the observed levels overlap and are unlikely to be significantly different. But this may just reflect a small sampling number. Neither is reported but the authors should address this deficiency.\n\nPage 5 paragraph 2. The authors state that “The size of the exosomes in the saliva of oral cancer patients are also larger compared to that of healthy individuals and range from 20-400nm in diameter”. So what are the sizes of healthy individuals for comparison? They must be extremely small if they are less than 20nm.\n\nPage 5, last sentence of paragraph 3. “Early-stage tumors release exosomes that contain several tumor markers into saliva and hence they can serve as non-invasive, efficient diagnostic tools.\" Ok, that is fine but what are these “several tumor markers”? and how can they serve as diagnostic tools?\n\nOn page 5, 5th paragraph the authors state that “hypoxic oral squamous cell carcinoma cells are found to deliver the miR-21 to normal OSCC cells.\" How is this possible? By definition “normal cells” can’t be OSCC (oral squamous cell carcinoma). Please correct and clarify what you mean.\n\nThe authors list several studies that identified numerous miRNAs (9 different miRNAs) in the exosomes of oral cancer patients and only one is shared amongst the reports. A review article should be synthesizing these reports and sifting through the observations to present the reader with the best evidence. That is not clear here.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Partly\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": [
{
"c_id": "10271",
"date": "04 Oct 2023",
"name": "Monica Charlotte Solomon",
"role": "Author Response",
"response": "The authors thank the reviewer for their suggestion and recommendations The first sentence of the Introduction is clearly untrue. I am not sure what the authors meant to say but to state that exosomes were first described in 2014 is incorrect by about 40 years. Exosomes were first described in the 1970s. Thank you, this has been corrected in the manuscript. Page 3 TEM section. This section contains a single sentence, and it requires a reference. And in the same section what are the pellets that the authors are referring to? The details of the same has been included in the manuscript. Page 3 ELISA section. The authors report the levels of CD63 observed in exosomes from the oral fluids from oral cancer patients compared to normal individuals; however, there is no mention as to whether the differences are statistically significant or how many patients were sampled. Looking at the numbers I would predict that the observed levels overlap and are unlikely to be significantly different. But this may just reflect a small sampling number. Neither is reported but the authors should address this deficiency. The details have been included in the manuscript. Page 5 paragraph 2. The authors state that “The size of the exosomes in the saliva of oral cancer patients are also larger compared to that of healthy individuals and range from 20-400nm in diameter”. So what are the sizes of healthy individuals for comparison? They must be extremely small if they are less than 20nm. This has been corrected in the manuscript. Page 5, last sentence of paragraph 3. “Early-stage tumors release exosomes that contain several tumor markers into saliva and hence they can serve as non-invasive, efficient diagnostic tools.\" Ok, that is fine but what are these “several tumor markers”? and how can they serve as diagnostic tools? The details of the same has been included. On page 5, 5th paragraph the authors state that “hypoxic oral squamous cell carcinoma cells are found to deliver the miR-21 to normal OSCC cells.\" How is this possible? By definition “normal cells” can’t be OSCC (oral squamous cell carcinoma). Please correct and clarify what you mean. This has been corrected. The authors list several studies that identified numerous miRNAs (9 different miRNAs) in the exosomes of oral cancer patients and only one is shared amongst the reports. A review article should be synthesizing these reports and sifting through the observations to present the reader with the best evidence. That is not clear here. The details are provided."
}
]
},
{
"id": "177886",
"date": "29 Jun 2023",
"name": "Ajaz Bhat",
"expertise": [
"Reviewer Expertise Cancer Biology",
"Immunology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nMain Findings:\nThe review by Solomon et al., focuses on the role of exosomes, extracellular vesicles that mediate intercellular communication, in the pathogenesis of potentially malignant oral lesions and head and neck cancers. The authors discuss the molecular characteristics of exosomes, highlighting their resilience due to their lipid bilayer membrane and their capacity to transfer biological material, such as miRNA, mRNA, long non-coding RNA, DNA, proteins, and lipids, between cells. They emphasize the importance of exosomes in tumor growth, invasion, and metastasis, and their potential use in diagnosing disease activity. The review also explores the potential of using exosomes as therapeutic vectors due to their size and ability to traverse biological barriers.\nStrengths:\nThe review provides a comprehensive discussion on the emerging role of exosomes in the context of potentially malignant oral lesions and head and neck cancers, a relatively novel area of research.\n\nIt delves into the molecular and genetic information carried by exosomes, thereby providing deep insights into their functioning and influence on cancer cells.\n\nThe review brings to light the potential of exosomes as biomarkers, which is crucial for early diagnosis and personalized treatment strategies.\n\nIt also explores the potential use of exosomes as therapeutic delivery vectors, which opens a new avenue in the treatment of these types of cancers.\nLimitations:\nThe title might benefit from minor rephrasing to improve readability. For example: \"Exosomes: Mediators of Cellular Communication in Potentially Malignant Oral Lesions and Head and Neck Cancers\" or \"The Role of Exosomes in Cellular Communication: Implications for Potentially Malignant Oral Lesions and Head and Neck Cancers.\"\n\nImportant literature is missing1,2. Authors should cite these and many other important recent references. Readers might benefit from references to key studies that have shown the importance of exosomes in potentially malignant oral lesions and head and neck cancers.\n\nIt does not address potential challenges or limitations in utilizing exosomes for diagnosis or therapy, which would provide a more balanced perspective.\n\nAuthors should have at least one or two figures in the paper.\n\nAlthough the conclusion acknowledges the need for further investigation in the area of salivary exosomes, it could also discuss potential challenges in this line of research or any practical barriers to using exosomes as diagnostic markers or therapeutic vectors.\n\nRather than simply stating the need for more research, the authors could suggest specific areas for future study or the kinds of experiments that could be valuable in this field.\nEnglish Language:\nThe language is generally clear and well-written. However, there are some phrases that could be reworded for clarity and flow. For instance, \"Exosomes provide a multitude of molecular and genetic information and have become valuable indicators of disease activity at the cellular level\" could be reworded to \"Exosomes, rich in molecular and genetic information, have emerged as valuable indicators of cellular disease activity.\" There are many such instances.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Partly\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Partly",
"responses": [
{
"c_id": "10270",
"date": "04 Oct 2023",
"name": "Monica Charlotte Solomon",
"role": "Author Response",
"response": "The authors thank the reviewer's for their suggestions and recommendation. Thank you for your time and patience. The title might benefit from minor rephrasing to improve readability. For example: \"Exosomes: Mediators of Cellular Communication in Potentially Malignant Oral Lesions and Head and Neck Cancers\" or \"The Role of Exosomes in Cellular Communication: Implications for Potentially Malignant Oral Lesions and Head and Neck Cancers.\" The title of the manuscript has been corrected as per the suggestion. Important literature is missing1,2. Authors should cite these and many other important recent references. Readers might benefit from references to key studies that have shown the importance of exosomes in potentially malignant oral lesions and head and neck cancers. The recommended references have been included in the manuscript. It does not address potential challenges or limitations in utilizing exosomes for diagnosis or therapy, which would provide a more balanced perspective. The potential limitation of utilizing exosomes for diagnosis and therapy has been addressed in the manuscript. Authors should have at least one or two figures in the paper. Figures have been included in the manuscript. Although the conclusion acknowledges the need for further investigation in the area of salivary exosomes, it could also discuss potential challenges in this line of research or any practical barriers to using exosomes as diagnostic markers or therapeutic vectors. The practical barriers has been included in the manuscript. Rather than simply stating the need for more research, the authors could suggest specific areas for future study or the kinds of experiments that could be valuable in this field. This has been included in the manuscript."
}
]
}
] | 1
|
https://f1000research.com/articles/12-58
|
https://f1000research.com/articles/12-808/v1
|
11 Jul 23
|
{
"type": "Method Article",
"title": "Novel five-phase model for understanding the nature of misophonia, a conditioned aversive reflex disorder",
"authors": [
"Thomas Dozier",
"Nathanael Mitchell",
"Nathanael Mitchell"
],
"abstract": "Background: Misophonia is a recently identified condition in which a person perceives a subtle stimulus (e.g., eating sounds, hair twirling) and has an intense, negative emotional response. Misophonia cannot be classified with established nosological systems. Methods: We present a novel five-phase model of misophonia from a cognitive-behavioral framework. This model identifies a learned reflex of the autonomic nervous system as the primary etiology and maintenance of misophonia. Phase one is anticipatory anxiety and avoidance. Phase two is a conditioned physical reflex (for example, the tensing of calf muscles) that develops through stimulus-response Pavlovian conditioning. Phase three includes intense negative emotional responses and accompanying physiological distress, thoughts, urges, and emotion-driven behavior. Phase four is the individual’s coping responses to emotional distress, and phase five is the environmental response and resulting internal and external consequences of the coping behaviors. Each phase helps explain the maintenance of the response and the individual’s impairment. Results: Anticipatory anxiety and avoidance of phase one contributes to an increased arousal and awareness of triggers, resulting in increased severity of the trigger experience. Both the Pavlovian-conditioned physical reflex of phase two and the emotion-driven behavior caused by the conditioned emotional response of phase three increase with in vivo exposure to triggers. Phase four includes internal and external coping behaviors to the intense emotions and distress, and phase 5 includes the consequences of those behaviors. Internal consequences include beliefs and new emotions based on environmental responses to anger and panic. For example, the development of emotions such as shame and guilt, and beliefs regarding how ‘intolerable’ the trigger is. Conclusions: We assert misophonia is a multi-sensory condition and includes anticipatory anxiety, conditioned physical reflexes, intense emotional and physical distress, subsequent internal and external responses, and environmental consequences.",
"keywords": [
"anxiety",
"emotional development",
"clinical",
"learning",
"neuropsychology",
"psychopathology",
"psychophysiology"
],
"content": "Introduction\n\nIvan Pavlov was awarded the Nobel Prize in Physiology in 1904 (Nobel Prize, 2022). For over a century extensive research has been conducted on Pavlovian or classical conditioning. Yet a newly identified condition known as misophonia illustrates a substantial deficiency in our understanding of Pavlovian conditioning; a condition which is fundamentally a Pavlovian conditioned reflex, likely affecting hundreds of millions of people worldwide (Kılıç et al., 2021; Cash, 2015).\n\nMisophonia was first identified in 1997 by audiologist Marsha Johnson as soft (or selective) sound sensitivity syndrome (Bernstein et al., 2013; Neal and Cavanna, 2012; Yılmaz and Hocaoǧlu, 2021), and later named by Jastreboff and Jastreboff (2002). For over a decade it was exclusively investigated and treated as a poorly understood hearing condition in which common specific sounds caused a person to experience intense negative emotions and distress (Kılıç et al., 2021; Swedo et al., 2022). Misophonia was (and sometimes still is) grouped with hyperacusis and referred to as “decreased sound tolerance” (Jastreboff and Jastreboff, 2002). Treatment/management was primarily provided by audiologists with ear-level sound generators and methods developed for tinnitus (Jastreboff and Jastreboff, 2014). Awareness of misophonia beyond the audiologist community was greatly enhanced in 2011 with a New York Times article titled, ‘When a Chomp or a Slurp is a Trigger for Outrage’ (Cohen, 2011). Soon after, understanding of the condition began to grow as research into the condition began.\n\nMisophonia is now commonly known as a condition whereby a person perceives an innocuous auditory or visual stimulus (e.g., hearing chewing, seeing hair twirling) and has an immediate, intense, negative emotional response, including physiological distress, and strong behavioral responses (Brout et al., 2018; Claiborn et al., 2020; Dozier et al., 2017; Edelstein et al., 2013; Jager et al., 2020; Rosenthal et al., 2021; Schröder et al., 2013; Swedo et al., 2022; Wiese et al., 2021). A misophonia trigger is based on specific pattern, meaning, and experience of the individual with that stimulus, rather than the intensity or frequency components of the stimulus (Brout et al., 2018; Jastreboff and Jastreboff, 2014; Swedo et al., 2022). Although oral and nasal sounds are the most prevalent triggers, each person has their own unique set of triggers. Emotional responses to triggers commonly include irritation, anger, disgust, anxiety, and escape (Brout et al., 2018; Swedo et al., 2022). Experiencing a misophonic trigger is often very distracting and causes dysregulation of thoughts and emotions which can impair social, occupational, or academic functioning. Severity of misophonia can vary from mild to debilitating. Onset of misophonia is typically in late childhood or early teens, but studies report onset in adulthood in 9% (Rouw and Erfanian, 2018) and 10% (Claiborn et al., 2020) of study participants.\n\nMisophonia is a clinically significant mental health issue, with prevalence estimates in adults based on community samples reported at 12.8% (Kılıç et al., 2021) and 13.5% (Cash, 2015). Surveys of clinical populations such as those seeking help from a psychiatric or psychological clinic have been reported at 35% (Ferrer-Torres and Giménez-Llort, 2021) and 66% (Quek et al., 2018), respectively. Misophonia is a poorly known condition in part because it was recently identified and is not included in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5; American Psychiatric Association, 2013) or International Classification of Diseases, 11th Edition (ICD-11; World Health Organization, 2019/2021).\n\nThere is a lack of consensus on both the etiology of misophonia and the putative mechanisms of the behaviors of the misophonic response, in part because of the limited supporting research for any theory of misophonia, with the exception of functional magnetic resonance imaging (fMRI) studies. Several neurological defect mechanisms and behavioral models have been proposed. However, theories generally lack specificity, and tend to be based on limited correlational data, work with patients, and the researcher’s worldview. Møller (2011) postulated that misophonia is caused by an anatomical anomaly in central nervous system regions (e.g., the inferior part of the temporal lobe), and Palumbo et al. (2018) suggested a breakdown in interaction processes between the limbic system and classical and non-classical auditory pathways. Furthermore, Edelstein et al. (2013) proposed that such a distortion of connections could cause a form of “sound-emotion synesthesia.”\n\nJastreboff and Jastreboff (2002) presented a theory of the neural systems and mechanisms involved in misophonia. The same model and connections are used in their models for tinnitus, hyperacusis, and misophonia, identifying the primary brain areas and strength of interconnection activation for each condition. This model shows interconnections between the auditory subconscious for detection and processing, the auditory and other cortical areas for perception and evaluation, the limbic system for emotions, and the autonomic nervous system all of which connect to ‘reactions’. The authors proposed that the primary areas of the brain for misophonia are the “auditory and other cortical areas for perception and valuation” and the limbic system (p.77). They theorize that misophonia might involve “abnormally strong reactions of the autonomic and limbic systems resulting from enhanced connections between the auditory, limbic and autonomic systems, or enhanced reactivity of the limbic and autonomic system to sound” (Jastreboff and Jastreboff, 2002, p.77). Additionally, they noted that “connections involved in misophonia are controlled by conditioned reflexes principles” (Jastreboff and Jastreboff, 2002, p.77). Activation of the autonomic nervous system (ANS) is an important component of this model, but the ANS is not identified as a primary brain area responsible for misophonia. This implies the misophonic trigger stimulus elicits the emotions (limbic system) and that, in turn, elicits the activation of the ANS. This theory attributes the etiology of misophonia to conditioning, and the authors recommend treatment with tinnitus retraining therapy (TRT) which includes counterconditioning/active extinction (i.e., pairing weak auditory triggers with positive sounds) to reduce the conditioned reflexes of misophonia. Although this theory was presented only for auditory triggers, it could be extended to other sensory modality triggers.\n\nKumar et al. (2017, 2021) proposed neural mechanisms for misophonia. Using fMRI, they identified significantly higher activity in structures involved with regulation and associative learning of emotions (i.e., ventromedial prefrontal cortex [vmPFC], and anterior insula cortex; 2017) among misophonic individuals. Furthermore, there were between-group differences in the emotional response to trigger stimuli, with the misophonic group showing increased vmPFC activation compared to controls. Given the crucial role of the vmPFC in the development of reflexive positive or negative affect responses to initially neutral stimuli, Kumar (2015) asserted the emotional response of misophonia appears to be a learned emotional reflex. Additionally, Kumar (2015) identified enhanced myelination in the misophonic group in the interconnection of these structures and the amygdala and hippocampus, implying enhanced neuron functioning. These findings were confirmed in a subsequent independent fMRI study (Schröder et al., 2019). Kumar et al. (2021) later proposed a motor basis for misophonia after reporting the involvement of mirror neurons for oral/facial movement of individuals experiencing a trigger. Mirror neurons are responsible for common copying behaviors (i.e., monkey-see, monkey-do). One limitation of this theory is that it does not seem to apply to non-human triggers (e.g., rooster crowing, motorcycle sound). A second limitation of both studies is that the research is correlational, so it is unclear whether these neural correlates are a cause or result of misophonia.\n\nMost other theories consider misophonia a phenomenon that develops through associative (i.e., classical conditioning) and/or non-associative (i.e., sensitization) learning (Bernstein et al., 2013; Cowan et al., 2022; Dozier, 2015b; Jastreboff and Jastreboff, 2002; Palumbo et al., 2018; Schröder et al., 2013; Webber and Storch, 2015; Wu et al., 2014). Various explanations for the conditioning of misophonic responses have been proposed. For example, some have argued that misophonia develops as a physical reflex where the trigger (e.g., eating sound) is the conditioned stimulus (CS), with anger, irritation, or stress as the unconditioned stimulus (US; Palumbo et al., 2018). Similarly, it has been proposed that with some individuals there is an US of negative interpersonal interactions with a specific family member and an unconditioned response (UR) of anger due to rigidity and judgement, so the otherwise neutral sounds of that family member (e.g., chewing) becomes the CS and anger becomes the conditioned response (CR; Cowan et al., 2022).\n\nOperant conditioning is broadly recognized as the process that leads to avoidance of triggers by virtually all individuals with misophonia. Citations for the avoidance component of misophonia might include all the above references.\n\nMany successful treatment cases applied components of a cognitive-behavioral framework (CBT) and acceptance based (acceptance and commitment therapy, ACT) interventions (Aazh et al., 2019; Alekri and Saif, 2019; Altýnöz et al., 2018; Bernstein et al., 2013; Cecilione et al., 2021; Dozier, 2015a, 2022; Dover and McGuire, 2021; Hocaoǧlu, 2018; Lewin et al., 2021; McGuire et al., 2015; Muller et al., 2018; Reid et al., 2016; Robinson et al., 2018; Roushani and Honarmand, 2021; Schneider and Arch, 2017; Tonarely-Busto et al., 2022; Vanaja and Abigail, 2020). The success of misophonia treatment trials using CBT and ACT components also provides support for the theory that misophonia is a learned condition (Frank and McKay, 2019; Rabasco and McKay, 2021; Schröder et al., 2017). Recently, Cowan et al. (2022) proposed a psychological model of misophonia which includes a recurring, circular interconnection of distress from sound, rigidity regarding sounds, and increased awareness of sounds. This contributes to the development of the misophonic responses and continually strengthens and maintains them. They state that the initial development of misophonia occurs through classical and operant conditioning as follows: 1) predisposing context (e.g., negative affect), 2) sound made, 3) rigidity (i.e., judgment the sound should not be made), 4) initial negative reaction (e.g., anger), 5) increased awareness of the sound, 6) negative association with sound (i.e., classical conditioning), and 7) avoidance which develops from operant conditioning and generalizes to other stimuli. They propose a treatment which they call “experiential acceptance and stimulus engagement” (EASE, Cowan et al., 2022, p.1) based on this model.\n\nDozier (2015b) proposed a behavioral model of misophonia. He theorized that the etiology of misophonia is a Pavlovian-conditioned initial physical reflex (IPR), which is typically a skeletal muscle response, but could be other responses (e.g., stomach constriction, nausea, intestine constriction, esophagus constriction, sexual arousal, urge to urinate, etc.). In this model, the trigger is the conditioned stimulus (CS) and the muscle response (IPR) is the conditioned response (CR). Dozier proposed that the IPR develops through stimulus-response conditioning, where there is a repeating stimulus (CS) and a temporally occurring muscle response (CR). For example, a person could hear someone sniff and think, ‘I don’t want to catch their cold’, and hold their breath. The sniff is not an unconditioned stimulus (US) and holding one’s breath is not an unconditioned response (UR). But with repeated sniffing and breath holding, the person could develop a reflex response (CR, holding breath) to the sound of the sniff (CS/trigger). With stimulus-response conditioning, a conditioned reflex can develop without a US/UR (Donahoe and Vegas, 2004). A detailed explanation of stimulus-response conditioning is provided below.\n\nOnce developed, the IPR strengthens with in vivo exposure to trigger stimuli. Emotional responses then develop due to the intrusive and aversive nature of the muscle reflex. This behavioral model was expanded to include the physiological distress that accompanies strong emotions and overt coping behaviors (Dozier, 2015d; Figure 1). In Figure 1, the trigger stimulus is perceived by the person and elicits the IPR. The internal sensation of the IPR in turn elicits the extreme emotions that are the hallmark of misophonia. Physiological responses elicited by intense emotions are shown as Stress Response. Finally, the experience of the extreme emotions and stress response elicit and evoke overt coping behaviors, which often consist of behaviors that reduce, terminate, or escape the trigger stimulus. Arched, dashed lines between the boxes indicate there are likely secondary, direct connections in addition to the primary response flow. In real life, the misophonic experience consists of repeating this linear model with each occurrence of the trigger, with increasing and co-occurring emotions, stress, and overt behavior. This model assumes the same mechanism is valid for auditory, visual, olfactory, and other sensory modality triggers. A strength of this model is that it is based on known neurological processes, namely Pavlovian conditioning and the development of learned emotional reflexive responses. Dozier presented brief cases that support Pavlovian conditioning of the IPR (2015b, 2017). Additionally, the model is supported by case studies that utilized this model (Dozier, 2015a, 2015c, 2022) and studies investigating the existence of the IPR (Dozier and Morrison, 2017; Dozier et al., 2020), which are discussed below in detail.\n\nThe (1) misophonia trigger stimulus elicits a (2) physical (muscle) reflex response, which in turn elicits the (3) extreme emotional response, (4) stress response, and (5) overt behaviors. Dotted line connections indicate secondary effects.\n\nThere is much commonality between the Jastreboff and Jastreboff (2002) neurophysiological model, the Cowan et al. (2022) psychological model, and the Dozier (2015b) behavioral models of misophonia. The Jastreboff model elucidates connections among brain structures for misophonia. The Cowan model focuses on the interplay of psychological traits and responses which cause misophonia to develop. The Dozier model identifies a behavioral chain of events that occurs when a person perceives a trigger. These models essentially look at the topic of misophonia from three different worldviews. Unlike the Dozier model, the Jastreboff and Cowan models do not identify the etiology of misophonia as a Pavlovian conditioned physical reflex. In the Jastreboff and Cowan models, misophonia develops as an emotional reflex, but in the Dozier model misophonia develops as a physical (usually a skeletal muscle) reflex, and then the emotional reflex develops. For example, with the Jastreboff and Cowan models, a person hears a chewing sound in connection with something negative, allowing the conditioned emotional reflex to develop. But with the Dozier model the person hears a chewing sound and develops a Pavlovian conditioned physical reflex (usually a skeletal muscle response), and then the emotional reflex develops.\n\nThe current study presents the Mitchell-Dozier model, based on our observations in clinical work with misophonia patients and widely accepted cognitive-behavioral explanations of pathology development. Some aspects of this model are broadly recognized as characteristics of individuals with misophonia, but others are underreported in the literature. Our goal is to clearly present this model, the components of which we see in patients on a daily basis. Our hope is that this model, along with plausible theoretical support, will provide novel predictions for misophonia treatment and a basis for directions of future misophonia research.\n\nThe model presented in this section builds on the Dozier behavioral model (Figure 1). Figure 2 shows the additional components of the Mitchell-Dozier model, compared to the Dozier model. Whereas the Dozier model is a behavioral model, the Mitchell-Dozier model is a cognitive-behavioral model. The additional components include anticipatory anxiety and avoidance (phase one), thoughts, urges, and emotion-driven behavior (part of phase three), covert mental review (part of phase four), and environmental response and consequences (phase five).\n\nAdditions to the Dozier behavioral model are shown in red.\n\nThe Mitchell-Dozier model consists of five phases, as shown in Figure 3. At the core of the five-phase Mitchell-Dozier model is a conditioned physical reflex that develops through stimulus-response Pavlovian conditioning (phase two). In this case a physical reflex refers to an automatic (and therefore without cognitive consideration) physical response to a stimulus, such as skeletal muscle contractions (including breathing muscles), internal muscles (esophagus, stomach, intestine), or physical sensations such as pain, numbness, heat on skin, flash of warmth, etc. For example, the sound of chewing (CS) could elicit the tensing of calf muscles or holding one’s breath (CR). Phase three includes intense, negative, emotional responses such as anger, disgust, and anxiety, as well as accompanying physiological distress, thoughts, urges, and emotion-driven behavior. Phases two and three occur while experiencing the trigger and phase three ends shortly after termination of the trigger stimulus. Phase four is the individual’s post-trigger coping responses to the emotional and physiological distress, including covert mental reviews of the trigger and overt behavior. The fifth and final phase is the environmental response and resulting internal and external consequences of the individual’s coping behaviors. Phases four and five include the period from the termination of the trigger stimulus until the effects of the trigger experience extinguish. The repeated, aversive experiences of phases two to five lead to feelings of anticipatory anxiety and avoidance in the individual’s daily life; thus, these feelings and behaviors form the pre-trigger phase one.\n\n(1) Anticipatory anxiety and avoidance, (2) the misophonic trigger stimulus elicits the initial physical reflex (e.g., muscle flinch), (3) intense emotional response of misophonia, physiological distress, thoughts, urges and emotion driven behaviors while the trigger continues, (4) coping responses after the trigger, including covert mental review and overt behavior, and (5) environmental response and internal and external consequences. The dotted connection indicates phase 3 contributes to strengthening of the initial physical reflex, phases 2 to 5 contribute to strengthening anticipatory anxiety and avoidance of phase 1 and phase 5 contributes to strengthening phases 3 and 4.\n\nEach phase explains the maintenance of the response and the individual’s subsequent impairment. Anticipatory anxiety and avoidance (phase one) contribute to increased arousal and greater awareness of triggers, resulting in an increased severity of the trigger experience. Phase two is a Pavlovian-conditioned physical reflex that strengthens with in vivo exposure to triggers. Phase three is a conditioned emotional response and associated physiological distress, thoughts, urges, and emotion-driven behavior, which also strengthens with in vivo exposure to triggers. Phase four includes both internal and external coping behaviors to the intense emotions and distress, in which patients regularly report a ‘mental review’ of the misophonic trigger as though it were an attack, which reinforces the belief that any subsequent trigger will be intolerable and must be avoided. Widely known are the aggressive or panic-like behavioral responses of individuals experiencing a misophonic trigger. Phase five includes internal and external consequences of misophonic individuals’ coping behaviors. Internal consequences include beliefs and new emotions based on environmental responses to anger and panic. These can include the development of emotions such as shame and guilt, beliefs regarding how ‘intolerable’ the trigger is, and intensified beliefs about the unfairness of having to experience the trigger. External consequences can serve as operant reinforcement for the explosive anger and/or panic behavior; for example, demands to stop the trigger and ‘death stares’ directed at the source of the trigger.\n\nTaken together, phases two through five create overwhelming anticipatory anxiety and avoidant behavior (phase one) that perpetuate much of the dysfunction and impairment of misophonia. Phase one-related avoidant behaviors and emotions further intensify the learned responses associated with phases two through five, thus creating a dynamic, cyclical pattern of increasing dysfunction and despair. We present this as a linear model rather than the familiar circular model such as one for panic disorder (Clark, 1986). With panic disorder, the individual may experience a cycle of increasing distress triggered by a single thought. With misophonia, it is likely that at a molar level, cyclical interactions and effects occur, but at a molecular level, phase one is a setting event for the severity of the misophonic response, which is fundamentally linear, initiated by each instance of the misophonic trigger stimulus. The sections that follow explain the phases in greater detail. We begin with phase one, but we emphasize that phase two is the vital component of Pavlovian conditioning of a physical reflex critical to the development of misophonia. We recognize that there are likely many predisposing factors, including emotional awareness of moods of others, sensory sensitivity, and genetics, but these are beyond the scope of this article.\n\n\nMethods\n\nWe believe the origins of misophonia begin with Pavlovian conditioning (phase two) and subsequent responses (phases three through five). However, once the misophonic trigger exists, patients often talk about the fear and avoidance of the trigger, which is one of the primary areas of dysfunction, as the first step in the process. Anticipatory anxiety and avoidance of triggers is commonly reported and seems to be a universal characteristic among misophonia sufferers (Cusack et al., 2018; Dibb et al., 2021; Edelstein et al., 2013; Jager et al., 2020; Quek et al., 2018; Schadegg et al., 2021; Siepsiak et al., 2020; Wu et al., 2014). Avoidance of typical communal activities, such as eating together, enjoying social activities, and being in school or work environments, creates much of the dysfunction of misophonia. However, because typical exposure to triggers increases the IPR (phase two) and intense emotions (phase 3), simply eliminating avoidance in non-therapeutic environments is contraindicated. Anxiety related to experiencing triggers can increase physiological distress and hypervigilant behavior, such as scanning for sources of triggers (e.g., individuals walking into a classroom and scanning to see if anyone is chewing gum). This increases the salience of triggers, strength of the IPR, and emotional responses. Since the person is looking for or anticipating triggers, they are thinking about them, re-experiencing them, and thus are more likely to find them. Anxious anticipation can cause tensing of the IPR muscle and result in the actual IPR muscle response being perceived and objectively measured as more intense than would be the case otherwise. For a person who immediately holds their breath as their IPR, if their chest muscles are already tightened because of anticipatory anxiety, the physical sensation of the IPR (holding breath) is intensified. Furthermore, regarding intensified emotional responses, individuals who are triggered when already experiencing anxiety typically perceive and exhibit intensified emotional responses. Most individuals, whether they suffer from misophonia or not, can attest to experiencing emotions more intensely when already stressed.\n\nAnticipatory anxiety can present differently between children and adults. We find that children often scan a particular family member for any indication of an increased likelihood of a trigger. For example, children may continuously scan a parent’s face to make sure their mouth is empty and chewing will not occur. This scanning behavior creates a dysfunctional environment, makes triggers more likely to be noticed and more severe, and can cause new triggers to develop to other physical actions. Per the previous example, the child becomes so intensely focused on possible chewing behavior that family functioning becomes difficult. The child may ask for reassurance, continually shift position to look at the face, and challenge the parent’s response that they don’t have anything in their mouth. The child may also have a strengthened or intensified response to the parent’s chewing behavior because of fight-or-flight responses prior to the trigger occurring. Further, as the child continuously observes the parent's facial expression, previously neutral events can become triggering stimuli; for example, a facial movement similar to chewing or something unrelated such as the parent adjusting their glasses.\n\nA largely understudied aspect of misophonia is the existence of an IPR, although it has been reported in several case and quasi-experimental studies. In one case, the patient reported experiencing tensing of face and shoulder muscles and a sharp pain in her sternum (Dozier, 2015a). The pain in her chest was later determined to be a reflex in which the IPR closed her windpipe and simultaneously cause her to inhale. Other case studies report an IPR of fist clenching (Dozier, 2015c) and jaw clenching (Dozier, 2022). Additionally, Dozier (2015b) reported IPR responses of seven individuals which included: shoulders; arms and chest; rightward head twist and right arm tense; arms, shoulders, and legs; goose bumps on upper arms; sensation behind the ears; and intestinal constriction. Therefore, phase two of the Mitchell-Dozier model is based on the limited data within some clinical case studies.\n\nIn a quasi-experimental study, 26 participants reported physical sensations in various locations when exposed to weak trigger stimuli (Dozier and Morrison, 2017). Weak triggers and infrequent exposure to triggers ensured participants did not experience strong emotions or physiological distress. The locations, while consistent with each participant, varied between participants, with the location of physical sensations ranging from head to toe. Most of the reported physical sensations can be attributed to muscle tightening (e.g., jaw muscle, shoulder sensation), but non-skeletal-muscle responses included numb skin, flash of warmth, sexual sensation, and nausea. A key limitation of this study was the reliance on self-report data and the absence of any temporal measurements (specifically the trigger-to-response delay). A subsequent pilot study with only three subjects addressed these limitations through electromyography and direct observation (Dozier et al., 2020). Direct observation revealed a movement of muscle or tissue that seemingly occurred with no perceptible delay to trigger onset. The electromyography data indicated a trigger-to-response delay of approximately 200ms for auditory triggers and 350ms for visual triggers. Collectively, these reports provide some evidence of the existence of an immediate misophonia-related IPR in some individuals with misophonia.\n\nFurthermore, two studies measured physiological arousal using skin conductance response (SCR) in response to triggers (Edelstein et al., 2013; Kumar et al., 2017). In both studies, the SCR response was stable for the first two seconds of the trigger, and then rose monotonically for the remainder of the 15s trigger. However, SCR measures stress or physiological arousal at the skin level and cannot be used to measure immediate muscular flinches. In contrast to the delayed SCR response, the IPR begins within the first half-second following stimulus onset, so the delayed SCR response reported in these studies was not the IPR.\n\nWe propose that the IPR is different from the physical responses commonly reported in other studies. These studies reported physiological responses, including tense muscles, warmth, and increased heart rate, as physical responses to triggers. For example, studies report general muscle tensing, but an IPR would be specific muscles tensing, and be different from person to person. General warmth and increased heart rate are also physiological responses and not an IPR. Furthermore, numerous studies report that muscle tensing is often experienced by individuals when triggered in response to emotions (e.g., anger, anxiety), physiological distress, and fight-or-flight (Dibb et al., 2021; Edelstein et al., 2013; Jager et al., 2020; Jastreboff and Jastreboff, 2014; Potgieter et al., 2019; Rouw and Erfanian, 2018; Schröder et al., 2013; Schröder et al., 2019; Wu et al., 2014; Zhou et al., 2017). Similarly, muscle tension and other physical responses reported by individuals as part of the misophonia response have generally been understood as part of the emotions and distress of misophonia. Within the Mitchell-Dozier model, however, these responses would be categorized as part of phase three (physiological distress), rather than the IPR of phase two.\n\nIt can be difficult to distinguish the IPR from other physical responses, but there are several ways to differentiate them. First, the IPR will be a consistent initial response for a specific trigger. For example, if a person’s IPR for a sniff trigger is shoulder tensing, then shoulder tensing will always occur when the person is triggered by a sniff. Also, the IPR will not contain topographic variations based on the current situation, such as orienting toward the person making the trigger. An orienting response would be part of phase three as a component of fight-or-flight or other defensive motivational responding. For example, one individual’s IPR was clenching his right arm and turning his head to the right. This response occurred every time he was triggered, regardless whether the trigger source was to the right, left, in front, or behind him. Further, because the IPR is a conditioned reflex, it will be elicited by the trigger stimulus and begin immediately (e.g., about 200ms) after onset of an auditory trigger (Dozier et al., 2020). For a single trigger (e.g., a sniff), any physical response occurring after the trigger stimulus stops is likely a defensive motivational system response, a physiological response to strong emotions, or other responses described in phases three and four. Finally, the IPR may be experienced without the emotional response or precursors of fight-or-flight when the trigger stimulus is very weak. Patients’ IPR responses reported by Dozier (2015b) were often experienced without emotional distress, and participants in another study often reported having a physical sensation but no emotional response or fight-or-flight precursors (Dozier and Morrison, 2017), indicating that the physical response and the emotional response can be dissociated. Furthermore, another patient perceived tensing her jaw and fists to be her emotional/physiological response to triggers (Dozier, 2022). However, with testing, she determined her IPR was jaw tensing, and clenching her fists and jaw was part of her general physiological arousal or anger response. These cases demonstrate that, because it has been understudied, what individuals report as part of the emotional response (phase three) may very well include their IPR, and therefore a thorough investigation is required.\n\nPavlovian conditioning and the initial physical reflex\n\nAs stated above, we propose that the IPR of misophonia develops through Pavlovian conditioning. Dozier (2015b) described four cases where the physical behavior (muscle tensing) that occurred when misophonia developed was the same as the muscles of the IPR. For example, a child who, during mealtime arguments, would stand and angrily extend both arms toward her brother. Her IPR for eating triggers was in her quadriceps, shoulders, and upper arms, which were the muscles used to stand and extend her arms. The aforementioned quasi-experimental study in which 26 individuals identified their physical sensations reported that the responses varied greatly between individuals (Dozier and Morrison, 2017). Although there may be multiple explanatory factors, this variation could indicate that responses are learned rather than developed through a common neurological abnormality, thus supporting Pavlovian conditioning as the etiology of these muscle responses to commonly occurring stimuli. Further support is provided by reports of individuals who developed muscle responses to a pager (Dozier et al., 2020), chemotherapy pump (Dozier and Morrison, 2017), and phone ring tone (Dozier, 2015b). One individual reported developing a new trigger to a sound that was paired with a trigger during an experimental treatment, where the initially neutral stimulus (a ‘ping’ sound) elicited the same IPR as the trigger (Dozier, 2015b). Additionally, spontaneous recovery has been reported in connection to treatments that reduced the IPR (Dozier, 2015b). Given that spontaneous recovery is a well-documented characteristic of conditioned reflexes (Catania, 2013), these findings support Pavlovian conditioning as the origin of the IPR (Dozier, 2015a, 2015b, 2015c, 2022).\n\nSometimes we understand the development of the IPR as a response to a truly US (e.g., yelling at a meal) causing a startle response (UR) which is paired with the sound of chewing, so that chewing sound becomes the CS, and the startle response becomes the CR (IPR). Furthermore, we also see potentially second-order classical conditioning examples, where emotional responses develop through recurrent conditioning events. We argue that emotional responses (e.g., concern, offense, worry) often include individual unconscious physical responses (e.g., one person may raise their shoulders, while another person tightens leg muscles). The unconscious physical component can then become associated over time with the sounds of a parent, sibling, or partner, so that the sound becomes a CS that elicits the CR (IPR). For example, a child may acquire a reflexive or consistent unconscious muscle response to a parent’s scowl (e.g., they hold their breath). If the parent scowls when hearing a chewing trigger, then the child will hold their breath and could develop a hold-breath reflex response (IPR) to that sound. We emphasize that this is a conditioned physical reflex (i.e., muscle tensing) and not a conditioned emotional reflex. The conditioned emotional reflex does develop, and this is described in phase three.\n\nFor the purpose of this manuscript, a response is any form of behavior. A response can either be a reflex response elicited by a specific stimulus or an operant response evoked by a stimulus and learning history (i.e., operant conditioning). A conditioned (learned) reflex response occurs immediately when the stimulus is perceived, without thought. A person can choose to not emit an operant response but has no willful control to prevent a reflex response. Emotions are reflexive behavior which can occur due to conditioning with a specific stimulus, or can occur due to a thoughtful, evaluative process. In this manuscript, we refer to conditioned emotional responses as those which develop and are emitted immediately upon experiencing the stimulus. Our distinction between physical and emotional reflex responses is critical. A physical reflex is a purely physical action of the body. For the IPR of this model, it is usually a skeletal muscle flinch, but it could be something else (e.g., pain sensation, sexual sensation, or goosebumps). A conditioned emotional reflex is an emotional response elicited by a stimulus with accompanying physiological responses. We always refer to physical responses from emotions as physiological responses, not physical reflexes. We consider the IPR a conditioned physical reflex and the emotional responses of phase three conditioned emotional reflexes, with accompanying physiological responses. Phase three also includes evoked operant behavior (e.g., screaming) and elicited reflexes (e.g., fight, fight, or freeze).\n\nStimulus-response Pavlovian conditioning\n\nThe typical understanding of Pavlovian conditioning is that learning takes place when a neutral stimulus (NS/CS) is paired with an US/UR, or for second-order conditioning, an established CS/CR, whereby acquisition of the CR is driven by the CS-US pairing (Ghirlanda and Enquist, 2019). However, with misophonia, there is usually no clear US/UR, and there have been no examples of US/UR reflexes reported in the misophonia literature. Interestingly, an alternative understanding of classical conditioning emerged in the mid-2000s, known as stimulus-response (S-R) Pavlovian conditioning, which has direct application to misophonia. S-R Pavlovian conditioning proposes that a response develops due to an association between the NS/CS and the physical response. For example, Donahoe and Vegas (2004) reported an S-R association in the muscle response of pigeons swallowing. The stimulus-to-response delay from water-into-mouth (US) to swallowing (UR) was a half-second. With this delay, the researchers tested forward and backward conditioning of the CS to the US (water-in-mouth) and to the UR (swallowing). Forward conditioning (CS before both US and UR) reliably developed a condition response, while backward conditioning (CS after both the US and UR), as expected, did not. However, backward-to-US and forward-to-UR (CS after the US and before the UR) reliably developed a CR. The study concludes that it is the CS-UR, or S-R, relationship that is critical to the development of a conditioned muscle response. Therefore, a US/UR reflex is not required. All that is required is a consistent pairing of a stimulus and a response.\n\nThe S-R view of Pavlovian conditioning is consistent with the neurology theory that the brain attempts to minimize expectation error by predicting responses based on prior experience, and thus tensing the muscle following the stimulus (Haruno and Kawato, 2006; McClure et al., 2003). In S-R Pavlovian conditioning, when a stimulus is predictably followed by a muscle response the stimulus becomes a CS and the muscle tensing becomes the CR. Note that the muscle tensing response must predictably follow the stimulus, but an US is not required to develop a S-R Pavlovian-conditioned reflex. Unfortunately, to date there are no published studies of S-R Pavlovian conditioning, either in animals or humans; nor are there any studies confirming or refuting the findings of Donahoe and Vegas (2004). This is clearly a research opportunity, so we only have case data for S-R conditioning in humans.\n\nFor example, in a case referred to above, a trauma center surgeon developed a shoulder flinch response to his pager (Dozier et al., 2020). The surgeon stated that when the pager initially sounded, he felt a sense of dread about what gruesome injury he might face in the trauma center. With the dread emotion, there was a slight physical response (i.e., shoulder tensing). With repeated pairing the CR developed and strengthened into a shoulder muscle jerk, and every time his pager went off (CS), his shoulders flinched (CR), until he changed jobs and stopped carrying a pager.\n\nS-R Pavlovian conditioning of a muscle response has direct application to our understanding of how misophonia develops and why the misophonic response strengthens with typical exposure to trigger stimuli. We begin with an explanation of how the IPR develops. When a particular person perceives a common stimulus (e.g., chewing sound) and consistently has a thought with an accompanying specific muscle tensing (e.g., biceps), the chewing sound becomes a CS/trigger that elicits the tensing of the biceps (CR/IPR). For example, a person could hold their breath when hearing eating sounds they deem inappropriate. This results in a temporal pairing of eating sounds and breath holding. The eating sounds would become the CS/trigger and breath holding would be the CR/IPR. This could describe the development of a person’s first misophonia trigger or a subsequent trigger that is unrelated to previously developed triggers. The stimulus and the response are likely mediated by a negative thought or emotion. Patients report varied situations in this regard. Possible scenarios include an unconscious behavior unrelated to the stimulus, such as the child struggling to breathe due to asthma (Dozier 2015a); annoyance, such as sound emanating from a neighbor’s property (Ferrer-Torres and Giménez-Llort, 2021); someone breaking etiquette rules, such as chewing loudly; or a sense of unfairness, such as being criticized for chewing loudly, but then hearing a sibling chewing. Indeed, there are numerous possibilities for a sound and negative thought to result in an unconscious muscle response that could enable the development of a Pavlovian-conditioned muscle response. Thus, the natural occurrence of a stimulus, followed by a specific muscle response, can easily develop a trigger/CS with a CR/IPR of that specific muscle.\n\nIndividual differences in perception of events and responsiveness to stimuli may cause one person to respond to a stimulus when others do not. Wu et al. (2014) reported a strong association between misophonia impairment and general sensory sensitivity, and moderate associations with anxiety, depression, and obsessive-compulsive symptoms. Additionally, individuals with anxiety display an attentional bias towards threatening stimuli (Cisler and Oster, 2010). Similarly, Fox et al. (2002) reported a correlation between heightened trait anxiety and increased attention to emotional facial stimuli. Thus, individual differences in awareness and responsiveness to common stimuli and family dynamics can cause one child to develop a misophonic trigger in response to common sounds but not their sibling.\n\nStrengthening of the initial physical reflex\n\nWe will next consider how misophonia triggers can strengthen. We propose that the IPR strengthens with typical in vivo exposure to triggers. With S-R conditioning, once the ANS has developed the CS/CR reflex, every experience of the CS (which includes context) creates an S-R conditioning learning event. When the CS is detected, the CR is elicited. If there is no additional response in the CR muscle, it creates an extinguishing event. If there is slight additional tensing in the CR muscle, it creates a reflex maintenance event, and if there is considerable additional tensing in the CR muscle, it creates a reflex strengthening event. Note that the traditional view of reinforcement of a conditioned response has questionable application for S-R conditioning. With S-R conditioning, the theory is that the brain tries to reproduce the CS/CR reflex to match prior behavior. As the physical response is intrusive, the person may tighten the muscle of the IPR after experiencing the reflex and so it maintains or strengthens the reflex. The intense emotions of misophonia (phase three) have accompanying physical responses which may include tightening the muscle of the IPR. This is shown in Figure 3 as the feedback connection from phase three to the IPR. A trigger thus creates a conditioning event because the muscle response after the reflex is stronger than the reflex response alone. This proposition is consistent with the report that mere exposure to misophonic triggers generally increases misophonia symptoms rather than reducing them (Schröder et al., 2017). We therefore posit that typical exposure to misophonic triggers maintains or strengthens the IPR.\n\nExpansion of trigger stimuli\n\nOnce misophonia has developed in an individual, evidence suggests that new triggers can develop in three ways: 1) independently of existing triggers, 2) by pairing with an existing trigger, or 3) though generalization of trigger stimuli. The same process that allows the first misophonia trigger to develop can allow the development of other triggers, independent of the first trigger. When a second trigger develops independently, it may have a different IPR than the first trigger, or it may have the same IPR. One study reported that 42% of the 26 people tested for their IPR had distinctly different IPRs for different triggers (Dozier and Morrison, 2017). For example, one individual reported an IPR of shoulders tensing in response to the sound of someone chewing and an IPR of fist clenching in response to the sound of someone sniffing. However, note that IPRs are not necessarily different for each trigger. A person may have a characteristic response to a stimulus they perceive as intrusive (e.g., tensing neck muscles), and therefore a new trigger that develops independently of other triggers may have the same IPR as one or many other triggers.\n\nWhen a NS (new CS) is paired with an existing trigger (CS), it is also temporally paired with the existing trigger response (CR/IPR), so the new CS has the same CR/IPR as the established trigger. For example, it is common for misophonic individuals with auditory eating triggers to develop a visual trigger of jaw movement (i.e., chewing; Claiborn et al., 2020; Dibb et al., 2021; Edelstein et al., 2013; Jaswal et al., 2021; Swedo et al., 2022). By noticing jaw movement while being triggered by the sound of chewing, jaw movement becomes a CS that elicits the same CR/IPR as the sound of chewing. Once the visual trigger develops, it can maintain or strengthen even without continued exposure to the auditory trigger. An example is the woman who had auditory and visual triggers of her husband scratching his beard (Dozier, 2015a). The auditory trigger was greatly reduced through counterconditioning, but the visual trigger remained unchanged.\n\nFinally, trigger stimuli will generalize to other settings, sources, and variations of the sound of the original trigger stimulus. Once a trigger generalizes to a new environment, source, or variation, the response will strengthen with continued exposure to the trigger. All three ways of developing new triggers are the result of natural S-R Pavlovian conditioning events that occur in typical daily life. As such, the perceived experience of misophonia is often one of ever-growing distress and dysfunction and seems to rarely subside without proper treatment.\n\nWe reiterate that while the IPR is overwhelmingly a skeletal muscle response, it can be virtually any muscle or physical response. Less common responses could be a sexual sensation, sensation of warmth, nausea, or numbness of skin (Dozier and Morrison, 2017). Additionally, our clinical experience includes IPR of pain at a specific location, sensation of burning on the skin, an itch, goose bumps, intestinal contractions, stomach contractions, and urge to urinate.\n\nThe third phase of the model is ‘intense emotional response’. At first glance, it may seem as though this aspect of misophonia is the most understood. Indeed, intense emotional responses are the primary complaint of both individuals who suffer from misophonia and their loved ones. The variety of emotional responses has been widely documented. There is little debate in the literature as to the many emotional experiences that overwhelm and plague individuals with misophonia. Dozier (2015b) proposed that the negative emotions develop because of the aversive and intrusive nature of the IPR. Aversive stimuli have been shown to elicit negative emotional responses. Research using rats showed an immediate aggressive response is elicited by electrical shock (Ulrich and Azrin, 1962), while research on humans indicates aversive stimuli evoke fight-or-flight emotions and overt behavior (Berkowitz et al., 1981; Berkowitz, 1983). Furthermore, aversive olfactory and gustatory stimuli were reported to elicit activation of the limbic system (Zald and Pardo, 1997; Zald et al., 1998). These studies provide plausible support for the assertion that the aversive nature of the IPR (phase two) contributes to the development and maintenance of the emotions of misophonia; however, once the IPR develops, there are many, varied emotional experiences that occur in the context of each trigger event.\n\nAdditionally, brain imaging research indicates the emotional response is a reflexive learned emotional response (Kumar, 2015; Kumar et al., 2017; Schröder et al., 2019), though no information on the temporal relationship of the emotional response and IPR is provided due to the three-second sample rate of fMRI. The anterior insula cortex, which is central to the misophonic emotional response, integrates interoceptive and exteroceptive stimuli, so the interoceptive sensation of the IPR would be included in the overall sensory experience which triggers the emotional response. The specific brain structures involved are described in the introduction, but do not include any of the brain structures identified for Pavlovian conditioning of a muscle response (Thompson, 1990). Therefore, we posit the learning of the emotional response of misophonia is separate from the learning of the IPR. Instead, the reflexive emotional response develops due to the repeated experience of the intrusive and aversive IPR, along with simultaneous emotional experiences (e.g., conflict with the person producing the trigger or frustration from lack of control).\n\nThough there is no published research on S-R conditioning and development of emotional responses in humans, there are three published misophonia cases where the individual experienced a weak physical response (IPR) but no emotional response with exposure to weak trigger stimuli during treatment (Dozier 2015a, 2015b, 2015c). This supports the distinct separation of the IPR and the emotional response. In the Mitchell-Dozier model, the trigger stimulus elicits the IPR (phase two), and the IPR elicits the emotional response (phase three).\n\nThe purpose of this section is not to provide new information regarding the intense emotional responses. Rather, we provide a cognitive-behavioral structure to understand these emotional responses, a structure which is linked to current understanding in the field at large, as well as to empirically supported treatments for other commonly comorbid disorders.\n\nIn our model we attempt to explain emotional responses from the tripartite model of emotions presented in the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (Barlow et al., 2018). This model presents emotions as having physical, cognitive, and behavioral components to responses (see Figure 2). From this model, we assert that the intense emotional responses reported by patients will have three vital aspects. First, we attempt to understand the intense physiological discomfort. It is important to note that while the physiological discomfort is separate from the IPR, it can present similarly. Second, we attempt to understand the unhealthy, automatic thoughts experienced by patients. Third, the intense emotional responses must also include an exploration of the strong behavioral urges to avoid the discomfort. Below, we provide a brief explanation of each of these three core components to emotional responses.\n\nDuring an intense emotional response, patients will experience physiological discomfort at a level tantamount to a physical attack. Patients often report feeling as though the misophonic trigger caused pain in some capacity. The IPR of phase two is very strong in some patients. One woman described her experience of being triggered as feeling as though a “shovel was run through her sternum and out her back” (Dozier, 2015a). Many patients have a strong muscle reflex that feels like receiving an electrical shock (Dozier, 2015c, 2022). The IPR occurs with each instance of a trigger stimulus and continues for the duration of the trigger, so for a longer trigger (e.g., a single long snore), the IPR triggers phase three and both phases continue until the trigger stimulus stops. Therefore, the misophonia sufferer experiences both phase two and phase three simultaneously, often with greater intensity due to the individual’s reflexive response to the sensation of the IPR. Additionally, there is an unconditioned physiological distress response to the intense emotions. Other commonly reported physical responses which occur in addition to the IPR include increased heart rate, sweating, general muscle tension, and tension of specific muscles associated with anger and distress (e.g., jaw and fist clenching). The physiological discomfort cannot be emphasized enough. We have found physiological discomfort is often the primary complaint of the patient during clinician assessments. However, because the intense emotional response is not always expressed behaviorally as ‘painful’, this aspect is often underappreciated by clinicians. Patients frequently report typical ‘fight, flight, or freeze’ responses, indicating the brain perceives the trigger as threatening.\n\nNext, it is vital to explore the unhelpful automatic thinking associated with the intense emotional responses of misophonia. Patients frequently report unhelpful thinking, such as very frequently perceiving the trigger as an ‘assault’ or an affront. Social media was used to identify thoughts in response to triggers including thinking that it is on purpose to irritate the individual, disgust, hyper-fixation on the sound, and even threats or violent thoughts. As such, it is understandable when patients frequently report specific thoughts regarding the unfairness of the trigger, worries about the next possible trigger, and beliefs about the intolerance of their discomfort. Further, from numerous patient encounters and interviews, we now understand it is an incredibly common occurrence for patients to ‘mentally review’ specific qualities of the trigger. While no research has examined this phenomenon in detail, we believe given the perception of the triggers being an ‘attack’, it makes sense that the brain would remember details of ‘the attacker’ (i.e., the sound). Further, the perception of the triggering event as an attack helps makes sense of the ‘hypervigilance’ patients naturally exhibit after the triggering event.\n\nFinally, from this model, emotions are also understood to ignite an automatic motivation, known as ‘action tendencies’, to engage in some behavior related to the strong physiological and thinking responses. Action tendencies generally result in “emotion-driven behaviors” (EDBs, Carver and Harmon-Jones, 2009; Christensen et al., 2019; Lewon and Hayes, 2014). The behavior feels out of control, automatic, and incredibly difficult to resist. Examples of EDBs include orienting responses, negative facial responses, verbal demands, or physical aggression (Bossuyt et al., 2014). The application of EDBs to misophonia seems very clear on the surface as there are numerous reports of explosive externalizing, destructive behaviors. However, when a patient with misophonia is triggered, a wide array of emotions can be elicited, and thus, a wide array of both external and internal action tendencies occurs.\n\nAvoidance and approach are action tendencies commonly reported as instinctive responses to anger and fear, respectively, although they can both be elicited by various emotional states (Bossuyt et al., 2014; Klein et al., 2011; Sawashima, 2019). Disgust, however, an emotion commonly reported by individuals with misophonia, has the dominant action tendency of behavioral avoidance (Izard, 1993). The observed avoidance can include both active and passive features, both of which can be viewed in individuals with misophonia. Active avoidance involves terminating exposure to the stimulus by moving away from the perceived trigger or shouting ‘stop’ at the individual performing the triggering behavior. Passive avoidance involves actions like closing the eyes or covering the ears. Approach and avoidance in various forms seem to be common action tendencies in misophonia.\n\nWith our patients, we discuss how behaviors/choices are seemingly automatic, but we try to emphasize that it is the ‘action tendencies’ or urges that are automatic, rather than the often-regrettable behaviors/choices. Doing so allows the patient to have hope that the EDBs are indeed modifiable and that the urges can eventually be resisted through treatment. Although these thoughts, urges, and EDBs occur as part of the intense emotions of phase three, they generally continue, along with the physiological distress, and become part of the coping behavior of phase four.\n\nPhase four is non-reflexive, operant behavior that occurs after the trigger stimulus has stopped plus residue of the behavior of phase three (e.g., emotions, physiological responses, and EDBs), and automatic behavior provoked by cognitions and actions after the trigger stimulus has terminated. It can be the time after a single trigger (e.g., a single sniff), the time between intermittent triggers, or the time after a series of triggers has ended (e.g., person leaves the room or puts on headphones to block triggering sound). Phase four is primarily the individual’s coping responses to intense emotional and physiological distress, including both internal (covert) and external (overt) coping behaviors. The duration of this phase can vary greatly between individuals, with one validation study of a misophonia instrument reporting the time to recover from a trigger experience and ‘feel normal’ varies from almost immediately to longer than 24 hours (Dibb et al., 2021). A key distinction for phase four is that the trigger stimulus has ceased, so the IPR and the learned emotional responses elicited by the trigger experience have ceased. However, the physiological distress and intense emotions do not instantly cease, thus they continue into phase four.\n\nInternal coping strategies are primarily a mental review of the specific nature of the trigger, anger rumination, and thoughts associated with the many possible misophonia emotions, including ways to escape the trigger. Patients regularly report a prolonged mental review of the misophonic trigger as though it were an attack, which reinforces the belief that the next trigger will be intolerable and must be avoided, thus strengthening the anxiety and avoidant behaviors of phase one. Research suggests that anger rumination, which has been identified as a component of other disorders (e.g., OCD), is associated with trait anxiety/negative affect rather than a specific disorder (Jessup et al., 2019). We find that the mental review of misophonia triggers often includes anger rumination. The mental review also prolongs the individual’s focus on the trigger and its source. This maintains or increases salience and responsiveness to subsequent trigger stimuli, likely strengthening phases two and three. The mental review of the trigger can cause the person to retrigger themselves, prolonging the distress and strengthening the urge to engage in hypervigilant behavior.\n\nWidely known are the aggressive or panic-like behaviors commonly reported by individuals with misophonia. One such behavior is mimicking of oral triggers sounds, for which a neurological basis has been proposed (Kumar et al., 2021). Additionally, as a method of eliminating the trigger or communicating to others in the environment that they are upset, patients commonly report they emit facial and bodily responses (e.g., death stares). Patients often become aggressive and ‘verbally snap’ or ‘verbally assault’ the person making the trigger. In some cases, patients, usually children, become physically violent. While these overt behaviors generally succeed in stopping the triggering behavior, they can also create undesired consequences.\n\nPhase five includes the internal and external consequences that result from coping behaviors. Internal consequences include beliefs and new emotions based upon environmental responses to anger and panic; for example, the development of emotions such as shame and guilt, and beliefs regarding how ‘intolerable’ the trigger is. Further, explosive anger or panic can produce consequences from others; namely, they try to stop the trigger.\n\nParents of children with misophonia can unintentionally reward explosive behavior by terminating the trigger; however, parents often blame the child for being ‘out of control’ or being ‘dramatic’. Parents and partners of individuals with misophonia report ‘walking on eggshells’ or ‘being controlled’ by the misophonic individual. But behaviorally, if screaming makes the pain stop, the individual is going to keep screaming. As such, these reactions from others, which seemingly accuse the patient of a deficit of character, are actually maintaining or increasing the explosive behavior. These environmental consequences shape the operant behavior in phase four and, though much of the behavior in phase three is reflexive or automatic in nature, consequences shape the operant behavior of phase three. This effect is shown in Figure 3 with a dotted line from phase five to phases four and three.\n\nWe often find environmental changes are necessary in order to decrease explosive behavior. Parents and loved ones must be trained to not engage in rescuing behaviors which inadvertently reward the misophonia sufferer’s explosive attempts at stopping the trigger. Further, we find that training parents and loved ones to properly view misophonia as an illness can help to decrease responses which cause guilt and shame in the sufferer.\n\nEnvironmental changes (putting in ear plugs or moving to another location) also function as a reinforcer because they allow the patient to escape the trigger stimulus. The reduction in exposure to the trigger is a reinforcing consequence for the overt behaviors and so the patient continues to emit these behaviors. Unfortunately, due to the prolonged duration of phase four, simply stopping the trigger may not alleviate the negative effects from being triggered, which can persist for an extended period of time, sometimes even continuing into the next day.\n\nThe misophonic response to triggers is a repeating cycle, whereby each phase strengthens both the previous and subsequent phase. As noted earlier, phases two to five contribute to the creation of an aversive emotional and physical experience, and can increase the sufferer's belief that the trigger experience is simply intolerable. This view of the misophonic experience as being intolerable increases hypervigilance, anticipatory anxiety, and avoidance, which is phase one of the Mitchell-Dozier model.\n\n\nDiscussion\n\nWe present a theoretical model of the development of pathology in misophonia to inform individuals, clinicians, and researchers in their implementation of interventions and research studies. We argue that the development of a pathology should be inextricably linked to treatment interventions. Furthermore, we want to be able to help patients understand why their pathology has developed and therefore why the chosen interventions are reasonable, understandable, and likely to produce benefit, including symptom reduction. Much like understanding the pathology development in social anxiety vs. panic disorder vs. phobias, the understanding of how misophonia is developed and maintained is vital to proper treatment. For every single disorder, there are researchers who have created sub-CBT models of pathology development to predict treatment.\n\nMuch of this model is likely viewed as common knowledge for those familiar with misophonia, so to emphasize the unique and critical features of this model, we repeat them here. The unique and critical features of this model are the IPR and mental review of phase four. The IPR has not been acknowledged by misophonia researchers, and it is generally not acknowledged by individuals with misophonia. However, within our clinical setting we find that virtually all of our patients acknowledge the IPR after simple tests are conducted in a treatment session. The other unique phase of this model, covert mental review, is often acknowledged, but the importance of this feature of misophonia in reducing misophonia severity is not appreciated. We find that reducing covert mental review of triggers can reduce the dysfunction of misophonia. Therefore, the unique and critical features of this model have found much support within the clinical setting (Dozier, 2015a, 2015c, 2022); however, more robust research is required to confirm these findings on a larger scale.\n\nThis Mitchell-Dozier model of misophonia provides a coherent theory of misophonia as a condition which develops initially as a Pavlovian-conditioned physical reflex (phase two, muscle reflex), and subsequent conditioned emotional responses (phase three). We posit that through Pavlovian conditioning, the misophonic trigger can be any sensory experience and can be created by any environmental source. Some have proposed that misophonia be limited to stimuli of particular sensory modalities and require specific types of triggers (i.e., mouth and/or nasal sounds) to occur in order to be considered misophonia (Schröder et al., 2013; Jager et al., 2020). We believe this definition is too narrow. While approximately 96% of misophonia sufferers have mouth-sound triggers and 85% have breathing/nasal-sound triggers (Claiborn et al., 2020; Jager et al., 2020; Rouw and Erfanian, 2018), there are individuals who have neither of these. We do not know of any Pavlovian conditioning research that restricts the sensory domain of a conditioned stimulus, and our work with patients provides examples of auditory, visual, olfactory, tactile, and vibration trigger stimuli. We therefore propose that misophonia is present when a person develops consistently intense negative emotions and/or dysfunction from any specific innocuous stimuli. For example, one patient did not have any oral or nasal triggers and therefore did not meet the criteria of misophonia per Jager et al. (2020), but she had severe distress and dysfunction from non-oral/nasal innocuous stimuli (e.g., sound of pouring dry dog food into a metal bowl). The patient exhibited a breath-holding reflex (phase two) regardless of volume. Therefore, even though the sounds were atypical for misophonia, we view the patient’s condition as misophonia. The existence of misophonia was further supported by the patient’s positive response to behavioral treatment (e.g., counterconditioning). As her conditioned physical response extinguished, all other phases of the model extinguished. We propose misophonia be defined based on the conditioned response of the individual rather than requiring specific stimuli that trigger the response. As such, we assert misophonia can be triggered by any innocuous stimuli across all sensory modalities.\n\nOutside of the phases of the Mitchell-Dozier model, we understand there are predisposing or vulnerability factors, some of which are known and some of which are not. For example, an association between general sensory sensitivities, (sensory over-responsivity) and misophonia has been reported (Wu et al., 2014). It is important to note that we believe misophonia is not an example of sensory over-responsivity but rather a conditioned response. Additionally, an association between anxiety and misophonia severity has been reported (Cusack et al., 2018; Quek et al., 2018; Schadegg et al., 2021; Wu et al., 2014). The predispositioning factors of anxiety are numerous and well documented. The second author utilized the current understanding of panic disorder as a means to better understand misophonia. For example, interoceptive awareness seems to be a commonly reported experience in his misophonia treatment practice. More specifically, individuals who are highly ‘attuned’ to their physiological changes may be more likely to develop a Pavlovian response to stimuli that cause a physiological change.\n\nWe understand there are neurological pathways and brain functions that are presently not fully known; however, there is a good deal of evidence supporting a neurological basis of misophonia. As with all mental health issues, there is likely a biological contribution to misophonia. Additionally, there is a genetic contribution, as reported by 23andMe DNA testing (Fayzullina et al., 2015). Environmental contributions are vital to the development of misophonia given that it is a conditioned/learned response. However, the contribution of all the social/cultural/demographic variables to the development and maintenance of the disorder remain unknown. Additionally, reported age-of-onset data indicate misophonia can develop at any age (Claiborn et al., 2020). There may be social disparities and discrimination which increase conditioned aversive responses and therefore may contribute to the onset of misophonia; however, there are no data on this, so it is an opportunity for future research. Taken together, we understand there are numerous and varied bio-psycho-social factors which may increase or decrease the probability of developing misophonia.\n\nWe assert that misophonia is a chronic illness which must be continually managed, but we do not propose a cure. We view misophonia as a result of a normally functioning neurological process (i.e., Pavlovian conditioning). Because misophonia is a conditioned response, even when all symptoms extinguish, the patient remains vulnerable to developing new triggers or the reemergence of prior triggers. A brain imaging study (Kumar et al., 2017) reported that, compared to control participants, misophonia individuals had higher activation in brain areas responsible for emotional responses when exposed to unpleasant sounds, possibly indicating that a person with misophonia is more responsive to sounds deemed unpleasant and therefore more likely to develop a misophonia trigger. CBT for misophonia emphasizes the importance of not only extinguishing triggers, but continuous practice of techniques as well as altering vulnerability factors when and where possible. Further, the importance of meaningfulness and quality of life is utilized to cope with accepting the reality of a chronic illness and providing motivation for consistent management.\n\nAs with other CBT theoretical models of pathology development, the Mitchell-Dozier model is directly linked to misophonia treatment, presently called “cognitive-behavioral therapy, misophonia” (CBT-M, second author) and “relaxation and counterconditioning therapy” (RCT, Dozier, 2022). Utilizing the Mitchell-Dozier model, CBT-M and RCT treatments have shown promising results in our practices, though there is a lack of scientific study of these treatments. Both therapies incorporate intensive progressive muscle relaxation training and counterconditioning. This model elucidates two important aspects of the nature and features of misophonia which are poorly understood implications for treatment: the Pavlovian response of phase two and the mental review of phase four. Within clinical settings, many patients report significant reduction in misophonia severity when the Pavlovian response is treated directly through behavioral techniques as reported in three case studies (Dozier, 2015a, 2015c, 2022). Additionally, patients often report increased quality of life by learning to address mental review, which is a newly identified feature of misophonia observed within our clinical practice.\n\nThis model identifies the need for basic research on stimulus-response (S-R) Pavlovian conditioning and applied misophonia research. S-R Pavlovian conditioning theory was experimentally demonstrated by Donahoe and Vegas (2004) and has received a lot of support. Also, crucially, we find no rebuttals of S-R Pavlovian conditioning theory, and no research studies refuting the findings. One supporting study focused on the role of responses in Pavlovian acquisition and reported that the datasets they analyzed support the response-dependent model, in which CR acquisition is based on the occurrence of the CR rather than the CS-US experiences (Ghirlanda and Enquist, 2019). Still, fundamental research on S-R conditioning is needed. Research opportunities include investigating the commonly reported learned reflex response to pagers. With the advent of the pager smartphone app, a surgeon can change the alert tone regularly to prevent the development of a conditioned response. This may allow real-life data to be collected on the acquisition of a CR to a repeating, innocuous stimulus. Additional study opportunities include cancer patients’ response to their chemotherapy pump, and study participants’ response to a unique sound that indicates an aversive consequence. This may help us understand how everyday life activities allow misophonia to develop.\n\nApplication of this model to applied misophonia research may be even more important. Several studies have reported success in reducing misophonia severity using CBT techniques (Frank and McKay, 2019; Jager et al., 2021; Lewin et al., 2021; Schröder et al., 2017). Specific components of reducing the IPR and covert mental review may be added to existing protocols to determine additional treatment benefit. Several case studies indicate that reducing the IPR, even when there are comorbid conditions, can reduce misophonia severity (Dozier, 2015a, 2015c, 2022).\n\nWe recommend misophonia treatment studies assess participants’ IPR, because muscle response IPRs (e.g., shoulder flinch) contribute to effective treatment after appropriate muscle relaxation training (Dozier, 2022), whereas others (e.g., sexual response or intestinal constriction) have made treatment difficult or impossible because these responses cannot be willfully controlled and they are very aversive. This may be an important variable to help understand differences in individual response to treatment. The method of determining the IPR is described by Dozier and Morrison (2017) and can be aided by the free Misophonia Reflex Finder app (https://apps.apple.com/us/app/misophonia-reflex-finder/id983574804).\n\nWe recommend independent research to validate the existence of the IPR of misophonia, which to date has only been identified by Dozier and his collogues. Dozier and Morrison (2017) report varied IPR sensations in a sample of 26 individuals. This study needs to be replicated and expanded. There are likely other ways to validate the existence of the IPR as a typical component of the misophonic response.\n\nResearch on the timing of the trigger stimulus, IPR, and emotional response could increase our understanding of the underlying reflex responses that cause the misophonic experience. A pilot study reports an interstimulus response (trigger to IPR) of 200ms for auditory triggers and 350ms for visual triggers (Dozier et al., 2020). Studies investigating the misophonia emotional response using fMRI have a sample time of 3 seconds, so we currently have no data on the relationship between the muscle response of the IPR and the misophonia emotional response.\n\nFinally, we recommend experimental evaluation of treatment protocols based on this model. The uniqueness and simplicity of the Mitchell-Dozier model can provide many opportunities for a wealth of research into the nature and features of misophonia.\n\n\nConclusion\n\nWe assert that the Mitchell-Dozier model provides a framework to understanding misophonia based on widely accepted neurological human learning processes.\n\nWhile the information presented herein is only preliminary supporting evidence for the Mitchell-Dozier model, we believe this model is fundamentally accurate, and provides a coherent, comprehensive theory of misophonia as a conditioned response disorder. Research to validate (or invalidate) the model may be critical to establishing a consensus view of misophonia, which would then facilitate incorporating misophonia into established nosological systems (DSM and/or ICD). Once validated, this model should be considered one possible definition of misophonia. Based on the Mitchell-Dozier model, misophonia is a conditioned aversive response disorder, and we propose that Conditioned Aversive Response Disorder (CARD) is a more appropriate name for this condition than misophonia.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nAcknowledgements\n\nWe express our appreciation to Bridget Andrews and Travis Armour for their assistance in editing the manuscript.\n\n\nReferences\n\nAazh H, Landgrebe M, Danesh AA, et al.: Cognitive behavioral therapy for alleviating the distress caused by tinnitus, hyperacusis and misophonia: Current perspectives. Psychol. Res. Behav. Manag. 2019; 12: 991–1002. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlekri J, Al Saif F: Suicidal misophonia: a case report. Psychiatr. Clin. Psychopharmacol. 2019; 29(2): 232–237. Publisher Full Text\n\nAltýnöz A, Unal N, Altýnöz S: The effectiveness of Cognitive Behavioral Psychotherapy in misophonia: A case report. Turkish J. Clin. Psychiatr. 2018; 21(4): 414–417. Publisher Full Text\n\nAmerican Psychiatric Association: Diagnostic and statistical manual of mental Disorders. 5th ed.2013. 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}
|
[
{
"id": "186207",
"date": "27 Jul 2023",
"name": "Jadon Webb",
"expertise": [
"Reviewer Expertise Misophonia",
"psychiatry",
"mental health",
"anxiety",
"PTSD"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis Method article addresses an important, unmet need in the emerging field of misophonia research, and the author should be commended for the hard work of advancing this nascent field.\nThe author specifically outlines a five-phase process to explain the development and maintenance of misophonia. This model is based on well-known neuroscience principles including conditioning towards an unpleasant stimulus, and the role of maladaptive psychosocial processes that may reinforce misophonia symptoms, in addition to increasing overall dysfunction.\nA number of researchers have speculated about the disease process that leads to misophonia, and it is clear that as of this writing, there is still no one consensus view for what causes this disorder. Perhaps this should not be surprising, since the understanding of other complex neuropsychological processes, such as depression or anxiety, are also still debated in the details.\nThe author specifically proposes in this five phase model the contribution of two elements that are unique and have not been tested or proposed by any other researchers, specifically, the initial physical reflex (IPR) and covert mental review. Of these, the IPR is perhaps the most unique.\n\nThe author states in the paper: “The IPR has not been acknowledged by misophonia researchers, and it is generally not acknowledged by individuals with misophonia. However, within our clinical setting we find that virtually all of our patients acknowledge the IPR after simple tests are conducted in a treatment session. The other unique phase of this model, covert mental review, is often acknowledged, but the importance of this feature of misophonia in reducing misophonia severity is not appreciated. We find that reducing covert mental review of triggers can reduce the dysfunction of misophonia. Therefore, the unique and critical features of this model have found much support within the clinical setting (Dozier, 2015a, 2015c, 2022); however, more robust research is required to confirm these findings on a larger scale.”\nFrom the above statement, the author acknowledges that the IPR is not recognized by other researchers and is typically not recognized by patients, at least outside of their own clinical setting. Similarly, covert mental review is not recognized by other groups as an obvious part of misophonia pathology.\nThe purpose of research and articles such as this, is to advance new hypotheses that may revolutionize our approach to diagnosis and treatment. However, until these proposed mechanisms are validated by empiric evidence, and replicated by outside researchers, caution must be exercised in how much confidence we can have in them.\n\nThe language style in this paper is enthusiastic, but also appears at times to sound almost insistent that this model is solid, while citing only evidence from within the author’s own lab. To the outside reader, this raises the obvious question of why elements such as the IPR have not gained more widespread recognition if there is obvious explanatory, diagnostic, or treatment utility to it.\nIt is certainly possible that the rest of the field simply has not caught up yet to this new truth. We know that this sometimes happens. However, it is incumbent on those developing the new model to take an appropriately tentative stance, and when possible, follow a classically scientific approach, which is to be the worst critic, and seek to falsify your own proposed hypothesis and show this work - not to try to convince the outside reader that the model is good.\nThis paper is well researched, the author is an expert that clearly understands misophonia as well as any other expert in the world, and this proposed model has a lot of potential. However, I suggest that the author attempt to change the language to be more classically scientific, taking a more critical look at this hypothesis, using more tentative language, and clearly highlighting the areas of uncertainty and weakness. And, proposing alternative explanations to this model that can be tested.\n\nFor example, as previously mentioned, perhaps the IPR is not always (or ever?) a causal agent in the chain of misophonia pathology. Perhaps it is an incidental observation, or a tangential symptom that can be observed, may sometimes be annoying or add in to the overall pathology, but does not necessarily *cause* the subsequent emotional response and reinforced learning.\nIt is one thing to note that misophonia patients often seem to have a muscle/somatic reflex to a trigger (which is a fantastic observation in its own right). It is another to propose that it is a necessary, causal step in the disease process. This is a huge claim, and there are no doubt many alternative hypotheses for if/how this reflex plays a role. Again, this need to be very clearly outlined so that the hypothesis can be rejected, and so that other labs could clearly understand how to test it.\n\nI suggest it should almost be written in a format that a graduate student trying to find a thesis project could use as their guiding document.\n\nOf note: it may also be of interest to speculate if the IPR is a unique signature for only misophonia, or if it may also be an undiscovered part of other disease processes, such as phobias or PTSD.\n\nIs the rationale for developing the new method (or application) clearly explained? Partly\n\nIs the description of the method technically sound? Partly\n\nAre sufficient details provided to allow replication of the method development and its use by others? Partly\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Partly",
"responses": [
{
"c_id": "10009",
"date": "09 Aug 2023",
"name": "Thomas Dozier",
"role": "Author Response",
"response": "We appreciate the comments of the reviewer and have attempted to address all recommendations. We acknowledge the enthusiastic language and have toned it down. Twelve statements that originally read as a 'fact' were change to read as a proposal or characteristic of the model. We added sections on alternate explanations and on implications of the IPR for other disorders. We acknowledge the comment to expand recommendations for research that would allow the model to be tested/rejected, but we have not identified such research methods. So, we added a paragraph on the issues that make research on the IPR difficult. In fact, for the past year we have looked for researchers that Misophonia Institute could fund for research on this model, but have yet to identify an institution interested in studying this model, even if funding is provided."
}
]
}
] | 1
|
https://f1000research.com/articles/12-808
|
https://f1000research.com/articles/12-87/v1
|
23 Jan 23
|
{
"type": "Research Article",
"title": "Brain-localized CD4 and CD8 T cells perform correlated random walks and not Levy walks",
"authors": [
"Dhruv Patel",
"Raymond Lin",
"Barun Majumder",
"Vitaly V. Ganusov",
"Dhruv Patel",
"Raymond Lin",
"Barun Majumder"
],
"abstract": "Background. For survival of the organism, T cells must efficiently control pathogens invading different peripheral tissues but whether such control (and lack of thereof) is achieved by utilizing different movement strategies remains poorly understood. Liver-localized CD8 T cells perform correlated random walks (CRWs)— a type of a Brownian walk – in liver sinusoids but in some conditions, these T cells may also perform Levy flights – rapid and large displacements by floating with the blood flow. CD8 T cells in lymph nodes or skin also undergo Brownian walks. A recent study suggested that brain-localized CD8 T cells, specific to Toxoplasma gondii, perform generalized Levy walks (LWs) – a walk type in which T cells alternate pausing and displacing long distances — which may indicate that brain is a unique organ where T cells exhibit movement strategies different from other tissues. Methods. We quantified movement patterns of brain-localized Plasmodium berghei-specific CD4 and CD8 T cells by using well-established statistical and computational methods. Results. We found that T cells change their movement pattern with time since infection and that CD4 T cells move faster and turn less than CD8 T cells. Importantly, both CD4 and CD8 T cells move in the brain by CRWs without long displacements challenging previous observations. We have also re-analyzed movement data of brain-localized CD8 T cells in T. gondii-infected mice from a previous study and found no evidence of LWs. We hypothesize that the previous conclusion of LWs of T. gondii-specific CD8 T cells in the brain was reached due to missing timeframes in the data that create an impression of large displacements between assumed-to-be sequential movements. Conclusion. Our results suggest that movement strategies of CD8 T cells are largely similar between LNs, liver, and the brain and consistent with CRWs and not LWs.",
"keywords": [
"T cells",
"movement strategies",
"Brownian walks",
"Levy walks",
"brain",
"mathematical model."
],
"content": "Introduction\n\nDifferent agents starting with large animals such as tigers and wolves and ending with individual cells such as T lymphocytes typically search for resources/targets. Theoretically, different search strategies may have different efficacies depending on the energy used for search, the number and distribution of targets in the environment, the effective dimension of the environment and other details.1 Finding that a particular type of agent, e.g., T cells, undergo a walk type that is highly efficient in some respects (e.g., in time to find a target) may indicate that such walk types may be evolutionarily selected.2 However, whether observed movement patterns are driven by agent-intrinsic programs or are the consequences of constraints in the environment has rarely been investigated.1,3–5\n\nDifferent search strategies can be roughly subdivided into two large classes: based on Brownian walks and on Levy walks (LWs).6 The key feature of Brownian walkers is that their displacements are short, consistent with a thin-tailed distribution that has a finite mean and variance.6 Pure Brownian walkers typically exhibit mean squared displacement (MSD) that changes linearly with time.6–8 In actual data, agents rarely show MSD to change linearly with time; it is more typical to observe super-diffusion at short time scales due to correlation between sequential speed vectors (so called correlated random walks, CRWs) and sub-diffusion at longer time scales due to environmental constraints.5,8–10 In contrast, Levy walkers typically perform both short and long displacements often consistent with a heavy-tailed distribution composed of a finite mean and infinite variance or both an infinite mean and infinite variance.6 Levy walkers exhibit super-diffusive behavior that is their MSD increases faster than being linear with time.6,8 Realistically, however, super-diffusion of Levy walkers may not be always observed over long periods of time due to environmental constraints and other experimental limitations. Both Brownian and Levy walk strategies may have multiple variations; for example, generalized LWs are a type of Levy walk in which there are both pauses and runs.2\n\nUnfortunately, there is no unique, well-established methodology that allows to fully characterize movement strategies of different agents. MSD is often used to determine if agents exhibit normal diffusion (Brownian) or super-diffusion (Levy); however, there are limitations of this method to infer movement types.2,8–15 An alternative method is to analyze the distribution of movement/displacement lengths and determine how quickly the tail of cumulative distribution declines with larger movement lengths.6,16 Finally, the distribution of turning angles made by the agents with every displacement can inform about specific movement strategies.7,17 Using these methods, many studies including those in immunology have reported movement patterns consistent with LWs.2,18–24 While it has been common to attribute specific movement patterns to agent-intrinsic programs, the relative contribution of internal and external processes in determining why agents move in a specific manner remains typically unknown. For example, we have recently shown that movement patterns of activated CD8 T cells in murine livers such as crawling or floating can be well explained by the physiological aspects of the liver blood vessels (sinusoids) and blood flow.5\n\nIntravital microscopy is typically used to record movement of various types of immune cells such as T cells or neutrophils in vivo.25 In such imaging experiments, cells to be imaged must express fluorescent markers (e.g., green fluorescent protein (GFP)). A small area of the tissue is then scanned by a microscope; a volume of 500×500×50 μm is typically scanned every 30 sec. The generated movies are then processed (segmented) by specialized software to determine individual cells and their positions over time. While the movies are typically very impressive at the details of how immune cells behave in tissues in vivo, the resulting coordinate data have many limitations. In particular, 1) cell positions are recorded only at specific time points while cell movements are often continuous; 2) cells may come into or leave the imaging volume over time reducing the amount of data available for each cell; 3) segmentation programs may allow the cells temporarily to leave imaging volume and introduce missing time frames into the data for individual cell trajectories; 4) while cells are typically moving, 3D imaging sometimes only records cell positions in 2D that may bias the interpretation. Exposing tissues to the laser may also impact tissue physiology which in turn may introduce artifacts into the cell position data.\n\nOne influential study suggested that brain-localized activated CD8 T cells, specific to Toxoplasma gondii, perform generalized LWs allowing these T cells to efficiently locate and eliminate T. gondii-infected cells.2 This movement pattern was different from movements T cells exhibit in other tissues such as lymph nodes or the liver, suggesting that brain may be a special organ allowing for a unique movement strategy.5,26 In this paper, we processed recently generated imaging data on brain-localized CD4 and CD8 T cells, specific to Plasmodium berghei,27 and characterized movement patterns of these cells using several alternative methodologies. Interestingly, we found that these T cells undergo CRWs that are characterized by a relatively short persistence time (∼ 5 min) and high speeds (7-10 um/min) that are similar to activated T cells localized to the liver. Importantly, brain-localized T cells undergo relatively small displacements that are fully consistent with Brownian walks and are not consistent with generalized LWs. We also analyzed the coordinate data of T. gondii-specific T cells from Harris et al.2 and found that the data contained missing timeframes for several cells that unless accounted for creates an impression of rare long displacements. After cleaning the data, main characteristics of the movement of T. gondii- and P. berghei-specific CD8 T cells such as MSD plots and displacement distribution were nearly identical. Our results thus suggest that movement patterns of activated CD8 T cells in the brain are similar to that of the liver and are consistent with correlated (Brownian-like) random walks.\n\n\nMethods\n\nMovement data. There are several different datasets used in our analyses. We obtained movies of previously published movements of CD4 and CD8 T cells, specific to Plasmodium berghei, in the brains of Plasmodium-infected mice,27 which were then segmented using Imaris (RRID:SCR_007370) (Bitplane). We also re-analyzed previously published data,2 provided by Dr. Chris Hunter to Dr. Vitaly V. Ganusov. This dataset focuses on the movement of activated CD8 T cells, specific to Toxoplasma gondii, in the brains of T. gondii-infected mice.\n\nImaging Plasmodium-specific CD4 and CD8 T cells in the brain. Imaging was performed in a previous study.27 Female C57BL/6 (B6) and the transgenic strains PbT-I and PbT-II mice along with the rodent malaria line Plasmodium berghei ANKA (PbA) clone 15cy1 were used in this study. The mice were injected intravenously (i.v.) with purified naive PbT-I (CD8) and PbT-II (CD4) T cells (5 × 104) in 0.2 ml PBS. One day later, the mice were infected i.v. with 104 PbA infected red blood cells (iRBCs). For the data used in this experiment, the brains were imaged 6.5 or 7 days post-infection (Figure 1A).\n\nA: 5×104 CD8+ (PbT-I) and CD4+ (PbT-II) T cells were injected i.v. into female B6 mice. 24 hours later, the mice were infected i.v. with 104 Plasmodium berghei ANKA (PbA)-infected red blood cells (iRBCs). 6.5 or 7 days post-infection, brains of infected mice were surgically exposed and imaged using two photon microscope at approximately 30 second intervals. Five movies were then processed in Imaris to trace coordinates of CD4 and CD8 T cells. Any tracks that contained gaps in time were split. B: To characterize cell movement, we calculated the mean square displacement (MSD, B(i)) and the movement length distribution (B(ii)); estimated parameters γ and μ allowed to determine if the cells exhibit Brownian (B(iii)) or Levy (B(iv)) walks.\n\nProcessing movies from PbA-infected mice with Imaris. We analyzed a total of five movies from Ghazanfari et al.27 experiments (Figure 1A). Within each movie there were multiple channels; however, only the channels containing signal of the CD8 T cells (PbT-I) and CD4 T cells (PbT-II) were relevant to our analysis, and these were the channels we used for the analysis. We used function “Spots” in Imaris (https://imaris.oxinst.com/) to identify and track individual T cells. Depending on the cell parameters chosen in Imaris, it is typical for Imaris’ basic algorithm to identify many more objects that there may be in reality. Every movie was manually inspected and objects that would not likely correspond to T cells were removed. We also removed objects that may result in biased interpretation including i) T cells being close to the imaging border, ii) cells sliced in half, or iii) immobile cells. By visually inspecting each movie and each track, we manually joined tracks of cells that were incorrectly split into independent tracks by Imaris. We also manually traced T cells that were clearly visible but missed by the standard algorithm of Imaris. Additional details of data segmentation are shown in Supplemental Information.\n\nCleaning cell position data. When tracking cells, default settings of Imaris allow several positions of a cell to be missing and still be considered as a single track. Unless correct, such segmentation results in missing timeframes in the cell coordinate data that may result in misspecification of cell movement types. All of our datasets contained cell trajectories with missing time frames. Following our previously outlined methodology, we “cleaned” the cell position data as follows (Figure 1A and Ref. 5):\n\n1. Checked for duplicates in the data and assign unique track IDs to each of them. We used trailing letters in this case.\n\n2. For any time gap between tracks of the same track ID that is greater than the imaging frequency plus a certain offset (1 second in our case), the track for that track ID should be split into two tracks with unique track IDs at that point. This is iterated until there are no time gaps larger than the imaging frequency plus the offset between tracks of the same track ID.\n\n3. All tracks are then shifted to begin at t=0 sec.\n\nWe initially had the data for 264 PbA-specific CD4 T cells; we generated 149 new (split) trajectories resulting in 413 T cells. After removing trajectories with only a single position, we were left with data for 355 tracks with 5247 positions. Similarly, for a total of 589 PbA-specific CD8 T cells, we generated 458 new trajectories resulting in 1047 T cells. After removing trajectories with only a single position, we were left with data for 873 tracks with total 10563 positions.\n\nTime standardization. Intravital imaging movies were generated with slightly different imaging frequencies: 30 sec, 30.68 sec, and 32.76 sec. To combine all track data into one dataset, we assumed that all movements were done in 30 sec time intervals.\n\nPublished dataset on movement of Toxoplasma gondii-specific CD8 T cells in the brain. We obtained the data from Harris et al.2 on movement of brain-localized CD8 T cells, specific to T. gondii. The data consisted of two separate datasets with different imaging frequencies (19.25 sec and 22 sec). To increase the power of analysis, we merged the datasets into one with the assumed imaging frequency of 20 sec. These data also had many cell trajectories that had missing timeframes that were split to ensure consistent time intervals between sequential cell movements. We initially had the data for 657 CD8 T cells; we generated 217 new cells resulting in a total of 874 T cell trajectories. After removing tracks with only a single position, we were left with data for 812 T cells with 18848 positions.\n\nTo characterize movement type of T cells, we followed a methodology outlined in our previous publication.5\n\nArrest coefficient and meandering index. We calculated the arrest coefficient which is the percent of the time each T cell was arrested (instantaneous speed < 2 μm/min).28 We also computed the meandering index which is the straightness of each T cell trajectory defined as the ratio between the overall displacement and the total distance traveled.29\n\nMean square displacement. We calculated the mean square displacement (MSD). While MSD can be calculated for individual cells or for the whole population (e.g., Ref. 30), here we used all tracks in a given dataset where imaging frequency was either the same or standardized to calculate the MSD using the formula\n\nBasic distributions to characterize cell movements. To characterize the type of walks performed by agents, a number of different distributions have been used. Our recent work suggested that the generalized Pareto distribution (GP) fits to movement length distribution of liver-localized CD8 T cells with the best quality.5 An interesting property of the GP distribution is that it can describe both Brownian and LWs and can be fitted to the whole dataset on movement length distribution.5 The GP distribution is defined as\n\nFitting GP distribution to data. We fit the models (equation (2)) to distribution of movement lengths r of cells calculated as the distance traveled by each cell between two sequential time points. To make sure that these displacements are calculated for the same time intervals, data were cleaned by splitting the trajectories (see above). The likelihood of the model parameters given the data is given as\n\nTail analysis of movement length distribution. In addition to fitting the GP distribution to the whole dataset of cell movement lengths, we used a previously suggested tail analysis [16, Figure 1B(ii)]. To fit the Pareto distribution to the subset of the data, it is critical to define which movement lengths will remain the data and which will be ignored, i.e., to define rmin in the Pareto distribution (equation (3)). The methodology of rigorous approach to define rmin has been outlined previously16 and implemented in the python package powerlaw31 that we used. The package takes an input of movement lengths and outputs the estimate of rmin and shape parameters μ. In some cases, parameter rmin could be defined by the user and not estimated from the data. This package uses the likelihood approach (equation (4)) to fit the Pareto distribution to the movement lengths data for different values of rmin and compares the quality of the model fit to data using a statistical test (e.g., Kolmogorov-Smirnov test).16\n\nComparing the data. Unless otherwise noted, we used Mann-Whitney tests to compare average/median values for two samples, e.g., difference between average meandering index for CD4 versus CD8 T cells.\n\nWe provide several python codes with the publication. First, we provide the code that cleans cell trajectories; that is trajectories that have missing time frames are split to generate a new track. Second, we provide the code to calculate MSD and step/movement length distribution, and perform regression analysis on MSD data and tail analysis of movement length distribution. Third and finally, we provide a code to simulate movement of agents according to Brownian walk, Levy walk, or generalized Levy walk. The codes are available here: https://github.com/DhruvPatel5701/TcellsInBrain.\n\nTo investigate whether the previously proposed methodology of determining the type of cell walk by fitting GP distribution to all movement length data or by fitting the Pareto distribution to the subset (tail) of the data is appropriate, we simulated cell movements as Brownian or Levy walkers where the parameters of cell movement are known.5,16,31 To simulate movement of Brownian or Levy walkers, we generated random numbers of cell movement lengths from a Pareto distribution (equation (3)) with parameter μ for every time step. In the case of Brownian walkers, we chose μ>3 and in the case of Levy walkers μ<3; specific value of the shape parameter μ was varied in different simulations, and we used a default value for rmin=1. We simulated movements in 3D by using von Mises-Fischer (vMF) distribution to generate random 3D vectors with the concentration parameter κ=0.01 ensuring no preferred direction for cell movement.17,32 To simulate T cell movement as generalized Levy walkers, we used the methodology outlined previously.2 Specifically, we created two Pareto distributions (equation (3)) with two shape parameters: μrun<3 and μpause<3. Since generalized Levy walkers can pause after each run, we incorporated a pause after each displacement. A pause time would be selected from the μpause of the Pareto distribution and pause time was a discrete number of time steps used in simulations. After the pause time elapses, the cell performs a movement. If the cell was to move rather than pause, a displacement length would be selected from the μrun Pareto distribution, and the cell would then proceed to pause again. The direction of displacement is selected from a vMF distribution with κ=0.01. All simulations were done in python. Random numbers of the Pareto distributions were generated using the python package SciPy.\n\n\nResults\n\nExperimental design and modeling analyses to rigorously characterize movement pattern of brain-localized T cells. T cells are typically activated in secondary lymphoid organs, and following activation and differentiation, migrate to peripheral tissues to control infections. Whether T cells utilize specific, evolutionary-selected strategies to locate and eliminate infections in peripheral tissues remains debated. Brain is an immunopriviledged site, and movement strategies of brain-localized T cells may be unique.2 Ghazanfari et al.27 developed novel TCR transgenic mice with T cells recognizing antigens of PbA on MHC-I and MHC-II molecules, allowing to track PbA-specific CD8 and CD4 T cell response with intravital imaging (Figure 1). In these experiments, mice received fluorescently labeled naive PbA-specific T cells, PbA-infected RBCs, and the movement of the labeled T cells in murine brains was followed with intravital microscopy. We then processed the imaging data with Imaris and cleaned the resulting cell trajectory data to avoid instances where cell positions were not clearly defined (Figure 1A and see Methods for more detail). In total, data from five movies were analyzed: three movies for 6.5 days post-infection and two movies for 7 days post-infection. We then applied a number of statistical methods to rigorously characterize movement pattern of T cells and whether these movements are consistent with Brownian walks or LWs (Figure 1B).\n\nFrom our imaging analyses, we found that in the imaging area of 512×512×44 μm there were more PbA-specific CD8 T cells than CD4 T cells, and while the number of CD4 T cells slightly declined with time (84 versus 81 cells/movie for 6.5 versus 7 days post-infection), the number of CD8 T cells increased with time since infection (145 versus 305 cells/movie, Figure 2A and Supplemental Movie S1); both changes, however, were not statistically significant due to a small number of movies analyzed. The constancy/decrease in CD4 T cell numbers is not fully consistent with flow cytometry data on kinetics of brain-localized endogenous T cell response to PbA.27 Given the number of cells observed in these imaging experiments, we next calculated the potential number of brain-localized T cells after PbA infection. The total volume imaged in these experiments was 512×512×44 μm3=0.0115 mm3, and given the volume of the brain of B6 mice is 509 mm3,33 the scaling factor to calculate the total number of cells per brain given the number of cells in the imaging area is 509/0.0115=4.42×104. This translates to 3.71×106 and 3.55×106 PbA-specific CD4 T cells at 6.5 and 7 days post-infection, and 6.38×106 and 1.35×107 PbA-specific CD8 T cells at 6.5 and 7 days post-infection. Interestingly, 100-fold lower numbers were calculated for brain-localized T cells obtained using flow cytometry.27\n\nA: Following experimental design (Figure 1), we segmented three movies for 6.5 days and two movies for 7 days since PbA infection and calculated positions of brain-localized CD4 and CD8 T cells (A). Tracking of T cells was done using Imaris (see Methods for more detail). In total, we analyzed tracks for n=252 CD4 and n=434 CD8 T cells at 6.5 days post-infection, and for n=161 CD4 and n=613 CD8 T cells at 7 days post-infection. B: meandering index for all CD4 and CD8 T cells. C: arrest coefficient for all CD4 and CD8 T cells. Examples of the movies are shown in Supplemental Movie S1. Statistical comparison in panels B-C was done using Mann-Whitney test with p-values from the test indicated on individual panels.\n\nIn addition to the difference in the number between CD4 and CD8 T cells, we found that their overall movement patterns were also slightly different: CD4 T cells have lower meandering index than CD8 T cells indicating less straight paths between sequential time frames (0.598 versus 0.649, p= 0.003); CD4 T cells also spend less time pausing (speeds<2 μm/min) with a slightly lower arrest coefficient (0.169 versus 0.193, p=0.01, Figure 2B-C).\n\nCD4 and CD8 T cells in the brain undergo correlated random walks (CRWs). A previous pioneering study proposed that brain-localized CD8 T cells perform generalized LWs characterized by rare but long displacements [Ref. 2, Figure 1B(iv)]. Visual inspection of the five movies did not reveal any long displacements by T cells; however, there were some visible cell-like objects moving rapidly with the blood flow similar to what we have observed for liver-localized CD8 T cells.5 We therefore performed rigorous analyses of the cell trajectory data by pooling data from different experiments together. An important step in the analysis was our recent recognition of missing timeframes in cell position data generated by Imaris and providing methodology to “clean” such data (see Methods for more detail).5\n\nWe first calculated the MSD for brain-localized Plasmodium-specific CD4 and CD8 T cell trajectories (equation (1)). Both cell populations displayed super-diffusive MSD that increased faster than linearly with time (slopes γ=1.59 and γ=1.39, for CD4 and CD8 T cells, respectively, Figure 3A). The super-diffusion was transient for about 5–7 min as MSD saturated at longer times as expected. Interestingly, fitting Furth equation to the MSD plots suggested much shorter persistence time of T cells of 1 min, [Ref. 34 results not shown]. While super-diffusion is the main feature of Levy walkers,8 some types of Brownian walks, such CRWs can also display super-diffusion.11\n\nWe calculated basic movement characteristics for CD4 and CD8 T cells in brains of PbA-infected cells (Figure 1) such as mean squared displacement (MSD, A), movement length distribution (B), instantaneous speeds (C) and turning angles (D), and average speed (E) and turning angle (F) for each track. The slope of the linear regression for the log (MSD) with respect to log(t) for first several minutes is denoted by γ. Estimated parameters of the Pareto distribution (equation (3)) fitted to the tails of the step length distribution are denoted as μ and rmin (see Methods for details). Difference in averages/medians was calculated using Mann-Whitney tests with associated p-values from the test indicated on individual panels (C-F). All panels indicate the number of measurements/data points n used in analysis and the average values for the parameters. Note that all calculations were performed on cleaned T cell tracks in which tracks with missing time frames were split into separate tracks (Figure 1A and see Methods for more detail).\n\nWe then analyzed the cumulative distribution of movement lengths which was similar for CD4 and CD8 T cells; interestingly, there were no very long displacements in these data (Figure 3B). By using an established “tail” analysis that fits the Pareto distribution to the tail of the cumulative movement length distribution (i.e., to a subset of data with longest movements), we found shape parameters for CD4 T cells (μ=6.66) and CD8 T cells (μ=9.85) to be consistent with Brownian (μ>3) and not Levy (μ<3) walks (Figure 3B). To ensure that data sub-selection in the tail analysis did not bias the results, we fitted the GP distribution (equation (2)) to all data using a likelihood approach (equation (4)); we have previously found that GP distribution provides the best fit of the movement lengths data for liver-localized CD8 T cells.5 Importantly, GP distribution fitted the data well and predicted a finite mean and variance for data for both T cell populations (Supplemental Table S1). A finite mean and variance are features of Brownian movement and not of Levy walkers.6\n\nWe finally investigated if other cell movement characteristics may be inconsistent with CRWs. Distribution of instantaneous speeds suggested that no cell had extraordinary speeds with maximum not exceeding 40 μm/min (Figure 3C). Turning angle distribution for both cell types was biased towards acute angles, which is a key feature of CRWs (Figure 3D). On average, CD4 T cells had higher instantaneous speeds than CD8 T cells (v¯=8.31 μm/min versus v¯=5.86 μm/min, Figure 3C) and smaller turning angles (θ¯=66.7° versus θ¯ = 72.2°, Figure 3D). There were more CD4 T cells displaying high speeds (>20 μm/min) than CD8 T cells (Figure 3E), and CD4 T cells exhibited lower average turning angles (and thus higher persistence in movement in one direction) as compared to CD8 T cells (θ¯=62.7° versus θ¯=67.9°, Figure 3F). Taken together, our analyses suggest that Plasmodium-specific, brain-localized CD4 and CD8 T cells performed CRWs with relatively high speeds and low turning angles and displayed transient superdiffusive displacement.\n\nT cells show increased speeds and turning as time after infection increases. For our first set of analyses, we pooled the trajectory data from imaging performed at 6.5 or 7 days after infection. We next sought to determine if movement patterns were different between the two times since infection. Importantly, regardless of the time after infection, all cell populations exhibited features of CRWs with transient super-diffusion (γ>1 in Supplemental Figure S1A and Supplemental Figure S2A) and relatively short movement lengths (μ>3 in Supplemental Figure S1B and Supplemental Figure S2B). Additionally, best fits of the GP distribution predicted a finite mean and variance further supporting that these cells exhibited Brownian-like walks.6\n\nTime since infection had a different impact on other movement characteristics of T cells. CD4 T cells increased their instantaneous speeds and turning angles between 6.5 and 7 days post-infection (v¯=7.92 μm/min versus v¯=9.49 μm/min and θ¯=65.7° versus θ¯=69.8°, respectively, Supplemental Figure S1C-D). Interestingly, however, the average speed or average turning angle per cell did not significantly change between 6.5 to 7 days post-infection (Supplemental Figure S1E-F). In contrast, CD8 T cells increased their instantaneous and average per cell speeds between 6.5 and 7 days post-infection (v¯=5.67 μm/min versus v¯=6.03 μm/min and v¯=6.29 μm/min versus v¯=7.04 μm/min, Supplemental Figure S2C&E) and the instantaneous and average (per cell) turning angles also increased with time since infection (θ¯=68° versus θ¯=76.2° and θ¯=64° versus θ¯=70.9°, Supplemental Figure S2D&F). The overall (although inconsistent) increase in speed and turning angle of both CD4 and CD8 T cells with time since infection may be related to the need for T cells increased efficiency of search for pathogen at later times after infection.35–37\n\nUncleaned trajectory data may result in misspecification of the walk type. In our analyses, we found that brain-localized CD4 and CD8 T cells perform Brownian-type (correlated random) walks which contradict a previous result suggesting that movement patterns of CD8 T cells in the brain are consistent with generalized LWs.2 We obtained the coordinate data of brain-localized CD8 T cells from Harris et al.2 and carefully inspected these data. We found that there were several technical issues with the data. First, the data had many missing timeframes (ngaps=217, Supplemental Figure S3A) which, if not cleaned, can produce long displacements between two-assumed-to-be-sequential timeframes. Several of these gaps are substantial (6 and 16 time-steps, Supplemental Figure S3A). Second, the data contained a duplicate name tag for a track that eventually diverged. This resulted in an extremely long displacement (80.4 μm, Supplemental Figure S3B) in the span of one timeframe (22 seconds). We performed tail analysis on the movement length distribution data and found that the best fit is found with the shape parameter μ=3.17 which is consistent with Brownian walks and not LWs (Supplemental Figure S3C). However, by varying the scale parameter rmin, we did find instances with shape parameter μ<3 suggesting that these data may be consistent with LWs (Supplemental Figure S3C). However, after cleaning the trajectory data (by splitting trajectories that have missing time frames), tail analysis resulted in highly consistent estimates of the shape parameter μ>3 for all reasonable values of rmin>5 μm consistent with Brownian walks (Supplemental Figure S3D).\n\nPlasmodium- and Toxoplasma-specific, brain-localized CD8 T cells behave similarly. To more rigorously characterize movement pattern of Toxoplasma-specific, brain-localized CD8 T cells from Harris et al.2 study, we performed the same analyses as we did for Plasmodium-specific T cells. Similar to Plasmodium-specific CD8 T cells, the Toxoplasma-specific CD8 T cells also displayed super-diffusive displacement (γ=1.54, Figure 4A), with rapidly declining distribution of movement lengths (μ=5.34, Figure 4B). Fits of the GP distribution to the movement length distribution data also predicted finite mean and variance (Supplemental Table S1). Despite targeting different parasites, other movement parameters were quite similar between Toxoplasma- and Plasmodium-specific CD8 T cells including similar instantaneous and average (per cell) speeds and turning angles (Figure 4C-F). Taken together, our analysis suggests that movement patterns of brain-localized CD8 T cells are similar between two infections and two independent studies, and are consistent with Brownian rather than LWs.\n\nWe calculated the same characteristics as in Figure 3 for Toxoplasma gondii-specific CD8 T cells from the previous publication2 after cleaning and renaming the cell tracks (see Methods for more detail). For comparison, the estimated characteristics for PbA-specific CD8 T cells from Figure 3 are plotted on the same graph to illustrate similarities in movement characteristics.\n\nOur methods of determining walk type are robust. While we have used previously proposed methods to determine the type of cell walk,16,38 there may be a possibility that these methods may fail for our trajectory data. Therefore, to check validity of these methods, we simulated cell movements as Levy walkers, generalized Levy walkers, and bullet motion walkers and fitted the GP distribution to these data (see Methods for details on simulations). In cases of Levy walkers, we found that variance of the best fit GP distribution is infinite, which is consistent with LWs.6 However, in all cases, when simulated movements were non-Brownian, we found that GP fits indicated infinite variance (and sometimes mean) suggesting that this approach allows to detect deviations from Brownian walks. Additionally, we also determined the walk type by fitting the Pareto distribution to the tail of the movement length data for simulated generalized Levy walkers when using a large range of possible parameters. We found that the tail analysis accurately determined the shape parameter μ (Supplemental Figure S4). We only found few exceptions when we used μ≈3 but found μ>3 in the fits which we believe is likely due to a combination of chance and package sensitivity.\n\n\nDiscussion\n\nOne could expect that T cells should utilize different movement strategies when responding to diverse pathogens and migrating to different lymphoid or non-lymphoid (peripheral) tissues. Brain is an important immunopriviledged site, and one recent study suggested that brain-localized CD8 T cells search for infection using generalized LWs that may increase the search efficiency, thus, may potentially minimize bystander damage to the delicate brain tissue.2 Here we rigorously analyzed data from novel experiments imaging movement of Plasmodium-specific CD4 and CD8 T cells in brains of PbA-infected mice (Figure 1). By using alternative complementary tools we found that brain-localized T cells display transient superdiffusive displacement, which is achieved by making small movements in the same direction (i.e., small turning angles) — both are cardinal features of Brownian-like (correlated random) walks (Figure 2).\n\nWhile the overall pattern of T cell movements was consistent with CRWs, there were differences between CD4 and CD8 T cells in details of the movement and how the movement was impacted by the time since infection. In particular, CD4 T cells moved faster and turned less than CD8 T cells (Figure 3). T cells also had higher speeds and higher turning angles between day 6.5 and 7 days post-infection even though specific details slightly varied whether we compared instantaneous or per cell average speeds and turning angles (Supplemental Figures S1 and S2). Increasing speeds and turning may allow for a more thorough search of the infection but also could be a stress response. Imaging did allow to detect some parasites in brains of PbA-infected mice27 suggesting that the parasites are likely to be present in the brain blood vessels and thus may result in mechanical obstruction of the vessels as observed in human cerebral malaria.35–37 Obstruction of brain blood vessels can lead to hypoxia,35 which may have caused the T cells to enter a “panic mode” later in infection. This would explain the increase in speed and turning angle with respect to time after infection in same cell types.\n\nBy using these imaging data, we predicted that brains of PbA-infected mice should contain 3−10 × 106 CD4 or CD8 T cells. However, flow cytometry-based measurements suggest only the presence of 0.1−5 × 104 T cells at these early (6.5 days) times since infection.27 Calculating the number of T cells in the whole brain from imaging only 0.002% of its total volume may be problematic as T cells tend to leave and enter the imaging area. Using the number of T cells identified per only one time frame did not dramatically change the estimate of the total number of cells in the brain (results not shown). These results are consistent with a previous observation of gross under-estimation of the number of T cells isolated from many nonlymphoid tissues for flow cytometry-based analyses.39 Because extraction of lymphocytes from nonlymphoid tissues may generate biases (e.g., non-specific enrichment for some cell subtypes39) caution needs to be taken when interpreting differences in numbers and phenotypes of brain-localized T cells from flow cytometry analyses.\n\nOur results that brain-localized, PbA-specific T cells perform CRWs are in contrast with results of another study suggesting that brain localized, Toxoplasma-specific CD8 T cells perform generalized LWs.2 When we cleaned and reanalyzed the data by Harris et al.2 we found that movement patterns of PbA- and Toxoplasma-specific CD8 T cells are very similar, both displaying transient super-diffusion and short movement lengths (Figure 4). We believe that the difference arose in part because of how the original position data were analyzed – we found that missing timeframes for some cell trajectories created unreasonably long movements that provided some support for LWs (Supplemental Figure S3); when we split these movements into new tracks, we found no long movements, and this ultimately allowed us to classify movement of Toxoplasma-specific CD8 T cells as Brownian-like walkers. Another limitation of the Harris et al.2 study was relatively poor description of how the models were fitted to movement length data and how the quality of the model fits was evaluated.\n\nOur finding that brain-localized T cells undergo correlated random walks is consistent with finding of a similar movement program of activated CD8 T cells in the liver or skin and naive/resting CD8 T cells in lymph nodes.5,26,40 CD8 T cell movements in other non-lymphoid tissues such as the lung have not been tested if they are consistent with BWs or LWs.41 Given the ability of T cells in tissues to do a persistent walk in a given direction (cell “inertia”17) and inability of T cells to make very long displacements in constrained tissue environments, it is likely that Brownian-like, correlated random walks are the rule for T cell movements in tissues rather than exception. Yet, specific details of these Brownian-like, persistent movements may vary significantly between different tissues including differences in instantaneous and average (per cell) speeds and turning angles. These details may dramatically impact the overall efficiency at which T cells survey the organ, and could be a result of specific sub-populations of T cells entering different tissues or could simply be due to different physiological constraints imposed by the environment. For example, CD8 T cells in the skin have much lower average speeds than CD8 T cells in the liver (3−4 μm/min versus 5−15 μm/min,5,40,42) although as far as we know, none of the previous studies have imaged T cells in multiple tissues in the same animal. Other factors such as the degree of inflammation in the tissue and imaging frequency may also influence inferred parameters such as speeds and turning angles.17,32\n\nSeveral recent studies have suggested there may be a cell-intrinsic program that links the ability of cells to move and to turn so that cells with higher speeds turn less.14,43 We found that indeed, T cells that have higher speeds tend to have lower turning angles (so they turn less); for example, PbA-specific CD4 T cells have higher average speeds and lower average turning angles than PbA-specific CD8 T cells (Figure 2). Furthermore, we found a strong negative correlation between average speed and average turning angle per cell for the whole population of CD4 or CD8 T cells (results not shown). We have recently shown that a negative correlation between average speed and average turning angle may simply arise as a sampling artifact.17 Indeed, we found that between 6.5 and 7 days post PbA infection, both speeds and turning angles of T cells increase, challenging the idea that the correlation between speed and turning is cell-intrinsic (Supplemental Figure S2).\n\nOur study has several limitations. Intravital imaging involved only a small cross-section of the brain, which limited the sample size and created a bias of generating longer trajectories for slower and more centrally located cells. Our analysis also assumed homogeneity among cells in a population as for most of our analyses, we pooled the data from individual movies to increase the statistical power. It may be possible that there are subpopulations of cells that exhibit different movement patterns. Given that in intravital imaging experiments it is typically hard to follow individual T cells for longer than 15-20 time frames, characterizing heterogeneity of movement of individual cells in vivo remains difficult (but see Ref. 14). Missing time frames for some cell trajectories necessitate to “clean” such data (split the tracks) further reducing the amount of data available to rigorously quantify heterogeneity in T cell movement behavior in vivo. We found that different metrics used to evaluate how persistent T cells are in their movement may give different answers. For example, CD4 T cells had lower turning angles than CD8 T cells and yet CD8 T cells had larger meandering index – lower turning angles and larger meandering index suggest straighter trajectories (Figure 2B and Figure 3F). There is a need for rigorous studies that compare these and other metrics such as persistence time to better understand conditions under which these metrics truly characterize the ability of T cells to exhibit persistent movement. We only had access to five movies to analyze, and it is possible that collecting more data may reveal deviations of T cell movement patterns from Brownian-like walks. However, it remains hard to justify long displacements of T cells found in some studies (e.g., Ref. 2) given the physiological constraints imposed by tissues on moving T cells. One exception to this rule are cells located in vasculature that allows such cells to float with the blood flow exhibiting Levy flights.5 Physiological relevance of these floating events to the search efficiency remains to be established, however. While imaging frequency used in the study by Ghazanfari et al.27 (30 sec) was sufficient to accurately detect movement of brain-localized T cells, it was clearly insufficient to better understand movement patterns of T cells in the vasculature, and as these cells move from the blood vessels into the parenchymal tissues. Using a higher frequency imaging may be needed to quantify movement patterns of T cells, located in the blood vessels of the brain.42 Finally, we did not have access to the original imaging data from Harris et al.2 study, and therefore, in our analysis we only relied on the coordinate data for wild-type CD8 T cells provided by Harris et al.2 and cannot comment on validity of the data except some technical issues such as missing timeframes for some cell trajectories.\n\nOur results raise questions for future research. There is a need for sanity checks of the coordinate data generated from intravital imaging experiments; in particular, whether such data have missing time frames and thus may require cleaning. We have provided a python-based script for cleaning trajectory data. It may be interesting to extend our calculations of the total number of T cells found from intravital imaging experiments and using more traditional approaches, e.g., flow cytometry, to other tissues and infections. It is possible that many more T cells localize to the peripheral sites that sometimes is assumed and this is likely to provide better estimate of the overall magnitude and kinetics of T cell responses to pathogens.39 Whether there are true differences in the movement patterns (e.g., speeds, turning angles) between CD4 and CD8 T cells in other infections and tissues may need to be explored. While we know that T cell populations are heterogeneous, we need better tools to track individual T cells from longer periods of time so we can rigorously evaluate the degree of kinetic heterogeneity of these cells in different settings. While we have shown that GP distribution can well describe movement length data of T cells in the liver and the brain, we need to test if the same model fits the data best in other cases. Furthermore, we need additional parametric distributions to describe other features of T cell movements, e.g., turning angles. Using vMF distribution may be particularly useful for that purpose.17,32 We expect that environmental constraints should influence movement patterns of T cells5; thus, there is a need to visualize and quantify these constraints. Finally, basic motility parameters for T cells in various tissues should be used in mathematical models to predict the optimal numbers of T cells needed to prevent or control infections. This would require a close collaboration between experimentalists and modellers and such collaborations should be explicitly supported by funding agencies.",
"appendix": "Data availability\n\nGithub: Brain-localized CD4 and CD8 T cells perform correlated random walks and not Levy walks: https://github.com/DhruvPatel5701/TcellsInBrain. 44\n\nThe project contains the following underlying data:\n\n- HeathLabData.xlsx (the file contains two spreadsheets with coordinates for CD4 or CD8 T cells in brains of Plasmoidum berghei-infected mice; imaging data are from Ghazanfari et al. 27 paper).\n\nGithub: Brain-localized CD4 and CD8 T cells perform correlated random walks and not Levy walks: https://github.com/DhruvPatel5701/TcellsInBrain. 44\n\nThe project contains the following underlying data:\n\n- Supplement.pdf (Supplementary information including supplemeary figures 1-4 and table 1.)\n\n- Tcells-in-brain-2clips.mp4\n\nData are available under the terms of the MIT license. The data on movement of brain-localized Toxoplasma gondii-specific CD8 T cells are available upon request from Dr. Chris Hunter (chunter@vet.upenn.edu).\n\n\nReferences\n\nReynolds A: Liberating Lévy walk research from the shackles of optimal foraging. Phys Life Rev. 2015; 14: 59–83. PubMed Abstract | Publisher Full Text\n\nHarris TH, Banigan EJ, Christian DA, et al.: Generalized Lévy walks and the role of chemokines in migration of effector CD8+ T cells. Nature. 2012; 486(7404): 545–548. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVolpe G, Volpe G: The topography of the environment alters the optimal search strategy for active particles. Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 11350–11355. PubMed Abstract | Publisher Full Text | Free Full Text\n\nReynolds AM: Current status and future directions of Lévy walk research. Biol. Open. 2018; 7. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nZenkov VS, O’Connor J, Cockburn IA, et al.: A new method based on the von Mises-Fisher distribution shows that a minority of liver-localized CD8 T cells display hard-to-detect attraction to Plasmodium-infected hepatocytes. Front. Bioinform. 2022; 1: 1–15. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBadea A, Ali-Sharief AA, Johnson GA: Morphometric analysis of the c57bl/6j mouse brain. NeuroImage. 2007; 37: 683–693. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStokes CL, Lauffenburger DA, Williams SK: Migration of individual microvessel endothelial cells: stochastic model and parameter measurement.99(Pt 2): 419–430.\n\nMacPherson GG, Warrell MJ, White NJ, et al.: Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am. J. Pathol. 1985; 119(3): 385–401. PubMed Abstract\n\nSchofield L, Grau GE: Immunological processes in malaria pathogenesis. Nat. Rev. Immunol. 2005; 5(9): 722–735. Publisher Full Text\n\nvan der Heyde HC , Nolan J, Combes V, et al.: A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction. Trends Parasitol. 2006; 22(11): 503–508. PubMed Abstract | Publisher Full Text\n\nEdwards AM, Phillips RA, Watkins NW, et al.: Revisiting Lévy flight search patterns of wandering albatrosses, bumblebees and deer. Nature. 2007; 449(7165): 1044–1048. PubMed Abstract | Publisher Full Text\n\nSteinert EM, Schenkel JM, Fraser KA, et al.: Quantifying Memory CD8 T Cells Reveals Regionalization of Immunosurveillance. Cell. 2015; 161(4): 737–749. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAriotti S, Beltman JB, Borsje R, et al.: Subtle CXCR3-Dependent Chemotaxis of CTLs within Infected Tissue Allows Efficient Target Localization. J. Immunol. 2015; 195(11): 5285–5295. 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}
|
[
{
"id": "161399",
"date": "22 Feb 2023",
"name": "Rob De Boer",
"expertise": [
"Reviewer Expertise Theoretical Immunology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an interesting paper first analyzing T cell migration data in the brain during Plasmodium infection (previously published data from Ghazanfari et al 2021), and then re-analyzing similar data during Toxoplasma infection (previously published data from Harris et al 2012). The main result is that, in contrast to what Harris et al concluded, there is no evidence for Levy walks in the data. Overall the analysis is rigorous and the results are convincing.\nMy major recommendation is to markedly improve the style of writing. The presentation is quite unclear in places. Several sentences are written very poorly. The presence and absence of \"the\", \"an\" and \"a\" and commas seems pretty random. The senior author should be able to improve this. Otherwise seek help from a native English speaker. At the end, I will give a number of examples, but there are more sentences and paragraphs that need to be improved linguistically.\nSecondly, the authors use both track-based analysis and cell-based analyses. Joost Beltman in his review [Ref 7] indeed emphasized the importance of this, calling it track-based to step-based. It would be good in this paper to clearly make this difference, as the previous errors of Harris et al largely seem to be a consequence of their -sometimes improper- track based analysis.\nPage 7: In the first paragraph of the results you fail to tell the reader this is about Plasmodium data, and what PbA is (we apparently have to remember that from the Methods). Very confusing because you did tell us you will be using two data sets: which one is this section about?\nPage 8: A previous pioneering study proposed that brain-localized CD8 T cells perform generalized LWs characterized by rare but long displacements [Ref. 2, Figure 1B (iv)]. => Now you are discussing Toxoplasma data (without telling us) and the next paragraph you switch back to Plasmodium again. Please make more clear which data set is being discussed. Actually, because both have been published before you could treat them more equally.\nPage 8: Interestingly, 100-fold lower numbers were calculated for brain-localized T cells obtained using flow cytometry.\n\n=> So? What do we need to make of this sentence here?\nPage 8: We first calculated the MSD for brain-localized Plasmodium-specific CD4 and CD8 T cell trajectories (equation (1)). => Track based? Page 8: We then analyzed the cumulative distribution of movement lengths which was similar for CD4 and CD8 T cells; => Step based?\nPage 8: To ensure that data sub-selection in the tail analysis did not bias the results, => Explain, or refer to the Methods for an explanation.\n\nPage 9: In our analyses, we found that brain- localized CD4 and CD8 T cells perform Brownian-type (correlated random) walks which contradict a previous result suggesting that movement patterns of CD8 T cells in the brain are consistent with generalized LWs. => In our analyses, we found that brain- localized CD4 and CD8 T cells DURING PLASMODIUM INFECTION perform Brownian-type (correlated random) walks which contradict a previous result suggesting that movement patterns of CD8 T cells in the brain DURING TOXOPLASMA INFECTION are consistent with generalized LWs. => Is that a contradiction or a difference?\nPage 11: Here we rigorously analyzed data from novel experiments imaging movement of Plasmodium-specific CD4 and CD8 T cells in brains of PbA-infected mice (Figure 1). => Not novel: previously published. See my remark above about treating the data more equally.\nPage 11: details slightly varied whether we compared instantaneous or per cell average speeds and turning angles => Is that a Step-based vs Track-based difference?\nPage 11: Calculating the number of T cells in the whole brain from imaging only 0.002% of its total volume may be problematic as T cells tend to leave and enter the imaging area. Using the number of T cells identified per only one time frame did not dramatically change the estimate of the total number of cells in the brain (results not shown). => Isn't that a Step-based vs Track-based difference?\nPage 12: Given the ability of T cells in tissues to do a persistent walk in a given direction (cell “inertia” => Is that an \"ability\" to a cellular constraint, i.e., a necessity?\nPage 12: the rule for T cell movements in tissues rather than THE exception.\nPage 13: that GP distribution => that the generalized Pareto distribution Page 13: Using vMF distribution => Using the von Moses-Fisher distribution => Both were only defined in the Methods!\nPage 13: such collaborations should be explicitly supported by funding agencies. => Is that really how you prefer to end, or are your scientific results the take home?\n------\nExamples of improving linguistics:\nFor survival of the organism, T cells must efficiently control pathogens invading different peripheral tissues but whether such control (and lack of thereof) is achieved by utilizing different movement strategies remains poorly understood. => Please split sentence, e.g., For survival of the organism, T cells must efficiently control pathogens invading different peripheral tissues. Whether or not such control is achieved by utilizing different movement strategies in different tissues remains poorly understood. <= Moreover: how can a \"lack of control\" be achieved?\nDifferent agents starting with large animals such as tigers and wolves and ending with individual cells such as T lymphocytes typically search for resources/targets => The sentence actually says that agents start to search with large animals and end to search with cells.\nIn actual data, agents rarely show MSD to change linearly with time => Agents don't show MSD: In actual data the MSD is hardly ever linear\nIn total, data from five movies were analyzed: three movies for 6.5 days post-infection and two movies for 7 days post-infection. => so you have 3 movies spanning the first 6.5 days of infection and 2 movies for a week? That is what the sentence says! How long do these movies take actually?\nThe constancy/decrease in CD4 T cell numbers is not fully consistent with flow cytometry data on kinetics of brain-localized endogenous T cell response to PbA. => Unclear. Later I read that the number of cells is not consistent. What is \"constancy/decrease?\"\nIn addition to the difference in the number between CD4 and CD8 T cells, we found => In addition to finding many more CD8 than CD4 T cells, we found\nVisual inspection of the five movies did not reveal any long displacements by T cells; however, there were some visible cell-like objects moving rapidly => Omit the visible, the inspection was already visual\nInterestingly, fitting Furth equation to the MSD plots suggested much shorter persistence time of T cells of 1 min => Interestingly, fitting THE Furth equation to the MSD plots suggested A much shorter persistence time of T cells of 1 min\nHowever, in all cases, when simulated movements were non-Brownian, we found that GP fits indicated infinite variance (and sometimes mean) suggesting that this approach allows to detect deviations from Brownian walks. => When simulated movements were non-Brownian, we found that THE GP fits always had an infinite variance (and sometimes mean), suggesting that this approach allows one to detect deviations from Brownian walks. => And, what is this approach: the variance?\nOne could expect that T cells should utilize different movement strategies when responding to diverse pathogens and migrating to different lymphoid or non-lymphoid (peripheral) tissues. => One could expect that T cells utilize different movement strategies when responding to diverse pathogens and when migrating to different lymphoid or non-lymphoid (peripheral) tissues. => could and should is double\nGiven that in intravital imaging experiments it is typically hard to follow individual T cells for longer than 15-20 time frames, characterizing heterogeneity of movement of individual cells in vivo remains difficult (but see Ref. 14). => Difficult sentence\n\nWhile imaging frequency used in the study by Ghazanfari et al.27 (30 sec) was sufficient to accurately detect movement of brain-localized T cells, it was clearly insufficient to better understand movement patterns of T cells in the vasculature, and as these cells move from the blood vessels into the parenchymal tissues. => While THE imaging frequency used in the study by Ghazanfari et al.27 (30 sec) was sufficient to accurately detect movement of brain-localized T cells, it was clearly insufficient to better understand movement patterns of T cells in the vasculature, and as these cells move from the blood vessels into the parenchymal tissues. => it remains unclear what the \", and as these cells move\" means\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10207",
"date": "16 Nov 2023",
"name": "Vitaly V. Ganusov",
"role": "Author Response",
"response": "This is an interesting paper first analyzing T cell migration data in the brain during Plasmodium infection (previously published data from Ghazanfari et al 2021), and then re-analyzing similar data during Toxoplasma infection (previously published data from Harris et al 2012). The main result is that, in contrast to what Harris et al concluded, there is no evidence for Levy walks in the data. Overall the analysis is rigorous and the results are convincing. Response. Thank you. My major recommendation is to markedly improve the style of writing. The presentation is quite unclear in places. Several sentences are written very poorly. The presence and absence of \"the\", \"an\" and \"a\" and commas seems pretty random. The senior author should be able to improve this. Otherwise seek help from a native English speaker. At the end, I will give a number of examples, but there are more sentences and paragraphs that need to be improved linguistically. Response. We would like to thank the reviewer to help us improve the text for better readability with pointing out specific places that could be misinterpreted. Our first author (Dhruv Patel) is a native English speaker. He went through the paper and updated the text including the proper use of articles. We do note, however, that other reviewers did not really have issues with understanding of our paper. We also refer to a recent paper that highlights challenges experienced by non-native English speakers in research (PMID: 37463136). Secondly, the authors use both track-based analysis and cell-based analyses. Joost Beltman in his review [Ref 7] indeed emphasized the importance of this, calling it track-based to step-based. It would be good in this paper to clearly make this difference, as the previous errors of Harris et al largely seem to be a consequence of their -sometimes improper- track based analysis. Response. This is a good comment, thank you. The same argument was raised in another recent paper on neutrophil movements (PMID: 34461315), and we will now highlight which analyses are track-based and which step-based (typically, instantaneous measures such as instantaneous speeds, movement lengths, or turning angles are step-based). Page 7: In the first paragraph of the results you fail to tell the reader this is about Plasmodium data, and what PbA is (we apparently have to remember that from the Methods). Very confusing because you did tell us you will be using two data sets: which one is this section about? Response. We now tried to improve the text on this issue but our key point is not about infection but about the tissue – the brain. Of course, it is possible that different infections may generate different types of CD8 T cells but that’s very unlikely (in our view). So, the point is that we focus on the tissue where T cells move irrespectively of the infection. This is also highlighted in the discussion. Page 8: A previous pioneering study proposed that brain-localized CD8 T cells perform generalized LWs characterized by rare but long displacements [Ref. 2, Figure 1B (iv)]. => Now you are discussing Toxoplasma data (without telling us) and the next paragraph you switch back to Plasmodium again. Please make more clear which data set is being discussed. Actually, because both have been published before you could treat them more equally. Response. PbA data were published but we did not get T cell coordinate data from the authors, we only got raw imaging data. We processed all the data ourselves, so these are new results! That was clearly stated in Materials and methods. Page 8: Interestingly, 100-fold lower numbers were calculated for brain-localized T cells obtained using flow cytometry. Response. It obviously means that flow cytometry may underestimate the number of brain-localized T cells by 100 fold. Page 8: We first calculated the MSD for brain-localized Plasmodium-specific CD4 and CD8 T cell trajectories (equation (1)). => Track based? Page 8: We then analyzed the cumulative distribution of movement lengths which was similar for CD4 and CD8 T cells; => Step based? Response. Yes. Updated. Page 8: To ensure that data sub-selection in the tail analysis did not bias the results, => Explain, or refer to the Methods for an explanation. Response. When one does tail analysis only some data are selected (using r_min cut-off, this is explained in Materials and Methods). This could generate bias – and we have shown how selecting different r_min values results in different values for power parameter mu (e.g., Suppl Fig 3 in previous version of the paper). Page 9: In our analyses, we found that brain- localized CD4 and CD8 T cells perform Brownian-type (correlated random) walks which contradict a previous result suggesting that movement patterns of CD8 T cells in the brain are consistent with generalized LWs. => In our analyses, we found that brain- localized CD4 and CD8 T cells DURING PLASMODIUM INFECTION perform Brownian-type (correlated random) walks which contradict a previous result suggesting that movement patterns of CD8 T cells in the brain DURING TOXOPLASMA INFECTION are consistent with generalized LWs. => Is that a contradiction or a difference? Response. Contradiction. (Per Occam’s razor) There is no reason to believe that two infections make two absolutely different types of T cells with completely different movement patterns. We also show that if we remove artifacts from the data from Harris et al. paper, Levy walks disappear. Page 11: Here we rigorously analyzed data from novel experiments imaging movement of Plasmodium-specific CD4 and CD8 T cells in brains of PbA-infected mice (Figure 1). => Not novel: previously published. See my remark above about treating the data more equally. Response. Coordinate data were not published, these are our results! Coordinate data from these imaging movies are not trivial to generate. Page 11: details slightly varied whether we compared instantaneous or per cell average speeds and turning angles => Is that a Step-based vs Track-based difference? Response. It depends. Instantaneous measures are step-based, and per cell quantities are track-based. Now this is explained in Materials and methods. Page 11: Calculating the number of T cells in the whole brain from imaging only 0.002% of its total volume may be problematic as T cells tend to leave and enter the imaging area. Using the number of T cells identified per only one time frame did not dramatically change the estimate of the total number of cells in the brain (results not shown). => Isn't that a Step-based vs Track-based difference? Response. No. Page 12: Given the ability of T cells in tissues to do a persistent walk in a given direction (cell “inertia” => Is that an \"ability\" to a cellular constraint, i.e., a necessity? Response. We don’t know for in vivo situation. We do now that in vitro T cells to tend to persist in movement due to physiology of the movement machinery (to change direction, actin filaments must move to another location on cellular membrane and that is “costly”, so moving in the same direction is energetically cheaper unless there environmental cues or barriers “telling” the cell otherwise). Page 12: the rule for T cell movements in tissues rather than THE exception. Response. Done. Page 13: that GP distribution => that the generalized Pareto distribution Response. Done. Page 13: Using vMF distribution => Using the von Moses-Fisher distribution => Both were only defined in the Methods! Response. Defined again here. (and von Mises-Fisher, ). Page 13: such collaborations should be explicitly supported by funding agencies. => Is that really how you prefer to end, or are your scientific results the take home? Response. Yes. ------ Examples of improving linguistics: Response: All done based on the decisions by Dhruv Patel (native English speaker). For survival of the organism, T cells must efficiently control pathogens invading different peripheral tissues but whether such control (and lack of thereof) is achieved by utilizing different movement strategies remains poorly understood. => Please split sentence, e.g., For survival of the organism, T cells must efficiently control pathogens invading different peripheral tissues. Whether or not such control is achieved by utilizing different movement strategies in different tissues remains poorly understood. <= Moreover: how can a \"lack of control\" be achieved? Response. Corrected. Different agents starting with large animals such as tigers and wolves and ending with individual cells such as T lymphocytes typically search for resources/targets => The sentence actually says that agents start to search with large animals and end to search with cells. Response. Corrected. In actual data, agents rarely show MSD to change linearly with time => Agents don't show MSD: In actual data the MSD is hardly ever linear Response. Corrected. In total, data from five movies were analyzed: three movies for 6.5 days post-infection and two movies for 7 days post-infection. => so you have 3 movies spanning the first 6.5 days of infection and 2 movies for a week? That is what the sentence says! How long do these movies take actually? Response. Corrected. The constancy/decrease in CD4 T cell numbers is not fully consistent with flow cytometry data on kinetics of brain-localized endogenous T cell response to PbA. => Unclear. Later I read that the number of cells is not consistent. What is \"constancy/decrease?\" Response. Corrected.# In addition to the difference in the number between CD4 and CD8 T cells, we found => In addition to finding many more CD8 than CD4 T cells, we found Response. Corrected. Visual inspection of the five movies did not reveal any long displacements by T cells; however, there were some visible cell-like objects moving rapidly => Omit the visible, the inspection was already visual Response. Corrected. Interestingly, fitting Furth equation to the MSD plots suggested much shorter persistence time of T cells of 1 min => Interestingly, fitting THE Furth equation to the MSD plots suggested A much shorter persistence time of T cells of 1 min Response. Corrected. However, in all cases, when simulated movements were non-Brownian, we found that GP fits indicated infinite variance (and sometimes mean) suggesting that this approach allows to detect deviations from Brownian walks. => When simulated movements were non-Brownian, we found that THE GP fits always had an infinite variance (and sometimes mean), suggesting that this approach allows one to detect deviations from Brownian walks. => And, what is this approach: the variance? Response. Corrected. One could expect that T cells should utilize different movement strategies when responding to diverse pathogens and migrating to different lymphoid or non-lymphoid (peripheral) tissues. => One could expect that T cells utilize different movement strategies when responding to diverse pathogens and when migrating to different lymphoid or non-lymphoid (peripheral) tissues. => could and should is double Response. Corrected. Given that in intravital imaging experiments it is typically hard to follow individual T cells for longer than 15-20 time frames, characterizing heterogeneity of movement of individual cells in vivo remains difficult (but see Ref. 14). => Difficult sentence Response. Corrected. While imaging frequency used in the study by Ghazanfari et al.27 (30 sec) was sufficient to accurately detect movement of brain-localized T cells, it was clearly insufficient to better understand movement patterns of T cells in the vasculature, and as these cells move from the blood vessels into the parenchymal tissues. => While THE imaging frequency used in the study by Ghazanfari et al.27 (30 sec) was sufficient to accurately detect movement of brain-localized T cells, it was clearly insufficient to better understand movement patterns of T cells in the vasculature, and as these cells move from the blood vessels into the parenchymal tissues. => it remains unclear what the \", and as these cells move\" means Response. Corrected."
}
]
},
{
"id": "187062",
"date": "17 Aug 2023",
"name": "Masato S. Abe",
"expertise": [
"Reviewer Expertise Movement ecology",
"complex systems"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this study, the authors quantitatively investigated the movement patterns of brain localized T-cells to determine whether they are Lévy walk or Brownian walk. A new analysis of the data as a separate trajectory starting from the missing data shows that T. gondii-specific CD8 T-cells, contrary to previous studies, do not exhibit a Lévy walk, but rather a correlated random walk pattern, similar to other T-cells. The approach is based on a variety of rigorous methods, including fitting a generalized Pareto distribution to whole movement length distributions and a power-law distribution to the tails, and so on. The characterization of movement patterns is an important for understanding cells and other biological systems. Therefore, the findings give insights into these research areas. Still, I have some comments below.\nMajor comments\nThe definition of movement length appears to be unwritten, which is an important factor since the results can vary depending on the definition of movement length.\n\nIs there a possibility that long movement length in T. gondii-specific CD8 T-cells is underestimated by splitting a trajectory with missing data?\n\nIn the analysis of movement patterns for some species (e.g., mammals), a truncated power law distribution is sometimes fitted. However, in this manuscript, a pure power law distribution for the tail of movement length distribution was used. Visually, it doesn't look like the tail of the distribution is cut off, so I don't think additional analysis is necessary, but what are your thoughts on analysis based on truncated power law for cell movement patterns?\n\nHow to determine r_min is very important as Clauset et al. (2009) pointed out, so please write it down in detail. The authors wrote they used the KS-test, but I think KS-statistic (i.e., distance between two distributions) is correct.\n\nI feel that the Supplement Fig.3 is important. So, it should be in the main text.\n\nMinor comments\nIn the description for the mean and variance of the GP distribution, the range of k is needed as k < 1 for the mean and k < 1/2 for the variance.\n\nWhole manuscript: Levy -> Lévy\n\nSupplemental Table S1: Why does the estimation of simulated Brownian walker and CRW walker have the same values?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10208",
"date": "16 Nov 2023",
"name": "Vitaly V. Ganusov",
"role": "Author Response",
"response": "In this study, the authors quantitatively investigated the movement patterns of brain localized T-cells to determine whether they are Lévy walk or Brownian walk. A new analysis of the data as a separate trajectory starting from the missing data shows that T. gondii-specific CD8 T-cells, contrary to previous studies, do not exhibit a Lévy walk, but rather a correlated random walk pattern, similar to other T-cells. The approach is based on a variety of rigorous methods, including fitting a generalized Pareto distribution to whole movement length distributions and a power-law distribution to the tails, and so on. The characterization of movement patterns is an important for understanding cells and other biological systems. Therefore, the findings give insights into these research areas. Still, I have some comments below. Response. Thank you. Major comments The definition of movement length appears to be unwritten, which is an important factor since the results can vary depending on the definition of movement length. Response. The movement length (or step length) is the displacement of a given cell between two sequential time points of imaging. We now put this definition in Materials and Methods section. Is there a possibility that long movement length in T. gondii-specific CD8 T-cells is underestimated by splitting a trajectory with missing data? Response. We don’t really know for sure. We believe that we had identified a major issue with the trajectory data generated from intravital imaging experiments (missing time time frames) and future experiments need to account for this issue and investigate it more thoroughly. In the analysis of movement patterns for some species (e.g., mammals), a truncated power law distribution is sometimes fitted. However, in this manuscript, a pure power law distribution for the tail of movement length distribution was used. Visually, it doesn't look like the tail of the distribution is cut off, so I don't think additional analysis is necessary, but what are your thoughts on analysis based on truncated power law for cell movement patterns? Response. This is an important point and we now discuss it in our Discussion. The key point here is “truncated” distribution, any truncated distribution will have finite mean and variance, and mathematically, movement pattern with such distribution will be Brownian like, not Levy (Levy must have infinite variance or both infinite variance and mean). So, detecting that movement is consistent with truncated powerlaw is to a degree irrelevant and perhaps is done to make a splashier conclusion rather than to get insight into the specifics of cell movements. How to determine r_min is very important as Clauset et al. (2009) pointed out, so please write it down in detail. The authors wrote they used the KS-test, but I think KS-statistic (i.e., distance between two distributions) is correct. Response. Thank you, it is KS-statistics implemented in the python package powerlaw that implemented the Clauset et al. (2009) method. We do note that we did explore how fixing r_min to different values influences our conclusion (it did not much) and also we fitted different distributions to the whole distribution of movement lengths, i.e., went above and beyond of some of the other analyses presented in previously published works (also see Rajakaruna et al. JI 2021). I feel that the Supplement Fig.3 is important. So, it should be in the main text. Response. Thank you for the suggestion. We moved the figure to the main text as Figure 5. Minor comments In the description for the mean and variance of the GP distribution, the range of k is needed as k < 1 for the mean and k < 1/2 for the variance. Response. We added this point. Whole manuscript: Levy -> Lévy Response. Corrected (hopefully we did all of them). Supplemental Table S1: Why does the estimation of simulated Brownian walker and CRW walker have the same values? Response. Because CR walkers are Brownian walkers in terms of movement length distribution. They only differ in the persistence time. We noted this point in our revision."
}
]
},
{
"id": "187061",
"date": "18 Aug 2023",
"name": "Jens Stein",
"expertise": [
"Reviewer Expertise Mouse immunology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the accompanying manuscript, Patel and colleagues have performed an in-depth re-examination of search strategies executed by brain-localized T cells, as assessed by published intravital microscopy data sets. Using a rigorous analysis pipeline, the authors identify a correlated random walk (CRW) pattern being consistent with T cell migration in two separate brain infection models. This contradicts a previous study, which has claimed that brain-resident T cells undergo Levy walks (LW), i.e., long displacements between periods of short displacements. Somewhat astoundingly, the previous conclusion of LW motility in brain-localized T cells appears to be mainly due to simple tracking errors, in which unrelated tracks were stitched together or missing time points filled in by the analysis program, giving rise to unphysiologically long displacements. In sum, the authors provide solid evidence of CRW as main movement pattern of T cells, a common strategy irrespective of the organ analyzed.\nI have only some minor concerns since the main take-home message for the \"intravital community\" - that careful image analysis is required to draw correct conclusions - is well documented. The author’s analysis is also timely, since erroneous claims on cell motility patterns are often pervasive (since presented as novel concepts) and therefore important to correct.\nMinor concerns:\nThe authors occasionally switch between the two infection models (Toxoplasma and Plasmodium), e.g., on p. 3. last paragraph, or p. 8, 3rd paragraph, which makes it difficult for the reader to follow the manuscript.\nThe authors describe on p. 5 that tracks with only a single position were removed. In other publications (e.g., Mempel et al, Nature, 2003), a more stringent selection is made, i.e., tracks followed by less than 5 consecutive time points are dismissed. This more stringent practice is routinely used in many laboratories, since very short tracks typically outnumber medium - to - long tracks. Can the authors comment on this?\nThe comparison of the total number of brain-localized T cells estimated by intravital imaging in relation to flow cytometry-based enumeration is interesting, and I agree that flow cytometry tends to underestimate the actual number of cells. Nonetheless, the authors should additionally consider that inflammation is often localized in certain foci, which are then recorded for intravital microscopy, whereas adjacent brain areas might be virtually free of infiltrating leukocytes.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10209",
"date": "16 Nov 2023",
"name": "Vitaly V. Ganusov",
"role": "Author Response",
"response": "In the accompanying manuscript, Patel and colleagues have performed an in-depth re-examination of search strategies executed by brain-localized T cells, as assessed by published intravital microscopy data sets. Using a rigorous analysis pipeline, the authors identify a correlated random walk (CRW) pattern being consistent with T cell migration in two separate brain infection models. This contradicts a previous study, which has claimed that brain-resident T cells undergo Levy walks (LW), i.e., long displacements between periods of short displacements. Somewhat astoundingly, the previous conclusion of LW motility in brain-localized T cells appears to be mainly due to simple tracking errors, in which unrelated tracks were stitched together or missing time points filled in by the analysis program, giving rise to unphysiologically long displacements. In sum, the authors provide solid evidence of CRW as main movement pattern of T cells, a common strategy irrespective of the organ analyzed. I have only some minor concerns since the main take-home message for the \"intravital community\" - that careful image analysis is required to draw correct conclusions - is well documented. The author’s analysis is also timely, since erroneous claims on cell motility patterns are often pervasive (since presented as novel concepts) and therefore important to correct. Response. Thank you. Minor concerns: The authors occasionally switch between the two infection models (Toxoplasma and Plasmodium), e.g., on p. 3. last paragraph, or p. 8, 3rd paragraph, which makes it difficult for the reader to follow the manuscript. Response. Corrected. The authors describe on p. 5 that tracks with only a single position were removed. In other publications (e.g., Mempel et al, Nature, 2003), a more stringent selection is made, i.e., tracks followed by less than 5 consecutive time points are dismissed. This more stringent practice is routinely used in many laboratories, since very short tracks typically outnumber medium - to - long tracks. Can the authors comment on this? Response. Any data omission is problematic as this could generate biases, e.g., shorter tracks are often for faster cells (or cells at the boundaries), so removing those may decrease the average speed per cell. In our analyses we did not intentionally remove any data but some data omission did occur due to data cleaning. Rather we split the tracks that had missing time frame and created complementary tracks to ensure sequential time points in each. This did result in tracks with a single position and these were not used to characterize movement patterns since there was no “movement” for such cells – hence, we did remove some data. The comparison of the total number of brain-localized T cells estimated by intravital imaging in relation to flow cytometry-based enumeration is interesting, and I agree that flow cytometry tends to underestimate the actual number of cells. Nonetheless, the authors should additionally consider that inflammation is often localized in certain foci, which are then recorded for intravital microscopy, whereas adjacent brain areas might be virtually free of infiltrating leukocytes. Response. This is a good point. We now added it to the Discussion."
}
]
}
] | 1
|
https://f1000research.com/articles/12-87
|
https://f1000research.com/articles/10-1129/v1
|
08 Nov 21
|
{
"type": "Opinion Article",
"title": "ELIXIR and Toxicology: a community in development",
"authors": [
"Marvin Martens",
"Rob Stierum",
"Emma L. Schymanski",
"Chris T. Evelo",
"Reza Aalizadeh",
"Hristo Aladjov",
"Kasia Arturi",
"Karine Audouze",
"Pavel Babica",
"Karel Berka",
"Jos Bessems",
"Ludek Blaha",
"Evan E. Bolton",
"Montserrat Cases",
"Dimitrios Ε. Damalas",
"Kirtan Dave",
"Marco Dilger",
"Thomas Exner",
"Daan P. Geerke",
"Roland Grafström",
"Alasdair Gray",
"John M. Hancock",
"Henner Hollert",
"Nina Jeliazkova",
"Danyel Jennen",
"Fabien Jourdan",
"Pascal Kahlem",
"Jana Klanova",
"Jos Kleinjans",
"Todor Kondic",
"Boï Kone",
"Iseult Lynch",
"Uko Maran",
"Sergio Martinez Cuesta",
"Hervé Ménager",
"Steffen Neumann",
"Penny Nymark",
"Herbert Oberacher",
"Noelia Ramirez",
"Sylvie Remy",
"Philippe Rocca-Serra",
"Reza M. Salek",
"Brett Sallach",
"Susanna-Assunta Sansone",
"Ferran Sanz",
"Haralambos Sarimveis",
"Sirarat Sarntivijai",
"Tobias Schulze",
"Jaroslav Slobodnik",
"Ola Spjuth",
"Jonathan Tedds",
"Nikolaos Thomaidis",
"Ralf J.M. Weber",
"Gerard J.P. van Westen",
"Craig E. Wheelock",
"Antony J. Williams",
"Hilda Witters",
"Barbara Zdrazil",
"Anže Županič",
"Egon L. Willighagen",
"Rob Stierum",
"Emma L. Schymanski",
"Chris T. Evelo",
"Reza Aalizadeh",
"Hristo Aladjov",
"Kasia Arturi",
"Karine Audouze",
"Pavel Babica",
"Karel Berka",
"Jos Bessems",
"Ludek Blaha",
"Evan E. Bolton",
"Montserrat Cases",
"Dimitrios Ε. Damalas",
"Kirtan Dave",
"Marco Dilger",
"Thomas Exner",
"Daan P. Geerke",
"Roland Grafström",
"Alasdair Gray",
"John M. Hancock",
"Henner Hollert",
"Nina Jeliazkova",
"Danyel Jennen",
"Fabien Jourdan",
"Pascal Kahlem",
"Jana Klanova",
"Jos Kleinjans",
"Todor Kondic",
"Boï Kone",
"Iseult Lynch",
"Uko Maran",
"Sergio Martinez Cuesta",
"Hervé Ménager",
"Steffen Neumann",
"Penny Nymark",
"Herbert Oberacher",
"Noelia Ramirez",
"Sylvie Remy",
"Philippe Rocca-Serra",
"Reza M. Salek",
"Brett Sallach",
"Susanna-Assunta Sansone",
"Ferran Sanz",
"Haralambos Sarimveis",
"Sirarat Sarntivijai",
"Tobias Schulze",
"Jaroslav Slobodnik",
"Ola Spjuth",
"Jonathan Tedds",
"Nikolaos Thomaidis",
"Ralf J.M. Weber",
"Gerard J.P. van Westen",
"Craig E. Wheelock",
"Antony J. Williams",
"Hilda Witters",
"Barbara Zdrazil",
"Anže Županič"
],
"abstract": "Toxicology has been an active research field for many decades, with academic, industrial and government involvement. Modern omics and computational approaches are changing the field, from merely disease-specific observational models into target-specific predictive models. Traditionally, toxicology has strong links with other fields such as biology, chemistry, pharmacology and medicine. With the rise of synthetic and new engineered materials, alongside ongoing prioritisation needs in chemical risk assessment for existing chemicals, early predictive evaluations are becoming of utmost importance to both scientific and regulatory purposes. ELIXIR is an intergovernmental organisation that brings together life science resources from across Europe. To coordinate the linkage of various life science efforts around modern predictive toxicology, the establishment of a new ELIXIR Community is seen as instrumental. In the past few years, joint efforts, building on incidental overlap, have been piloted in the context of ELIXIR. For example, the EU-ToxRisk, diXa, HeCaToS, transQST, and the nanotoxicology community have worked with the ELIXIR TeSS, Bioschemas, and Compute Platforms and activities. In 2018, a core group of interested parties wrote a proposal, outlining a sketch of what this new ELIXIR Toxicology Community would look like. A recent workshop (held September 30th to October 1st, 2020) extended this into an ELIXIR Toxicology roadmap and a shortlist of limited investment-high gain collaborations to give body to this new community. This Whitepaper outlines the results of these efforts and defines our vision of the ELIXIR Toxicology Community and how it complements other ELIXIR activities.",
"keywords": [
"Toxicology",
"ELIXIR",
"interoperability",
"FAIR"
],
"content": "Introduction of the ELIXIR Toxicology Community\n\nToxicology as a field tries to understand the negative consequences that may arise from the interactions of chemicals with living organisms. In this ELIXIR (European life-sciences Infrastructure for biological Information)1 Community, the focus will be primarily the protection of human health. There are a number of both chemical and biological “interoperability” issues key to the toxicology field that translate into data interoperability issues. These include the connection between the action and activity of a particular chemical compound to its effective amount available at a biological target (the link between toxicodynamics and toxicokinetics). Typically this is also a link between biological data analysis (including large-scale multi-omics) and kinetic modelling. Other examples include interactions between a compound and its target (a protein, nucleic sequence or membrane structure for instance). This is primarily based on the interplay between chemistry (the chemical structure and, for example, its related properties in terms of functional groups, charge, shape and related binding affinity) and biochemistry (like biomolecular 3D structures). Also, mixture toxicity needs to be considered as combinations of chemicals with synergistic or antagonistic behaviour, or a combination thereof. While chemicals with similar modes of action may act in terms of concentration addition, those with different modes may rather act according to independent action.2,3 Substances with low toxicity may interact in concentration addition rather than as excess toxicity drivers of one compound. Often there is a need to translate the knowledge about one compound into knowledge about other compounds, where approaches like quantitative structure-activity relationships (QSARs) help to elucidate this knowledge and predict required property and toxicity, and in more general when “read-across approaches” come into play that are based on chemical data only, biological data only, or are hybrid.4,5 These again need detailed information about the relationships between related chemical compounds, specific properties and toxicological endpoints and, when considering chemical-biological interactions, details regarding both the chemical structures and adequate descriptions of the biological targets. Since toxicological endpoints can be represented in a myriad of ways, the toxicological effect data are often scattered over multiple repositories and databases hosting different types of data; i.e. chemical structures, toxicity data (in vivo and in vitro), biological target details, and omics data. This itself is not a problem, but the separation and segregation make the data difficult to find and to connect. Currently, many of these deposition databases (where datasets can be archived) do not provide adequate descriptions regarding typical toxicological study designs and parameters, quality control, data acceptance criteria, or even clear identification of the compounds tested. This all adds to the need for an adequate FAIRification process, to make toxicology data more Findable, Accessible, Interoperable and Reusable (FAIR - see Go-FAIR).6,7\n\nThe field of toxicology would certainly benefit from clear, standardized guidelines for data capture, approaches to integrate and connect across multiple databases, clear data licensing for these data repositories, and tools that support accessing the data (as being developed by the ELIXIR Converge data brokerage work). Existing study capture tools can be extended with templates defined for toxicology, which end up in a central place (e.g. Biosamples8) with links to omics and other data distributed over technology-specific deposition databases and BioStudies.9 Relevant portals (e.g. FAIRsharing.org10,11) should then be able to identify these studies, also linking to existing but scattered toxicology databases.\n\nRisk assessment, consisting of hazard identification, characterisation and risk evaluation in relation to exposure, involves expert opinions based on discussions and data interpretation. Streamlining this process is important also because of the huge number of chemicals known and produced in chemistry, biotechnology or food production, with over 350,000 chemicals documented on the global market.12 However, expert evaluation is and will remain crucial and calls for extensive data provenance both for the actual data (how was it measured, where was it published, whom to give credit for it), and for the risk assessments themselves. Interestingly this process stumbles on problems and solutions that have much in common with other fields, where part of the data need to be hidden and other parts can be publicly accessed, as observed in pilot approaches in genetics, or patient data repositories.\n\nToxicology, while established as discipline, is also rapidly developing in areas, where, for example, new molecular methods to describe the adverse outcome of exposure to a toxic substance are not yet fully established. This offers opportunities for integration in systems biology approaches building on molecular pathway descriptions that benefit from modern network biology approaches. Compound profiling, where, for example, using omics methods to characterize the effect of compounds on cells, are generally useful for categorizing compounds, or for the development of predictive pathway models. For such studies, the availability of high-quality annotations for compounds is of paramount importance to enable the use of omics profiles in toxicology.\n\nToxicology is also an applied field. There are important applications of toxicity tests in the regulatory field and large amounts of data are collected for that purpose, often for different (governmental) agencies. Making this data more Findable and Reusable is often seen as an important way to reduce both animal testing and the cost of registration of new compounds. If some data is not available to the public due to ownership by companies or other constraints, indexes should be developed to enable the use of this data in an aggregated form (such as the SPIN index of the Swedish Chemicals agency (KEMI) and other Nordic chemical agencies). Typically, regulatory use requires very precise and rigid descriptions of protocols, including reporting methods. On the other hand, better insights into the toxicological mechanisms, including interactions between chemicals, benefit from more innovative research methods (e.g. single-cell omics, induced stem cell applications, imaging methods) and from creative development of new analysis methods. While it is beneficial to combine results from both types of approaches (termed New Approach Methods (NAM) in the regulatory field), the corresponding interoperability issues are often quite different.\n\n\nUser community\n\nEurope is steadily increasing demands on the risk assessment of chemicals, drugs, cosmetics ingredients and nanomaterials to lead to safer products, resulting in a strong toxicology research community with sub-communities in, for example, the drug development, environmental, nanomaterial and rare-disease areas. Recent changes in European law for animal testing and new demands for testing of lower-volume chemicals and nanomaterials have triggered large-scale research into alternative testing approaches. These activities not only produce new biological and mechanistic insights, but also large amounts of new data, which have to be managed and shared for re-usage to avoid unnecessary duplication of experiments and, in this way, reduce animal testing. The goal is that the combination of data from integrated in vitro and in silico approaches will support (ultimately personalized) risk/benefit health analysis, safer drug innovation with fewer needs to withdraw after registration, a fact-based perception of chemical safety, safe-by-design nanomaterials and sustainable and safe economies.\n\nThe European Union supports toxicological and risk assessment projects with various funding programs. Recently, large collections of data have been released, resulting from research clusters, such as SEURAT-1,13 the EU NanoSafety Cluster (NSC) with NANoREG, EU-ToxRisk,14 the NORMAN Network, and the EU Innovative Medicines Initiative (IMI) funded projects related to drug toxicology, including eTOX,15 eTRANSAFE,16 and Eurion.17 Data from these and other projects are becoming available, sometimes as Open Data (e.g. NANoREG) and sometimes as FAIR data. An example of the latter is European REACH data, which has recently been made FAIR by the Cefic-LRI-funded project AMBIT-LRI.18 Furthermore, the FAIRplus project is collaborating with eTOX on making their data more FAIR, and the new Precision Toxicology will develop a data commons following the FAIR principles.\n\nHowever, there are a few opportunities for data handling that need to be taken.19,20 Recent studies show how powerful the combination of toxicology information and omics data is,21,22 but to be able to obtain the statistical significance to draw these conclusions, data from the US and Japan had to be combined. In contrast to large data sets like DrugMatrix,23 ToxCast/Tox21,24 and TG-GATEs25 from these countries, data from European projects is often not sufficiently integrated. Luckily, there are signs that the community is going in the right direction, e.g. the aforementioned data integration by diXa,26 NANoREG and REACH.27 With respect to the European Chemical Industry, various authors have been involved in other Cefic-LRI activities related to data management (AIMT-3, AIMT-4).\n\nIn addition, the eTOX project28 has established data integration approaches e.g. to enable the development of QSARs relating chemical structures to in vivo toxicopathological outcomes. As such, the project also delivered databases and approaches to ontology development, text mining approaches, and approaches for prediction of drug metabolism and pharmacokinetic features. Moreover, in 2017 the Organisation for Economic Co-operation and Development (OECD) performed an online survey underscoring the fact that data integration for safety is of global concern for ultimate risk assessment. The purpose of the resulting knowledge base is the integration of eCHEMportal (The Global Portal to Information on Chemical Substances29), IUCLID (International Uniform ChemicaL Information Database30), and OECD’s QSAR Toolbox31 supporting the development of Adverse Outcome Pathways and associated infrastructures (AOP-Wiki).32 Despite these positive developments, the ‘data integration struggle’ from various perspectives (omics, computational chemistry and more ‘conventional’ toxicological data within REACH and pharmaceutical industry setting) remains a challenge.\n\n\nRoadmap\n\nThe above initiatives are mainly driven by user communities themselves: chemical industry, funding agencies, pharmaceutical companies, governmental agencies and organisations such as Member State organisations, the OECD and non-governmental organisations (NGOs). ELIXIR can contribute strongly to the existing infrastructure projects from a cheminformatics and bioinformatics perspective, providing tools and guidelines, linking and harmonizing the ongoing activities, serving the toxicology users.\n\nFor future risk assessment paradigms solely based on human-derived models, and in this way of higher relevance for human adverse effects,33 various data types will need to be integrated into and cross the conventional boundaries of risk assessment. This involves external exposure assessment (e.g. via workplace or environmental modelling and measurements34,35), internal exposure characterisation (ADME-TK (absorption, distribution, metabolism, and excretion - toxicokinetics) e.g. via modelling and biomarker-based detection), toxicodynamics on a molecular level, and cell and systems biology. In this way, more data-driven mechanism-based evaluations and supporting data can integrate into regulatory risk assessment. There will not only be more but also more diverse data as e.g. internal exposure data may be inferred from biomonitoring data and/or physiologically-based toxicokinetic modelling to estimate target dose available at the active sites involved in the molecular initiating events of Adverse Outcome Pathways (AOPs).\n\nAnother relevant topic is the concept of the exposome,36–38 which aims at characterising lifetime exposure (not only to chemicals in the narrowest sense, but also dietary components, lifestyle factors, environmental exposures, etc) in relation to health outcome. Often, vulnerable periods of life (infancy, childhood, and old age) are investigated, and the evaluation also integrates epidemiology. This is one clear demonstration of the trend that the previously distinct areas of toxicology, drug and product design and personalized/precision medicine39 but also environment and health and epidemiology are moving closer together. Data sharing will be increasingly necessary across these disciplines. High throughput data analysis in exposomics, for instance, shares many parallels with metabolomics and other higher level omics analyses, with an added layer of chemical complexity on top.38\n\nThe toxicology community is large and well established. The current list of proponents of an ELIXIR Toxicology Community only reflects a subset of a much larger community with a lot of commitments to, and activities around open collaboration. It has clear omics, knowledge management and data infrastructure needs to accommodate the increasing wish to predict toxicology without animal testing (e.g. in SEURAT-1, EU-ToxRisk, eTOX OBERON40). Foreseeing this need for better infrastructures, the community has previously contacted ELIXIR for collaboration. Various domain-specific projects exist that service the toxicology community with computational and database knowledge (OpenRiskNet, NanoCommons) that can translate ELIXIR knowledge to the respective communities. These infrastructure projects are the successors of research projects focusing on data management, including diXa,26 ToxBank41 and eNanoMapper.42\n\nTo benefit the research community, small and medium-sized enterprises (SMEs) and larger industry, and to enable further future support to regulatory applications and upcoming calls (e.g. Green Deal43,44), we need to reach an inclusive ecosystem of data, evaluation and modelling tools. The current separate consortia from different toxicity-related and neighbouring disciplines already work towards data and knowledge that is FAIR.6 After all, these aspects are essential to efficiently assess the risk of new compounds and materials, as well as combined risks of current stressors (e.g. under the exposome concept). To further accelerate these activities, more toxicology-related data and knowledge need to be linked, such as on physiologically based toxicokinetic (PBTK) modelling, biological pathways describing affected metabolism and cell biology processes, metabolism, metabolic models and metabolism predictions, drug-response, omics (biological identity), chemical structures and associated metadata (use, hazard, transformations), QSARs, AOPs, REACH dossiers, etc. Simultaneously, an extension towards the human (preclinical toxicology) discipline should be initiated, in which exposure data are combined with internal exposure and early biomarkers of effect data (e.g. from the European Human Biomonitoring Initiative (HBM4EU)45 and environmental data from NORMAN46,47) towards pathways of toxicity. Interoperability with the standardization efforts of clinical research by CDISC is important.\n\nHowever, to reach such interoperable toxicology, resources need to be better integrated. Despite the work of many projects, their FAIR features can still be improved and applying newly developed FAIR metrics will help steer this.48 Even though there is overlap in content with existing ELIXIR Communities (Table 1, key demands specifically fostering the integration for interoperable toxicology and risk assessment include the following roadmap19,20):\n\n• chemical structure interoperability challenges (e.g. links to ELIXIR Metabolomics Community49)\n\n• metadata, open standards (e.g. links to ELIXIR Interoperability Platform, and TeSS50)\n\n• continued ontology development (e.g. links to ELIXIR Interoperability Platform and Ontology Lookup Service)\n\n• interoperable computation (e.g. links to the Galaxy51 and bio.tools52 communities)\n\n• interactions with other ELIXIR Core Data Resources (e.g. Ensembl and Europe PMC)\n\n• interactions with other communities, including nanomedicine and health\n\n• deployment of existing tools and modelling approaches on the ELIXIR Compute infrastructure (also allowing future growth towards risk estimations needing Monte Carlo approaches)\n\n• integration of ELIXIR AAI\n\n• InChI implementation for small molecule data\n\n• Spectral database functionality (open implementations)\n\nThe concrete steps forward proposed in this roadmap include:\n\n1. Leverage from open solutions (models, ontologies, educational material, standards etc) developed by past and ongoing toxicology and ELIXIR projects\n\n2. Connect more closely with the core ELIXIR resources (FAIR data, database interoperability, etc), strengthen and connect the inclusive communities that have evolved over the past few years (OpenTox, eNanoMapper, diXa, OpenRiskNet, NORMAN) and older communities like the Federation of European Toxicologists & European Societies of Toxicology (EUROTOX), the Society of Environmental Toxicology and Chemistry (SETAC) and European Environmental Mutagenesis and Genomics Society (EEMGS, formerly known as EEMS)\n\n3. Develop open community standards to support common interest (ontologies, APIs, data formats, deposition databases and publication recommendations)\n\nSpecifically, we will continue to grow the list of involved toxicology research groups, projects, and ELIXIR Node activities. This Community has already held a joint meeting to select the key priorities and use cases (see Tables 2 and 3), resulting in this positioning paper. The ELIXIR Toxicology Community will continue to expand and search for contributors with relevant expertise as the community and activities mature. By bootstrapping from Open Science approaches developed in aforementioned projects (e.g. Open PHACTS53), the new Community will focus on mutual benefit, an open and inclusive community, solving practical community problems. The goal is not to design domain-specific approaches, but a pragmatic approach that provides FAIR and open tools from the start, allowing all toxicology and neighbouring communities to benefit from these harmonized solutions. The inclusive community will involve the existing sub-communities in pharmaceuticals, e.g. from eTOX, transQST,54 and eTRANSAFE,16 cosmetic ingredients, e.g. from SEURAT-1, high and low-volume chemicals, e.g. from HBM4EU and soon from Horizon Europe Partnership for the Assessment of Risk from Chemicals (PARC),47 or from different Cefic-LRI (Lang-Range Research Initiative) projects, and nanomaterials, via the NanoSafety Cluster, building on shared needs and community solutions and strongly aligned to other ELIXIR communities. Open licensing and interfaces (ontologies, standards, formats) will encourage new solutions and collaborations, which will be accessible to any organisation and every project within and outside Europe. This will allow close interoperability with toxicology communities outside Europe that also use open approaches, while at the same time allowing compatibility with closed approaches too. This dual model has been demonstrated successfully in recent projects. A prioritized roadmap is essential; the label “ELIXIR Community” would enable us to set priorities at a level above the individual projects. Existing components that will give this Community an initial boost, include, software (e.g. AMBIT with OpenTox API55), databases (e.g. diXa, eNanoMapper, AMBIT-LRI, NORMAN-SLE, MassBank), ontologies (e.g. the eNanoMapper ontology,56 AOP ontology57), interoperability concepts (e.g. annotation of OpenAPIs, in collaboration with bio.tools, semantic structural searches with IDSM), teaching/education material (Bioschemas annotation of outreach activities, in collaboration with TeSS), and virtual infrastructures (e.g. OpenRiskNet Virtual Research Environment and the NORMAN Digital Sample Freezing Platform). However, each of these approaches would benefit from integration in the ELIXIR Platforms (see examples in Table 1) and with Core and National Resources. Various existing ELIXIR Communities need similar solutions, e.g. for chemical structure handling, toxicology needs proteomics and metabolomics, toxicology involves human data, and ecotoxicology has significant impact on crops and health.\n\nEach step comes with a 10-year aim, further detailed with possible work that could be done in ELIXIR activities.\n\nThe following projects have been adopting and integrating FAIR toxicology concepts, but need integration with ELIXIR Platforms and Communities: eTOX, NanoCommons (NanoSafety Cluster), EU-ToxRisk, OpenRiskNet, OpenTox Foundation, Open PHACTS Foundation, and the diXa platform. Many other projects have a specific scientific focus but also need integration and some will work on the FAIR concepts. A non-exhaustive list is ACEnano, SmartNanoTox, HeCaToS, NewGeneris, EnviroGenoMarkers, EXPOsOMICS, HELIX, ASAT,58 PATROLS, and HEALS, as well as new projects e.g. new Horizon 2020 projects RISK-HUNT3R and HARMLESS and the new Horizon Europe project PARC. Companies and organisations will profit from this Community either as users or as providers of services on top of the infrastructure, including ECHA (FI), Edelweiss Connect (CH), IdeaConsult Ltd. (BG), Misvik Biology (FI), TNO (NL), Seven Past Nine (SI), and the Swedish Academic Consortium for Chemical Safety (SwACCS, SE). Industries showed a strong interest in toxicology, demonstrated by their activities: Cosmetics Europe was participant in the SEURAT-1 cluster; chemical industries (Nanotechnology Industries Association) are participant of the NSC; chemical branch organisation (Cefic) funds LRI projects around toxicology; pharmaceutical industries funds toxicology research via IMI projects like eTOX, eTRANSAFE, and Open PHACTS. The Research Data Alliance (RDA) organized a workshop recently about integration of toxicogenomics resources,59 and collaboration with international organizations has already been established with, for example, the CompTox Chemicals Dashboard team of the US EPA60 and PubChem from the US National Institutes of Health.61\n\n\nCompeting interests\n\nNone.\n\n\nGrant information\n\nThis work received funding from the European Union’s Horizon 2020 research infrastrcuture programme via the OpenRiskNet project under grant agreement No. 731075. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 681002 (EUToxRisk). This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 814572. SN acknowledges BMBF funding under grant number 031L0107. This work was supported by OBERON (https://oberon-4eu.com), a project funded by the European Union’s Horizon 2020 research and innovation program under the grant agreement No. 825712. This work was supported by the European Union,’s Horizon 2020 research and innovation program HBM4EU, grant agreement No. 733032 (https://www.hbm4eu.eu). Supported by the European Union’s Horizon 2020 programme under the Marie Skłodowska-Curie grant agreement No. 859891. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization. This work was supported by the European Union,’s Horizon 2020 research and innovation program HARMLESS, grant agreement No. 953183. This work was supported by the European Union,’s Horizon 2020 research and innovation program Gov4Nano, grant agreement No. 814401. This work was supported by the Swedish Fund for Research Without Animal Experiments under grant number N2020-0005. This work was supported by the European Union,’s Horizon 2020 research and innovation program NTS-EXPOSURE, Grant agreement ID: 896141. This work was supported by the European Union,’s LIFE program LIFE-APEX, Grant agreement ID: LIFE17 ENV/SK/000355. This study was funded by the German Environment Agency within the PHION project (grant number 3718 674150). The Data Readiness Group is supported, in this ELIXIR Community, by the H2020 Precision Toxicology project (H2020-EU 965406). The Data Readiness Group is supported, in this ELIXIR Community, by the Wellcome ISA-InterMine project (208381/A/17/Z). The Data Readiness Group is supported, in this ELIXIR Community, by the Wellcome FAIRsharing project (212930/Z/18/Z). This work received funding from the European Union’s Horizon 2020 research and innovation programme RiskGONE Project under grant agreement No. 814425. NR’s research is funded by a Miguel Servet contract (CO19/00060) from Instituto de Salud Carlos III, cofinanced by the European Union. UM (Uni. of Tartu) is grateful for support to Ministry of Education and Research, Republic of Estonia through Estonian Research Council (grant number IUT34-14) and to European Union European Regional Development Fund through Foundation Archimedes (grant number TK143, Centre of Excellence in Molecular Cell Engineering). Development and Implementation of a Sustainable Modelling Platform for NanoInformatics. Linking LRI Ambit chemoinformatic system with the IUCLID substance database to support read-across of substance endpoint data and category formation. This work was supported by the French Ministry of Research and National Research Agency as part of the French MetaboHUB, the national metabolomics and fluxomics infrastructure (Grant ANR-INBS-0010). This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement GOLIATH No. 825489.\n\n\nDisclaimer\n\n\n\n• Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization.\n\n• The views expressed in this manuscript are solely those of the authors and do not represent the policies of the U.S. Environmental Protection Agency. Mention of trade names of commercial products should not be interpreted as an endorsement by the U.S. Environmental Protection Agency.",
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Reference Source\n\nVitali F, Lombardo R, Rivero D, et al.: ONS: an ontology for a standardized description of interventions and observational studies in nutrition. Genes Nutr. 12, 2018; 13(1): 12. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAmstutz P, Crusoe MR, Nebojša TN, et al.: Common Workflow Language, v1.0. Specification, Common Workflow Language working group.2016. Reference Source"
}
|
[
{
"id": "124032",
"date": "21 Mar 2022",
"name": "Christopher Southan",
"expertise": [
"Reviewer Expertise Bioinformatics and cheminformatics (see LinkedIN)"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis wide-ranging review circumscribes an important data integration task with a major cat-herding dimension. Whilst also appearing herculean, this esteemed author collective fully understands what they are letting themselves in for and I wish them the best for this endeavor. It is, of course, early days, but I will make a few points (whether these might be addressed in a revision and blending in what other reviewers may come up with I will leave to the authors)\n\nHarvesting tox data from the extant and future literature seems to neither be specifically addressed nor proposed via direct interactions with the pharmaceutical companies generating most of it. Standardised data from their large historical internal sets only surfaces sparsely and heterogeneously public databases. Companies such as LahsaVtic, Instem, and ToxPlanet claim to have large databases compiled from the literature. Might ChEMBL come into the frame here if they could strategically increase their toxicology data extraction from the literature, both prospectively and retrospectively? (So far with only 24 assays)\n\nMy impression is there are simply too many resources mentioned for realistic overarching harmonisation. Could these be cut back to a smaller “active membership” prioritised by the amount of data they have and will continue to generate?\n\nQuote “standardized guidelines for data capture, approaches to integrate and connect across multiple databases”. As we know, this is going to be the really tough bit. It needs the major sources to share not only their data schema and metadata indexing but push for a level of convergence. It has to be said that ELIXIR does not have a good record on this. Unless I have missed it, none of the core data resources has made any significant changes in their individual (and often decades-old) data models to really enhance interoperability.\n\nPubChem has 113,110 compounds from ~ 30 annotation sources (although most relatively small) indexed under “PubChem Compound TOC: Toxicological Information” and toxicology-related submitting sources cover over 0.5 million substances. In addition, the term “toxicology” matches 3,774 BioAssays covering 86,068 compounds. This makes PubChem a de facto toxicology integration hub. The ELIXIR effort should consolidate and expand this, including where an increase in toxicology curation by ChEMBL could feed into BioAssay and thus become interoperative with the 294,000 biological activity data points already in there.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": [
{
"c_id": "10301",
"date": "17 Nov 2023",
"name": "Marvin Martens",
"role": "Author Response",
"response": "Point by point replies: This wide-ranging review circumscribes an important data integration task with a major cat-herding dimension. Whilst also appearing herculean, this esteemed author collective fully understands what they are letting themselves in for and I wish them the best for this endeavor. It is, of course, early days, but I will make a few points (whether these might be addressed in a revision and blending in what other reviewers may come up with I will leave to the authors) Thank you. Now that the first implementation study has been submitted, the first face-to-face is organized, we have a mailing list, things start to become more practical. Harvesting tox data from the extant and future literature seems to neither be specifically addressed nor proposed via direct interactions with the pharmaceutical companies generating most of it. Standardised data from their large historical internal sets only surfaces sparsely and heterogeneously public databases. Companies such as LahsaVtic, Instem, and ToxPlanet claim to have large databases compiled from the literature. Might ChEMBL come into the frame here if they could strategically increase their toxicology data extraction from the literature, both prospectively and retrospectively? (So far with only 24 assays) Data collection has not been written down as a core activity for this community. We will support the adoption by toxicology projects of the ELIXIR resources. ChEMBL and ChEBI along with a few more databases are ELIXIR services, but most of them with a particular focus. Interoperability with large databases, like PubChem, is obviously envisioned, as also stated in the second theme Table 3. Currently, the Toxicology Community will support sharing data, but not expect deposition nor open licenses. My impression is there are simply too many resources mentioned for realistic overarching harmonisation. Could these be cut back to a smaller “active membership” prioritised by the amount of data they have and will continue to generate? A broader ELIXIR Community does not exclude such smaller activities. See our relpy about the “open world” assumption to the other reviewer: let the Toxicology Community organically grow their community practices, extending, of course, on the core ELIXIR activities. Quote “standardized guidelines for data capture, approaches to integrate and connect across multiple databases”. As we know, this is going to be the really tough bit. It needs the major sources to share not only their data schema and metadata indexing but push for a level of convergence. It has to be said that ELIXIR does not have a good record on this. Unless I have missed it, none of the core data resources has made any significant changes in their individual (and often decades-old) data models to really enhance interoperability. We cannot comment here on the work of ELIXIR at large. So far, we have collaborated on interoperability with, for example, Bioschemas and do see convergence. The MolecularEntity and ChemicalSubstance types and profiles are adopted by a growing number of resources (e.g. ChEBI, Wikidata Scholia, MassBank) and EU projects (e.g. VHP4Safety, NanoCommons, NanoSolveIT). PubChem has 113,110 compounds from ~ 30 annotation sources (although most relatively small) indexed under “PubChem Compound TOC: Toxicological Information” and toxicology-related submitting sources cover over 0.5 million substances. In addition, the term “toxicology” matches 3,774 BioAssays covering 86,068 compounds. This makes PubChem a de facto toxicology integration hub. The ELIXIR effort should consolidate and expand this, including where an increase in toxicology curation by ChEMBL could feed into BioAssay and thus become interoperative with the 294,000 biological activity data points already in there. In absense of a “European PubChem”, the link with PubChem is indeed important. At the 2022 BioHackathon Europe, the Toxicology Community invited and worked with PubChem on interoperability. We have updated the manuscript to reflect this. At the end of the paper, just above “how to join”, two examples are added on collaboration with PubChem and with the EPA. See also the collaboration with Mortensen et al. (2022)., doi: 10.3389/ftox.2022.803983. Finally, there are other non-ELIXIR services of importance, like the international AOP-Wiki and the EPA CompTox Dashboard. Keeping our interactions with international organizations like the RDA, GO FAIR, and IUPAC continues to be important. Workshops, Face-to-Face meetings, Biohackathons, etc will formalize these interactions by making them practical."
}
]
},
{
"id": "124031",
"date": "08 Apr 2022",
"name": "Marta Eide",
"expertise": [
"Reviewer Expertise Environmental toxicology",
"endocrine disruption",
"bioinformatics",
"systems toxicology",
"marine toxicology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this opinion article, the authors describe the establishment of a new ELIXIR Toxicology Community in order to enable the transition from traditional disease-specific observational models to target-specific predictive models. The article introduces the rapidly developing field of toxicology and the interoperability issues arising in combining chemical and biochemical analysis, biological data, and kinetic modelling. The authors argue for “clear, standardized guidelines for data capture, approaches to integrate and connect across multiple datasets, clear data licensing for these data repositories, and tools that support accessing the data”. The ELIXIR Toxicology Community is suggested to 1) connect the different user communities (including industry, governmental agencies, NGOs, and more), 2) strongly contribute to link between, and harmonize the already existing relevant infrastructure projects, resources, and activities, and 3) provide useful tools, guidelines, and training.\nAcknowledging the vast number of chemicals that are currently being produced, and the limited knowledge of the consequences of exposure to humans and the environment, this is a timely and important effort. From my impression, an ELIXIR Community is a good tool to drive and coordinate such an international initiative.\nI find the article comprehensive and well-written, and their arguments well discussed. However, I have some points that I hope the authors will take into consideration when taking the initiative further:\nIt is early stated that “in this ELIXIR Community, the focus will be primarily on the protection of human health”. I would argue that this is an unfavorable restriction for three reasons:\nIt disregards the ‘OneHealth approach’ recognized by WHO, FAO, OIE, and UNEP, which is defined as “an integrated, unifying approach that aims to sustainably balance and optimize the health of people, animals and ecosystem. It recognizes the health of humans, domestic and wild animals, plants, and the wider environment (including ecosystems) are closely linked and inter-dependent” (One Health High-Level Expert Panel Annual Report 2021). EFSA, ECHA, EMA et al. are also organizing a conference on the topic in June 2022 (https://www.one2022.eu). Seeing that animals and ecosystems are closely linked to human health, for example through foods, their responses to and effects from toxicant exposures are also highly important to study and include in risk assessments.\n\nLive animals, as well as animal tissue, cells, and molecules, are often used as models for toxicological studies. As the toxicological defense systems are highly preserved through evolution, they can give a good indication of human outcomes. Thus, it is important to also ensure supporting infrastructure for integrating these as well.\n\nOntologies, standards, and data resources (like omics repositories, data analysis tools, etc.) are often already overlapping.\n\nAlthough I welcome different stakeholders being identified as “user communities”, I am concerned by the, from my understanding, lack of industry and governmental/administrative agencies in the author list of this article. I believe that if the aim of improving FAIR data integration for safety to enable ultimate risk assessments is to be met, it is eminent to include non-academic perspectives, experiences, and concerns into the initiative from early on. Experiences from the PARC project could for example be useful in how to approach this.\n\nFrom my experience, the field of toxicology in general has limited experience with FAIR data management and is not familiar with the resources that are in place. I see that toxicologists’ communication, dissemination, and training are mentioned in the proposed roadmap, but I am missing a more targeted approach to engaging with the communities. For example, such activities could include organizing toxicology-specific workshops, presenting at toxicology conferences, and targeted information through different channels. As the proposed ELIXIR Community seems to have a good overview of ongoing initiatives and infrastructures and a good anchoring in the scientific community, a mapping of their target audience and users in the field could be suggested as a starting point.\n\nAs mentioned in the paper, systems biology approaches are also getting implemented in toxicology, i.e. systems toxicology (described in Sturla et al., 20141. From my point of view, I am missing mentioning of tools for this, such as the FAIRDOM SEEK platform that integrates ISA-structured metadata and workflows with JWS-based biological systems modelling. However, there might already be other solutions for this that I don’t recognize in the paper\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": [
{
"c_id": "10300",
"date": "17 Nov 2023",
"name": "Marvin Martens",
"role": "Author Response",
"response": "Point by point replies: In this opinion article, the authors describe the establishment of a new ELIXIR Toxicology Community in order to enable the transition from traditional disease-specific observational models to target-specific predictive models. The article introduces the rapidly developing field of toxicology and the interoperability issues arising in combining chemical and biochemical analysis, biological data, and kinetic modelling. The authors argue for “clear, standardized guidelines for data capture, approaches to integrate and connect across multiple datasets, clear data licensing for these data repositories, and tools that support accessing the data”. The ELIXIR Toxicology Community is suggested to 1) connect the different user communities (including industry, governmental agencies, NGOs, and more), 2) strongly contribute to link between, and harmonize the already existing relevant infrastructure projects, resources, and activities, and 3) provide useful tools, guidelines, and training. Acknowledging the vast number of chemicals that are currently being produced, and the limited knowledge of the consequences of exposure to humans and the environment, this is a timely and important effort. From my impression, an ELIXIR Community is a good tool to drive and coordinate such an international initiative. We are happy to read that Dr. Eide agrees with our observation. I find the article comprehensive and well-written, and their arguments well discussed. However, I have some points that I hope the authors will take into consideration when taking the initiative further: It is early stated that “in this ELIXIR Community, the focus will be primarily on the protection of human health”. I would argue that this is an unfavorable restriction for three reasons. It disregards the ‘OneHealth approach’ recognized by WHO, FAO, OIE, and UNEP, which is defined as “an integrated, unifying approach that aims to sustainably balance and optimize the health of people, animals and ecosystem. It recognizes the health of humans, domestic and wild animals, plants, and the wider environment (including ecosystems) are closely linked and inter-dependent” (One Health High-Level Expert Panel Annual Report 2021). EFSA, ECHA, EMA et al. are also organizing a conference on the topic in June 2022 (https://www.one2022.eu). Seeing that animals and ecosystems are closely linked to human health, for example through foods, their responses to and effects from toxicant exposures are also highly important to study and include in risk assessments. This choice is based on the earlier focuses of ELIXIR itself. We agree that a wider idea of toxicology is important and we note that ELIXIR actually has broadened its focus too. We have updated the text to “will be on the focus areas of ELIXIR, including the protection of human, animal, and environmental health.” Live animals, as well as animal tissue, cells, and molecules, are often used as models for toxicological studies. As the toxicological defense systems are highly preserved through evolution, they can give a good indication of human outcomes. Thus, it is important to also ensure supporting infrastructure for integrating these as well. Ontologies, standards, and data resources (like omics repositories, data analysis tools, etc.) are often already overlapping. The Toxicology Community is whenever possible using the ELIXIR Core Resources, and we note data Core and Node Services (https://elixir-europe.org/services) like Ensembl, deposition databases, and WikiPathways capture knowledge across species and often visualize homology where applicable. Indeed, the opportunity as an ELIXIR Community is that we can benefit from these overlaps, see the third roadmap theme in Table 3. Although I welcome different stakeholders being identified as “user communities”, I am concerned by the, from my understanding, lack of industry and governmental/administrative agencies in the author list of this article. I believe that if the aim of improving FAIR data integration for safety to enable ultimate risk assessments is to be met, it is eminent to include non-academic perspectives, experiences, and concerns into the initiative from early on. Experiences from the PARC project could for example be useful in how to approach this. This concern is shared. The way ELIXIR is set up, industry cannot be a direct beneficiary of ELIXIR funding. This reflects on the Toxicology Community. We expect to overcome this in various ways: the user communities and community members themselves do include the industries, e.g. via the EU-funded projects or projects like PARC; second, ELIXIR has dedicated industry-oriented activities, which we plan to take advantage of too. At the time of writing, the latter had not yet materialized. Our first Toxicology Community face-to-face meeting was/is actually co-located with a PARC meeting in Brussels, besides that multiple co-authors are members in PARC. This interaction with PARC also involves the Toxicology Community Implementation Study, which will involve focused workshops on various aspects that were presented in the Toxicology Community roadmap. One of the proposed workshops is aimed at leveraging FAIR solutions for Adverse Outcome Pathways, with a practical case study that is aligned with the PARC project. From my experience, the field of toxicology in general has limited experience with FAIR data management and is not familiar with the resources that are in place. I see that toxicologists’ communication, dissemination, and training are mentioned in the proposed roadmap, but I am missing a more targeted approach to engaging with the communities. For example, such activities could include organizing toxicology-specific workshops, presenting at toxicology conferences, and targeted information through different channels. As the proposed ELIXIR Community seems to have a good overview of ongoing initiatives and infrastructures and a good anchoring in the scientific community, a mapping of their target audience and users in the field could be suggested as a starting point. Indeed, projects like NanoCommons, VHP4Safety, RiskGONE, Gov4Nano have done research into how to “do” FAIR in Toxicology. The Toxicology Community will help channel this exchange of your gained insights. The use of the ELIXIR training platform TeSS in the whitepaper is a specific example activity in this area. We now also added an additional note in Table 3 to emphasize the need for dissemination of FAIR solutions by “organising and participating in e.g. toxicology-specific workshops, toxicology conferences, and through other targeted dissemination channels”. In reality, we have already presented the Toxicology Community aims at various toxicology and computation biology meetings and conferences. As mentioned in the paper, systems biology approaches are also getting implemented in toxicology, i.e. systems toxicology (described in Sturla et al., 20141. From my point of view, I am missing mentioning of tools for this, such as the FAIRDOM SEEK platform that integrates ISA-structured metadata and workflows with JWS-based biological systems modelling. However, there might already be other solutions for this that I don’t recognize in the paper This paper is a whitepaper where we tried to find a balance with a high-level sketch and some practical examples based on already ongoing activities. There are a lot of possibilities, more than ELIXIR will be able to support (financially or resource wise). We will have to continously look for activities between ELIXIR (and projects ELIXIR is involved in) and funded toxicology projects. For example, the first Toxicology Community face-to-face meeting is/was focused on seeking synergies and collaboration with PARC. Therefore, where this whitepaper does not mention something, this does not imply the unmentioned approach (such as the FAIRDOM SEEK platform as Dr. Eide mentions) is excluded. In other words, this whitepaper is written with an “open world” assumption. We have added a ‘how to join’ section at the end of the article."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1129
|
https://f1000research.com/articles/10-1161/v1
|
16 Nov 21
|
{
"type": "Research Article",
"title": "Effect of cogon grass root ethanol extract on fatty acid binding protein 4 and oxidative stress markers in a sepsis mouse model",
"authors": [
"Mirasari Putri",
"Bening Mauliddina Rastiarsa",
"Raden Aliya T. M. Djajanagara",
"Ghaliby Ardhia Ramli",
"Neni Anggraeni",
"Nugraha Sutadipura",
"Nur Atik",
"Mas Rizky A. A. Syamsunarno",
"Mirasari Putri",
"Bening Mauliddina Rastiarsa",
"Raden Aliya T. M. Djajanagara",
"Ghaliby Ardhia Ramli",
"Neni Anggraeni",
"Nugraha Sutadipura",
"Nur Atik"
],
"abstract": "Background: Sepsis causes several immunological and metabolic alterations that induce oxidative stress. The modulation of fatty acid-binding protein 4 (FABP4) has been shown to worsen this condition. Extract of cogon grass root (ECGR) contains flavonoids and isoeugenol compounds that exhibit anti-inflammatory and antioxidant properties. This study aimed to assess the effects of ECGR on FABP4 and oxidative stress–related factors in a sepsis mouse model. Methods: Twenty-nine male mice (Mus musculus) of the Deutsche Denken Yoken strain were divided into four groups: group 1, control; group 2, mice treated with 10 μL/kg body weight (BW) lipopolysaccharide (LPS); and groups 3 and 4, mice pre-treated with 90 and 115 mg/kg BW, respectively, and then treated with 10 μL/kg BW LPS for 14 d. Blood, liver, spleen, and cardiac tissue samples were collected and subjected to histological and complete blood examinations. Antioxidant activity, FABP4 levels, and immune system-associated biomarker levels were also measured. Results: Significant increases in platelet levels (p = 0.03), cardiomyocyte counts (p =0.004), and hepatocyte counts (p = 0.0004) were observed in group 4 compared with those in group 2. Conversely, compared with those in group 2, there were significant decreases in TNF-α expression in group 3 (p = 0.004), white pulp length and width in group 4 (p = 0.001), FABP4 levels in groups 3 and 4 (p = 0.015 and p = 0.012, respectively), lymphocyte counts in group 4 (p = 0.009), monocyte counts (p = 0.000) and polymorphonuclear cell counts in the livers (p = 0.000) and hearts (p = 0.000) of groups 3 and 4. Gpx3 activity was significantly higher in group 3 than in group 1 (p = 0.04). Conclusions: Cogon grass root may aid in the development of herbal medicines and specific treatments for sepsis.",
"keywords": [
"Cogon grass",
"FABP4",
"sepsis",
"oxidative stress",
"inflammation"
],
"content": "Introduction\n\nSepsis significantly contributes to morbidity, mortality, and healthcare expenditure worldwide, with approximately 20 million cases of sepsis occurring each year.1 According to the 2015 International Multicenter Prevalence Study on Sepsis (IMPRESS STUDY), Asia has the highest global sepsis morbidity rate.2 Sepsis is a life-threatening condition characterized by unregulated systemic inflammation and oxidative responses to infection that can cause organ damage.3 Sepsis involves several molecular mechanisms of inflammation and cell damage, including the release of cytokines, eicosanoids, and free radicals.4 Specifically, free radicals may mediate cell damage and contribute to the development of liver, spleen, and heart failure,5–7 resulting in multiple organ failure (MOF) and mortality.8 In mammals, glutathione peroxidase (GPx) and superoxide dismutase (SOD) are the main antioxidants that protect cells from damage caused by free radicals through synergistic action.9,10\n\nIn addition to the immunologic response and oxidative stress, various metabolic alterations also occur in sepsis. Serious infections cause increased lipolysis of adipose tissue, allowing free fatty acids (FFAs) to be used for triglyceride synthesis in the liver.11,12 This phenomenon aligns with the high levels of triglycerides and FFAs found in patients in sepsis, which are associated with reduced hepatic fatty acid oxidation.12,13 Specifically, cytosolic fatty acid-binding protein 4 (FABP4, or adipocyte protein 2) is a lipid chaperone that regulates lipid transport in adipocytes and macrophages.14 Recent studies have found that FABP4 increases the severity of inflammation-related diseases by elevating the expression of cytokines, such as TNF-α, IL-1, IL-6, and monocyte chemo-attractant protein 1 (MCP 1).15 In contrast, deletion of the FABP4 gene protects against the inflammatory activity of macrophages and adipocytes. Furthermore, inhibition of FABP4 through pharmacological intervention was found to mitigate LPS-induced tissue damage and improve the survival rate in mice.16 Previous studies have shown that systemic infection jeopardizes the liver by damaging parenchymal cells. In response to the FABP4-induced release of proinflammatory cytokines, especially TNF-α, Kupffer cells in the liver produce IL-6.17,18\n\nThe pathophysiology of sepsis can be studied in a sepsis mouse model injected with bacterial lipopolysaccharide (LPS).19 LPS is the main endotoxin component of the membrane of gram-negative bacteria. It activates macrophages by triggering the toll-like receptor 4 (TLR4) signaling pathway within Kupffer cells and inducing inflammatory cytokine release.20 LPS play a vital role in acute and chronic inflammation,21 including that caused by gram-negative bacteria in sepsis.19\n\nImperata cylindrica (L.), commonly known as cogon grass, is used to treat multiple conditions, such as fever, hepatitis, dysentery, diarrhea, hepatitis, typhus muscle pain, cancer, and hypertension.22–24 Phytochemical screening has shown that extract of cogon grass root (ECGR) contains potent antioxidants, including isoeugenin, tannins, saponins, flavonoids, terpenoids, and alkaloids.24,25 Specifically, isoeugenin demonstrates potent antioxidant activity through nitrite oxide (NO) scavenging, significantly inhibiting the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and proinflammatory mRNA, which play essential roles in sepsis.26 However, the use of cogon grass root for the treatment of sepsis has not been explored. Therefore, this study aimed to investigate the effect of ECGR on a mouse model of sepsis. We hypothesized that ECGR would ameliorate sepsis by reducing inflammatory responses and oxidative damage via antioxidant activity.\n\n\nMethods\n\nEthical clearance was granted by the Research Ethics Committee of Universitas Padjadjaran, Bandung, Indonesia (approval number: 921/UN6.KEP/EC/2019).\n\nCogon grass was obtained from Solo, Central Java, Indonesia, and its authenticity was tested by the Bandung Institute of Technology. The roots of the cogon grass were separated, washed with water, and dried for two weeks. The roots were then macerated, filtered, and extracted. The extract was filtered and separated from the solvent using a vacuum rotary evaporator R220 pro (BUCHI Indonesia, Tangerang, Indonesia). The ECGR was then diluted in 0.5% carboxymethylcellulose (CMC) (Merck, U.S.A) and administered at a dose of either 90 or 115 mg/kg body weight (BW), as in our previous study.27\n\nMale mice (Mus musculus sp.) of the Deutsche Denken Yoken strain (8–10 weeks of age, 30–35 g body weight) were provided by the Biofarma Company (Bandung, Indonesia). All efforts were made to relieve any pain and distress of the animals by strictly following the procedures. The mice were acclimatized for seven days in the laboratory. They were then kept in cages at the animal laboratory of Universitas Padjadjaran at a controlled room temperature and on a 12 hours light/12 hours dark cycle. The mice were provided regular food, drinking water ad libitum, observed daily to confirm lack of behavior, and weighed every three days. This study was conducted following the ARRIVE Essential 2.0 checklist for pre-clinical animal studies.\n\nA randomized post-test control group design was used. Determination of the number of samples for each treatment group was determined using the Frederer formula. The mice were divided into the following four experimental groups (5–8 mice per group; 29 mice total): group 1 (control), mice treated with CMC 0.5% (the solvent of ECGR); group 2, mice treated with CMC 0.5% + 10 μL/kg BW LPS; group 3, mice treated with 10 μL/kg BW LPS + 90 mg/kg BW ECGR; and group 4, mice treated with 10 μL/kg BW LPS + 115 mg/kg BW ECGR.\n\nBriefly, groups 1 and 2 were treated with 0.5% CMC, while groups 3 and 4 were treated with ECGR in 0.5% CMC at doses of 90 and 115 mg/kg BW, respectively, for two weeks. The mice were weighed every 3 days to determine the effects of ECGR on body weight. The ECGR solutions were administered daily for two weeks, between 3 and 5 pm.27 After two weeks, groups 2, 3, and 4 were injected intraperitoneally with LPS (10 μL//kg BW; Sigma-Aldrich, St. Louis, MO) diluted in 50 μL PBS, as in previous studies.28 At 8 hours after injection, the mice were euthanized by cervical dislocation, and portions of their livers, spleens, and hearts were snap-frozen in liquid nitrogen and stored at −80 °C until further use. The remaining liver, spleen, and heart tissues were processed for histological examination.\n\nBlood was collected from the inferior vena cava. A complete blood count profile (CBCP) was drawn automatically using the CLIA Waived Hematology Analyzer Sysmex XW-100 (Sysmex America, Lincolnshire, U.S.A). Serum was separated by centrifugation at 1,500 × g for 15 minutes at 4 °C, and the lysates were stored at −80 °C until further examination.\n\nLiver, spleen, and heart tissues were prepared for histopathological evaluation using the Kiernan method.29 Briefly, they were fixed in 4% paraformaldehyde, embedded in paraffin, and stained with hematoxylin and eosin (H&E) according to the Harris method.30\n\nGPx3 activity was measured using a commercial kit Randox-Backpack RS 505 (RANDOX Laboratories Ltd, Antrim, U.K), following the method described by Paglia and Valentine (1967).31 Briefly, Glutathione Peroxidase (GPx) catalyses the oxidation of Glutathione (GSH) by Cumene Hydroperoxide. In the presence of Glutathione Reductase (GR) and NADPH the oxidised Glutathione (GSSG) is immediately converted to the reduced form with a concomitant oxidation of NADPH to NADP+. The decrease in absorbance at 340 nm is measured.\n\nFABP4 levels in the samples were measured using commercial enzyme-linked immunosorbent assay (ELISA) kits Mouse FABP4 ELISA Kit, catalog number EM1506 (Fine Biotech, Wuhan, China) according to the manufacturer's protocol.\n\nTotal RNA was isolated from the organs using TRIzol™ Reagent catalog number 15596026 (Invitrogen, Massachusetts, US). DNA synthesis was performed using ReverTra AceTM qPCR RT Master Mix with gDNA Remover product number FSQ-301 (Toyobo, Osaka, Japan) according to the manufacturer's protocol. Quantitative real-time RT-PCR was performed using the SensiFAST™ SYBR ® No-ROX Kit product number BIO-98020 (Bioline, United Kingdom) according to the manufacturer's instructions and used Rotor-Gene Q quantitative real-time PCR machine (Qiagen, USA). The first step of Quantitative real-time RT-PCR was polymerase activation for one cycle at 95 °C for two minutes, then denaturation prosses at 95 °C for five seconds and annealing at 60 °C for 30 seconds. The denaturation and annealing process took 40 cycles. The PCR was performed using mGAPDH as a housekeeping gene and the primers from Integrated DNA Technologies, USA. The gene-specific primers for the cDNA used in this study are listed in Table 1.\n\nStatistical analyses were performed using the GraphPad Prism version 7.0a for Mac (GraphPad Software, Inc. CA, 92037 USA). Normally distributed data are represented as the mean ± SD and skewed data as the median ± interquartile range (IQR). Normality was assessed using the Shapiro-Wilk test. The p-values were calculated using analysis of variance (ANOVA) with Tukey’s post hoc test for normal distributions and the Kruskal-Wallis test with Dunn’s post hoc test for skewed distributions. Differences were considered statistically significant at p < 0.05 (for two-tailed p-values).\n\n\nResults\n\nIn the blood profiles, platelet levels were significantly lower in group 2 (LPS treatment only) than in group 1 (control) (417.6 × 103 vs. 732.60 × 103 cells/μL, p < 0.01). Additionally, platelet levels were significantly higher in group 4 (115 mg/kg ECGR) than in group 2 (550.3 × 103 vs 417.6 × 103 cells/μL, p < 0.05; Figure 1). Conversely, LPS induced a substantial increase in the lymphocyte and monocyte counts in group 2 compared with those in the control (lymphocytes: 4.13 × 103 vs. 2.26 × 103 cells/μL, p < 0.05; monocytes: 0.84 × 103 vs. 0.37 × 103 cells/μL, p < 0.05). In addition, a significant decrease in the lymphocyte count was observed in group 4 compared with that in group 2 (2.26 × 103 vs. 4.13 × 103 cells/μL, p < 0.05). Furthermore, significant decreases in the monocyte count were observed in groups 3 and 4 compared with that in group 2 (0.43 × 103 and 0.29 × 103, respectively, vs. 0.84 × 103 cells/μL, p < 0.05). Finally, a significant increase in the leukocyte count was observed in group 2 compared with that in group 1 (6.19 × 103 vs. 3.05 × 103 cells/μL, p < 0.05). However, no significant difference in the leukocyte count was observed between the treatment groups (Figure 1).\n\nGroup 1, control; group 2, mice stimulated with LPS; groups 3 and 4, mice treated with 90 and 115 mg/kg BW ECGR, respectively, and stimulated with LPS. Data are represented as the mean ± SD, n = 5–8 per group. One-way ANOVA with Tukey's post hoc test and the Kruskal-Wallis test with Dunn's post hoc test were performed for normal and skewed data, respectively. *p < 0.05, significant; **p < 0.01, very significant.\n\nGroup 2 exhibited a significantly decreased percentage of packed cell volume (PCV) compared with that in the control (0.15% vs. 0.26%, Figure 2). Additionally, group 4 also showed a decreased PCV percentage compared with that in group 2, although the difference was not statistically significant.\n\nGroup 1, control; group 2, mice stimulated with LPS; groups 3 and 4, mice treated with 90 and 115 mg/kg BW ECGR, respectively, and stimulated with LPS. Data are represented as the mean ± SD, n = 5–8 per group. One-way ANOVA with Tukey's post hoc test and the Kruskal-Wallis test with Dunn's post hoc test were performed for normal and skewed data, respectively. *p < 0.05, significant; **p < 0.01, very significant. Abbreviations: PCV, packed cell volume; MPV, mean platelet volume; PDW, platelet distribution width; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration.\n\nThe typical architectural structures of the liver, heart, and spleen tissues were observed in group 1. Additionally, neither necrosis or apoptosis were observed, and the hepatic sinusoids and heart vessels were not dilated. In group 2, abnormalities in the architectural structures of the three organs were observed. Several areas of necrosis, cellular swelling, vessel dilation, and inflammatory cell infiltration, especially that of PMNs, were observed. In contrast, fewer areas of necrosis and cellular swelling were observed in the treatment groups (groups 3 and 4). In addition, the treatment groups demonstrated reduced PMN infiltration (Figure 3).\n\nGroup 1, control; group 2, mice stimulated with LPS; groups 3 and 4, mice treated with 90 and 115 mg/kg BW ECGR, respectively, and stimulated with LPS. Abbreviations: Nc, necrotic area of hepatocyte; Ap, apoptotic hepatocytes; SD, sinusoidal dilatation; PMN, polymorphonuclear cell; NS, normal sinusoid; NH, normal hepatocyte; NM, necrotic area of the myocardium; VD, vascular dilatation; NC, normal cardiomyocyte; LN, lymph node; WP, white pulp; RP, red pulp.\n\nECGR significantly affected the numbers of PMN cells and hepatocytes in the liver tissues. In the mice treated with only LPS (group 2), an increase in the number of PMN cells and significant decrease in that of hepatocytes were observed. Conversely, a decrease in the number of PMN cells and significant increase in that of hepatocytes were observed in the groups treated with ECGR (groups 3 and 4; Figure 4).\n\nGroup 1, control; group 2, mice stimulated with LPS; groups 3 and 4, mice treated with 90 and 115 mg/kg BW ECGR, respectively, and stimulated with LPS. Data are represented as the mean ± SD, n = 5–8 per group. One-way ANOVA with Tukey's post hoc test and the Kruskal-Wallis test with Dunn's post hoc test were used for normal and skewed data, respectively. *p < 0.05, significant; **p < 0.01, very significant; ***p < 0.001, extremely significant.\n\nSimilar conditions were observed in the heart, with significant differences in cardiomyocyte numbers in groups 1 and 4 compared with those in group 2 (277.3 and 251.6 vs. 212.5 cells; p < 0.01). There was also increased dilatation in the length and width of the white pulp lymph vasculature in the group treated with LPS compared with that in the control group, although the difference was not statistically significant. In contrast, there was a significant difference in length (p < 0.05) and width (p < 0.01) between groups 2 and 4 (Figure 4).\n\nThe GPx activity of the mice in group 3 was significantly higher than that in group 1 (585.9 vs. 876.5 U/L), p < 0.05; Figure 5). We also found that the LPS-treated groups developed significantly higher FABP4 expression than the control (27.69 vs. 3.98 pg/mL, p < 0.01; Figure 6). Compared with that in group 2, FABP4 expression was suppressed in groups 3 and 4 (the ECGR treatment groups) (27.69 vs. 5.19 and 6.55 pg/mL, p < 0.05).\n\nGroup 1, control; group 2, mice stimulated with LPS; groups 3 and 4, mice treated with 90 and 115 mg/kg BW ECGR, respectively, and stimulated with LPS. Data were analyzed via the Kruskal-Wallis test with Dunn's post hoc test. *p < 0.05, significant.\n\nGroup 1, control; group 2, mice stimulated with LPS; groups 3 and 4, mice treated with 90 and 115 mg/kg BW ECGR, respectively, and stimulated with LPS. Data were analyzed via the Kruskal-Wallis test with Dunn's post hoc test. *p < 0.05, significant.\n\nWe also observed a significant increase in the expression of TNF-α and IL-6 in group 2 compared with that in the control group (p < 0.05). However, a significant decrease in TNF-α expression was observed in group 3 compared with that in group 2 (p < 0.05). Decreased expression of IL-6 and IL-1β was also observed in group 4, although the differences were not statistically significant. No significant differences in the expression of SOD1 and SOD2 were observed among the groups (Figure 7).\n\nGroup 1, control; group 2, mice stimulated with LPS; groups 3 and 4, mice treated with 90 and 115 mg/kg BW of ECGR, respectively, and stimulated with LPS. Data are represented as the mean ± SD, n = 5–8 per group. One-way ANOVA with Tukey's post hoc test and the Kruskal-Wallis test with Dunn's post hoc test were performed for normal and skewed data, respectively. *p < 0.05, significant; **p < 0.01, very significant.\n\n\nDiscussion\n\nOverall, ECGR treatment provoked robust increases in platelet levels, GPx3 activity, hepatocyte numbers, and cardiomyocyte numbers. Treatment also induced decreases in lymphocyte numbers, monocyte numbers, TNF-α levels, and FABP4 levels. Furthermore, the expression of other related septic proinflammatory cytokines, including IL-6 and IL-1β, was also decreased by ECGR.\n\nSepsis is a systemic response that endangers the body, causing organ hypofunction and even death.32 The pathogenesis of sepsis is complex due to the involvement of various immune components. In experimental animals, LPS treatment causes the same pathophysiological changes as sepsis in humans.33 This is due to the presence of LPS-binding protein (LBP) in the blood and extracellular fluid, which binds to lipid A (the bioactive part of LPS) and carries LPS to cluster of differentiation 14 (CD14) in monocytes, macrophages, and neutrophils.34 The interaction between the LBP-LPS complex and the CD14 receptor allows LPS to bind to TLR4, signaling the cell nucleus to stimulate the production and release of inflammatory mediators.35 These inflammatory mediators activate the endothelium, causing increased expression of adhesion molecules, such as selectin-E, intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), which serve as ligands for leukocyte integrins. The proinflammatory cytokines also enhance the proliferation and differentiation of naive T lymphocytes into effector T lymphocytes. In addition, TNF-α and IL-1 increase the secretion of chemokines, such as CXCL1 and CCL2, which bind to neutrophils and monocytes, respectively. This increases the affinity of leukocyte integrins for their ligands and enhances leukocyte migration.35,36\n\nIn this study, leukocyte, monocyte, and lymphocyte counts were observed to be significantly increased in the group treated with LPS alone (group 2) compared with those in the control (group 1; Figure 1). However, no significant differences were observed between these cell counts in the treatment groups (groups 3 and 4) and those in group 2. Increased PMN cell counts were also observed in group 2 via histopathological quantification (Figures 3, 4). In addition, significant decreases in the lymphocyte and monocyte counts were observed in the treatment groups compared with those in group 2 (Figure 1). The PMN cell count in groups 3 and 4 was also decreased compared with that in group 2, as observed in the histopathological analysis (Figure 4). These observations were likely due to ECGR treatment.\n\nPrevious studies have found that ECGR contains phenols in the form of flavonoids and isoeugenin.25,26,37 Phytochemical screening has shown that the flavonoid content of cogon grass root is 4.8%.37 Hyo-Jin An et al. also reported the isoeugenin content of cogon grass as approximately 0.268 mg/g dry ECGR.26\n\nFlavonoids are known to inhibit inflammatory reactions. Their mechanism may involve the recruitment and regulation of neutrophils through chemokines, IL-8, and leukotriene B4.38 This mechanism has also been observed in isoeugenol, which specifically decreases the expression of proinflammatory cytokines.26 This is consistent with our results, which demonstrated significant decreases in TNF-α expression in group 3. IL-6 and IL-1β expression was also decreased in group 4, although not significantly (Figure 7). Thus, ECGR demonstrated potential anti-inflammatory activity through the inhibition of lymphocytes, monocytes, and PMN cell infiltration in the livers and hearts of mice with LPS-induced sepsis.\n\nProinflammatory cytokines play essential roles in sepsis through several pathways. Specifically, activation of the TLR4 signaling pathway21 causes plasminogen stimulation and the activation of antithrombin III in the fibrinolysis system. These effects trigger fibrinolysis, causing depletion of fibrinogen substances, induction of disseminated intravascular coagulation, and increased platelet damage.39 The pathogenesis of sepsis also involves the formation of free radicals. Endotoxins produced during sepsis induce mitochondrial production of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and hydroxyl.33,40 This further stimulates ROS production in endothelial cells, leading to perpetual free radical production. ROS cause macrostructural changes in the mitochondria that ultimately lead to the dysfunction of multiple organs.40 In addition, ROS production induces damage through the pathological redox cycle, which occurs independently, leading to cell damage and enhanced apoptosis of cardiomyocytes and hepatocytes.41,42\n\nThe flavonoids and isoeugenin in ECGR also demonstrate antioxidant properties through the inhibition of NO activity and iNOS, COX-2, and nuclear factor-kappa B (NF-κB) expression. These substances play essential roles in the perpetuation of the pathological redox cycle that damages cells.38,43 Thus, the sustained numbers of hepatocytes and cardiomyocytes in the sepsis mouse model may be attributed to the two-week ECGR pre-treatment.44 In this study, group 4 demonstrated improvement in the liver and heart tissues and increased hepatocyte and cardiomyocyte numbers compared with those in group 2 (Figures 3, 4).\n\nFlavonoid antioxidants are considered secondary, exogenous, or non-enzymatic antioxidants. Primary antioxidants, such as SOD, catalase (Cat), and GPx, are produced endogenously. Deficiencies in GPx, which is the first-line defense against oxidative stress, have previously been found to be associated with sepsis.45 In this study, the GPx3 activity in group 3 was significantly higher than that in group 1 (Figure 5). In contrast, no significant differences in the expression of SOD1 and SOD2 were observed among the groups (Figure 7).\n\nEnhanced proinflammatory release and LPS activity in sepsis have been found to cause immunologic and metabolic alterations, especially of lipid metabolism.46,47 Higher fatty acid levels in patients with sepsis are associated with increased lipolysis due to reductions in mitochondrial acyl-CoA synthetase (ACS), which aids the synthesis of triglycerides for energy storage. LPS and cytokine release are also associated with lower ACS expression, thereby assisting the mobilization of FAs.12 A previous study has shown that increased levels of FABP4 are associated with a robust inflammatory response in septic conditions.15 We observed a remarkable increase in FABP4 levels after LPS induction in group 2. In contrast, the mice pre-treated with ECGR (groups 3 and 4) exhibited decreased FABP4 expression (Figure 6). This may be attributed to the ability of FABP4 to modulate the NF-kB pathway, resulting in the expression of inflammasome complexes (e.g., NLR family pyrin domain containing 3 [NLRP3] and pro-IL-1β). In addition, NLRP3 activation is associated with the overproduction of IL-1β, resulting in detrimental effects in sepsis.48,49 Inhibition of FABP4 expression through surgical and pharmacological interventions may alleviate LPS-induced tissue damage.15,50\n\nCogon grass root contains flavonoids that phenotypically demonstrate anti-inflammatory effects. Quercetin and icariin, which are kaempferol derivatives, have been shown to demonstrate prominent inhibition of FABP4 expression.51,52 The attenuation of FABP4 in macrophages subsequently inhibits the NF-kB pathway through induction of SIRT3 and diminishes proinflammatory cytokine production.50,53 Quercetin also suppresses NF-kB activation and blocks NLRP3 inflammasome activation.54 These findings suggest that cogon grass root may exhibit direct and indirect inhibitory effects on FABP4 and associated protein complex expression in inflammatory pathways. The limitation of this study was that we did not measure the active substance of ECGR and did not pursue an in vitro study to explore the mechanism of ECGR in sepsis conditions\n\n\nConclusions\n\nIn this study, we established that ECGR played a beneficial role in mitigating severe conditions in a sepsis mouse model. This suggests that cogon grass root may ameliorate sepsis by increasing the platelet level, GPx3 activity, hepatocyte count, and cardiomyocyte count, as well as by reducing the lymphocyte count, monocyte count, TNF-α expression, and FABP4 level. Further understanding of the mechanisms involved in the metabolic and inflammatory effects of cogon grass root is needed. This requires continued exploration of the TLR pathway and other metabolic markers associated with sepsis. Our findings emphasized the potential of cogon grass root as an herbal medicine for sepsis.\n\n\nData availability\n\nFigshare: Data measurement of Sepsis Mice Model with Ethanol Extract of Cogon Grass Root (Imperata cylindrica L.) pre-treament, https://doi.org/10.6084/m9.figshare.16530654.v8.55\n\nFigshare: Original unedited histopathology image of the liver, heart, and spleen of a sepsis mouse model after pre-treatment with ECGR, https://doi.org/10.6084/m9.figshare.16894813.v2.56\n\nThis project contains the following underlying data:\n\n- Spleen, group 4, 115 mgkg BW ECGR + LPS.jpg\n\n- Spleen, group 3, 90 mgkg BW ECGR + LPS.jpg\n\n- Spleen, group 2, mice stimulated with LPS.jpg\n\n- Spleen, group 1, control.jpg\n\n- Heart, group 4, 115 mgkg BW ECGR + LPS.jpg\n\n- Heart, group 3, 90 mgkg BW ECGR + LPS.jpg\n\n- Heart, group 2, mice stimulated with LPS.jpg\n\n- Heart, group 1, control.jpg\n\n- Liver, groups 4, 115 mgkg BW ECGR + LPS.jpeg\n\n- Liver, groups 3, 90 mgkg BW ECGR + LPS.jpeg\n\n- Liver, group 2, mice stimulated with LPS.jpeg\n\n- Liver, group 1, control.jpeg\n\nFigshare: ARRIVE Essential 10 checklist-Effect of cogon grass root ethanol extract on fatty acid binding protein 4 and oxidative stress markers in a sepsis mouse model, https://doi.org/10.6084/m9.figshare.16895506.v2.57\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
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}
|
[
{
"id": "100358",
"date": "14 Dec 2021",
"name": "Katrin Roosita",
"expertise": [
"Reviewer Expertise Nutrigenomic",
"Nutraceuticals",
"herbal medicine",
"stress oxidative and human nutrition."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript has an acceptable scientific standard, but I have concerns about some details, as follows:\nHow was the antioxidant activity measured/determined?\n\nPlease elaborate/explain the parameters of the immune system-associated biomarker levels that were also measured.\n\nThis study aimed to assess the effects of ECGR on FABP4 and oxidative stress-related factors, meanwhile, the conclusion only mentions that cogon grass root may aid in the development of herbal medicines and specific treatments for sepsis, not specifically addressing the purpose of this study.\n\nIt will also be valuable to explain the concentration of flavonoid antioxidants as bioactive compounds, such as Quercetin and icariin if authors have information about these.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7642",
"date": "13 Jan 2022",
"name": "Mirasari Putri",
"role": "Author Response",
"response": "We greatly appreciate the reviewer’s time and effort in providing useful feedback and corrections. These are our answers: 1. How was the antioxidant activity measured/determined? Response: We measured the antioxidant by measuring the activity of Glutathione peroxidase 3 (GPx3 ) and superoxide dismutase gene expression (SOD). In mammals, GPx and SOD are the main antioxidants that protect cells from damage caused by free radicals through synergistic action. We have revised the abstract (Line 26) 2. Please elaborate/explain the parameters of the immune system-associated biomarker levels that were also measured. Response: We measured gene expression of TNF-α, IL-6, and IL-1β, we revised the abstract (Line 27) 3. This study aimed to assess the effects of ECGR on FABP4 and oxidative stress-related factors, meanwhile, the conclusion only mentions that cogon grass root may aid in the development of herbal medicines and specific treatments for sepsis, not specifically addressing the purpose of this study. Response: We have revised the conclusion according to the purpose of this study (Line 35) 4. It will also be valuable to explain the concentration of flavonoid antioxidants as bioactive compounds, such as Quercetin and icariin if authors have information about these. Response: In our study, we did not isolate the bioactive compounds. Still, we found in other studies that they determined the amount of flavonoid and quercetin concentration. However, No study found icariin in cogon grass extract. This compound is mainly found in horny goat weed (Yin Yang Huo), a Chinese herbal medicine. We added some information about Quercetin (Line 305-307)."
}
]
}
] | 1
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https://f1000research.com/articles/10-1161
|
https://f1000research.com/articles/12-1257/v1
|
02 Oct 23
|
{
"type": "Review",
"title": "Tapping into the plasticity of plant architecture for increased stress resilience",
"authors": [
"Maryam Rahmati Ishka",
"Magdalena Julkowska",
"Maryam Rahmati Ishka"
],
"abstract": "Plant architecture develops post-embryonically and emerges from a dialogue between the developmental signals and environmental cues. Length and branching of the vegetative and reproductive tissues were the focus of improvement of plant performance from the early days of plant breeding. Current breeding priorities are changing, as we need to prioritize plant productivity under increasingly challenging environmental conditions. While it has been widely recognized that plant architecture changes in response to the environment, its contribution to plant productivity in the changing climate remains to be fully explored. This review will summarize prior discoveries of genetic control of plant architecture traits and their effect on plant performance under environmental stress. We review new tools in phenotyping that will guide future discoveries of genes contributing to plant architecture, its plasticity, and its contributions to stress resilience. Subsequently, we provide a perspective into how integrating the study of new species, modern phenotyping techniques, and modeling can lead to discovering new genetic targets underlying the plasticity of plant architecture and stress resilience. Altogether, this review provides a new perspective on the plasticity of plant architecture and how it can be harnessed for increased performance under environmental stress.",
"keywords": [
"plant architecture",
"root architecture",
"shoot architecture",
"leaf architecture",
"stress resilience",
"plant fitness"
],
"content": "Introduction\n\nPlants evolved a wide range of architectural designs, ranging from compact rosettes to sprawling vines. Selective breeding or genetic engineering has been used to alter plant architecture, creating dwarf varieties of crops that are less likely to lodge, thereby providing significant contribution to yield increase.1–3 Plant architecture changes with plant development, as younger plants rely on development of the growth axis determined by the primary root and shoot meristems, while the final plant architecture depends on activation or dormancy of the axillary branches, which is controlled by internal and external signals. Every potential lateral organ is determined through cell priming into primordia, which can be dormant, aborted, or develop into new sink/source tissues. Transient environmental changes can cause changes in plant growth patterns, such as light availability throughout the day.4,5 However, these changes are often reversible, and contribute to short-term stimuli responses.6,7 On the other hand, long-lasting environmental changes will result in permanent changes in altered plant architecture, e.g., internode elongation upon the decrease in light availability.8 The absolute length of time required for permanent alterations in plant architecture will depend on the specific environmental factor, as well as developmental, genetic, and physiological contexts.\n\nCurrent breeding strategies utilize the most heritable traits, with low interaction between the genotype and the environment, resulting in reliable plant performance across environmental conditions.9–11 While focusing on trait stability, many components that contribute to plant performance are lost, such as interactions with the microbiome,12 and stress-inducible changes in plant architecture.13,14 Thus, the plant performance components that rely on phenotypic plasticity remain to be harnessed. Here, we review the concepts of plant architecture that have thus far contributed to plant productivity and stress resilience, and propose how integrating phenotypic plasticity into discovery pipelines can further expand the resilience potential of the plant.\n\n\nAspects of plant architecture\n\nPlant architecture describes a three-dimensional (3D) organization of plant above- and below-ground biomass between the main and lateral growth axes, through resource allocation to individual meristems.15 Additionally, the activation of the vascular cambium leads to formation of secondary xylem (wood) and phloem,16–18 thereby contributing to the plant width, as opposed to primary growth, which leads to an increase in the length of the plant. Both primary and secondary growth respond to internal signals and external stimuli. Within this review we divide the plant architecture into root, shoot and leaf system architecture, and describe them in the context of their contributions to environmental resilience.\n\nThe root architecture encompasses the spatial configuration of the roots, including root elongation, lateral root numbers, and orientation (Figure 1, Table S1 in Extended data374). Root architecture affects a plant’s ability to absorb available water and nutrients, anchorage, and plant interactions with the soil microbiome. During the seedling establishment, the biomass investment into the main root is prioritized as it anchors the plant and determines the axis along which the soil is explored for water and nutrients.19 At later developmental stages, the root architecture is dominated by lateral roots.20 Lateral roots can develop into long non-determinant roots, which help with soil exploration, or shorter and thinner roots, which contribute directly to water and nutrient absorption.21,22 While we are still learning to understand the fundamental differences between main roots and various kinds of lateral roots,23–25 the growth of each root is determined by root apical meristem. The auxin maximum within the meristem prevents the meristem cells from differentiating and regulates cell division rates.26–29 The size of the meristematic zone is affected by the environment and plant’s genetic makeup.30,31 The cell elongation occurs due to the activation of plasma-membrane H+-ATPases resulting in apoplast acidification.32–34 Low pH activates EXPANSINs (EXP) that loosen the network of cellulose strands and other cell wall components.35 The increasing pressure from the vacuole, which becomes less fragmented along the root developmental axis, results in increased turgor pressure, which contributes to cell elongation.36,37\n\nThe plant architecture determines how the biomass is distributed between primary and secondary growth axes, thereby affecting plant capacity for foraging for water and nutrients, as well as light capture. Here, we list individual genes that have been associated with components of 1) Root System Architecture: Root Depth,31,108,263–270 Root Angle,44,45,271–277 and Root Branching,57,85,89,96,265,278–298 2) Shoot System Architecture: Plant Height,138–140,266,269,299–305 Shoot Branching,306–323 Phyllotaxy,112,116,127,324–329 Inflorescence Architecture,174–177,183–186,330–336 and 3) Leaf System Architecture: Leaf Angle,148,211,212,273,337–354 Leaf Size,355–360 Leaf Shape306,324–326,360–369 and Leaf Number developed prior to reproductive stage transition.236,327,330,367,370–373 The genes that were observed to have pleiotropic effects on multiple components of plant architecture are listed in bold. Genes that have positive and negative effect on trait value are listed in black and white, respectively. Loci for which the causal gene has not yet been identified are listed in italics. We send our sincere apologies to researchers whose work is not included within this overview.\n\nWhile main root tends to grow into the gravity axis, the lateral or crown roots emerge and grow initially at nearly horizontal orientation. The lateral roots reach a vertical orientation, but this “gravitropic set-point angle” (hereafter referred to as “root angle”) is determined by plant’s genetic makeup rather than gravity, and is regulated independently of the main root gravitropism.38 Root angle is one of the most heritable root architecture traits.39–42 Steep root angle allows for denser planting, and thus have been selected throughout the modern breeding programs. The “steep, cheap, and deep” ideotype43 benefits water and nitrogen foraging.42,44–46 On the other hand, shallow root systems improve foraging for less mobile nutrients, such as phosphate.47 Therefore, root angle determines the overall profile of soil exploration, and impacts plant nutrient and water foraging. Additional anchoring of the plants can be also promoted through the production of adventitious and brace roots48,49 that prevents the plants from being uprooted by strong winds or water flow. The root angle has been thus far predominantly explored in the monocotyledonous species in breeding programs,50–53 providing better water and nutrient use efficiency, with limited or no yield penalty under non-stress conditions.\n\nAlong the growth axis of the main root, the lateral organs are initiated. The first sign of cell initiation into the lateral root primordia is the initiation of founder cells,54 demarcated by the migration of cell nuclei towards each other in the two neighboring pericycle cells. The position of the founder cells follows the auxin fluctuation in the root apical meristem,55,56 and relies on auxin-dependent signal transduction.57,58 Auxin maximum is required to form the primordium, and surrounding cytokinin inhibits formation of new primordia.59–61 The first step in differentiating the founder cells morphologically from the neighboring cells is the change in the cell division plane, from anticlinal to periclinal, resulting in a bulging structure within the root.62 This change in the division plane requires repositioning of the microtubule and F-actin cytoskeleton.63–65 Endogenous and exogenous factors underlying this cytoskeletal reorganization remain to be characterized. The transition from primed founder cells into lateral root primordium requires maintenance of auxin signaling66,67 to establishing a new quiescent center and lateral root meristem.68 Additionally, the developing lateral root primordium needs to orchestrate its clear passage through the surrounding tissues, including the endodermis and the degradation of the Casparian strip.69–71 Moreover, the boundary between the proliferating and non-proliferating cells within the developing root primordium must be maintained for the successful development of new lateral roots.72 The control of primordium quiescence and emergence is exerted through developmental and environmental signals that determine the final root system architecture.73 The environmental signals affect lateral root primordium development at multiple points, with the majority of abiotic stresses, including hypoxia, osmotic stress, and salt stress, leading to reduced lateral root development.74–80\n\nThe root architecture is determined by the distribution of biomass between the main and lateral root growth axes and the angles at which individual lateral roots develop. Nutrient deficiency, drought, and salt stress, strigolactones promote the elongation of main root growth while inhibiting the formation of lateral roots, mainly through inhibiting polar auxin transport.81 Similarly, abscisic acid (ABA) reduces the growth of the main root to a lesser extent compared to the lateral root through inhibition of gibberellic acid and brassinosteroid signaling, as well as polar auxin transport, resulting in overall deeper root systems.82–84 On the other hand, ethylene promotes the emergence of existing lateral root primordia while inhibiting the main root elongation,75 resulting in shallower root systems.85,86 Additionally, the development of individual lateral roots is also determined by the water gradients within the growth media—where lateral roots either a) continue to grow in the areas with high water availability (hydro-patterning87,88), b) cease their formation when roots grow through large air-gaps in the soil (xerobranching89,90). Of note, both processes seem to depend on ABA signaling.87,89 The distribution of lateral root formation is also changing in response to salt stress,91 nutrient availability,92,93 and mechanical stimuli.94,95\n\nAs root development at both architectural and anatomic levels is highly susceptible to environmental inputs,96–100 it is becoming paramount to identify genetic components that contribute to root architecture development under various conditions. While the fundamental programs that guide root development and elongation have been well established, the allelic variation and genetic components that contribute to maintained root growth under adverse conditions need to be identified. Maintained root growth has been associated with increased resilience to salt stress and contributing to reduced soil erosion.101–104 Additionally, combination of individual stresses often results in different root architectures compared to individual stress.105 Therefore, performing more discovery-based research to identify genes controlling specific aspects of root architecture under stress conditions and their validation needs to be explored in future studies. Additionally, the aggregation of phenotypes, also known as integrative phenotypes, has been more useful in characterizing water foraging strategies between individual genotypes. The wider use of integrated phenotypes will not only diversity the possible strategies of environmental resilience, but also highlight the importance of new traits, such as penetration of hardened soils106 that increases with the root diameter107 and maintenance of elongation while exposed to mechanical stress.108\n\nThe shoot system architecture is determined by all the scaffolding plant structures that determine the spatial distribution of leaves, branches, and flowers (Figure 1, Table S2 in Extended data374). Shoot system architecture determines the efficiency of light capture, evapotranspiration, and the fruit-bearing capacity of the plant. Additionally, in dicotyledonous plants, the secondary growth contributes to the plant’s ability to increase the height or fruit-bearing capacity by providing additional structural support.109,110 During the initial vegetative stage, the main growth axis is established by the activity of the shoot apical meristem, which produces primordia, that give rise to new leaves and lateral buds in the process called phyllotaxy.111 The position of primordia is guided by the self-emergent properties of auxin112–114 and cytokinin distribution.115–117 High levels of auxin trigger new lateral organ initiation,112,118,119 whereas cytokinin field that surrounds each auxin maximum creates an inhibitory field that prevents the formation of new lateral organs, which strength decreases with the distance.120 Through a stochastic process, the first primordium develops at a random position within the shoot apical meristem,121–124 giving the origin to auxin maximum and a new inhibitory cytokinin field.120 The position of subsequent primordium depends on the size of the meristem, meristem growth rate, and hormone transport within the apical meristem.125 The patterns of phyllotaxis are determined by the push-and-pull dynamics between auxin and cytokinin,116,126 which in case of a round meristem, results in self-emergent spiral phyllotaxis, as demonstrated using the magnetic cactus experiment.114 The complex geometry of the shoot apical meristem that allows phyllotactic patterns to develop relies on differential cell wall integrity, providing structural support for developing new organs as well as sufficient flexibility for cell division. This complexity in meristem geometry is accommodated by the xyloglucans,127 which are responsible for the separation of the cellulose microfibrils and tethering them to other cell wall components.128 Phyllotaxy has thus far not been a target in plant improvement or environmental resilience, possibly as the patterns that are present in cultivated and wild plants are already optimized for light use efficiency through reduced self-shading.129\n\nThe plant height contributes to plant performance, as reducing plant height provides more resources to be allocated to the inflorescence and final yield. The “Green Revolution” targeted gibberellin biosynthesis and sensitivity,130 thereby increasing nitrogen assimilation and allocation of assimilates to the grain.131 While high plants might produce increased yield due to increased access to light, this requires additional mechanical support, that can be provided by secondary growth. However, as secondary growth is absent in monocotyledonous plants that constitute the majority of our staple crops, shorter plant statues are a desirable agronomic trait. The plant height is an ideal breeding target, as the heritability is high, it significantly contributes to lodging resistance, facilitates denser cultivation, and easy manual and mechanical harvest.132–135 While many stresses decrease plant height,136,137 it is still undetermined whether this phenomenon is due to an overall decrease in plant growth rate, or rather active reprogramming of plant architecture and investment into lateral branches. One clear example where limiting plant height is beneficial is Sub1 locus in rice,138,139 containing three ethylene response factors (SUB1A, SUB1B, SUB1C, Table S2 in Extended data374). In the event of flooding, Sub1 locus restricts ethylene production and gibberellin responsiveness, which effectively arrests the growth.140 This allows the plant to endure submergence and resume growth once floodwaters recede, without any yield penalty under non-flooded conditions.\n\nApical dominance results in height gain at the expense of lateral growth by inhibiting the auxiliary buds. Similar to plant height, reduced branching is an important target in plant improvement and domestication, as it redirects the assimilates to the fruit and grain, and limits the resource investment into the vegetative phase to the absolute minimum. The advantage of apical dominance or highly branched shoot architecture depends on the species and environment. In competitive environments, such as densely cultivated plots in our current agriculture, vertical growth is necessary to ensure access to light, and thus apical dominance provides an advantage.141,142 For perennial species in low competitive environments, increased branching results in higher levels of source tissues, as the number of leaves that sustain plant growth and fruit production increase with each lateral branch.143 Environmental signals of light quality and quantity,144–149 as well as water and nutrient availability150,151 were previously described to modulate branching, presumably to balance the respiratory and nutritional demands of leaves in limiting conditions. Apical dominance is maintained by dormancy of auxiliary buds, which requires high levels of strigolactones and auxin, and low levels of cytokinin,152–155 and is released by high availability of sugars.156–158 Increased sugar availability promotes cytokinin biosynthesis, while reducing the strigolactone signaling.157,159,160 During the dormancy release, the sugar availability is also promoting the local auxin biosynthesis, which in turn activates the gibberellins.161 Sustained bud outgrowth is dependent on continued sugar supply and auxin-dependent production of gibberellins, which promotes the sink strength of the developing bud, thereby ensuring continued bud development into a new branch.161 Brassinosteroids also play an important role in the release of apical dominance, through release of the transcription factor (BZR1, Table S2 in Extended data374), that suppresses the expression of BRANCHED1 (BRC1), an inhibitor of bud outgrowth.162 Stress-induced repression of branching is orchestrated through ABA, which acts downstream of the BRC1.163 The plasticity of branching was significantly reduced during domestication,164,165 allowing for more space-efficient high-density planting and less labor-intensive agronomic practices. The manipulation of strigolactone-related genes is also used to enhance domestication characteristics—such as suppressed branching and tillering.166,167 Although apical dominance is agronomically desirable trait, it is a risky strategy from the environmental resilience perspective, as all the resources are invested into one main growth axis, rather than “spreading the risk” with the indeterminate growth form. As apical dominance limits vegetative biomass, it might limit yield potential, as recently demonstrated in the case of buckwheat.168 While apical dominance is highly preferred by modern agriculture, it is possible that improving resilience of our food production systems might require rethinking of this strategy.\n\nThe inflorescence architecture determines the arrangement of flowers on the plant and is key determinant of plant reproductive success. Inflorescence architecture is determined by the initiation of the inflorescence meristem, developing a branching pattern within the inflorescence meristem, and initiation of floral meristems.169 Some inflorescence are determinate—giving rise to only one flower—whereas others undergo a number of rounds of inflorescence branching prior to developing terminal flowers. Similarly to shoot branching, this process is balanced through interactions between auxin, cytokinin, and sugar signaling.170–172 Various architectures of inflorescence can be explained using a simple model,173 where LEAFY/FALSIFLORA gene174–176 determines the branching capacity of the inflorescence meristem, while TERMINAL FLOWER 1/SELF-PRUNING gene is regulating the timing where branches develop into determinant floral meristems.177–182 While excessive branching leads to many small fruits that undergo developmental arrest,183 plant breeding programs focus on finding the Goldilocks ratio between branching and determinate growth, which in most species are regulated by MADS-box transcription factors.185–189 Inflorescence architecture is highly affected by environment, which significantly contributes to yield gap under adverse conditions.190–192 Identification of molecular factors that affect inflorescence development under stress conditions, as well as exploring environmentally sensitive aspects of cytokinin, auxin and sugar signaling, can lead to increased environmental resilience and significant alleviation of the yield penalty.193–196\n\nLeaf system architecture constitutes the specific characteristics of the leaves, such as size, shape and angle, as well as the number of leaves that the plants produce prior to initiation of reproductive phase (Figure 1, Table S3 in Extended data374). These aspects differ from each other in their plasticity and response to the environment. While leaf shape is determined predominantly by the developmental cues, leaf angle and leaf number prior to flowering are highly influenced by the environment.197–200 Leaf system architecture plays an important role in crop productivity, as it impacts light capture, photosynthesis and transpiration rates.201,202 While leaf angle can maximize the light capture and contribute to maximizing the photosynthetic rate,7 desert plants are known to orient their leaves to minimize direct exposure to sunlight, thereby minimizing water loss.203 The leaf angle is typically determined by the structure and development of petiole or pulvinus cells in dicotyledonous plants, while in monocotyledonous plants the leaf angle is determined between the degree of bending between the leaf sheath and leaf blade.199,204,205 A pulvinus is a specialized structure located at the base of leaf blade in certain plants (grape, legumes, citrus), functioning as a joint between leaf and stem.206–209 The petiole constitutes the stalk that attaches the leaf blade to the stem, also plays a critical role in determining leaf angle. Variations in cell elongation and thickness across all of these structures affect leaf angle199 through auxin and brassinosteroid signaling that control ion fluxes207,210 and cell wall stiffness211,212(Figure 1, Table S3 in Extended data374). Maintained flexibility in leaf angle has been hypothesized to be an adaptive trait under high temperature, drought, salt and flood conditions.199,213\n\nAnother trait that seems to be highly adaptive to the environment is leaf size. Plants that are native to arid areas typically develop smaller or narrower leaves compared to their relatives from wetter regions.214–217 Similar to other lateral organs, the leaf size is controlled by coordination of cell division and expansion, regulated by auxin and cytokinin, as well as their interactions with other hormones, that were reviewed elsewhere.218–220 Overall, the increase in leaf area index (ratio between the area of one leaf to plant ground coverage) leads to more efficient light capture up to a certain point, after which self-shading reduced the plant’s overall light use efficiency.221,222 As reduction of leaf size is typically associated with reduced overall light capture and yield, and is not exhibiting high phenotypic plasticity, it has thus far not been utilized in breeding programs.\n\nSimilarly to leaf size, the leaf shape is a highly heritable trait that is mainly controlled by the developmental program of the plant,223,224 albeit it is receptive in some species to light and sugar availability.198 The differences in leaf shape are due to development of serrations, lobes or secondary leaflets during its development.224 The more complex leaf shapes are caused by re-initiation of auxin maxima within the developing leaf, resulting in cell dedifferentiation, maintained by genes involved in auxin and cytokinin signaling (Table S3 in Extended data374). Narrower leaves tend to be more common in the plants adapted to climates with extreme temperatures and low freshwater availability, whereas species with highly dissected leaves show higher rates of carbon gain and water loss compared to species with less-dissected leaves.225–227 Although many molecular markers were identified to underlie variation in leaf shape, they are yet to be used as targets in plant breeding, and further evaluation between leaf shape, plant productivity and stress resilience.228–230 Future studies are necessary to identify not only specific leaf shapes as well as integrated leaf shape and anatomy phenotypes (set of characteristics) that provide more insight into the relationship between optimizing light and carbon capture, while minimizing water loss and heat damage.\n\nThe number of leaves produced by a plant prior to initiation of inflorescence meristem determines the duration of the vegetative growth phase, and thus the total photosynthate that can be produced and turned into yield. In the changing climate, shortening the vegetative growth is becoming more desired to either a) escape the most severe conditions during the growth season or b) spread the risk between two or three growth cycles in more tropical regions.231,232 The transition from vegetative to reproductive stage is typically regulated by a combination of developmental and environmental signals, and is currently explored through the speed breeding approach.233,234 The alternative to shortened life cycle would be an indeterminate growth that is exhibited by many wild crop relatives that flower soon after germination and continue to produce flowers and fruit until the resources run out.235,236 While an increase in indeterminate growth might help spread the environmental risks, this approach would require tremendous efforts in adopting the modern agronomic systems for indeterminate growth. Additionally, the wild indeterminate growth of wild crop relatives would have to be tamed by optimizing the crop’s architecture and re-allocation of photosynthate and nutrients into developing fruits.\n\n\nChallenges and future directions\n\nAs discussed above, many components of plant architecture show plasticity in response to environment and the fundamental processes underlying development of plant architecture in major plant species (Arabidopsis, tomato, maize, rice, Tables S1-S3 in Extended data374) are well characterized. However, identification of loci contributing to plant architecture either constitutively, or in response to environment, in wider diversity of crops remains to be identified. Previous studies suggest that inducible controls of plant architecture, such as SUB1A or HKT1 (Tables S2 and S1 in Extended data374) provide improved environmental resilience without the trade-offs under non-stress conditions. Additionally, harnessing the potential of new discoveries by high-throughput phenotyping and molecular technologies, will provide improved understanding of nuanced control of plant architecture and functional relationships, and their contextual dependencies, between plant architecture and anatomy components and environmental resilience.\n\nCurrent studies of plant architecture focus on a handful of species that are either of high economic importance or have been developed as model species throughout the years for the specific questions. However, the genetic information within one species is not providing exhaustive representation of the mechanisms that contribute to plant productivity and environmental resilience across the plant kingdom. Improved understanding of fine-tune points of developmental mechanisms will provide more reliable selection of breeding targets and increased likelihood that selected alleles will provide improved performance across wide variety of elite varieties. This can be achieved through comparative genomics and phylogenetic analyses of genes that were previously identified to be involved in regulating plant architecture, and their functional characterization.237–239\n\nImproving genomic resources for wild crop relatives and indigenous crops provide better resources for development of diversity panels and mapping populations.240–243 Forward genetic studies, such as genome-wide association studies (GWAS) and quantitative trait locus (QTL) mapping, combined with more accessible plant phenotyping,244–246 will help to identify new genetic regions associated with changes in plant architecture, productivity and stress resilience. As in-depth phenotyping will provide more insight into timing of plant architecture development, we will be able to predict the tissues and time points that undergo transcriptional and/or metabolic reprogramming with increasing precision. Targeting specific tissues and time points for omics analyses will further reveal the molecular networks underlying regulation of plant architecture and its plasticity in response to environment.247\n\nAs plant architecture focus until now has been predominantly to study the highly heritable components of architecture, the loci that determine the plant architecture plasticity remain to be identified. And thus, it is important to identify the specific developmental stages at which changes in plant architecture have the highest contribution to plant performance and stress resilience.248 Controlled environment experiments, while they simplify the environmental responses, can provide systematic exposure to altered conditions at various developmental stages.249,250 Combining controlled environment stress exposure with high-throughput phenotyping, can provide insight into how specific stress applications affect plant growth and development over time, thereby identifying critical growth stages and architectural traits that contribute to plant performance and environmental resilience.251 Increasing the throughput of screening large amounts of plants and automated extraction of traits of interest will unlock the opportunities for genomic and genetic approaches that typically require large population screenings.\n\nTogether, these new developments will improve our general understanding of plant physiology and inform the expansion of future modeling approaches. Identification of key developmental stages for individual aspects of architecture will allow optimal timing for application of treatments and agronomic interventions, such as application of fertilizer, pesticide or additional irrigation. Additionally, we can focus our breeding programs or gene expression studies focusing on specific developmental stages where the specific aspects of architecture are being determined. Moreover, understanding how plant architecture develops throughout the plant lifecycle will provide insights into how different growth stages interact and contribute to the overall performance and stress resilience of the plant. Understanding how stress susceptibility changes with plant developmental stages can guide the timing of interventions to improve resilience and enhance the accuracy of predictive crop growth models.\n\nCurrent methods for quantifying plant architecture are still mainly relying on the manual characterization of plant characteristics taken at one-time point.245 While we can learn a lot from counting the number of leaves, branches and roots, there is more to plant architecture than a static image of traits that are easily scored. Quantifying plant architecture beyond canonical traits involves understanding the functional and structural components of the plants, and incorporating plant architecture plasticity in response to time and the environment.\n\nThe complementation of high-throughput phenotyping methods with mathematical models allows for a more comprehensive understanding and characterization of plant architecture, including its trajectory through the dimensions of time and environment. The mathematical models can be classified as either “Growth and Development” or “Functional-Structural Plant” models. The growth and development models are typically simulating the progress of plant growth and development based on physiological factors, and provide how plant architecture changes over time.252 Examples of growth and development models range from simple linear growth models to estimate growth of individual organs100 to Lindenmeyer-system (L-system) models, where the growth of the entire plant is summarized by the set of context-free grammar rules.253 The functional-structural plant models, on the other hand, combine plant structure with physiological processes, such as photosynthesis, respiration, and transpiration.254 Examples of functional-structural plant models include models of water and ion uptake255,256 and estimations of plant architecture efficiency concerning transportation cost and speed trade-offs.257,258\n\nThe limitations of current models include that they often consider only a very specific developmental stage or tissue, and allow very limited input from the environment. While such models can provide tremendous insight, they often rely on plant architectural or anatomical data that can be collected only using semi-automated methods.259–261 These quantification methods require substantial user input for model corrections, and thus are not suitable for large population screens. Additionally, many 3D reconstruction tools are limited to the root systems, where individual roots can be distinguished, but does not produce suitable images for shoot or inflorescence architecture, where foliage/fruit obstructs the insight into the branching structures. The implementation of technologies such as X-ray imaging could provide additional push towards simplifying the data necessary for such models.262\n\n\nConclusions\n\nAs described above, plant architecture provides significant contributions to plant productivity and stress resilience, with multiple components showing varying levels of plasticity in response to changing environment. Tapping into this plasticity, by performing discovery-based studies across various environmental conditions and wider variety of species, will provide better understanding of plant development, as well as improved selection of breeding targets for improved resilience. Automated imaging and modification of environmental aspects under controlled conditions will provide better understanding of specific developmental stages that are crucial for development of specific aspects of plant architecture. Combining high-throughput phenotyping with mathematical modeling will not only provide better noise-to-signal ratio in forward genetic studies, but will also provide improved understanding of functional aspects of plant architecture. Finally, including more species in the study of resilience and plant architecture will provide more holistic understanding of genetic and molecular modules responsible for fine-tuning plant architecture for improved resilience and ensuring food security for various agronomic and cultural regions.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\nFigshare: Genes and genetic loci involved in regulation of plant architecture. https://doi.org/10.6084/m9.figshare.24018564. 374\n\nThis project contains the following extended data:\n\n‐ Table S1 (root architecture)\n\n‐ Table S2 (shoot architecture)\n\n‐ Table S3 (leaf architecture)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nLiu S, Zhang M, Feng F, et al.: Toward a “Green Revolution” for soybean. Mol. Plant. 2020 May 4; 13(5): 688–697. PubMed Abstract | Publisher Full Text\n\nRichards RA, Cavanagh CR, Riffkin P: Selection for erect canopy architecture can increase yield and biomass of spring wheat. Field Crops Res. 2019 Dec 1; 244: 107649. 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PubMed Abstract | Publisher Full Text\n\nTimmermans MC, Hudson A, Becraft PW, et al.: ROUGH SHEATH2: a Myb protein that represses knox homeobox genes in maize lateral organ primordia. Science. 1999 Apr 2; 284(5411): 151–153. Publisher Full Text\n\nByrne ME, Barley R, Curtis M, et al.: Asymmetric leaves1 mediates leaf patterning and stem cell function in Arabidopsis. Nature. 2000; 408(6815): 967–971. PubMed Abstract | Publisher Full Text\n\nBaekelandt A, Pauwels L, Wang Z, et al.: Arabidopsis Leaf Flatness Is Regulated by PPD2 and NINJA through Repression of CYCLIN D3 Genes. Plant Physiol. 2018 Sep; 178(1): 217–232. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJasinski S, Tattersall A, Piazza P, et al.: PROCERA encodes a DELLA protein that mediates control of dissected leaf form in tomato. Plant J. 2008 Nov; 56(4): 603–612. PubMed Abstract | Publisher Full Text\n\nWeigel D, Alvarez J, Smyth DR, et al.: LEAFY controls floral meristem identity in Arabidopsis. Cell. 1992 May 29; 69(5): 843–859. Publisher Full Text\n\nHake S: Inflorescence architecture: the transition from branches to flowers. Curr. Biol. 2008 Dec 9; 18(23): R1106–R1108. Publisher Full Text\n\nMandel MA, Gustafson-Brown C, Savidge B, et al.: Molecular characterization of the Arabidopsis floral homeotic gene APETALA1. Nature. 1992 Nov 19; 360(6401): 273–277. PubMed Abstract | Publisher Full Text\n\nPalatnik JF, Allen E, Wu X, et al.: Control of leaf morphogenesis by microRNAs. Nature. 2003 Sep 18; 425(6955): 257–263. Publisher Full Text\n\nRahmati Ishka M, Julkowska M: Genes and genetic loci involved in regulation of plant architecture. [Dataset]. figshare. 2023. Publisher Full Text"
}
|
[
{
"id": "234668",
"date": "09 Feb 2024",
"name": "Rumyana Karlova",
"expertise": [
"Reviewer Expertise Plant physiology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a very well written review paper describing genetic control of plant architecture traits (root and shoot architecture) and their effect on plant performance under environmental stress. There is a very useful Figure 1 summarizing the molecular regulators of the plant architecture as well as 3 supplemental figures! This review is very relevant and provides further understanding of genetic and molecular regulation of plant architecture for improved crop resilience in the changing climate.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": []
},
{
"id": "224113",
"date": "21 Feb 2024",
"name": "Adriana Garay Arroyo",
"expertise": [
"Reviewer Expertise Develpmental biology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript “Tapping into the plasticity of plant architecture for increased stress resilience” by Maryam Rahmati Ishka and Magdalena Julkowska has important and accurate information in each of its sections. It is an interesting review that will be useful for the plant development community.\nSome comments: in bold are some phrases written by the authors and I wrote below the phrase, some comments on them.\nRoot architecture:\n“Selective breeding or genetic engineering has been used to alter plant architecture, creating dwarf varieties of crops that are less likely to lodge, thereby providing significant contribution to yield increase” It could be interesting to put more examples of using selective breeding or genetic engineering as it seems that this was the only goal of these kind of studies. “while the final plant architecture depends on activation or dormancy of the axillary branches, which is controlled by internal and external signals” Also, the primary root and shoot meristems depends on internal and external signals, you said this later in the text, but I suggest that you put this paragraph here: “Both primary and secondary growth respond to internal signals and external stimuli”. “The absolute length of time required for permanent alterations in plant architecture will depend on the specific environmental factor, as well as developmental, genetic, and physiological contexts” This is a very relevant information, please put references. It would be very interesting to know how this length is mechanistically determined. “Current breeding strategies utilize the most heritable traits, with low interaction between the genotype and the environment, resulting in reliable plant performance across environmental conditions” This phrase seems contradictory, the breeding strategies are meant to be useful in specific environments and not across different environmental conditions. Please comment on this. “Lateral roots can develop into long non-determinant roots, which help with soil exploration, or shorter and thinner roots, which contribute directly to water and nutrient absorption” Many lateral roots display contrasting development in homogeneous growth conditions, a phenomenon that has been called developmental instability (Muller et al., 2019). Please comment on this. Figure 1. There are more genes that participate in root depth: XAL1 ref [4], XAL2 ref [3] and also, ANR1 ref [1], ref [2]. “Nutrient deficiency, drought, and salt stress, strigolactones promote the elongation of main root growth” I do not completely understand this phrase. I think it would be important to talk in general about the participation of the phytohormones in the control of development in general. “when roots grow through large air-gaps in the soil (xerobranching). Of note, both processes seem to depend on ABA signaling” The second one depends also on ethylene and auxin (Bennett M). “combination of individual stresses often results in different root architectures compared to individual stress” Use more than one stress under controlled conditions? This looks like a proposal to me that can be incorporated in the Conclusions section.\nShoot architecture\n“Through a stochastic process, the first primordium develops at a random position within the shoot apical meristem” It will be important to consider the stochasticity in modelling, please comment on this. “and leaf number prior to flowering are highly influenced by the environment” and after flowering? “However, the genetic information within one species is not providing exhaustive representation of the mechanisms that contribute to plant productivity and environmental resilience across the plant kingdom” and in the same paragraph “This can be achieved through comparative genomics and phylogenetic analyses of genes that were previously identified to be involved in regulating plant architecture, and their functional characterization”. Seems contradictory to me, the genes important in one species might be important in another.\n\nConclusions. These two conclusions could be together “including more species in the study of resilience and plant architecture will provide more holistic understanding” “by performing discovery-based studies across various environmental conditions and wider variety of species, will provide better understanding of plant development, as well as improved selection of breeding targets for improved resilience”\nAnother conclusion could be: Using high-throughput phenotyping with genome approaches.\nI suggest making a Table with the comparisons of the most important data on breeding programs and genetic engineering, that has been done in root, shoot and leaves.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": []
},
{
"id": "245280",
"date": "23 Feb 2024",
"name": "Sadikshya Poudel",
"expertise": [
"Reviewer Expertise Plant stress physiology",
"barley breeding",
"biofortification"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReviewer comments The review paper is well-written and easy to understand. The authors have done an excellent job of explaining the fundamentals of plant architecture and its plasticity under various stress conditions. The detailed explanation of the root, shoot, and leaf systems is particularly commendable, providing a comprehensive understanding of how plants adapt to their environment. Additionally, the authors have effectively discussed the genetic components that regulate plant architecture, supplementing their explanations with a self-explanatory figure, which enhances the clarity and accessibility of the content. Furthermore, the paper adeptly addresses the challenges and future directions in an easily understandable manner, which is essential for the readers. By outlining the obstacles and potential paths forward, the authors have not only provided a valuable summary of the current state of research but have also offered a roadmap for future investigations in this critical area of study. This forward-looking approach adds significant value to the paper, making it a relevant and insightful resource for both researchers and practitioners in the field of plant biology and agriculture. Comment: Page 5, second paragraph; Nutrient deficiency, drought, and salt stress, strigolactones promote the elongation of main root growth while inhibiting the formation of lateral roots, mainly through inhibiting polar auxin transport. This line needs to be edited. “Under nutrient deficiency, drought…...” Comment: Page 5, third paragraph; “The wider use of integrated phenotypes will not only diversity the possible strategies of environmental resilience…” Does the author mean to diversify? Please edit the line as needed. Comment: Page 5, last paragraph; “High levels of auxin trigger new lateral organ initiation whereas cytokinin field that surrounds each auxin maximum creates an inhibitory field that prevents the formation of new lateral organs, which strength decreases with the distance.” This sentence is complex to understand. Please check the structure of the sentence and make it simpler. Please split the sentence into two to make it simpler and more understandable. Comment: Page 6, second paragraph; “While high plants might produce increased yield due to increased access to light, this requires additional mechanical...” Here does the author refer to taller plants by mentioning high plants? I suggest using the term tall or taller plants instead of high plants if you are referring to height. Comment: Page 6. The author has mentioned the term strigolactone multiple times. I suggest adding a brief line about this term in the paper. Comment: Page 6. I suggest the author explain the term Goldilocks ratio for a better understanding to a layman. Comment: Page 7. “Plants that are native to arid areas typically develop smaller or narrower leaves compared to their relatives from wetter regions.” I suggest the authors add literature on why the leaves are narrower in arid natives. Comment: The author has provided a comprehensive explanation of plant architecture; however, there appears to be limited mention of plasticity and how it changes under different stress conditions. I suggest that the authors incorporate references to additional studies highlighting the plasticity of various crops in response to diverse stressors. Acknowledging and integrating a wider range of research in this area can enhance the depth of the discussion and contribute to a more comprehensive understanding of crop resilience.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1257
|
https://f1000research.com/articles/11-566/v1
|
25 May 22
|
{
"type": "Research Article",
"title": "Prevalence and associated factors of adolescent pregnancy among sexually active adolescent girls: Evidence from the Peruvian Demographic and Family Health Survey, 2015-2019",
"authors": [
"Brenda Caira-Chuquineyra",
"Daniel Fernandez-Guzman",
"Adria Meza-Gómez",
"Beatriz Milagros Luque-Mamani",
"Shawny Luz Medina-Carpio",
"Carlos S. Mamani-García",
"Marilia Romani-Peña",
"Cristian Díaz-Vélez",
"Brenda Caira-Chuquineyra",
"Daniel Fernandez-Guzman",
"Adria Meza-Gómez",
"Beatriz Milagros Luque-Mamani",
"Shawny Luz Medina-Carpio",
"Carlos S. Mamani-García",
"Marilia Romani-Peña"
],
"abstract": "Background: To determine the prevalence and associated factors of adolescent pregnancy in Peru, 2015-2019. Methods: A population-based analytical cross-sectional study was conducted using pooled data from the Demographic and Family Health Surveys of Peru 2015-2019. A total weighted sample of 6892 adolescent girls aged 15 to 19 years with a history of sexual intercourse were included. Finally, the adjusted prevalence ratio (aPR) with 95% confidence interval (CI) were reported to determine the factors that were significantly associated with adolescent pregnancy. Results: The prevalence of adolescent pregnancy in Peru was 30.1% (95%CI: 28.4–31.8%). In the multivariable analysis; being 17-19 years (aPR: 1.38; 95%CI :1.22–1.56), having a partner (aPR: 4.08; 95%CI: 3.46–4.81) and belonging to the Quechua ethnicity group (aPR: 1.20; 95%CI: 1.09–1.32), were associated with a higher prevalence. Whereas, having an occupation (aPR: 0.81; 95%CI: 0.75–0.88), currently studying (aPR: 0.42; 95%CI: 0.36–0.49), belonging to the second (aPR: 0.91; 95%CI: 0.84–0.98), third (aPR: 0.80; 95%CI: 0.72–0.89), fourth (aPR: 0.76; 95%CI: 0.64–0.89) and fifth (aPR: 0.55; 95%CI: 0.41–0.73) wealth quintile, initiating sexual relations between 17-19 years (aPR: 0.52; 95%CI: 0.46–0.59), perceiving a future pregnancy as a problem (aPR: 0.77; 95%CI: 0.70–0.83) and knowledge of the moment in the cycle when she could become pregnant (aPR: 0.84; 95%CI: 0.76–0.93), were associated with a lower prevalence of pregnancy. Conclusions: About three in 10 adolescents who initiated their sexual life presented with at least one pregnancy. Age, marital status, employment, education, wealth, ethnicity, age at first intercourse, knowledge of when in the cycle she may become pregnant, and perception of future pregnancy were associated with adolescent pregnancy. It is necessary to increase national policies on family planning and sex education among adolescents to reduce the prevalence of adolescent pregnancy in Peru.",
"keywords": [
"Adolescents",
"pregnant women",
"pregnancy in adolescence",
"pregnancy and motherhood",
"Peru"
],
"content": "Introduction\n\nThe World Health Organization (WHO) defines adolescents as those between 10 and 19 years of age.1 Adolescence is a period of progression towards adulthood, necessary to reach physical, sexual, mental and social maturity.2 However, it is during middle and late adolescence (15-19 years) when there is a greater development of responsibility for decisions and a greater search for autonomy.3 Therefore, the culmination of this period together with pregnancy can lead to various difficulties for the adolescent and the infant,4 with delayed prenatal care and a greater number of obstetric and perinatal complications5 being common, as well as a higher incidence of maternal mortality.6\n\nAccording to the WHO, 12 million women aged 15-19 years and, approximately, 1 million girls under the age of 15 give birth each year.7 Latin America and the Caribbean have the second highest adolescent fertility rate in the world. Although this rate decreased from 65.6% (2010-2015) to 60.7% (2015-2020), there are still significant variations between sub regions and countries.8 In Peru, the Demographic and Family Health Survey (ENDES, for its Spanish acronym) revealed that the percentage of adolescents aged 15 to 19 years who were already mothers or were pregnant for the first time did not decrease notably and was maintained during 2014 to 2019 (prevalence of 14.6% and 12.6%, respectively).9 This issue of teenage pregnancy has been observed at a higher proportion in women with low educational levels, who reside in rural areas, belong to low socioeconomic strata and according to ethnicity.10–12\n\nAlthough in Peru, different factors associated with teenage pregnancy have also been reported in small studies or in gray literature,13,14 it is not known which factors are associated with pregnancy during middle and late adolescence, which are the groups in which teenage pregnancy is most prevalent. In addition, there is no evidence in the literature on the factors associated with teenage pregnancy, taking as the baseline population those adolescents who initiated sexual relations, which could overestimate the effects found in other studies.10–12 Therefore, the aim of the present study was to estimate the proportion and factors associated with pregnancy in adolescents aged 15 to 19 years who initiated their sexual life. The identification of associated factors with adolescent pregnancy could be an input for the strengthening of policies on reproductive education and prenatal care.\n\n\nMethods\n\nWe conducted a secondary analysis of the 2015-2019 ENDES database, developed through the National Institute of Statistics and Informatics (INEI, for its Spanish acronym) of Peru. This was a national survey whose target population was private households and their members, women aged 15-49 years, children under 5 years and one person aged 15 years and older per household. The present study used an observational study design, analytical cross-sectional type. The sections on demographic and social characteristics, reproductive history, use of contraceptive methods, pregnancy and breastfeeding, nuptiality, fertility preference, spouse's background and women's work of the Women's Individual Questionnaire, were used.\n\nThis study did not require the approval of an ethics committee because the ENDES database is in the public domain and does not allow identification of the subjects, which maintains the corresponding confidentiality. The primary data collection was carried out with the prior signed consent of the interviewees. In addition, the present research project was registered in the “Plataforma de Proyectos de Investigación en Salud” (PRISA) of “Instituto Nacional de Salud” (INS) in Peru with code EI00000001763.\n\nThe ENDES is a survey with annual representativeness at the national, urban-rural level, by geographic domain and for the 25 departments of Peru. The sampling design of ENDES is two-stage, probabilistic by clusters and stratified at the departmental level and by urban and rural area. The primary sampling unit was made up of the selected clusters. The secondary sampling unit was made up of the selected homes.15\n\nA total of 24 419 adolescent women aged 15-19 years were surveyed during the period 2015-2019, the effective sample for the analysis was composed of 6892 women who were those who responded to the dependent variable of interest (currently pregnant or who are mothers) and who reported having initiated sexual intercourse (Figure 1). Additional information on the ENDES survey methodology is available from Technical Report.15\n\nENDES (Spanish acronym), Demographic and Family Health Survey.\n\nAdolescent pregnancy was considered as the dependent variable of the study, which was collected by self-reporting through the ENDES 2015-2019 Individual Woman Questionnaire with the following questions: “Are you currently pregnant?”, which was coded as V213 in the database (“No or not sure” / “Yes”) and the total children born, coded as V201 in the database (numerical variable), which was considered if the total number of children born was greater than or equal to 1.\n\nThe following independent variables were considered: Sociodemographic variables, such as age (middle adolescence [15-16 years], late adolescence [17-19 years]), geographic region (Costa, Sierra, Selva), wealth level (first quintile, second quintile, third quintile, fourth quintile, fifth quintile), area of residence (urban, rural), ethnicity (mestizo, quechua, negro - moreno o zambo, other), presence of a partner (no, yes), education level (secondary or higher, primary or lower), current occupation (no, yes) and currently studying (no, yes), and gynecology-obstetric variables, such as age of first sexual intercourse in late adolescence (no, yes), perception of pregnancy (positive, negative), knowledge of the time of the cycle when she could become pregnant (no, yes) and use of contraceptive methods (no, yes). The selection and inclusion of these independent variables in the study was based on a review of the literature.10–12\n\nThe 2015-2019 ENDES databases were downloaded and imported into Stata® v.16.0 software (Stata Corporation, College Station, Texas, USA) (Stata, RRID:SCR_012763). All analyses were performed considering the complex sampling design for ENDES using the svy module.\n\nFor the descriptive analysis of categorical variables, absolute frequencies and weighted proportions were calculated, and for numerical variables, means with standard deviation were calculated. For bivariate analysis, the association between categorical variables was evaluated using the chi-square test. A value of p<0.05 was considered statistically significant.\n\nTo evaluate the association of interest, generalized linear models of the Poisson family with logarithmic link function were used, and we calculated crude prevalence ratios (cPR) and adjusted prevalence ratios (aPR). For the adjusted model, the method of forward manual selection and the Wald test were used to select the variables to obtain a final parsimonious model. In this way, the variables, including age, marital status, current occupation, currently studying, wealth index, ethnicity, age at first sexual intercourse, knowledge of the time of the cycle when you can get pregnant and perception of pregnancy were entered into the final model. The analyses were reported with their respective 95% confidence intervals (95% CI) and p values <0.05 were considered statistically significant. Furthermore, to examine the possible role of the area of residence as a modifier of the effect, the adjusted model was analyzed stratified into urban and rural areas.\n\n\nResults\n\nFrom a total of 24 419 adolescent women aged 15 to 19 years during the study period, 14 552 were excluded because they were not at risk of becoming pregnant (no history of sexual intercourse) and 2975 were excluded because they had variables with missing data, resulting in a final study population of 6892 (Figure 1).\n\nThe highest percentage of the study population corresponded to late adolescence (17 to 19 years) (83.2%), adolescents without a partner (67.9%), those with secondary or higher education (92.0%), those belonging to the second wealth quintile (23.1%), those currently in an occupation (58.0%), and those belonging to the mestizo ethnic group (37.8%), to the coast region (63.7%) and to an urban area (78.9%) (Table 1).\n\n* Weighted values according to complex sampling of the survey.\n\nThe prevalence of pregnancy among adolescents aged 15 to 19 years who initiated sexual relations was 30.1%, with a higher proportion among adolescents aged between 17 to 19 years (32.0; p<0.001), those with primary education or lower (64.8%; p<0.001), those with a partner (73.3%; p<0.001), those who belonged to the first wealth quintile (54.8%; p<0.001), those who did not work (35.0%; p<0.001), those who were not studying (51.5%; p<0.001), those who belonged to the jungle region (41.5%; p<0.001), as well as those from rural areas (55.4%; p<0.001) (Table 2).\n\n* Percentages weighted according to complex survey sampling.\n\nFurthermore, the prevalence of adolescent pregnancy was higher among those who initiated their first sexual intercourse between 10 and 16 years (38.0%; p<0.001), those who used contraceptive methods (40.6%; p<0.001), individuals who did not know the time of the cycle when they could become pregnant (35.0%; p<0.001) and those who did not perceive pregnancy as a problem (39.4%; p<0.001) (Table 2).\n\nWhen we performed the multivariate analysis, we found that the factors independently associated with a higher frequency of teenage pregnancy were as follows: Being in late adolescence (aPR: 1.38; 95%CI: 1.22–1.56), having a partner (aPR: 4.08; 95%CI: 3.46–4.81) and belong to the Quechua ethnicity group (aPR: 1.20; 95%CI: 1.09–1.32). The factors associated with a lower frequency of adolescent pregnancy were as follows: Being in an occupation (aPR: 0.81; 95%CI: 0.75–0.88), currently studying (aPR: 0.42; 95%CI: 0.36–0.49), and belonging to the second (aPR: 0.91; 95%CI: 0.84–0.98), third (aPR: 0.80; 95%CI: 0.72–0.89), fourth (aPR: 0.76; 95%CI: 0.64–0.89) and fifth (aPR: 0.55; 95%CI: 0.41–0.73) wealth quintile. Similarly, to have initiated sexual relations between 17-19 years of age (aPR: 0.52; 95%CI: 0.46–0.59), to perceive a future pregnancy as non-problematic (aPR: 0.77; 95%CI: 0.70–0.83) and to know the moment in the cycle when she could become pregnant (aPR: 0.84; 95%CI: 0.76–0.93) were also associated with a lower prevalence of teenage pregnancy (Table 3).\n\nFactors associated with teenage pregnancy in urban and rural areas are presented in Table 4 and Table 5, respectively.\n\n\nDiscussion\n\nIn Peru, about three in 10 adolescents between 15 and 19 years of age who have initiated sexual relations have had at least one pregnancy. The high prevalence of adolescent pregnancy could favor the appearance of a higher rate of obstetric and perinatal complications in this group.5 It was found in the present study that older age (17 to 19 years), the presence of a partner, ethnicity, having a job, being in school, level of wealth, early initiation of sexual relations (≤16 years), the perception of a future pregnancy as non-problematic, and knowledge of the moment in the cycle when pregnancy may occur were independently associated with adolescent pregnancy.\n\nWe found that belonging to late adolescence (between 17 to 19 years) was associated with a higher prevalence of teenage pregnancy. This is consistent with previous studies16,17 and could be explained by the greater development and mental maturity in this group to assume a pregnancy, as well as a greater development of female identity and greater capacity to adapt to parenting roles.3 Similarly, the literature has described a greater desire to become pregnant in late adolescence compared to the rest of adolescence.18 Furthermore, it should be taken into account that the sociocultural and economic context could influence the age of onset of risky sexual behaviors in adolescents,19 which could lead to a higher risk of becoming pregnant.\n\nThe presence of a partner among the adolescents was associated with a higher prevalence of teenage pregnancy. In this regard, this association was previously evidenced in studies focusing on sexually active adolescents.20,21 In Latin American countries, the high prevalence of adolescent pregnancy could be due to the fact that among adolescents with a partner there is a greater desire to become pregnant and achieve motherhood in order to start a family at an early age.22 In Peru, it has been reported that 69% of adolescents aged 15 to 19 years who were pregnant or had children were in some type of early union (65.8% cohabiting and 3.2% married).23 Thus, the association with the presence of a partner could be due to the fact that after adolescents become pregnant, parents put pressure on the couple to marry or cohabit. Given that, family planning measures should be widely encouraged for both female and male adolescents.\n\nWe also found that belonging to the Quechua ethnicity group was associated with a higher prevalence of adolescent pregnancy. In this regard, it has been reported that women from ethnic minorities tend to experience social and economic exclusion, which could generate greater inequity in access to family planning services and contraceptive methods,24,25 leading to higher maternal mortality.26 In Peru in 2016, it was observed that the population of native origin (Quechua, Aymara or Amazonian origin) had a higher level of fertility and a lower proportion of contraceptive methods used.27 In these ethnic groups, a greater acceptance of early marriage and pregnancy has also been reported.25 Therefore, greater state intervention is required in these population groups to reduce the gaps in access to sexual and reproductive health information for adolescents.\n\nHaving an occupation or being a student was associated with a lower frequency of adolescent pregnancy. Adolescents who engage in these activities may prioritize education or economic income over starting a family.28 This contrasts with previous studies conducted in middle- and low-income countries, where a higher risk of pregnancy has been reported among adolescents who do not have an occupation26 or who do not attend school.29 Having an education could be related to a better knowledge of sexual health and a greater ambition to complete higher education, postponing reproductive desire until greater emotional and economic stability is achieved.30 In Peru, dropout at the secondary education level in 2015 was 7.6% among adolescents.31 Given this, it would be important to implement national programs that promote and ensure education and find vulnerable adolescents who have dropped out of school.\n\nIt was also found in the present study that belonging to the third, fourth or fifth wealth quintile was associated with a lower frequency of adolescent pregnancy. In Latin America and the Caribbean, an early onset of sexual relations32 and a higher proportion of adolescent pregnancy33–35 were reported among lower income social groups. This could be explained by lower use of and limited access to contraceptive methods in these groups.35 Similarly, unfavorable economic conditions could lead women to think of motherhood as a better life option, since they would have a partner to take care of household needs.16,17 In Peru, the “Juntos” Program was implemented in 2005 with the aim of reducing the impact of poverty and its intergenerational transmission through the bimonthly delivery of a monetary incentive of 200 nuevos soles (S/200) to low income households, plus an additional S/100 for pregnant women who attend antenatal visit care and S/100 for each child under 3 years of age who comply with growth and development checkups.36 This initiative could favor vulnerable groups such as pregnant adolescents in low socioeconomic strata.\n\nRegarding the age of initiation of sexual intercourse, we found that late initiation of sexual intercourse (17 to 19 years) was associated with a lower prevalence of adolescent pregnancy. This finding is consistent with the literature,20 which has reported earlier ages of sexual intercourse,32,37 and higher proportions of a first pregnancy between 15 and 19 years of age.38 This could be explained by the lack of promotion of sexual and reproductive health information, including family planning methods, at earlier ages. Therefore, the general population should be made aware of the importance of regulating access to sexual and reproductive health information from puberty and adolescence.\n\nAnother variable that was associated with a higher prevalence of adolescent pregnancy was the perception of a future pregnancy as non-problematic in the crude analysis. In this regard, it has been previously reported that a positive attitude toward pregnancy among postpartum adolescents is strongly associated with a higher prevalence of a second pregnancy.39 Likewise, a greater likelihood of feeling stigmatized during pregnancy has been observed when they did not have a romantic relationship with a partner or felt verbally abused by family, friends, partners or other adolescents.40 This could be due to the fact that the greater emotional stability achieved through the support of a partner and family, friends and social environment during pregnancy could generate a non-problematic perception of a subsequent pregnancy.41,42 However, in our analysis, when adjusting for other variables, we found a reversal in the direction of the association. This could be explained by the fact that the sample evaluated included adolescents with no history of pregnancy, who could have a biased perception of a possible pregnancy and be influenced by the desire to start a family. This explanation is consistent with the fact that there is a high prevalence of desire for pregnancy among adolescents in Latin America.22\n\nKnowledge of the moment in the cycle when pregnancy is possible was associated with a lower prevalence of adolescent pregnancy. This is consistent with previous studies, where ignorance of the fertile days was a risk factor for adolescent pregnancy.16 Thus, among adolescents with a greater concern for avoiding unwanted pregnancy, it was reasonable that there is greater interest in knowing the dates of the cycle when there is a greater probability of becoming pregnant.43\n\nAdolescent pregnancy is one of the main public health problems among the adolescent and young adult population in Peru.6 The findings of the present study suggest the impact of different individual, sociodemographic and cultural factors on a higher prevalence of adolescent pregnancy. The sociocultural and economic context in Peru determines a high unmet demand for family planning, lack of access to contraception and a low level of knowledge about risky sexual behavior.6,44\n\nThe usefulness of applying prevention policies in other countries to reduce the prevalence of adolescent pregnancy has been described.45,46 In this regard, Peru has established the Multisectoral Plan for the Prevention of Adolescent Pregnancy 2012-2021,9 which aims to guide the actions of the public sector, civil society and international cooperation agencies in the prevention of adolescent pregnancy, with emphasis on the most vulnerable and poorest groups. Likewise, the Technical Health Standard on Family Planning47 promotes comprehensive care with emphasis on sexual and reproductive health, with the aim of achieving the promotion and the access to contraceptive methods in differentiated schedules and exclusive environments for adolescents.\n\nTherefore, it is important to expand family planning services in order to have an adolescent population informed about sexual and reproductive health with access to traditional or modern contraceptive methods. Likewise, a constant evaluation of the success of these interventions should be reported annually to identify whether there is an improvement or not in the indicators of adolescent pregnancy.\n\nAlthough our results are consistent with those reported in previous studies,10–12,20 the following limitations should be considered in the present study: First, it should be recognized that because of the cross-sectional design of the study, the associations reported do not imply causality due to the lack of temporality. Second, there may have been recall bias or inadequate understanding of the questions in some subgroups. Third, since the data evaluated came from a secondary database, some variables or risk factors of interest for gestation in adolescents were not included in the measurements made by the ENDES. Despite the above, the ENDES is a nationally and regionally representative survey that has quality control processes and is widely used for the study of health issues in the Peruvian population. For the present study, only data from adolescents between 15 and 19 years of age who initiated sexual relations were included, given that the history of having initiated sexual relations is the causal factor in the existence of pregnancies, thus providing a closer and more homogeneous measurement of the factors associated with adolescent pregnancy, compared to previous reports that evaluated adolescents in general.\n\n\nConclusions\n\nBetween 2015 to 2019, in Peru about a third of adolescents aged 15 to 19 years who initiated sexual activity, presented with at least one pregnancy. We identified that being between 17 and 19 years old, having a partner and being of Quechua ethnicity were independently associated with a higher prevalence of adolescent pregnancy. On the other hand, having an occupation, being in school, belonging to the second, third, fourth and fifth quintiles of poverty, having had their first sexual intercourse between 17 and 19 years of age, perceiving a future pregnancy as non-problematic and knowing the moment in the cycle when they could become pregnant were independently associated with a lower prevalence of adolescent pregnancy. It is necessary that the sustained increase of local and national strategies regarding family planning and sexual education in adolescents be carried out in a timely and inclusive manner, given that the avoidance of early initiation of sexual relations together with the acquisition of competencies on adolescent pregnancy prior to the initiation of sexual relations is a reasonable option to reduce the prevalence of adolescent pregnancy and therefore potential obstetric-neonatal complications in Peru.\n\n\nData availability\n\nData used in this study are from the secondary dataset of the Peruvian Demographic and Family Health Surveys - ENDES (2015-2019), available from the “El Instituto nacional de Estadística e Informática” website (http://iinei.inei.gob.pe/microdatos/). The dataset modules used were: Basic data of women at childbearing age (“Datos Basicos de MEF”); Birth story (“Historia de Nacimiento - Tabla de Conocimiento de Metodo”); Pregnancy, Childbirth, Puerperium and Lactation (“Embarazo, Parto, Puerperio y Lactancia”); and Fertility and partner (“Nupcialidad - Fecundidad - Cónyugue y Mujer”).",
"appendix": "References\n\nWorld Health Organization: Adolescence: a period needing special attention - recognizing-adolescence.2014. Reference Source\n\nChristie D, Viner R: Adolescent development. BMJ. 2005; 330(7486): 301–304. PubMed Abstract | Publisher Full Text\n\nPatton GC, Sawyer SM, Santelli JS, et al.: Our future: a Lancet commission on adolescent health and wellbeing. Lancet. 2016; 387(10036): 2423–2478. PubMed Abstract | Publisher Full Text\n\nTodhunter L, Hogan-Roy M, Pressman EK: Complications of Pregnancy in Adolescents. Semin. Reprod. Med. August 10, 2021. Publisher Full Text\n\nNjim T, Tanyitiku BS, Babila CS: Prevalence of adolescent deliveries and its complications in Cameroon: a systematic review and meta-analysis. Arch Public Heal. 2020; 78(1): 24. PubMed Abstract | Publisher Full Text\n\nMendoza W, Subiría G: El embarazo adolescente en el Perú: situación actual e implicancias para las políticas públicas. Rev. Peru. Med. Exp. Salud Publica. 2014; 30(3). Publisher Full Text\n\nWorld Health Organization (WHO): Adolescent Pregnancy.2020. Reference Source\n\nOrganización Panamericana de la Salud/Organización Mundial de la Salud: El Embarazo En La Adolescencia En América Latina y El Caribe. Reseña Técnica, Agosto Del. 2020; 2020. Reference Source\n\nMinisterio de Salud: Plan Multisectorial para la Prevención del Embarazo en Adolescentes 2012-2021.2013. Reference Source\n\nKassa GM, Arowojolu AO, Odukogbe AA, et al.: Prevalence and determinants of adolescent pregnancy in Africa: a systematic review and Meta-analysis. Reprod. Health. 2018; 15(1): 195. PubMed Abstract | Publisher Full Text\n\nPoudel S, Upadhaya N, Khatri RB, et al.: Trends and factors associated with pregnancies among adolescent women in Nepal: Pooled analysis of Nepal Demographic and Health Surveys (2006, 2011 and 2016). Uthman O, ed. PLoS One. 2018; 13(8): e0202107. PubMed Abstract | Publisher Full Text\n\nHubert C, Villalobos A, Abreu AB, et al.: Factors associated with pregnancy and motherhood among Mexican women aged 15-24. Cad. Saude Publica. 2019; 35(6): e00142318. PubMed Abstract | Publisher Full Text\n\nCastañeda Paredes J, Santa-Cruz-Espinoza H: Factores de riesgo asociados al embarazo en adolescentes. Enfermería Glob. 2021; 20(2): 109–128. Publisher Full Text\n\nNiño-García R: Embarazo adolescente en el Perú: características y factores asociados, según la encuesta demográfica y de salud familiar del Perú 2019 [TESIS].2021. Reference Source\n\nInstituto Nacional de Estadística e Informática: Ficha Técnica – Encuesta Demográfica y de Salud Familiar. Lima: Perú INEI; 2019. Reference Source\n\nPinzón-Rondón ÁM, Ruiz-Sternberg ÁM, Aguilera-Otalvaro PA, et al.: Factores asociados al inicio de vida sexual y al embarazo adolescente en Colombia. Estudio de corte transversal. Rev. Chil. Obstet. Ginecol. 2018; 83(5): 487–499. Publisher Full Text\n\nGómez-Mercado CA, Montoya-Vélez LP: Factores sociales, demográficos, familiares y económicos relacionados con el embarazo en adolescentes,área urbana, Briceño, 2012. Rev. Salud Pública. 2014; 16(3): 393–406. PubMed Abstract | Publisher Full Text\n\nNeal S, Channon AA, Chandra-Mouli V, et al.: Trends in adolescent first births in sub-Saharan Africa: a tale of increasing inequity?. Int. J. Equity Health. 2020; 19(1): 111–151. PubMed Abstract | Publisher Full Text\n\nVillalobos-Hernández A, Campero LS-LL, Atienzo EE, et al.: D la V-SE. Embarazo adolescente y rezago educativo: análisis de una encuesta nacional en México. Salud Publica Mex. 2015; 57(2): 135–143. Publisher Full Text Reference Source.\n\nWorku MG, Tessema ZT, Teshale AB, et al.: Prevalence and associated factors of adolescent pregnancy (15–19 years) in East Africa: a multilevel analysis. BMC Pregnancy Childbirth. 2021; 21(1): 253. PubMed Abstract | Publisher Full Text\n\nGabriel ESE, Halle-Ekane GE, Isah M, et al.: Prevalence and Associated Factors of Teenage Pregnancy among Secondary and High School Students in the Tiko Health District, South West Region, Cameroon. J. Biosci. Med. 2020; 08(09): 99–113. Publisher Full Text\n\nEstrada F, Suárez-López L, Hubert C, et al.: Factors associated with pregnancy desire among adolescent women in five Latin American countries: a multilevel analysis. BJOG An Int J Obstet Gynaecol. 2018; 125(10): 1330–1336. PubMed Abstract | Publisher Full Text\n\nInstituto Nacional de Estadistica e Informatica: Censos Nacionales 2017 – XII de Población, VII de Vivienda y III de Comunidades Indígenas.2017. Reference Source\n\nOrganización Panamericana de la Salud and Organización Mundial de la Salud: Educación, ingreso y etnia son los factores sociales que más influyen en la salud de niños, niñas adolescentes y madres - Hallazgos del informe.2021. Reference Source\n\nUnited Nations Children’s Fund: Vivencias y relatos sobre el embarazo en adolescentes.2014. Reference Source\n\nVerona-Balcázar M, Fernández-Mogollón JL, Neciosup-Puican E: Características epidemiológicas, clínicas y demoras en el proceso de atención en casos de muerte materna, Región Lambayeque. 2011 – 2016. Rev. del Cuerpo Médico del HNAAA. 2019; 12(2): 97–103. Publisher Full Text\n\nInstituto Nacional de Estadística e Informática: Condiciones de Vida de La Población Según Origen Étnico.2016. Reference Source\n\nInformática IIN de E e, Berrocal Montoya L: Adolescentes que no estudian ni trabajan y su condición de vulnerabilidad: sobre la base de los resultados de los Censos Nacionales 2017 XII de Población, VII de Vivienda y III de Comunidades Indígenas. Minist Educ; 2018.\n\nFavara M, Lavado P, Sánchez A: Understanding teenage fertility in Peru: An analysis using longitudinal data. Rev. Dev. Econ. 2020; 24(4): 1217–1236. Publisher Full Text\n\nLiang M, Simelane S, Fortuny Fillo G, et al.: The State of Adolescent Sexual and Reproductive Health. J. Adolesc. Health. 2019; 65(6): S3–S15. Publisher Full Text\n\nWesley VA: Deserción Escolar: Evolución, Causas y Relación Con La Tasa de Conclusión de Educación Básica.2016. Reference Source\n\nSánchez Valencia YA, Mendoza Tascón LA, Grisales López MB, et al.: Características poblacionales y factores asociados a embarazo en mujeres adolescentes de Tuluá, Colombia. Rev. Chil. Obstet. Ginecol. 2013; 78(4): 269–281. Publisher Full Text\n\nPradhan R, Wynter K, Fisher J: Factors associated with pregnancy among adolescents in low-income and lower middle-income countries: a systematic review. J. Epidemiol. Community Health. 2015; 69(9): 918–924. PubMed Abstract | Publisher Full Text\n\nGomes C: Adolescent fertility in selected countries of Latin America and the Caribbean. J. Public Heal. Epidemiol. 2012; 4(5): 133–140. Publisher Full Text\n\nAzevedo JP, Favara M, Haddock SE, et al.: Teenage Pregnancy and Opportunities in Latin America and the Caribbean: On Teenage Fertility Decisions, Poverty and Economic Achievement.2012.\n\nCavero-Arguedas D, Cruzado de la Vega V, Cuadra-Carrasco G: Los efectos de los programas sociales en la salud de la población en condición de pobreza: evidencias a partir de las evaluaciones de impacto del presupuesto por resultados a programas sociales en Perú. Rev. Peru. Med. Exp. Salud Publica. 2017; 34(3): 528. Publisher Full Text\n\nCavazos-Rehg PA, Krauss MJ, Spitznagel EL, et al.: Age of sexual debut among US adolescents. Contraception. 2009; 80(2): 158–162. PubMed Abstract | Publisher Full Text\n\nSmid M, Martins S, Whitaker AK, et al.: Correlates of Pregnancy Before Age 15 Compared With Pregnancy Between the Ages of 15 and 19 in the United States. Obstet. Gynecol. 2014; 123(3): 578–583. PubMed Abstract | Publisher Full Text\n\nJaccard J, Dodge T, Dittus P: Do adolescents want to avoid pregnancy? Attitudes toward pregnancy as predictors of pregnancy. J. Adolesc. Health. 2003; 33(2): 79–83. PubMed Abstract | Publisher Full Text\n\nWiemann CM, Rickert VI, Berenson AB, et al.: Are pregnant adolescents stigmatized by pregnancy?. J. Adolesc. Health. 2005; 36(4): 352.e1–352.e7. Publisher Full Text\n\nPeñafiel F, Solís R, Xavier K, et al.: Percepción de las adolescentes frente al embarazo: revisión sistemática.2020. Publisher Full Text\n\nAtkin L, Alatorrerico J: Pregnant again? Psychosocial predictors of short-interval repeat pregnancy among adolescent mothers in Mexico City1, 2. J. Adolesc. Health. 1992; 13(8): 700–706. PubMed Abstract | Publisher Full Text\n\nCastillo Riascos LL: Weaknesses in preventing teen pregnancy. Salud Uninorte. 2021; 32(3): 543–551. Publisher Full Text\n\nGutiérrez M: La planificación familiar como herramienta básica para el desarrollo. Rev. Peru. Med. Exp. Salud Publica. 2013; 30(3): 465–470. PubMed Abstract | Publisher Full Text Reference Source\n\nRodríguez RC: Adolescent pregnancy, public policies, and targeted programs in Latin America and the Caribbean: a systematic review. Rev. Panam Salud Pública. 2021; 45: 1. PubMed Abstract | Publisher Full Text\n\nBrindis CD, Decker MJ, Gutmann-Gonzalez A, et al.: Perspectives on Adolescent Pregnancy Prevention Strategies in the United States: Looking Back. Looking Forward. Adolesc. Health Med. Ther. 2020; 11: 135–145. PubMed Abstract | Publisher Full Text\n\nMinisterio de Salud: Norma Tecnica de Salud de Planificación Familiar.2017. Reference Source"
}
|
[
{
"id": "140010",
"date": "20 Jun 2022",
"name": "Dora Blitchtein-Winicki",
"expertise": [
"Reviewer Expertise Public health"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper explores a relevant public health issue about the factors associated with teenage pregnancy, the resulting information has a significant potential in selecting and directing strategies in for rural and urban adolescent population.\nMethodology\n1.1: It is necessary to specify the selection criteria of the study population, the inclusion and exclusion criteria are not clear or fully described, it is stated in the results section that people with missing data for all the independent variables were excluded, it should be explicit in the section on population.\n\n1.2: It is necessary to encompass information about the statistical power of the study with the amount of population that met the selection criteria of the study, it is possible to select prevalence of two factors with lower prevalence in the exposed and unexposed population to do so.\n\n1.3: More details are needed on the basis of which questions and how the independent variables were categorized, for example, how the positive or negative perception of pregnancy, the knowledge of the cycle in which she could become pregnant, and the use of contraceptive methods (any? or modern? in her life, current use?) were categorized. In regard to the latter, the articles cited include the unmet need for modern contraceptive methods as one of the related factors, however, it is not understood in the study whether the knowledge and/or use of modern contraceptive methods has been included as a factor.\n\n1.4: Please clarify regarding the ethnicity variable from which questions it was taken and how it was classified, the categories presented in the descriptive table called ethnicity that includes mestizo, quecha, negro/moreno/zambo and others, are only included in the Peruvian Demographic Health Survey ENDES survey since 2018 and 2019. The question encompassed from 2015 to 2019 was mother tongue during childhood and the categories were Spanish, Quechua, Aymara, other language. http://iinei.inei.gob.pe/microdatos/\n\n1.5: Describe the study procedures for data collection of main variables of the present study in the Demographic Health Survey of Peru ENDES, was it a face-to-face interview, were the personnel expressly trained for these modules, are there any particular characteristics related to women aged 15 to 17 years? Or in women in general for the information modules encompassed?\n\nData Analysis\n2.1: It is not clear whether multicollinearity was evaluated in the adjusted models.\n\nResults\n3.1: Figure 1. In the ENDES annual information of participants, 2017 information is missing and 2019 is repeated with different information (n). It is not specified how many were excluded due to missing data for each variable encompassed as factors.\n\n3.2: It is not understood how 24,419 can have information of pregnancy and of those 14,552 had not initiated sexual intercourse? this needs to be reworded or clearly explained.\n\nDiscussion\n4.1 The discussion should include aspects of gender and cultural relations according to ethnicity or context, such as the type of family they come from (no parents, nuclear, extended), age of cohabitation and types of cohabitation\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "9772",
"date": "17 Nov 2023",
"name": "Brenda Sofia Caira-Chuquineyra",
"role": "Author Response",
"response": "Response #1 We appreciate your comment. We have added information on inclusion and exclusion criteria in the population section. “During the period of 2015-2019, a total of 31,858 adolescent women between the ages of 12 and 19 were included in the survey. However, for the purpose of our analysis, the effective sample consisted of 8850 women met the criteria of being currently pregnant or already mothers and reported having initiated sexual intercourse. Additionally, those respondents with incomplete information on any of the covariates of interest were excluded” Response #2 We appreciate your comment. We calculated the statistical power for each association presented and added a paragraph noting the results. Statistical analysis section: “Finally, considering a sample size of 8850 respondents and a confidence level of 95%, we assessed the statistical power for each factor analyzed in this study. The statistical power, which indicates the likelihood of detecting a true association, was found to be greater than 80% for all the associations presented. This demonstrates that the sample size included in this study was adequate to detect significant associations between the variables analyzed ” Response #3 We appreciate your comment. We have detailed and used the appropriate terms to differentiate the concept of the variable to be used. For example, for the variable use of contraceptive methods we categorized the different methods used into three groups: no use, use of traditional methods and use of modern methods. On the other hand, for the variable knowledge of the fertile period, we have expanded when it corresponded to a response of no and yes respectively. “On the other hand, we also consider gynecology-obstetric variables, such as age of first sexual intercourse (early adolescence [10 to 13 years], middle adolescence [14 to 16 years], and late adolescence [17 to 19 years]), use of contraceptive methods (no, traditional contraceptive methods, and modern contraceptive methods), knowledge of fertile period (no, and yes), and perception of future pregnancy (problematic, not problematic). The variable \"knowledge of fertile period\" was categorized into two groups: those who did not have knowledge of when pregnancy could occur during the menstrual cycle (no) and those who had knowledge of the fertile period (yes). The variable \"perception of future pregnancy\" was categorized into two groups: those who perceived a future pregnancy as problematic and those who did not perceive it as problematic.” Response #4 We appreciate your comment. Your observation is correct, as of the ENDES 2017 the specific question was considered to know the ethnicity of the respondents. However, since it is an important variable for our study, we consider those women surveyed in 2015 and 2016 as Mestizas if they reported that the mother tongue was Spanish, while we consider as Quechua ethnicity if the mother tongue was Quechua and as other ethnicities if they reported having another mother tongue. Additionally, we highlight such limitation in the description so that it can be taken into account by readers. Independent variables section: “It is important to note that for the years 2015 and 2016, the ENDES survey did not specifically collect information on ethnicity. As a result, in this study, an alternative approach was taken to approximate ethnicity by considering the information on mother tongue. Specifically, individuals who reported that their mothers spoke Spanish were categorized as mestizos. Those who reported speaking the Quechua language were categorized as Quechua. Individuals who reported other languages were classified under the category of other ethnicities. It is important to acknowledge this limitation when interpreting the results related to ethnicity in the study.” Response #5 We appreciate your comment. We add the relevant information to better clarify the process of obtaining the information. Population, smaple, and sampling section: “It is important to highlight that the DHS implemented a face-to-face survey methodology, specifically targeting women of reproductive age (15 to 49 years in the 2015, 2016, and 2017 DHS, and 12 to 49 years in the 2018 to 2019 DHS). Within the scope of the ENDES, the survey of women in this age group was carried out in a personalized, confidential, and respectful manner, without requiring the presence of parents. Moreover, it is worth noting that participants who chose not to answer a particular question were recorded as having missing data. This approach aimed to ensure the privacy and comfort of the respondents, fostering an environment where they could provide accurate and honest responses.” Response #6 We appreciate your comment. We added multicollinearity assessment as part of the statistical analyses. “To assess collinearity, the variance inflation factor (VIF) was used, where a value > 10 determined multicollinearities between variables; however, all values obtained were less than 10.” Response #7 We appreciate your comment. We reconstructed Figure 1 to clarify the selection process. Response #8 We appreciate your comment. We reconstructed Figure 1 to clarify the selection process. The corresponding doubt corresponded to the total number of respondents with information on the indicated item, but as it was confusing, we decided to change the flow chart. Response #9 We appreciate your comment. With respect to the culture of ethnic groups, we found that ethnic groups have a higher level of fertility and lower use of contraceptive methods, as well as a higher acceptance of marriage. This information is found in the fourth paragraph of the discussion. “In Peru in 2016, it was observed that the population of native origin (Quechua, Aymara or Amazonian origin) had a higher level of fertility and a lower proportion of contraceptive methods used. 27 In these ethnic groups, a greater acceptance of early marriage and pregnancy has also been reported. 25 Therefore, greater state intervention is required in these population groups to reduce the gaps in access to sexual and reproductive health information for adolescents.” With respect to the type of family, the types of cohabitation, we consider that we do not have enough information based on our findings to provide more information on the subject, since we only consider the fact of being with or without a partner (married/cohabiting)."
}
]
},
{
"id": "170294",
"date": "26 Apr 2023",
"name": "Angelo Mark Walag",
"expertise": [
"Reviewer Expertise Science and Health Education",
"Natural Sciences"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper demonstrates an initial study exploring the prevalence and associated factors of adolescent pregnancy in Peru from 2015-2019. This study will be meaningful to research scholars interested in sociological and behavioral aspects of adolescent pregnancy as well as policymakers interested in the phenomena.\nWhile the study has interesting results, it needs some revisions.\n\nIn the abstract, minimize the presentation of specific results as this is intimidating to readers. Just present key findings of the study. Keywords that already appear in the title need to be replaced to maximize visibility and online reach.\n\nThe introduction section may be expanded covering literature outside of Peru. The authors may also present some findings related to prevalence of adolescent pregnancy in different parts of the globe. This will help the authors to establish novelty and gap in the literature.\n\nIt is highly commendable that the researchers discussed ethical consideration of the study.\n\nMethods are appropriately and thoroughly discussed\n\nThe result that there is higher prevalence of adolescent pregnancy in those who use contraceptives need to be discussed further as this is a surprising result. Authors may need to offer possible explanation for this.\n\nThe rest of the discussion is well-done\n\nConclusion is sufficient\n\nReferences are appropriate.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "9773",
"date": "17 Nov 2023",
"name": "Brenda Sofia Caira-Chuquineyra",
"role": "Author Response",
"response": "Response #1 We appreciate your comment. We have restructured the results section of the summary to make it clearer. We have also added some keywords “The prevalence of adolescent pregnancy among sexually active adolescents in Peru was 30.9% (95%CI: 29.4–32.4%). In the multivariable analysis; being 17-19 years (aPR: 1.48; 95%CI :1.33–1.64), being married or cohabitant (aPR: 4.01; 95%CI: 3.48–4.61) and belonging to the Quechua ethnicity group (aPR: 1.16; 95%CI: 1.07–1.25), were associated with a higher prevalence. Conversely, the following factors were associated with a lower prevalence of pregnancy: being employed (aPR: 0.81; 95%CI: 0.76–0.86), being currently studying (aPR: 0.43; 95%CI: 0.38–0.49), belonging to the second (aPR: 0.91; 95%CI: 0.85–0.97), third (aPR: 0.81; 95%CI: 0.74–0.89), fourth (aPR: 0.79; 95%CI: 0.69–0.91) and fifth (aPR: 0.59; 95%CI: 0.47–0.75) wealth quintile, initiating sexual relations in middle adolescente (aPR: 0.76; 95%CI: 0.69–0.83) or late adolescence (aPR: 0.40; 95%CI: 0.35–0.46), perceiving a future pregnancy as a problem (aPR: 0.77; 95%CI: 0.72–0.83) and having knowledge of the moment in the cycle when pregnancy can occur (aPR: 0.84; 95%CI: 0.77–0.92)” Response #2 We appreciate your comment. In the second paragraph of the introduction, we detailed adolescent pregnancy rates globally and in the Latin American region. “According to the WHO, approximately 12 million women between the ages of 15 and 19, and around 1 million girls under the age of 15, give birth each year. 7 Latin America and the Caribbean have the second highest rate of adolescent fertility worldwide. Although the overall rate has decreased from 65.6% (2010-2015) to 60.7% (2015-2020), significant variations persist among sub regions and countries” Response #3 We appreciate your comment. The section on \"Ethical aspects\" was considered as the second subtitle of Methods. Response #4 We appreciate your comment. Response #5 We appreciate your comment. While it is true that this finding is surprising. We should point out that temporality for this item could be an important point to consider. Given that the use of these methods refers to a current use, which could be a consequence of having experienced a pregnancy, she began to take care of herself so as not to have more children. On the other hand, in those women with no history of pregnancy, it is possible that they are initiating their sexual life and were not using any method. Despite the implications that this finding could represent, it was not considered in the adjusted analysis and was therefore not a widely discussed point. Response #6 We appreciate your comment. Response #7 We appreciate your comment Response #8 We appreciate your comment."
}
]
}
] | 1
|
https://f1000research.com/articles/11-566
|
https://f1000research.com/articles/12-1073/v1
|
31 Aug 23
|
{
"type": "Research Article",
"title": "ASEAN as network governance: An alternative lens to evaluate policymaking and performance",
"authors": [
"Pushpanathan Sundram"
],
"abstract": "Background: This article offers a new perspective of the Association of Southeast Asian Nations (ASEAN) as network governance (NG) using the policy network theory (PNT) for the analysis. Methods: Two case studies were selected from the ASEAN Community to examine the applicability and effectiveness of NG in promoting ASEAN cooperation. These case studies were chosen due to their prominence and the prevalence of critical comments about their effectiveness in promoting cooperation. The content analysis utilised primary data from ASEAN reports, documents, research articles and processes, and studies on NG and policy networks. A literature review was conducted using online academic databases and ASEAN-related websites. The search covered the period from June 2019 to March 2021, with further searches conducted between January and July 2023. These data collection efforts provided a robust analysis of the case studies within the NG and ASEAN integration contexts. Results: The findings show ASEAN as a hybrid structure which has supported its survival and relevance. This approach provides legitimacy for ASEAN globally by purposefully adopting structures similar to the EU without the supranational elements. It also showcases ASEAN’s motivation for asserting its centrality. Adopting a hybrid structure has led to ASEAN's soft institutionalisation, driven by its norms and characterised by a less empowered secretariat, where the member states are the decision-makers and implementors of policies. It opens a pathway to recognising ASEAN states’ autonomy, where the actors’ will and interests affect decision-making and defines performance. Conclusions: This article demonstrates NG's viability in promoting ASEAN's centrality in regional cooperation and institutional arrangements and allows for a nuanced assessment of its performance considering the context of the issue and ASEAN's history and emphasising the member states' primacy in policymaking. The NG framework contributes to ASEAN’s legitimacy, regional cooperation and performance despite its inherent limitations.",
"keywords": [
"ASEAN",
"network governance",
"policy networks",
"soft institutionalisation"
],
"content": "Introduction\n\nDespite the tremendous diversities, the Association of Southeast Asian Nations (ASEAN) has been primarily recognised for maintaining the peace and security of Southeast Asia (SEA) and promoting economic and sociocultural cooperation among its members. ASEAN attributes its success to the “adherence to the fundamental principles of non-interference and sovereignty with respect for shared values and norms” that have paved the path of tolerance for differences while highlighting the importance of keeping the region peaceful, secure, and stable (ASEAN Secretariat, 2015). Notwithstanding this, the principle of non-interference and the lack of legally binding institutions in ASEAN underscore the ‘ASEAN Way’ and invite disapproval from critics and sceptics who regard it as an informal regional organisation incapable of achieving its goals and implementing its agenda in the absence of a central authority. Several scholars (Leifer, 1999; Nischalke, 2002; Jones and Smith, 2006; Narine, 2009; Jones and Jenne, 2016; Emmerson, 2020) have pinpointed the inadequate formal institutions or mechanisms and legally binding agreements, soft institutionalisation, process-driven and normative structures led by weaker states as major shortcomings of ASEAN. As a result, ASEAN is often criticised for lacking meaningful progress in its regional integration prompting sceptics to propose that ASEAN adopt the more formal European Union (EU) institutions to perform better. These include a strengthened ASEAN Secretariat with legislative powers and enforcement authority like the European Commission and more robust dispute settlement mechanisms (Hoang et al., 2016). In 2009, ASEAN embarked on building an ASEAN Community comprising the ASEAN Economic Community (AEC), ASEAN Political Security Community (APSC), and ASEAN Social Cultural Community (ASCC). It continues to develop the ASEAN Community through its blueprints for the three sectoral communities from 2016 to 2025. However, discrepancies observed between the “rhetorical goals and outcomes” of ASEAN integration or “implementation gaps” (Jetschke, 2009) have underscored the Association’s norms and principles as shortcomings in its community-building agenda. While the adoption of central institutions and a legal framework to ‘force’ member states to comply and be accountable for their decisions has been a subject of dispute as a means to strengthen ASEAN’s institutions (Koh et al., 2009), it should be recalled that ASEAN’s current institutional design is but a deliberated and purposeful choice of the founders of ASEAN without which we would not have seen the survival of ASEAN. As such, these perceived weaknesses within ASEAN institutions impacted much of the Association’s history, as well as the work that has gone into the policymaking process in the pursuit of ASEAN goals while balancing member states’ interests. Therefore, it will be important to recognise the embedment of norms and principles in ASEAN policies and agreements. Yet, it does not necessarily impede or obstruct ASEAN goals and policy implementation in issue areas where member states’ interests precede that of the underlying norms and principles of ASEAN.\n\nAccordingly, the article proposes an alternative framework of network governance (NG) to provide a nuanced account of policymaking, taking into account the networked institutional design of ASEAN using the policy network theory (PNT) of Michael Howlett (2002). Here, we can acknowledge the progress and performance of ASEAN via the PNT, which assesses ASEAN’s policy processes and outcomes through the interaction between the role of actors, ideas, and interests in the policymaking process. This makes way for the inclusion and consideration of ASEAN norms and principles (ideas) and how it intersects with member states’ will (actors) and ASEAN goals (interests). This context of policymaking considers ASEAN’s norms and principles (underpinnings) and will assist in evaluating the Association without prejudice to these underpinnings. Utilising PNT, this article will present case studies from the AEC and APSC to evaluate the performance of the communities, going beyond identifying the Association’s shared norms, such as the principle of non-intervention and sovereignty, as the cause for implementation failure or a lack of performance. In particular, by focusing on the interaction between actors, ideas, and interests, attributing more responsibility to member states in strengthening implementation gaps and enhancing performance and thereby recognising that the ’non-institutionalised form of regionalism’ of ASEAN (Acharya, 2008) can bring performance and non-performance.\n\nEstablished in August 1967 by Indonesia, Malaysia, the Philippines, Singapore, and Thailand as the five founding members of ASEAN, they held the vision of promoting and maintaining security and peace in the SEA region. Against the backdrop of the Cold War, most SEA states found themselves “threatened by subversive communist movements” (Kefale, 2015) in addition to a series of territorial and border disputes. The latter led to the task of state consolidation for the founding members during the development of ASEAN for fear of neighbouring conflicts and history from their colonial past. It was clear that distrust between SEA states ran deep during those times, especially with Konfrontasi (or Confrontation) pursued by then-Indonesian President Sukarno between 1963 to 1966. It was ultimately a policy which opposed the formation of the Federation of Malaysia since it was viewed as a “British imperial project” (Kefale, 2015). Konfrontasi paints a clear picture of the then-faltering dynamics between Indonesia and other SEA states and Indonesia’s ambition to project its foreign policy goals abroad through armed conflicts, which bred scepticism and potentially undermined regional cooperation and multilateral ties among regional states. Nonetheless, ASEAN still managed to emerge from these complex dynamics, with its main objectives focused on mitigating regional threats and maintaining regional security.\n\nHistory has shown that the norms of engagement in ASEAN would take a different trajectory from other regional organisations like the EU, considering the colonial occupation that most ASEAN member states have been through. For instance, it would be difficult to reconcile the idea of ‘pooling sovereignty’ as seen in the EU and even delegate some legal mandate to an extra-national body like ASEAN when sovereignty is a hard-earned freedom in the nation states of SEA. Only by being able to exercise a traditional understanding of sovereignty and non-interference as a regional principle (Chetchaiwong, n.d.) do member states ensure that domestic issues remain an internal affair of the relevant member states, safeguarding their right towards conflict management. While this may reflect a realist position and may be incompatible with policymaking in a regional organisation, it provided autonomy and safeguarded the principle of non-interference sacrosanct to all ASEAN member states, thereby allowing for cooperation and, in the later years, regional integration. The ASEAN founders, when establishing the Association in 1967, had based its principles and norms on ‘musyawarah’ (consultation) and ‘mufakat’ (consensus), which characterise what many have termed as a ‘loose and informal’ cooperation style.\n\nTo recommend ASEAN undergo institutional evolution to emulate the successes of the European integration project proposes an approach which lacks an understanding of ASEAN and the rationale behind the principles and norms. As such, it would be important to recall some critical components that critics have conjectured as reasons that resulted in the gaps between ASEAN’s rhetoric goals and its actual performance or implementation gaps. The reliance on socially rather than legally binding rules and norms and its lack of a centralised and autonomous secretariat (Jetschke, 2009) highlights ASEAN’s light form of institutionalisation, which in turn produces network forms of governance (Jetschke, 2009) encapsulated by the concept of NG reasoned to be behind ASEAN’s implementation gaps due to the inability to command compliance from its member states. In Jetschke’s argument, the concept of NG reiterates member states’ high regard for their autonomy and their unyielding attitude toward the principle of non-interference and a weak manner of institutionalisation that affects the unanimity on policy issues, decision outcomes, and the rate of implementation or adoption of a policy in ASEAN. However, this article views NG as a viable alternative theoretical framework which can better account for ASEAN’s performance and non-performance without prejudice to its norms and principles.\n\nNG has more prominence in its own field of study in the literature on policy networks. First, networks indicate non-hierarchical and knowledge-based forms of policymaking that enable the progression of ideas, communication, and consensus-building processes for specific policies (Mayntz, 1993; Rhodes, 2003). These characteristics are aligned with the policy networks of ASEAN that focus on networks as communication devices. At the fundamental level, the policy network theory (PNT) proposes a framework detailing how different subsystem setups relate to specific paradigmatic processes of policy change, suggesting that some are linked to propensities for particular types of policy change (Howlett, 2002). Policy networks are also interdependent as networks are mutually reliant on each other’s resources (Bevir, 2011) and often referred to as “mutual resource dependence” (Bevir, 2009). Klijn (1997) suggests that interdependencies engender interactions between actors and sustain relation patterns in policy networks. Hence, policy network theory or the ‘network approach’ is pivotal in examining ASEAN as a ‘network structure’ and the effectiveness of the numerous types of networks contained in the Association. This approach deconstructs how we view the organisation’s structure, policy process, and outcomes.\n\nFor Jetschke (2009), “if one subtracts Europe’s effects on the organisation, ASEAN’s formalisation since 1967 might well amount to pure NG”. Hence, the maintenance of autonomy, strong regard for the principle of non-interference, and the Westphalian notion of sovereignty are obstacles to the development of an EU-like institutional design in ASEAN, reinforcing the preference for an informal policy style and a non-binding set of rules and principles (Jetschke, 2009). Yet, without the agreement to those norms and principles, the establishment of ASEAN would not have been possible. Since these norms are practically non-negotiable at this juncture, developing a framework to reflect these underpinnings is paramount. Therefore, the article seeks to utilise the concept of NG to conceive of ASEAN’s institutional design but concludes on a different note from Jetschke by highlighting the potential that NG holds in evaluating and nurturing the potential of ASEAN.\n\nFirst, NG is an apt framework for ASEAN because it is “an alternative to hierarchy and a viable approach for theorising questions of order while not downplaying the extent of egoism among ASEAN members” (Jetschke, 2009). Where networks are “lighter on their feet than hierarchies”, and exchanges are carried out only by the members of the network(s) through “reciprocal, preferential, mutually supportive actions” (Powell et al., 1990). A similar definition was also proposed in the work of Jones, Hesterly, and Borgati, which views NG as a select, persistent, and structured set of autonomous organisations engaged in non-legally binding contracts to adapt to environmental contingencies and to coordinate and safeguard exchanges (Jones et al., 1997). Thus, NG presents itself as a useful framework with its emphasis on the importance and precedence of states (states’ autonomy) and the exchanges between member states that define the networks forged in the organisation itself (Kim, 2006). In this regard, it reflects the intergovernmental nature of ASEAN but does not point to an absence of institutional structure. It gives room to consider an alternative to hierarchy. Moreover, it suggests that ASEAN’s light institutionalisation is not a compromised design or a ‘middle ground’.\n\nIt would be noteworthy to consider how Powell indicated that in a network organisation, the method of conflict resolution would be heavily dependent on the ’norm of reciprocity agreed among members’ and, as such, subject members to an interdependent relationship (Powell et al., 1990). It means that the concept of NG would view the overarching norms of engagement and/or means of conflict management as a key essence of the organisation’s core. This would indicate NG’s capacity to view ASEAN’s norms and principles as essential makings to the character and performance of ASEAN. Highlighting the norm of reciprocity also suggests member states take lead roles when engaging or enacting specific policies depicting that power lies with them (Coen and Thatcher, 2008). Finally, it validates ASEAN’s current functioning by emphasising ’consultation, negotiation and soft law’ (Coen and Thatcher, 2008).\n\nUsing the NG framework, the article views ASEAN’s norms and principles as inevitable and permanent components defining the norms of engagement and degree of institutionalisation in the Association. It highlights the interplay between the former and the role of member states which will define how it manages and mitigates challenges. In addition, it allows us to view member states as conscious and active actors responsible and accountable for the interplay we witness or observe during policymaking. As Powell signalled, a key to network forms of organisation is that “expectations (within the organisation) are not frozen but change as circumstance dictate” (Powell et al., 1990). Here, member states hold the authority and power to make changes. Hence, as Powell stipulates, complementarity and accommodation are pertinent features to hone for a network organisation to succeed and where the article holds ASEAN’s challenges to be as we observe if the will or interests of member states precedes that of the maintenance of ASEAN’s norms and principles especially in the political and security issue-areas. While the Association could find itself in a deadlock as the policies in place are not backed up by legally binding rules and regulations (Stubbs, 2019), NG can help to identify the stage or phase at which a deadlock occurs, that could further hone its success in areas of policy formulation, coordination, and implementation. As such, the light institutionalisation of ASEAN would be better represented in a nuanced manner through the concept of policy networks supported by NG.\n\nGiven the central role of member states’ beliefs and perceptions in shaping ASEAN policymaking, it may appear redundant for sceptics to question granting states a high degree of autonomy within a regional organisation. The fact that sceptics, realists, and neo-realists often believe ASEAN to be an organisation in which “style trumps substance” and an organisation in which process, especially the ASEAN Way, is “emphasised over progress” (Stubbs, 2019) stresses how inefficient ASEAN is perceived in their view. Yet, to expect a change of the ASEAN Way to a more legalistic approach, less focused on the values, beliefs, and norms imbued since the beginning and defined by colonial past and history for a more effective organisation could just be ideal. From a divisive region (during the Cold War era) to a region that can now boast about more amicable diplomatic ties among member states, the importance of identity, values, and norms is not stressed sufficiently. The member states’ preferences and interests should be acknowledged as key to ASEAN’s performance in shaping policy outcomes.\n\nA brief comparison between the economic and political realms to showcase the degree of the interests of the member states would illustrate the above. In matters of economic pursuits, ASEAN member states are keen to pursue and establish free trade areas (FTAs) and the lowering of tariffs and non-tariff barriers. It is evident in the ASEAN Free Trade Area (AFTA) agreement signed in 1992, the ASEAN Trade in Goods Agreement (ATIGA) in 2009, and ASEAN member states’ interest and willingness to be a part of the Regional Comprehensive Economic Partnership (RCEP) concluded in 2020. On the other hand, issues in the political realm tend to be at a standstill, with member states seemingly ‘handicapped’ despite an expressed interest in resolving them due to the ASEAN principles and norms. For example, the territorial dispute in the South China Sea (SCS) has stretched over 20 years, with consultations in place to establish a code of conduct in the SCS, but to date, it has not been successful. As such, the will of member states is the critical variable affecting the cooperation and performance of ASEAN. Cooperation ensues when the interest and will converge, and when they diverge, non-performance occurs depending on the norms and principles impacted.\n\nWith this, an alternative theoretical framework of NG will be utilised to capture a more nuanced understanding of the underpinnings of ASEAN while focusing on the role of member states as active actors capable of shaping decisions and wielding the authority to act beyond what the norms and principles of ASEAN would dictate in issue-areas where the will or interests of member states take precedence.\n\nIn establishing the framework of NG first and foremost, the article adopts a specific definition of the framework provided by Ostrom, which identifies it as “a set of general variables and relationships that could be studied to understand a particular phenomenon but assigns no values to the variables and does not specify the direction of relationships between them” (Araral et al., 2015). A framework is essential to capture the essence of ASEAN and identify the interactions between actors that dominate and participate in the policy processes of ASEAN. It would also be supported by Michael Howlett’s PNT, which gives impetus to “thinking about policy making as involving more-or-less fluid sets of state and societal actors linked together by specific interest” (Howlett, 2002). The article uses the PNT approach to organise “actors and institutions into identifiable sets of policy-relevant interactions” (Howlett, 2002). It looks beyond structure (institutional mode of analysis) or agency (behavioural mode of analysis) when assessing a policymaking process. This offers a fresh perspective on the role of actors and interests and evaluating policy outcomes – whether they are/were successful or failed outcomes.\n\nUtilising the concept of a policy universe which “can be thought of as an all-encompassing aggregation of all possible state, private and social actors at various levels (local, regional, national, international) working within the institutions that directly or indirectly affect a specific policy area” (Howlett et al., 2017), ASEAN is conceptualised as a policy universe. The idea of a policy universe is a nuanced manner of conceptualising the institutional arrangement of ASEAN. It differs in terms of organisational design, where the latter is directly concerned with the institutions and degree of formalisation, while the former goes beyond the notion of institutional design as it looks at how the relationships and dynamics between member states and the actors and stakeholders outside of ASEAN who may be involved in the policymaking process. This could affect the agenda and outcome of the organisation and thereby impact the performance or non-performance of the Association.\n\nIf we recall how ASEAN founders established ASEAN for the purpose that “had to do mainly with regional peace and security” (Severino, 2003), it becomes clear that this rationale will impact the performance of ASEAN. This means that ASEAN’s ability to overcome or adapt to changes in the geopolitical landscape within the region shaped by great power, regional interests and transnational issues will be the points of assessment. In this regard, managing its centrality in regional geo-political arrangements and socialising or influencing decisions aligned with ASEAN’s views are geopolitical considerations rather than pursuing through materialistic means. Thus, ASEAN’s performance will be related to how it safeguards its relevance in any arrangement or drive its centrality.\n\nHere, ASEAN’s centrality relates to how ASEAN is able to assert its shared norms and values as an organisation, and one of the essential roles of ASEAN is to manage its centrality in regional geo-political arrangements. Where ASEAN’s centrality does not simply refer to its identity in the region, it stresses and signals the capacity, in terms of its influence and power, the organisation wields in the region. It would be apt to refer to how “centrality is seen to indicate the social power of an actor based on how extensively it is connected to the entire network” (Caballero-Anthony, 2014). The more ASEAN can assert itself, the better it can drive centrality in the networks it belongs to. To further make sense of the gravity of ASEAN’s centrality to the organisation, the article turns to the Resource Dependence Theory (RDT) to underscore how the relevance and the continued survival of the Association can be argued to be as critically connected to the survival of the Association’s member states. From an RDT’s perspective, which refers to the (regional) organisation as a ‘critical resource’ that members belonging to that regional organisation depend upon, and thus, understood as “important resource providers” (Drees and Heugens, 2013). As such, to a large extent, driving ASEAN’s centrality is an important task of the organisation. Since ASEAN’s survival is dependent on how it engages with its cluster of networks to facilitate interdependencies and solidify its legitimacy (Drees and Heugens, 2013), it becomes all the more crucial to conceive of the dynamics and relationships in ASEAN as a policy universe to pinpoint member states exercise of leadership towards consolidating ASEAN goals in an intergovernmental organisation setting. As such, centrality provides another expression of ASEAN’s power in a constructivist sense (Caballero-Anthony, 2014), where we view how capable member states are at driving ASEAN’s centrality in pursuing its goal and international legitimacy.\n\nOn the other hand, a policy subsystem defines as “the actors active in each sector or issue area” and/or are “forms of networks which encompass the interrelationships existing between elements of the policy universe active in specific knowledge and political spaces” (Howlett et al., 2017) This article views the three pillars of the ASEAN Community: ASEAN Economic Community (AEC), ASEAN Political Security Community (APSC), and ASEAN Socio Cultural Community (ASCC) as policy subsystem where each is unique with varying degree of significance to different member states including actors’ bargaining ability would define the performance or policy outcomes of the community. In utilising the concept of NG, the interactions between actors in the policy network are critical to understanding the interplay between various actors’ will and interests.\n\n\nMethods\n\nA qualitative content analysis and case studies related to the significance of NG and policy networks in ASEAN were undertaken. Through qualitative content analysis, relevant information was systematically analysed to identify patterns and themes. The case studies provided specific examples that shed light on the dynamics of policy networks, member states’ motivations, and the role of ASEAN’s centrality in policymaking. Combining these methods, the study aimed to understand the relevance and application of NG and policy networks within ASEAN.\n\nThe primary data used for the content analysis was ASEAN reports, documents, and research articles, besides analysis of studies and research papers on NG, policy networks, and ASEAN processes. They provided an understanding of the policy process phases and their varying degrees of success in the individual ASEAN communities.\n\nThis study’s search strategy for documents and sources involved a comprehensive approach. A systematic literature review was conducted using online academic databases such as Google Scholar, ResearchGate, Academia.edu, and ASEAN Secretariat and ASEAN member states websites. The search terms included the following keywords: ASEAN, ASEAN Economic Community, ASEAN Political Security Community, ASEAN Secretariat, AFTA, ASW, ARF, AMMTC, network governance, hybrid organisations, policy network, resource-dependence, state actors, non-state actors, soft institutionalisation, norms, non-interference, sovereignty, EU network governance, and EU policy networks. They were searched in relation to network governance, policy networks and policymaking and effectiveness. The words were primarily identified prior to the analysis. They were categorised and classified under several headings for systematic comparisons and analysis: EU and network governance; ASEAN and network governance; ASEAN network structures; EU network structures, state and non-state actors in ASEAN; norms, soft institutionalisation and hybrid organisation; and ASEAN motives, policy-making and performance in AFTA, ASW, ARF and AMMTC. The search was conducted between June 2019 to March 2021, covering a wide range of scholarly articles, books, reports, and policy documents as part of the author’s doctoral research. The author conducted further searches between January to July 2023 in developing this article.\n\nData collation involved a two-step process. First, relevant literature was gathered through the systematic literature review. The selected documents were then subjected to content analysis using the categories identified and mapped to compare and contrast the case studies and the differences between ASEAN and EU network governance. The variables included in the analysis focused on understanding the structure, functioning, and effectiveness of ASEAN as a hybrid organisation with network governance at its core. These variables encompassed aspects such as organisational legitimacy, decision-making processes, policy implementation, and the role of member states in shaping ASEAN’s performance.\n\nThe methods of analysis employed in this study were qualitative. Content analysis was used to examine the gathered literature and identify recurring themes, patterns, and theoretical frameworks related to network governance and hybrid organisations. The findings from the literature analysis were synthesised and interpreted to provide a comprehensive understanding of ASEAN’s hybrid structure and its implications for the organisation’s legitimacy and pursuit of centrality.\n\nTwo case studies, one from AEC and another from APSC covering two policy networks each, were utilised to study the presence and workings of NG in ASEAN alongside the resource dependence among member states that impacted policymaking.\n\nThe selection of AFTA as a case study within the ASEAN Economic Policy Subsystem (AEPS) is a deliberate choice, as the AFTA was established before the AEC itself. Moreover, with its long and substantive history, AFTA is a significant policy network to examine the performance of AEPS. Its significance is pertinent because AFTA’s framework-agreement approach was used to launch negotiations for the AEC and establish other regional free trade arrangements. Besides, the ASEAN Single Window (ASW), a core component of AFTA, was selected as it is a relevant micro case study on the operations of NG in AFTA, where custom cooperation and trade facilitation are forged across the region. Likewise, the ARF was identified as a case study since it is recognised as a “venue for multilateral and bilateral dialogue and consultations and the establishment of effective principles for dialogue and cooperation” (ASEAN Secretariat, n.d.-b), where a myriad of political and security issues is discussed. On the other hand, the ASEAN Ministerial Meeting on Transnational Crime (AMMTC) policy network was chosen as a contrast to ARF, where the focus on non-traditional security has often relied on the partnerships and cooperation of non-state actors (NSAs), which points to some acceptance of them in the APSS and at the discretion of member states. Figure 1 depicts the policy universe of the ASEAN Community with the two communities (AEC and APSC) and the policy networks (AFTA, ASW, ARF and AMMTC).\n\n\nResults\n\nTheories of regional economic integration would see the formation of the AFTA as one that encourages trade creation within the ASEAN bloc and would propel intra-regional trade flows and boost member states’ economies. It would result in greater integration as member states’ economies become increasingly interdependent. As such, the performance or non-performance of the economic integration is assessed through quantitative indicators such as changes in the share of intra-regional trade and investment since these are closely involved with indicators of interdependence. However, when these traditional quantitative indicators are applied to ASEAN, it paints a disappointing outlook since trade creation was highlighted upon as a main reason for entering regional economic arrangement, yet the share of intra-regional trade remained low at 20% or less (Bowles, 1997).\n\nHence, mainstream theories of regional economic integration coupled with traditional metrics tend to reduce ASEAN’s ambitions and objectives to a linear wealth creation project. Bowles argued that the role of AFTA was to bring “global capital to the ASEAN region” by adopting liberalisation in ASEAN and moving towards a “rules-based, fully liberalised global economic system” (Stubbs, 2019). Through Bowles, we understand that the establishment of AFTA by ASEAN is an exemplification of open regionalism and a characteristic of the new regionalism, allowing members of AFTA to actively participate in the global economy and receive economic advantages by establishing economic benefits ties within a global network. When the role of AFTA is understood as such, an innocent inspection will highlight the desire of ASEAN to be a part of the “liberalised global economic order” as well as AFTA as a “stepping-stone” to reaching it (Stubbs, 2019). Yet this narrative places AFTA in a tricky position in suggesting that its primary purpose is to increase regional integration outcomes (Menon, 2021), thereby inviting scrutiny from a perspective lacking an understanding of the ASEAN context. While AFTA may be perceived as an initiative encouraged by new regionalism (Stubbs, 2019), the supposed benefits of participating in the global economy subsume what should be achieved for the AEC to be deemed successful.\n\nFrom the policy network perspective, it is known that ASEAN member states agreed to establish the AFTA policy network even though agreeing to participate in FTA signals the loss of some sovereignty as member states’ economies become closely tied. Therefore, the interests that once moved the policymaking process can be understood via RDT, where the Association is a ’critical resource’ for member states as an organisation made up of new states. As such, member states would not only harbour the goal of economic growth but also pursue economic viability as a region to become economically competitive compared to other regions to boost its centrality by demonstrating its relevance to the international society by joining the global economic order. Therefore, where ASEAN is a critical resource to its member states, and member states are to the Association, the policy network of AFTA becomes all the more pertinent and connected to each other’s survival as stipulated by RDT.\n\nHere, it would also be constructive to consider what Menon (2021) has articulated, where “an outsider observing these outcomes would have declared the program (AFTA) a failure while an insider would have understood that they achieved exactly what they were designed to achieve: very little” (Menon, 2021). This goes back to the main issue where “low shares of intra-ASEAN trade have attracted a lot of critical comment, and some have used it to question ASEAN’s viability as a regional group” (Hill and Menon, 2011), going further to suggest that this indicates non-performance. However, the crux of the issue lies with a superficial interpretation of intra-ASEAN trade shares. Where it would be essential to bear in mind that “the ASEAN economies only account for a small share of global trade flows”, thus “when adjusted for this scale factor—through the computation of trade intensity measures for instance—the picture that emerges is quite different” (Hill and Menon, 2011).\n\nIn addition, it would be essential to understand the rationale of the program based on ASEAN’s role and needs where since “AFTA trade concessions are multilateralised, the observed increase in intra-regional trade shares must be explained by complementarities and market-driven factors rather than deliberate policy measures” (Hill and Menon, 2011). For instance, in the case of “both Singapore and Malaysia, ASEAN markets constitute more than one-quarter of total exports. The “share is much lower for Indonesia, where natural resource exports to extra-regional markets are important, and for the Philippines, whose commercial patterns have always been the least ASEAN-centred of the five original member countries” (Hill and Menon, 2011). This helps to elaborate how economic integration served ASEAN both in terms of the pursuit of globalisation and one that pertains to the continued relevance and survival of the Association and its very own centrality in the face of an international system.\n\nGiven this, it would be fatal to conflate the goal of pursuing regional resilience with that of an inward-focused task unreceptive to open regionalism (Stubbs, 2019). It differs because we approach it from the understanding of centrality, where we view member states’ motivation to push through the AFTA policy network as a result of resource dependency – a crucial element of NG, where it becomes a significant variable influencing member states’ involvement since member states depend on ASEAN and ASEAN relies on its members to maintain relevance in the global economy, the international system, and its survival.\n\nDue to the economic benefits and to facilitate intra-ASEAN trade liberalisation and facilitation, the member states have worked towards the integration of customs procedures, documentation and information exchange systems reducing paperwork, duplication, and processing time through the ASW, thereby saving business costs, streamlining trade processes and improving efficiency in cross border trade. By providing a single electronic gateway for customs-related processes and documentation, the ASW reduces administrative burdens, enhances transparency, and expedites the clearance of goods at borders (Sithanonxay and Neo, 2022). This strengthens intra-ASEAN trade, and the trickle-down effect will be the increased trade flows, accounting for a quarter of ASEAN’s total trade. It also makes the region competitive and attracts trade and investment from its free trade agreement partners, such as China, Japan, South Korea, India, Australia and New Zealand. In fact, member states such as Singapore and Malaysia, which see a benefit from intra-ASEAN trade, have accelerated the adoption of the ASW. In contrast, those member states which see lesser benefits have been slower to take up. In addition, state actors such as customs authorities and relevant ministries collaborated within each member state and within a network governance framework to harmonise policies and regulations and enhance coordination to enhance intra-ASEAN trade facilitation.\n\nWith this, ASEAN’s move towards AFTA has more to do with its self-preservation as a leading regional entity in East Asia and to buffer against external economic shocks. Creating FTA between member states for economic benefits establishes a footing for all ASEAN member states, especially since ASEAN comprises developing and smaller economies than other regions. This also moves away from the rationale that the AEC is a relatively more successful policy subsystem due to pure economic gains from the global economy. But it highlights member states’ focus on regional resilience, which in this case, is the ability to withstand financial crises or external political threats. After all, an organisation emphasising the principle of sovereignty and non-interference naturally articulates the preference to adhere to a self-help mentality, and purely economic gains could not be sufficient for AFTA’s establishment.\n\nAs part of the ASEAN Community, the ASEAN Political Security Policy System (APSS) oversees political and security cooperation to preserve and safeguard the ASEAN region’s peace and security, encompassing the ARF inaugurated in 1994. The objectives of ARF are to foster constructive dialogue and consultation on political and security issues of common interest and concerns and make significant contributions to efforts towards confidence building and preventive diplomacy in the Asia-Pacific region (ASEAN Secretariat, n.d.). The participants of ARF are the ASEAN member states and Australia, Bangladesh, Canada, China, India, the EU, Japan, Mongolia, New Zealand, North Korea, Pakistan, Papua New Guinea, Russia, South Korea, Sri Lanka, Timor Leste, and the US. This set of fixed members in the ARF network hold repeated interactions with each other over time through annual ministerial meetings, aligns with the concept of NG as involving a “select, persistent, and structured set of autonomous entities [firms] based on implicit contracts to adapt to environmental contingencies and to coordinate and safeguard exchanges” (Jones et al., 1997).\n\nBy encapsulating the interaction of these stakeholders in a policy network, NG helps us to approach the idea of a structural position where each stakeholder is understood as a “node” (Caballero-Anthony, 2014). Where member states’ drive, interest, and willingness to participate from the standpoint of policy network analysis are linked to the RDT as they understand the importance of the Association to their own survival, it would suggest the pursuit of interaction within the network from member states to a stakeholder or partner within ARF, prompting a high level of actors-to-actors (node-to-node) interactions (Caballero-Anthony, 2014) to keep this network relevant. This is where the notion of centrality is invoked again, as seen in the AFTA under AEC, where regional resilience is pursued through participation in the global economy and in the case of the ARF, ASEAN’s attempt to configure its relevance by probing itself as a significant “bridging player” (Caballero-Anthony, 2014) by initiating and convening the regional forum. It is significant as it expresses how ASEAN achieves its goal via the ARF by acting as a middle platform for world leaders to congregate and provide opportunities in two areas. One, dialogue partners to meet others to promote their interests; and two, dialogue partners to extend, promote or strengthen their presence in the Asia Pacific region, including with ASEAN. The Association prides itself and strives to continue playing its role as an honest broker facilitating the ARF network, which adds to ASEAN being relevant to the security and peace of Asia Pacific. Yet, while this may be aligned with ASEAN goals, the ARF can be bounded by ASEAN’s norms and principles, limiting it to only mere deliberation over security and political issues since it is highly dependent on how member states pursue ’node-to-node’ interaction.\n\nRegarding AMMTC, ASEAN’s development of a coordinated approach stemmed from the abuse of narcotics and trafficking in illegal drugs. On 24 February 1976, ASEAN member states signed the Declaration of ASEAN Concord, tightening the resolve to fight transnational crime and intensifying cooperation among member states, including relevant international bodies, in the prevention and eradication of the abuse of narcotics and the illegal trafficking of drugs (Sundram, 1999; Parameswaran, 2000). ASEAN resolved to take firm and stern measures to combat transnational crimes such as drug trafficking, trafficking in women and children, and other transnational crime at their 2nd Informal ASEAN Summit in 1997 by adopting the ASEAN Vision 2020 document whose main objective is the creation of a drug-free Southeast Asia and a region of agreed rules of behaviour and cooperative measures to deal with problems that can only be met on a regional scale (Parameswaran, 2000).\n\nThis shows that transnational crime remains a significant concern for the Association, especially with the diversification of transnational crime to include terrorism, arms smuggling, money laundering, illegal migration, and piracy, and more notably, cyber security crimes, which are becoming highly organised in nature (Sundram, 1999). Moreover, the transnational crime policy networks involved cooperation from many areas, such as law enforcement, regional and international organisations, and local authorities’ cooperation. Transnational crime policy networks rely upon both ASEAN member states and NSAs and, as such, can be understood as inclusive policy networks where the roles of any parties within the policy network are not undermined. It returns to the concept of RDT, which views the Association as an essential critical resource for members. The transnational nature of the policy network required ASEAN member states to rely on local authorities and NSAs. As explained by Howlett, the dynamic nature of such interaction among different actors fosters a healthy balanced policy network that would produce dynamic policy outcomes.\n\nThe transnational crime policy networks have exemplified how issues under APSS seek to operationalise a strong policy network of information and resource exchange by highlighting the proactive role that ASEAN can play in reinforcing an open, transparent, and inclusive regional architecture while maintaining its centrality through its centred role in driving initiatives and mechanisms to combat transnational crime (ASEAN Secretariat, 2009). With this, it could be further understood how networks established to cooperate over transnational crime issues boost policy networks by strengthening policymaking, decision-making and implementation phases. Using policy network analysis, the idea of the ’node-to-node relationship’ (Caballero-Anthony, 2014) (also understood as actors-to-actors interaction) and how it encapsulates ASEAN’s centrality and the central position of ASEAN in the network is exemplified through ARF. It is an essential working concept for APSS and the transnational crime policy network(s).\n\nIn the AMMTC policy networks, engagement with NSAs in addressing counterterrorism issues and implementing ASEAN plans emphasized the importance of developing strong ties and positive engagement with ASEAN external parties (ASEAN Secretariat, 2017). A distinct difference between transnational crime and policy networks related to territorial disputes and traditional security issues is the openness underlying the patterns of interactions and flow of resources. It also highlights that the interests and will of member states are key factors influencing policy outcomes.\n\nGiven the sensitive nature of the APSS, policies concerning the maintenance of security are approached with caution, guided by the ASEAN principles of sovereignty and non-interference. This could lead to a standstill or implementation gaps in policymaking. However, the transnational crime policy network presents a contrasting picture, characterised by high dynamism and the active involvement of NSAs in non-traditional security-related issues. This highlights the significant role member states (state actors) play in shaping the policy network, underscoring their autonomy within ASEAN. Consequently, NG assumes vital importance in ASEAN as it allows for a better understanding of the policy network’s nature and role and the overall policy subsystem. It employs the concept of centrality and resource dependence to depict the dynamics of the policy network. Despite varying characteristics, ASEAN’s norms and principles can influence policymaking if member states are willing to align with them.\n\n\nDiscussion\n\nThe article employed the lens of NG to analyse the case studies from the AEPS and APSS. By examining AFTA and ASW in the AEPS and the ARF and AMMTC policy networks in the APSS, insights are gained into the dynamics of policy networks, member states’ motivations, and the role of ASEAN’s centrality in policymaking.\n\nIn the case of AFTA, traditional indicators such as the share of intra-regional trade failed to capture the true purpose and achievements of ASEAN’s economic integration. Mainstream theories of regional economic integration focused solely on economic gains, but in reality, AFTA served as a catalyst for ASEAN’s participation in the liberalised global economic order and its quest for enhanced centrality in regional institutional arrangements. Despite the lack of growth in intra-ASEAN trade, it was partly a sign of success, as it reflected ASEAN’s tariff liberalisation strategy and the pursuit of globalisation. In this case, AFTA has brought the region closer through economic ties where member states can be recognised for playing an active role in establishing the AFTA policy network. Therefore, it is crucial to understand the ASEAN context regarding economic integration and map it to what the AFTA aims to achieve. This highlights the importance of going beyond traditional quantitative indicators of intra-ASEAN trade share to total trade and understanding the needs of member states in pursuing multilateralism.\n\nSimilarly, the analysis of the ASW in the AEPS showcased the dynamics of NG, where customs cooperation and trade facilitation were achieved through collaboration among state actors within the policy network. The ASW’s implementation demonstrated the potential for enhancing intra-ASEAN trade and improving the region’s competitiveness. However, it was observed that the adoption of the ASW varied among member states, reflecting the heterogeneity of their interests within the policy network. This highlights the need to consider diverse motivations and interests when examining policy networks within ASEAN.\n\nShifting to the APSS, the case of the ARF exemplified NG through its structured set of autonomous entities engaged in persistent interactions. As a platform for dialogue and consultation on political and security issues, the ARF enabled member states and dialogue partners to meet, promote their interests, and extend their presence in the Asia-Pacific region. However, the effectiveness of the ARF was limited by the member states’ commitment to node-to-node interactions. The success of the ARF in fostering confidence-building and preventive diplomacy depended on the willingness of member states to engage and pursue cooperation actively.\n\nIn the context of AMMTC, ASEAN’s coordinated approach aimed to combat various forms of criminal activities, including drug trafficking, terrorism, and cybercrimes. The policy network involved not only member states but also local authorities, international organisations, and NSAs. The inclusive nature of the transnational crime policy network illustrated the importance of collaboration and information exchange in addressing complex security challenges. Unlike traditional security concerns, transnational crime exhibited a more dynamic policy network due to actors’ openness and willingness to exchange resources and information.\n\nThe strengths of this study lie in its application of NG to analyse the ASEAN policy subsystems. By adopting this theoretical framework, insights into the motivations of member states, the role of ASEAN centrality, and the dynamics of policy networks within the AEPS and APSS could be discerned. However, there are certain limitations to consider. Firstly, the study focused on only a few case studies within the AEPS and APSS, which limits the generalizability of the findings to other policy areas within ASEAN. Secondly, the analysis relied heavily on qualitative data, and while this allowed for a rich understanding of the dynamics, it may be beneficial to incorporate quantitative data and statistical analysis in future research. Additionally, the study did not extensively explore the role of NSAs and civil society organisations in the policy subsystems, which could be an area for further investigation.\n\nFuture research should consider the following directions further to advance the understanding of ASEAN’s policy subsystems. Firstly, expanding the analysis to other policy areas within the policy subsystem of the ASEAN Community, including the ASEAN Socio Cultural Community, would provide a more comprehensive understanding of the dynamics and outcomes of policy networks in ASEAN. For instance, while the ARF and AMMTC policy networks fall under APSS, they both harbour ubiquitous dynamics where the extent to which ASEAN’s norms and principles have different reach is reflected by how NSAs are more welcome in the latter. As such, there needs to be more study of other policy networks under the same policy subsystem to ratify the Community’s performance further. Secondly, incorporating quantitative data and statistical analysis would strengthen the empirical basis of the findings and allow for more robust comparisons and generalisations. Lastly, exploring the role of NSAs and civil society organisations in ASEAN’s policy networks would contribute to a more inclusive understanding of regional governance structures and processes and, thereby, ASEAN policymaking and performance.\n\n\nConclusion\n\nThe article studied ASEAN as NG concerning its regionalism, action, and performance, considering its institutional design and processes. It exhibited the significance of the norms and principles of ASEAN and their substantive weight in policymaking within the three ASEAN communities. It highlighted that the interplay between the interests/will of the member states and the dynamics of stakeholders in a policy network offered a means to assess the functioning of both policy networks and policy subsystems in ASEAN. By establishing another framework of NG, ASEAN could recognise the value that the utilisation of NG could offer in assessing its performance or non-performance and use it as a tool to plan future policies and initiatives. The NG framework would also provide a channel to engage NSAs and evaluate their value in specific regional integration initiatives.\n\nSignificantly, the article could contribute to ASEAN’s understanding of its own regionalism, the policymaking process, and institutional structures to address the implementation gaps to support its ASEAN Community 2025 agenda and beyond. It would also provide ASEAN officials, the ASEAN Secretariat, scholars, and future research into ASEAN regionalism another framework to assess ASEAN and similar regional and intergovernmental organisations.",
"appendix": "Data availability\n\nDryad: ASEAN as network governance: an alternative lens to evaluate policymaking and performance. https://doi.org/10.5061/dryad.g1jwstqwp (Sundram, 2023a).\n\nThe project contains the following underlying data:\n\n• Dataset – An alternative lens to evaluate policymaking and performance P.Sundram.xlsx. (All underlying sources including in-text citations and sources with links, case studies and information/data sources, and keywords and public sources, and accessible locations of the data).\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nZenodo: ASEAN as Network Governance: An Alternative Lens to Evaluate Policymaking and Performance. https://doi.org/10.5281/zenodo.8181228 (Sundram, 2023b).\n\nThis project contains the following extended data:\n\n• ASEAN as NG Figure 1. (JPEG and TIFF files for figure 1).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAcharya A: Theoretical perspectives on international relations in Asia. International Relations of Asia. 2008; 57–82.\n\nAraral E, Fritzen S, Howlett M: Routledge handbook of public policy (First published in paperback). Routledge; 2015.\n\nAssociation of Southeast Asia Nations: ASEAN Regional Forum. Asean Regional Forum Dev.n.d. Retrieved January 13, 2023. Reference Source\n\nAssociation of Southeast Asian Nations: ASEAN Security Outlook (ASO) 2015. ASEAN.2015. Retrieved July 13, 2023. Reference Source\n\nAssociation of Southeast Asian Nations: ASEAN Plan of Action in Combating Transnational Crime (2016-2025).2017. Retrieved on May 5, 2023. https://asean.org/wp-content/uploads/2012/05/ASEAN-Plan-of-Action-in-Combating-TC_Adopted-by-11th-AMMTC-on-20Sept17.pdfReference Source\n\nAssociation of Southeast Asian Nations: Secretariat. Asean Political-Security Community Blueprint. 2009. Reference Source\n\nAssociation of Southeast Asian Nations. Secretariat: The ASEAN stronger health systems our lifeline in a pandemic. Association of Southeast Asian Nations; 2020. Secretariat. Reference Source\n\nAssociation of Southeast Asian Nations. Chairman’s statement on the ASEAN leaders’ meeting, 24 April 2021 and five-point consensus. Main Portal, ASEAN; 2021, April 24. Reference SourceReference Source\n\nBevir M: Key concepts in governance. SAGE; 2009. Reference Source\n\nBevir M: The SAGE handbook of governance Policy Network theory.2011. Reference SourceReference Source\n\nBowles P: ASEAN, AFTA and the “New Regionalism.”. Pac. Aff. 1997; 70(2): 219–233. Publisher Full Text Reference Source\n\nCaballero-Anthony M: Understanding ASEAN’s centrality: Bases and prospects in an evolving regional architecture. Pac. Rev. 2014; 27(4): 563–584. Publisher Full Text Reference Source\n\nChetchaiwong K: ASEAN and Non-Interference Principle: Political Rhetoric and Practices in ASEAN’s Approach to a Dilemma: Maintaining Regional Order and Promoting Justice. Lancaster University; n.d.\n\nCoen D, Thatcher M: Network governance and multi-level delegation: European networks of regulatory agencies. J. Publ. Policy. 2008; 28(1): 49–71. Publisher Full Text\n\nDrees JM, Heugens PPMAR: Synthesizing and extending resource dependence theory: A meta-analysis. J. Manag. 2013; 39(6): 1666–1698. Publisher Full Text Reference Source\n\nEmmerson D: The Deer and the Dragon: Southeast China and China in the 21st Century. Shorenstein APARC/ISEAS Yusof Ishak Institute; 2020.\n\nHa HT, Thuzar M, Das SB, et al.: Diverging Regionalisms: ASEAN and the EU. ASEAN Focus - ASEAN and the EU in Perspective: Brexit and Beyond.2016. Retrieved May 23, 2023.Reference SourceReference Source\n\nHill H, Menon J: ASEAN Economic Integration: Features, Fulfillments, Failures and the Future. ADB Working Paper Series on Regional Economic Integration. Asian Development Bank (ADB). 2011.\n\nHowlett M: Do networks matter? Linking Policy Network structure to policy outcomes: Evidence from four Canadian policy sectors 1990–2000. Can. J. Polit. Sci. 2002; 35(2): 235–267. Publisher Full Text Reference Source\n\nHowlett M, Mukherjee I, Koppenjan J: Policy learning and policy networks in theory and practice: The role of policy brokers in the Indonesian biodiesel policy network. Polic. Soc. 2017; 36(2): 233–250. Publisher Full Text Reference Source\n\nJetschke A: Institutionalizing ASEAN: Celebrating Europe through network governance. Camb. Rev. Int. Aff. 2009; 22(3): 407–426. Publisher Full Text Reference Source\n\nJones C, Hesterly WS, Borgatti SP: A general theory of network governance: Exchange conditions and social mechanisms. Acad. Manag. Rev. 1997; 22(4): 911. Publisher Full Text Reference Source\n\nJones MJ, Smith MLR: ASEAN and East Asian international relations: Regional delusion. Edward Elgar Publishing; 2006.\n\nJones DM, Smith MLR: Making process, not progress: ASEAN and the evolving East Asian regional order. Int. Secur. 2007; 32(1): 148–184. Publisher Full Text Reference Source\n\nJones DM, Jenne N: Weak regionalism: ASEAN and the limits of security cooperation in Asia–Pacific. Int. Relat. Asia-Pac. 2016; 16(2): 209–240. Publisher Full Text\n\nKefale A: Regional organizations and security governance: A comparative assessment of IGAD and ASEAN. London School of Economics and Political Science, LSE Global South Unit WORKING PAPER SERIES (Working Paper No. 1/2015) 2015; pp. 1–31.\n\nKim J: Networks, network governance, and networked networks. Int. Rev. Public Adm. 2006; 11(1): 19–34. Publisher Full Text\n\nKlijn E-H: Policy networks: An overview.Kickert WJM, Klijn E-H, Koppenjan JFM, editors. Managing complex networks: Strategies for the public sector. London: Sage; 1997.\n\nKoh TTB, Manalo RG, Woon WCM, et al.: The making of the ASEAN Charter. World Scientific Pub. Co.; 2009.\n\nLeifer M: The ASEAN process: A category mistake. Pac. Rev. 1999; 12(1): 25–38. Publisher Full Text\n\nMayntz R: Modernization and the logic of interorganizational networks.Childs J, Crozier M, Mayntz R, editors. Societal change between market and organization. Avebury; 1993; pp. 3–16.\n\nMenon J: Using regionalism for globalization: The ASEAN way. ISEAS-Yusof Ishak Institute; 2021.\n\nNarine S: ASEAN in the twenty-first century: A skeptical review. Camb. Rev. Int. Aff. 2009; 22(3): 369–386. Publisher Full Text Reference Source\n\nNischalke TI: Does ASEAN measure up? Post-Cold war and the idea of regional community. Pac. Rev. 2002; 15(1): 89–117. Publisher Full Text\n\nParameswaran P: Combating and preventing drug and substance abuse, by Pratap Parameswaran. Asean Main Portal. 2000, April 29. Reference Source\n\nPowell W, Staw BM, Cummings LL, et al.: Neither market nor hierarchy; network forms of organization. JAI Press; 1990; 12. .\n\nRhodes R: Understanding governance: Policy networks, governance, reflexivity and accountability. Open University Press; 2003.\n\nSeverino RC: Regional integration in Europe and in Asia. The future of ASEAN economic integration. Asia-Europe Foundation, Springer; 2003; 1(4): pp. 475–479.\n\nSithanonxay S, Neo GWK: Assessing the benefits of the ASEAN+6 Single Window for ASEAN members. ISEAS-Yusof Ishak Institute; 2022.\n\nStubbs R: ASEAN skeptics versus ASEAN proponents: Evaluating regional institutions. Pac. Rev. 2019; 32(6): 923–950. Publisher Full Text Reference Source\n\nSundram P: Combating transnational crime in ASEAN, by S. Pushpanathan. Asean Main Portal. 1999, November 26. Reference Source\n\nSundram P: ASEAN as network governance: an alternative lens to evaluate policymaking and performance. Dataset. Dryad. 2023a. Publisher Full Text Reference Source\n\nSundram P: ASEAN as network governance: an alternative lens to evaluate policymaking and performance. Dataset. Zenodo. 2023b. Publisher Full Text Reference Source"
}
|
[
{
"id": "203215",
"date": "08 Sep 2023",
"name": "Illango Karuppannan",
"expertise": [
"Reviewer Expertise International relations with an interest in ASEAN regionalism."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI truly enjoyed reading this article. Although it is rather complex it makes a significant contribution to the field of regionalism. The focus on ASEAN enriches scholarship on regionalism, a field that is heavily influenced by EU and often regarded as the gold standard of regionalism.\nThe author's extensive experience and knowledge of ASEAN's inner workings, as a professional staff in the ASEAN Secretariat comes clearly through this article.\n\nThe article presents a strong argument in support of the concept of Network Governance (NG) as a theoretical framework to appreciate why ASEAN regionalism has proceeded the way it has. The choice of the cases studies within the ASEAN Economic Policy Subsystem (AEPS) and ASEAN Political Security Policy Subsystem (APSS) are well chosen for this purpose.\n\nThe article also convincingly argues that broader goals and dynamics within the region should also be taken into account in in assessing ASEAN's economic integration rather than limiting to the traditional quantitative indicators, such as the share of intra-regional trade.\nHowever, I believe the article could benefit from a more elaborate explanation of how Network Governance (NG) can practically be employed as a tool to plan future policies and initiatives, as suggested. Clarifying this aspect would add practical relevance to the theoretical framework and enhance the article's overall utility. The author should provide explanation how this can be done. This would enhance the utility of the paper. If not, that statement should be deleted and it would not affect the rest of the paper.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10200",
"date": "08 Sep 2023",
"name": "Pushpanathan Sundram",
"role": "Author Response",
"response": "Thank you for the valuable comments and suggestions. As suggested, I will remove the statement on the applicability part, which appears in the conclusion. This suggestion could be better taken up in a separate article, which I could consider next. My main focus for this article is to show how NG can work for ASEAN in the first instance. With this understanding, perhaps the reviewer could kindly consider approving the manuscript."
},
{
"c_id": "10309",
"date": "06 Oct 2023",
"name": "Pushpanathan Sundram",
"role": "Author Response",
"response": "I have revised the article to take on board your comments as well as the other peer reviewer. Instead of deleting the utility part that I have mentioned in my concluding paragraph, I have incorporated a detailed explanation of how the lens can be utilised to look at future issues in the ASEAN community following a process to identify the issue-area, the policy network that governs that issue, the interests and will of member states and the resource dependency dynamics that would impact the individual member states decision on a particular issue. Once these variables have been mapped and studied, the appropriate policy interventions can be taken to address any implementation gaps and achieve the desired outcomes."
}
]
},
{
"id": "205200",
"date": "25 Sep 2023",
"name": "Aladdin Rillo",
"expertise": [
"Reviewer Expertise Trade integration",
"financial integration",
"regionalism",
"regional economy"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article takes an innovative approach by applying the Network Governance framework to ASEAN policy subsystems. This offers a fresh perspective on regional integration and policymaking dynamics, going beyond traditional indicators. The use of the case studies is also appropriate as they provide application of the NG in different policy contexts, thus enhancing the article’s overall credibility. Recognizing the intricacies of policy making in ASEAN, the article also highlights the need to look at ASEAN policy making as one that is shaped by each country’s development needs as well as the interaction of various stakeholders, particularly non-state actors.\n\nThe article's emphasis on the Network Governance framework offers a unique perspective that diverges from traditional approaches to assessing regional integration. This framework provides a more nuanced understanding of ASEAN's policymaking processes by recognizing the importance of collaborative networks and the interplay of member states' interests. This different perspective is instrumental in enhancing ASEAN's performance by facilitating informed decision-making, promoting inclusivity, and optimizing resource allocation.\nWhile the article provides valuable suggestions for future research, including expanding the analysis to other policy areas, incorporating quantitative data, and further exploring the role of NSAs, it will be good if the article provides forward-thinking approach to understanding ASEAN's policy subsystems by analyzing the implications of the future agenda of regional integration (e.g., ASEAN’s post-2025 vision) as well as the emerging new trends and challenges (e.g., issues on twin transition such as green/circular economy and digital transformation). Since the issues facing ASEAN in the future are expected to be more entrenched with global economy (e.g., impact of intensifying geo-political tensions and economic fragmentation), will the NG framework still remain robust or will it be expanded to include a more structural analysis of governance issues in the region. It will be interesting how the framework can elaborate these changes.\nNonetheless, based on the strengths identified and the unique perspective offered by the Network Governance framework, I recommend approving this article for publication. The article's contribution to a deeper understanding of ASEAN's regionalism, policymaking processes, and institutional structures is substantial. Furthermore, the insights gained from this study could enhance ASEAN's performance in achieving its regional integration goals.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10310",
"date": "06 Oct 2023",
"name": "Pushpanathan Sundram",
"role": "Author Response",
"response": "Thank you for your review. I have taken on board your key suggestions on the utility of the NG lens, especially in assessing ASEAN's response to the current and critical issues as well as future issues as it considers its post-2025 community-building agenda. The lens could be utilised to study other issues if the issue-area/s can be identified, the policy network/s ascertained, the interest and will (determination) of ASEAN member states are assessed specific to that issue/s and the resource dependency dynamics for each member in terms of the benefits and risks or disadvantages can be studied. Once these variables are mapped, there is a likelihood of gaining a better insight into ASEAN's response and any implementation lag. Appropriate policies can then be developed regionally to address the various aspects of the issue/s. One caveat is that there needs to be further studies on the approach to look at different issues to understand better the variables involved and how ASEAN norms impede or support a policy issue."
}
]
}
] | 1
|
https://f1000research.com/articles/12-1073
|
https://f1000research.com/articles/11-1183/v1
|
17 Oct 22
|
{
"type": "Method Article",
"title": "Co-cultures of cerebellar slices from mice with different reelin genetic backgrounds as a model to study cortical lamination",
"authors": [
"Adalberto Merighi",
"Laura Lossi"
],
"abstract": "Background: Reelin has fundamental functions in the developing and mature brain. Its absence gives rise to the Reeler phenotype in mice, the first described cerebellar mutation. In homozygous mutants missing the Reelin gene (reln-/-), neurons are incapable of correctly positioning themselves in layered brain areas such as the cerebral and cerebellar cortices. We here demonstrate that by employing ex vivo cultured cerebellar slices one can reduce the number of animals and use a non-recovery procedure to analyze the effects of Reelin on the migration of Purkinje neurons (PNs). Methods: We generated mouse hybrids (L7-GFPrelnF1/) with green fluorescent protein (GFP)-tagged PNs, directly visible under fluorescence microscopy. We then cultured the slices obtained from mice with different reln genotypes and demonstrated that when the slices from reln-/- mutants were co-cultured with those from reln+/- mice, the Reelin produced by the latter induced migration of the PNs to partially rescue the normal layered cortical histology. We have confirmed this observation with Voronoi tessellation to analyze PN dispersion. Results: In images of the co-cultured slices from reln-/- mice, Voronoi polygons were larger than in single-cultured slices of the same genetic background but smaller than those generated from slices of reln+/- animals. The mean roundness factor, area disorder, and roundness factor homogeneity were different when slices from reln-/- mice were cultivated singularly or co-cultivated, supporting mathematically the transition from the clustered organization of the PNs in the absence of Reelin to a layered structure when the protein is supplied ex vivo. Conclusions: Neurobiologists are the primary target users of this 3Rs approach. They should adopt it for the possibility to study and manipulate ex vivo the activity of a brain-secreted or genetically engineered protein (scientific perspective), the potential reduction (up to 20%) of the animals used, and the total avoidance of severe surgery (3Rs perspective).",
"keywords": [
"Reelin",
"Neuronal migration",
"Cerebellum",
"Purkinje neurons",
"Secreted proteins",
"Ex vivo methods",
"Cellular sociology",
"Voronoi tessellation"
],
"content": "\n\n\n\nScientific benefit(s):\n\n\n\n• Co-culturing slices from animals with different reln genetic backgrounds allows studying ex vivo the effects of Reelin in cortical lamination\n\n• Co-cultures can be pharmacologically manipulated and transfected with different types of fluorescent reporter proteins (FRP)\n\n• They are amenable to electrophysiological recordings and immunocytochemical labeling\n\n3Rs benefit(s):\n\n\n\n• As several viable slices can be obtained from every single animal, these cultures substantially reduce the necessary number of mice in different experiments\n\n• When a secreted molecule is to be studied (such as in the case of Reelin), this approach can be used to replace in vivo experiments where the substance has to be administered through more or less invasive routes, involving heavy surgery for molecules that are unable to pass the blood-brain barrier\n\nPractical benefit(s):\n\n\n\n• As experiments in vivo are more expensive than those in ex vivo/in vitro conditions, slice co-cultures are highly valuable in terms of cost vs. effectiveness\n\n• They allow mid-throughput screening of different culture conditions, e.g., days in vitro, the chemical composition of the medium, etc., offering the possibility to save time and plan fewer in vivo confirmatory experiments, if necessary\n\n• They are less technically demanding than in vivo experiments\n\nCurrent applications:\n\n\n\n• Study of the effect of Reln dosage on the differentiation of the laminated structures of the brain, primarily the cerebral and cerebellar cortex\n\nPotential applications:\n\n\n\n• Co-cultures can be used for the study of cerebellar neuronal wiring ex vivo, e.g., to reconstruct in a dish the olivo-cerebellar tract (climbing fibers) by cultivating together slices from cerebellum and medulla oblongata\n\n• Co-cultures can be used to study the development and/or neurodegeneration in other areas of the brain and spinal cord\n\n\nIntroduction\n\nLike any other animal tissue, the nervous tissue is made up of cells and the surrounding extracellular matrix. Proteins that are released from the neural cells consist of those in the extracellular matrix itself, as well as extracellular signaling and adhesion molecules.1 Compared to neurons and neural precursor cells, glial cells release a comparatively modest amount of proteins with a narrower range of functions, and according to a two-dimensional (2D) gels and liquid chromatography/mass spectrometry study, about 22% of the proteins secreted by neural cells intervene in cell-to-cell interactions.1\n\nReeler was the first discovered mouse cerebellar mutation,2 it was distinguished by typical gait changes (\"reeling\"), and thus thereafter named. In recessive homozygous mutants (reln-/-), Reelin, a large secreted extracellular matrix glycoprotein, was completely absent and proved to be required for the normal development of layered brain structures (i.e., the cerebral and cerebellar cortices) being directly involved in neuronal migration.3 Reelin absence causes severe cerebellar hypoplasia in reln-/- mice. During the development of the cerebellar cortex, the granule cells synthesize and release the molecule into the neuropil, and Reelin acts as an attractant for correct migration and placement of the Purkinje neurons (PNs).3 Remarkably, only 5% of these neurons align into their typical location between the mature molecular and granular layers, 10% remain in the internal granular layer, and those left behind are distributed throughout the white matter of the medullary body in a rather compact central mass.4–6 Differently from reln-/- mice, heterozygous reln+/-, and homozygous reln+/+ animals, do not display obvious disturbances in cortical histology, although the size and number of the PNs, as well as their topology, may be somewhat altered also in the former.7\n\nMore recently, it was demonstrated that not only Reelin is implicated in neuronal migration but, after development, it intervenes in synaptogenesis, neuronal plasticity,8–10 and several neuropsychiatric disorders.11–13 In addition, as Reelin is somehow the prototype of the brain extracellular matrix proteins because of its widely demonstrated intervention in the process of neural migration, there is a wide interest in gaining more information about its role in the normal and pathological brain. Finally, it seems reasonable to hold that the development of a reliable method to study the effects of Reelin on neuronal migration on live cells would be of benefit to the study of many other secreted brain proteins that regulate cell-to-cell interactions.\n\nSeveral approaches are available for the study of these proteins. Among those in vitro, one can, for example, mention the above proteomic study, which was carried out on cortical neurons and astrocytes, as well as cell lines that were derived from dividing neural precursor cells of E16 rats.1 Other approaches have used in vivo microdialysis combined with proteomics to discover new bioactive neuropeptides in the striatum14 or biopanning, an affinity selection technique that selects for peptides binding to a given target to identify proteins of the extracellular matrix.15 These and other more sophisticated secretome studies, for example,16 are very important in the initial identification of individual proteins in specific neural cell populations but do not offer any cues about their function and are not suitable to be used in longitudinal studies aiming to understand the effects of a given protein over time.\n\nLongitudinal studies in vivo that are necessary to follow Reelin (and other brain-secreted proteins) intervention at different time points of development or in adulthood require a high number of animals at different ages to lead to conclusive and biologically relevant results. We here report on an ex vivo procedure to study the effect of Reelin on neuronal migration. Our procedure is based on the use of organotypic co-cultures of the mouse postnatal cerebellum17 but can be broadly employed in the study of the biological role of this (and other) secreted molecule in the brain. Alternatively, one could use three-dimensional (3D) cultures, but a reliable reconstruction of neural circuits is still very difficult to achieve and one should very well know these circuits in vivo such is e.g., the case of the retina.18 Moreover, the approach is usually expensive, time-consuming, and cellular and biomolecular analysis difficult to perform.19\n\nThe 3Rs relevance of our approach is primarily related to 1. The reduction of the number of experimental animals; 2. The refinement of the procedures eluding the administration in vivo of molecules with (potential) toxic effects and the use of heavy brain surgery (e.g., the intraventricular administration of substances that are unable to cross the blood-brain barrier and/or the need to implant osmotic pumps for sustained administration over time).\n\nPotential end-users are neurobiologists chiefly interested in brain development and neurodegeneration from a structural, functional, and pharmacological point of view. Neuromodulation, i.e., the continuous change of synaptic network parameters, is required for adaptive neural circuit performance. This process is primarily based on the binding of a variety of secreted “modulatory” ligands to G protein-coupled receptors, which govern the operation of the ion channels affecting synaptic weights and membrane excitability.20 The possibility to also apply our approach to studies on neuromodulation substantially widens the number of potentially interested researchers and opens yet unexplored avenues to implement the 3Rs principles.\n\nThe need for 3Rs research in these fields is supported by quantitative data. It is difficult to give an accurate estimate of the number of animals used for the purpose locally and worldwide. Yet one can reasonably hold that at least a 20% reduction (a figure based on the number of slices that can usually be generated per mouse) in their total number could be achieved by the adoption of this (and other) procedures ex vivo, as discussed in Ref. 17.\n\nWith specific regard to Reelin activity in normal and pathological conditions, a PubMed search (June 2022) with the string “reelin brain” gives back 1,499 results with a peak of 98 papers published in 2010 and a mean of 57 papers/year starting from 1993 (year of the first publication). A similar number of papers is retrieved from the Web of Science™ (1,349) and groups that have published at least two papers belong to 46 different countries. One has to consider that these figures increase substantially if the search is widened to secreted proteins more generally (i.e., 3,154 papers in PubMed for the string: secreted proteins AND “cell migration” AND brain). Although not often easy to glean from the Material and Methods section, in a typical publication in vivo, animal number ranges from 50 to 80 depending on the types of experiments, the number of experimental groups, and the approaches used.\n\nThe severity classification of our procedure as defined under the Directive 2010/63/EU is non-recovery.\n\n\nMethods\n\nMouse model\n\nEthical statement\n\nAll experimental procedures described here have been approved by the Italian Ministry of Health (n. 65/2016-PR del 21/01/2016 and n.1361.EXT.1 del 27/12/2016) and the Bioethics Committees of the University of Turin and the Department of Veterinary Sciences (DSV). The number of animals (8 reln-/- and 8 reln+/-) was kept to a minimum and all efforts were made to minimize their suffering.\n\nMouse housing and husbandry\n\nAnimals were housed in the facility of DSV under the following conditions: temperature 19–21 °C, humidity 55% ± 10%, light-dark cycle 12-12 h. Food (normal maintenance diet – meat-free rat and mouse diet SF00-100, Specialty Feeds, Glen Forrest Western Australia) and water (normal tap water) were given ad libitum. The bedding was non-sterile wood-chip. Environmental enrichment consisted of mini tubes, sizzle nests, and burrowing treats (Volkman Seed Small Animal Rodent Gourmet). Animals were bred in couples in a standard 484 cm2 mouse cage. The mice themselves were not health-screened, the animal enclosure was free of the major rodent pathogens but some sentinels were positive for adventitious agents, i.e., mouse hepatitis virus after indirect fluorescent antibody (IFA) test and Multiplexed Fluorometric ImmunoAssay (MFIA) and Entamoeba sp. after annual mouse health monitoring (HM) Federation of European Laboratory Animal Science Associations (FELASA) screen.\n\nGeneration of L7-GFPrelnF1/mouse hybrids\n\nHybrids (L7-GFPrelnF1/) were generated by crossing L7-green fluorescent protein (GFP) (RRID:IMSR_JAX:004690) female mice (L7GFP+/+) with Reeler heterozygous (reln+/-) male mice (RRID:IMSR_JAX:000235).7 L7GFP+/+ mice express GFP under the control of the L7 promoter.21,22 As the L7 gene is specifically expressed by the PNs, these neurons are tagged by GFP, allowing their visualization without the need for immunocytochemical labeling. Before use, all animals were sexed and genotyped by routine methods to ascertain GFP expression (Note 1) and their appropriate reln genetic background.3\n\nMethods for the model development\n\nPreparation of organotypic co-cultures from L7-GFPrelnF1/of different genetic backgrounds\n\nExperiments are reported in compliance with the ARRIVE guidelines,42 including randomization of samples in culture inserts (slices in a single insert came from different mice), blinding of the experimenter who performed image analysis with unblinding at end of image processing, and/or automation of quantification, as indicated in the following sections.\n\nA step-to-step protocol for the preparation of cerebellar organotypic cultures (Figure 1A) has been deposited on protocols.io (https://dx.doi.org/10.17504/protocols.io.6qpvr67bbvmk/v1). This protocol is a refinement of previously published procedures from our laboratory.23,24\n\nA: Flowchart showing the main steps for co-culture preparation (see protocols.io for details). B-D: Histological aspects of four DIV single- and co-cultured slices after immunostaining with different markers of cerebellar neurons and glia. B-C: Immunostaining of the cerebellar granule cells with PAX6 permits clear identification of these neurons (red) and the GFP-tagged PNs (green). D: Two co-cultured slices with different reln genetic backgrounds. The slices have originally plated at a distance from each other but tend to expand with time in vitro and thus are in contact in this image. The slice from an L7-GFPreln-/-F1/mouse is indicated by the dotted white line. Note that in D PNs have been stained for calb 28k and thus appear yellowish-orange for the superimposition of the green GFP signal and the red calb 28k fluorescence. Abbreviations: calb 28k = 28kD calbindin; ChP = choroid plexus; CM = central mass; DIV = days in vitro; GFAP = Glial fibrillary acidic protein; GFP = green fluorescent protein; PAX-6 = paired-box protein PAX6; PCL = Purkinje cell layer; PNs = Purkinje neurons.\n\nIn the co-culture protocol, slices from reln heterozygous (reln+/-) and homozygous (reln-/-) hybrid mice were plated together. The positions of each genotypically identified slice in the insert were recorded so that they could be identified and monitored for the entire duration of the experiments (Note 2). Slices in each insert were numbered in a clockwise direction starting from a point indicated by a permanent mark on the bottom of the plastic dish and in the following analysis, the experimenter remained unaware of the matching between the slice number and the genotype of the donor mouse.\n\nQualitative analysis of PN migration\n\nTo analyze PN migration, organotypic cultures were photographed under a transmitted fluorescence light microscope. A series of six concentric circles spaced by 100 μm was superimposed on each photograph and roughly centered to the geometric center of the slice (Figure 2).\n\nA: Low magnification view of the slice with superimposed concentric circles surrounding the center of the slice. B-F: Higher magnification of the same slice and its evolution over time. The apparent dispersion of the PNs is mainly due to the death of individual cells. The inserts in B-D show the histological features of two PNs at the periphery of the central mass. Note the reduction of fluorescence in D and the disappearance of the two cells in E-F. Arrows in the main panels point to the PNs shown in the inserts at higher magnification. Arrows in the inserts indicate the PN axon, arrowheads the main dendrites. Abbreviations: DIV = days in vitro; GFP = green fluorescent protein; PNs = Purkinje neurons.\n\nImmunocytochemistry\n\nA step-to-step protocol for the immunofluorescence staining of organotypic cultures can be found in Ref. 23. In this report, we simply show exemplificative staining with a rabbit anti-glial fibrillary acidic protein (GFAP – astrocytic marker) polyclonal antibody (Abcam Cat# ab7260, RRID: AB_305808), a mouse anti-28kD calbindin (a marker of the PNs) monoclonal antibody (Abcam Cat# ab9481, RRID: AB_2811302), and with a mouse anti-paired-box protein PAX6 (PAX6 – a marker of the differentiating granule cells) monoclonal antibody (Santa Cruz Biotechnology Cat# sc-81649, RRID: AB_1127044). All antibodies were used at dilutions ranging from 1:100 to 1:200.\n\nMicroscopy and photography\n\nCultures were photographed directly under a 10× or 20× objective of a Leika DM 6000 transmitted light microscope taking care not to expose them to environmental contaminants. Alternatively, they have been maintained in a microscope stage incubator fitted to a Leika SP5 Laser confocal microscope and photographed with a 20× lens (see Note 2).\n\n\n\n1. Genotyping was done by sampling a small piece of the pinna so that at the same time it was possible to identify the subject and extract the genomic DNA.\n\n2. Although not strictly necessary, one can use an incubator that is fitted to the microscope stage (see e.g., Figures 2 and 3 in Reference 25) to longitudinally monitor cultures and easily take photographs of the same slice so that individual microscopic fields can be easily recognized. Although this is ideal when it is necessary to pharmacologically challenge the cultures over time, it may be unpractical when several cultures must be processed together such is the case of the co-culture protocol here described.\n\nMethods for the characterization and validation of the model\n\nCell dispersion was analyzed using Voronoi tessellation26 aiming at demonstrating the precise relationship with cultural conditions, as this cellular sociology approach has proved useful in other biological contexts.27\n\nThe numbers of technical repeats (individual slices from a single cerebellum) and independent biological repeats (organotypic cultures/co-cultures made by adding 3–6 individual slices to a single culture dish) are indicated in figure legends.\n\nCultures were obtained from two groups of mice: L7-GFPreln(+/-)F1/ (n = 5) and L7-GFPreln(-/-)F1 (n = 5). Cerebellar slices from these animals were subdivided into three groups:\n\n1) single cultured L7-GFPreln(+/-)F1/ slices, 2) single cultured L7-GFPreln(-/-)F1/ slices, and 3) co-cultured L7-GFPreln(+/-)F1/ slices + L7-GFPreln(-/-)F1/ slices. In co-cultures, the ratio of L7-GFPreln(+/-)F1/to L7-GFPreln(-/-)F1/slices was 2:1/3:1. At least eight slices from each group were used for the analysis of cellular sociology (see below). The sample size (number of slices) was calculated using the G*Power calculator 3.1.9.4.28 Input parameters were (unpaired t-test power calculator): tails, Two; parent distribution, Normal; α error probability, 0.05; power (1-β error probability), 0.95; effect size d, 2. The effect size was considered high based on qualitative observations and considering the mean area of the Voronoi polygons as the primary outcome. Output parameters were: non centrality r δ, 3.9088201; critical t, 2.1557656; Df, 13.2788745; sample size group 1, 8; sample size group 2, 8; Total sample size, 16; actual power, 0.9508778.\n\nThe eight slices/group of mice were randomly selected after sectioning the cerebella of at least five different animals.\n\nThe detailed procedure for calculation of Voronoi diagrams has been deposited on protocols.io (https://dx.doi.org/10.17504/protocols.io.yxmvmnrx6g3p/v1).\n\nThe parameters extracted from the analysis were: the mean area of Voronoi polygons (forms), the average roundness factor of those forms (RFav), the measure of the roundness factor homogeneity (RFH), and the measure of their area heterogeneity (area disorder (AD)). The last three parameters are characteristic of the population topography.26\n\nWe have used GraphPad Prism (RRID:SCR_002798) version 9.0.2 for Windows, GraphPad Software, San Diego, California USA, to assess the variations in the mean areas of Voronoi polygons, and RFav using a 95% confidence interval. Data were checked for outliers with the ROUT method (Q = 1) and normality with the Kolmogorov-Smirnov test. Further details of the tests used are given in figure legends. Inferential statistics were performed using ordinary one-way ANOVA followed by Tukey’s multiple comparison tests when data had a Gaussian distribution. The Brown-Forsythe test for equality of means and the Welch test was used for data sampled from populations with different variances.\n\nProtocol for establishing the co-culture model\n\nThe protocol below describes the step-by-step procedure required to establish and validate the long-term co-cultures of the postnatal murine cerebellum. With minimal modifications, it could be adapted to co-cultures of other areas of the brain, e.g., the hippocampus and entorhinal cortex or the cerebellum and the medulla oblongata containing the caudal (inferior) olivary nucleus. It stemmed from the single culture protocol previously developed in our laboratory.23\n\nEquipment\n\n• Surgical instruments for brain dissection: universal scissors (length 13 cm), fine scissors straight and curved, Adson forceps, student anatomical standard pattern forceps, Dumont #7 forceps, gross anatomy blade (#20) and handle (#4), straight and curved spatulas, razor blades\n\n• Dissecting microscope, e.g., Stereo microscope EZ4, Leica 10447197\n\n• CO2 incubator, e.g., Certomat CS-18 Sartorius BBI-8863385\n\n• McIlwain tissue chopper with Petri dish modification Campden Instruments Model TC752-PD – see Note 1.\n\n• Millicell-CM® Cell Culture Inserts, 30 mm, hydrophilic PTFE, 0.4 μm, Merck, PICM0RG50\n\n• Sterile 35-mm Petri dishes\n\n• Nalgene® vacuum filtration system, filter capacity 1000 mL, pore size 0.2 μm, Sigma-Aldrich, Z358207\n\n• 500 μL disposable insulin syringes\n\n• Sterile glass/disposable Pasteur pipettes\n\n• Sterile filter paper dishes\n\nChemicals\n\n• Pentobarbital sodium, Sigma-Aldrich, Y00021941\n\n• D-(+)-Glucose, Sigma-Aldrich, G8270\n\n• L-Ascorbic acid, Sigma-Aldrich, A92902\n\n• Pyruvic acid, Sigma-Aldrich, 107360\n\n• N-Methyl-D-glucamine, Sigma-Aldrich, M2004\n\n• Sodium bicarbonate, Sigma-Aldrich, S5761\n\n• Potassium chloride, Sigma-Aldrich, P3911\n\n• Sodium phosphate monobasic, Sigma-Aldrich, S0751\n\n• Calcium chloride, Sigma-Aldrich, C1016\n\n• Magnesium chloride, Sigma-Aldrich, M8266\n\n• Basal Medium Eagle, Sigma-Aldrich, B9638\n\n• Horse serum, Sigma-Aldrich, H1138\n\n• Hanks′ Balanced Salt solution, Sigma-Aldrich Catalog, H6648\n\n• L-Glutamine solution, Sigma-Aldrich Catalog, G7513\n\n• Antibiotic Antimycotic Solution (100×) Stabilized, Sigma-Aldrich, A5955\n\n• Paraformaldehyde, powder, 95%, Sigma-Aldrich, 158127\n\nStep 1: Preparation of solutions and culture medium (see Note 2)\n\n1a. Stock solutions: 1 M CaCl2; 1 M MgCl2; 5% volume pentobarbital sodium in ddH2O.\n\n1b. Cutting solution: 130 mM n-methyl-D-glucamine Cl (NMDG); 24 mM NaHCO3; 3.5 mM KCl; 1.25 mM NaH2PO4; 0.5 mM CaCl2; 5 mM MgCl2; 10 mM D-(+)-glucose; 1 mg/mL ascorbic acid; 2 mg/mL pyruvic acid.\n\nTo make 1 L, pour 850 mL of double-distilled water into a volumetric flask. Add 25.38 g NMDG, 2.017 g NaHCO3, 261 mg KCl, 172 mg NaH2PO4, 1.80 g D-(+)-glucose, 1 g ascorbic acid, 2 g pyruvic acid. After complete dissolution SLOWLY add 5 mL MgCl2 stock solution and 500 μL CaCl2 stock solution. Bring to pH7.2-H7.4 with HCl. Sterile filter and store at 4 °C. The solution is stable for several months. Discharge if it becomes turbid. The addition of MgCl2 and CaCl2 is a critical step. If added too quickly, they precipitate making the solution cloudy. In this case, it must be discharged.\n\n1c. Culture medium: 50% Basal medium Eagle (BME), 25% horse serum; 25% Hank's balanced salt solution (HBSS); 0.5% D-(+)-glucose; 0.5% L-glutamine (200 mM solution); 1% antibiotic antimycotic solution (100×).\n\nTo prepare 50 mL work under a laminar flow hood and use sterile glassware/plasticware. In a 100 mL cylinder add the components in the following order: 25 mL BME, 12.5 mL horse serum; 12.5 mL HBSS; 250 μL D-(+)-glucose; 250 μL L-glutamine; 500 μL antibiotic antimycotic solution. Transfer in a glass bottle and protect from light with aluminum foil. Store at 4 °C. Medium is stable for at least six months. Discharge if color changes and/or it becomes turbid.\n\n1d. Fixative: Paraformaldehyde (PFA) 4% in 0.1 M phosphate buffer (PB), pH 7.4.\n\n1e. Buffer solution: Phosphate-buffered saline (PBS) pH 7.4.\n\nStep 2: Tissue sampling\n\nHave ready the following: ice-cooled cutting solution; 50 mL sterile glass or plastic becker; 150 mm diameter sterile glass or plastic Petri dishes; sterile dissection/slice handling tools; sodium pentobarbital stock solution (room temperature); 500 μL disposable insulin syringes; sterile razor blades; sterile glass/disposable Pasteur pipettes; sterile filter paper dishes.\n\n• Dissection of the brain and separation of individual slices after cutting (see Slice seeding below) should be carried out under sterile conditions as far as possible. If it is not possible to place the stereomicroscope under the laminar flow hood, dissection should be carried out under a simple plastic box opened in the front. The entire dissecting area should be cleaned and wiped off with 70% volume ethanol. During the production of slices, all procedures must be carried out in an ice-cold cutting solution. To keep the temperature a few degrees above 0 °C during the dissection, prepare some blocks of the frozen cutting solution to be added to the 4 °C chilled cutting solution contained in the Petri dish used to dissect the brain.\n\n• Euthanize mice at the required post-natal age with an overdose of intraperitoneal sodium pentobarbital (60 mg/100 g body weight). Check for the absence of specific signs of life, i.e., absence of withdrawal reflexes that normally disappear within 5 min of the pentobarbital injection. When the animal is dead cut the head with scissors and drop it into a small plastic box or a 50 mL beaker filled with ice-cooled cutting solution (about 2–4 °C). Wait a couple of minutes for the head to be cooled and at the same time washed from the blood.\n\n• Transfer the head to a glass Petri dish (10 cm diameter or more) filled with the clean cutting solution at 2–4 °C. Quickly remove the brain from the skull while the head is kept submerged in the ice-cooled cutting solution. To do so use straight fine scissors: insert scissors laterally in the foramen magnum and cut the bone at the basis of the skull on both sides of the brain, use a scalpel to make a transversal cut at the level of the olfactory bulbs, and lift the calvarium. Scoop out the brain with a curved spatula to prevent damage.\n\n• Before separating the cerebellum from the other parts of the brain, completely remove the meninges with a pair of N.7 Dupont forceps.\n\n• Isolate the cerebellum under the stereomicroscope: use a razor blade to make a transversal cut at the level of the mesencephalon and to separate the cerebellum from cerebellar peduncles connecting it to the cerebral trunk.\n\n• Place the cerebellum on the stage of the tissue chopper within a drop of the ice-cooled cutting solution. Operate the chopper and cut 350 μm-thick parasagittal slices. Once terminated slicing, collect slices with a curved spatula (they are usually stuck together) and place them in a sterile 50-mm Petri dish filled with the ice-cooled cutting solution. Store at 4 °C until ready to separate slices. Slices should be separated and plated as soon as possible. We have stored slices for at least 30 min before slicing with no obvious detrimental effects on survival. However, it could be possible to culture slices that have been stored for longer.\n\n• Separate individual slices under the stereomicroscope with a spatula and a needle, trying not to damage the tissue. During the entire procedure, slices must be submerged in the ice-cooled cutting solution. Discharge the damaged slices and/or very small (lateral) slices. If cutting was done smoothly, at least 10-12 slices should be obtained from a P5-P7 cerebellum. If the cerebellum is not submerged by an excess of the cutting solution, cutting with the chopper is easier. Set section thickness to any value between 200 μm - 400 μm after wiping out the solution with a piece of filter paper. Other cutting parameters, such as blade force, must be adjusted based on the type of chopper in use. With the McIlwain tissue chopper in use, we set the blade force knob at ¾ of its rotation clockwise, and the speed control knob at ½ of its rotation clockwise.\n\n• Use a spatula with curved edges to collect slices and transfer them from the cutting stage of the chopper to the Petri dish.\n\nStep 3 Slice seeding\n\n• Before starting to seed slices onto the Millicell inserts bring the culture medium to room temperature and fill the required number of sterile 35-mm plastic Petri dishes with a 1.1 mL medium. Work under sterile conditions. The number of dishes required depends on the number of recovered slices, their size, and the experimental setup. In general, slices of the mouse post-natal cerebellum at day 5 have a maximum size of about 5 mm2. Therefore, one can easily plate 5-6 slices (technical replicate when not co-culturing)/insert (experimental unit). Working with older animals or larger areas of the brain, i.e., the cerebral cortex allows plating a maximum of (roughly) three slices/insert.\n\n• If planning co-culture experiments, like those described here, remember to have all slices ready, i.e., the L7-GFPreln(+/-)F1/ slices and the L7-GFPreln(-/-)F1/slices, before plating.\n\n• Collect slices one by one and carefully lift them onto the dry Millicell membrane using a curved spatula. In co-culture experiments (Figure 1) carefully mark the positions of individual slices so that it will be possible to easily recognize them during subsequent manipulations. See Note 3.\n\n• Once the required number of slices has been plated in the insert, place it inside a 35-mm Petri dish filled with the medium as indicated at the beginning of this section. Be careful to avoid air bubbles forming between the insert membrane and the medium, i.e., check that the membrane's lower surface is completely wet. Slices should be also wet but not submerged by the medium.\n\n• Incubate at 34 °C in 5% volume CO2 for up to 30 days in vitro (DIV) – see Note 4. Cultures can be maintained in vitro even longer, if necessary. Medium has to be changed twice a week. Allow slices to equilibrate to the in vitro conditions for at least 4 DIV before follow-up or starting a pharmacological treatment (if applicable), because during this initial interval there is a massive phase of cell death, as a consequence of the cutting procedure, see Ref. 29.\n\nNotes\n\n1. Slices can also be prepared with an oscillating vibratome. This is often required for subsequent electrophysiological studies as the cutting procedure is less destructive than chopping. However, cutting with the chopper is easier and less time-consuming, which is advantageous if one has to plate many slices in the course of a single experiment.\n\n2. Several media are available and the best medium must be chosen according to the experimenter’s needs. Table 1 below compares the solutions/media in our protocol with two protocols used by other authors that have been employed to also cultivate adult brain slices.\n\n3. To recollect the slice positions in the insert it is advisable to mark a reference point in the insert border with a waterproof pen and to make a drawing of the insert and the slices seeded inside.\n\n4. Slices obtained from the cerebellum (and other central nervous system (CNS) areas) survive better at temperatures below 37 °C, hence the temperature settings of the incubator are important for survival. However, it should be noted that the neuroprotective effect of mild hypothermia on cultured neurons may obscure the action of certain apoptotic inductors if one is interested in the study of cell death.\n\nProtocol for the characterization and validation of the model\n\nThis protocol is advantageous to analyze cellular migration and dispersion in longitudinal studies.\n\nStarting from biological images, it can be used to study cellular sociology, i.e., to study the interactions of cells based on mathematical algorithms that rely on the analogies between cells and human societies.32 It relies on a model of parametrization and quantitation of cellular population topographies developed by Marcelpoil and Usson (1992).26\n\nSoftware\n\n- Voronoi Diagram Generator by Frederik Brasz\n\n- ImageJ (RRID:SCR_003070) by NIH\n\n- FIJI (RRID:SCR_002285) (Image J) by NIH\n\n- Microsoft Windows 10 by Microsoft\n\nStep 1: Generation of Voronoi diagrams (see Note 1)\n\n• Open the interactive Voronoi diagram (Thiessen polygon) generator. Figure 3 (left) shows the aspect of the generator mask.\n\n• Upload the image to be analyzed (size must be 900×900 pixels and preferably saved as a PNG file). To do so your image has to be uploaded to the internet first (e.g., using Figshare or a personal website) so that it is possible to copy and paste its URL into the Voronoi generator. After uploading, the generator displays the image in its working space as shown in Figure 3 (right).\n\n• Using the mouse, click above the center of each cell to generate the Voronoi polygons. Due to the thickness of the slice, it may be possible that two very close cells in the Z axis are not easily distinguished. This introduces an error that can be neglected considering that all slices are cut at the same initial thickness. In the end, you will obtain the image shown in Figure 4A. Save the image on your computer (right-click on the image and choose “save” from the drop-down menu).\n\n• Choose “Visualization Normal” from the Visualization mode drop-down menu of the generator. The tessellation appears as shown in Figure 4B. Again, save the image on your computer (right-click on the image and choose “save” from the drop-down menu).\n\n• Select “Hide sites” from the Options menu of the generator. The tessellation appears as shown in Figure 4C as the black dots corresponding to cell centers have disappeared. Again, save the image on your computer (right-click on the image and choose “save” from the drop-down menu).\n\nLeft – The mask of the Voronoi diagram generator with indications of its main commands and some hints for image elaboration. Right – The diagram generator with an uploaded example image of a single-cultured cerebellar slice from an L7-GFPreln-/-F1/mouse. GFP = green fluorescent protein.\n\nThe image of Figure 1 is taken as an example to show the individual steps of the technique. A: Generation of Voronoi polygons over the microscope image. Note that the center points (black dots) correspond to the cell centers; B: Color visualization of Voronoi polygons with center points; C: Color visualization of Voronoi polygons without center points; D: Elimination of the open polygons, i.e., the polygons with one or more summits/sides outside the picture frame; E: Construction of the convex hull; F: Elimination of the polygons intersected by the convex hull. Note that the image in C (without center points) is used for this elaboration. This is because center points will be otherwise counted as particles by the ImageJ program in the subsequent elaboration; G: Elimination of the sides of the marginal polygons; H: Generation of the thresholded image to be elaborated by ImageJ with the Analyze Particles command; I: Generation of the overlay image with the indication of the number of each polygon analyzed by ImageJ. Note the number 1 circled in red at the center of the image. This number identifies the area in red in the following image; J: Image showing in red the area that ImageJ processes as a single particle. This area is discarded in the following elaborations; K: The values of Area, Perimeter, and Circularity (in red with gray background) of the first 25 particles (polygons) analyzed by ImageJ. In the example image processed here, ImageJ has analyzed a total of 318 particles of which particle #1 (highlighted in yellow) has to be discarded.\n\nStep 2: Elimination of the marginal polygons\n\nDue to the properties of the Voronoi partition, some polygons of the paving are not statistically representative of the set of polygons.26 Those polygons, referred to as the marginal polygons are associated with points located on the border of the cell population and have one or more summits that do not contain total information on their “surround”. Such summits are created by points that belong to a half-plane outside the image area. Therefore, every point of the cell population whose associated polygon satisfies one of the two following conditions must not be taken into account in the subsequent computations:\n\n- The polygon is open (the central point belongs to the convex hull) - see Figure 4D.\n\n- At least one of the summits of the polygon is outside the convex hull - see Figure 4E.\n\nThe convex hull of a set of N points, i.e., the centers of the cells, is defined as the smallest convex set that contains all of the points. In the plane, this is a convex polygon.\n\n• Elimination of the open polygons is carried out with Adobe Photoshop (RRID:SCR_014199) using the Magic wand tool to select and erase them from the image shown in Figure 4B. The result is shown in Figure 4D.\n\n• Construct the convex hull from the image in Figure 4D. The convex hull is constructed with the Line tool by drawing segments that join the site points (cell centers) of the eliminated open polygons so that there are no concavities, as shown in Figure 4E.\n\n• Using Photoshop, eliminate the polygons intersected by the convex hull and the polygons with open sides using the image of Figure 4C (without cell sites). The result is shown in Figure 4F.\n\n• Cancel the sides of the marginal polygons. Use the Magic wand tool of Photoshop followed by the commands: Selection → Expand 2px; Selection → Contract 1px; Cancel; Modify →Stroke (color black) 2px. You should obtain an image in which the area of the marginal polygons is empty as in Figure 4G. This is the last elaboration that will be used for the subsequent steps of analysis.\n\nStep 3: Analysis of Voronoi polygons\n\n• Open the image to be analyzed with ImageJ. Set the appropriate scale with Analyze → Set scale.\n\n• Run the following Macro by selecting Plugins → Macros → Run → Voronoi Macro (Box 1).\n\n• The macro enhances image contrast (optional – line 1), converts the image into a black and white (B&W) 8-bit image (line 2), finds the edges of the Voronoi polygons (line 3), and optimizes their contrast (lines 4-6) as shown in Figure 4H. It then sets up the measurements necessary for the following analysis of polygons: Area, Shape descriptors, and Perimeter (line 7). It also permits the creation of an image (Figure 4I) with the overlay numerical indication of the individual polygons that the program has measured (Add to overlay and Display label). It also sets the number of Decimal places to 6 (line 7). Finally, the Macro performs the command Analyze Particles (line 8). Note the number 1 at the center of Figure 4I (encircled in red). This corresponds to the first counted particle that the program considers being the ensemble of the marginal polygons (highlighted in red in Figure 4J). Note that the red circle is only added here for clarity but not displayed at the end of the elaboration by ImageJ.\n\n• At the end of the Macro, save all computed values in a .csv or a .xls file (according to the version of ImageJ used). This file must then be converted into a.xlsx Microsoft Excel file.\n\nrun(\"Enhance Contrast…\", \"saturated=2\");\n\nrun(\"8-bit\");\n\nrun(\"Find Edges\");\n\n//run(\"Brightness/Contrast…\");\n\nsetMinAndMax(0, 0);\n\nrun(\"Apply LUT\");\n\nrun(\"Set Measurements…\", \"area perimeter shape limit display redirect=None decimal=6\");\n\nrun(\"Analyze Particles…\", \"display summarize add in_situ\");\n\nStep 4: Analysis of data\n\n• Open the .csv or .xls file generated by ImageJ with Microsoft Excel (RRID:SCR_016137). A table extracted from the file is shown in Figure 4K. It contains the following information: Column A: progressive numbering of the particles (polygons) counted by ImageJ; Column B: Identification of the image analyzed; Column C: Area (in μm2 if the Set scale command has been set properly); Column D: Perimeter (in μm if the Set scale command has been set properly); Column E: Circularity (or Roundness factor); Columns F-H: Other shape descriptors computed by ImageJ that are not used in the analysis. Note that line 2 (highlighted in yellow) corresponding to Particle 1 must be deleted (as indicated above).\n\n• Save the file as a.xlsx file.\n\n• Open the.xlsx file in Microsoft Excel and calculate the following:\n\n‐ Mean of area, perimeter, and circularity (roundness)\n\n‐ Standard deviation of area, perimeter, and circularity (roundness)\n\n‐ Area Disorder (AD)\n\n‐ Roundness Factor Homogeneity (RFH)\n\nThe mean circularity (roundness) (RFav) is computed directly by the ImageJ program using the following formula:\n\nThe AD is calculated as follows:\n\nThe RFH is calculated as follows:\n\nBoth are pure numbers with values >0 and ≤1.\n\n• Transfer the values of RFav, AD, and RFH to a new Microsoft Excel spreadsheet for subsequent statistical analysis.\n\nNotes\n\n1. It is possible to use several other Voronoi generators that can be found online as freeware or in dedicated programs. We found it particularly advantageous to use this generator because it is possible to directly upload the image to be analyzed and draw the sites, i.e., the cell centers, straight on it. As an alternative, it is possible to upload the X-Y coordinates of the sites in this and other generators. To do so one can use the ImageJ program and the Multipoint tool to obtain the spatial coordinates to be then uploaded to the Voronoi generator.\n\n\nResults\n\nOrganotypic cultures from L7-GFPrelnF1/ (Figure 1A)39–41 permit a dynamic study of the effects of Reelin on neuronal migration and lamination of the cerebellar cortex. Thanks to GFP fluorescence, PNs can be visualized without the need for immunocytochemical labeling. In addition, our approach makes it unnecessary to use several groups of mice to be sacrificed at given postnatal ages to properly follow the cerebellar maturation. Figure 1B-D shows that, at the end of the experiments, cultures can be easily stained with two common markers of the cerebellar neurons. Figure 1D shows two co-cultured slices from a reln+/- (top right) and a reln-/- (bottom left). A comparison of the histology of the two slices permits clear identification of the phenotypical differences deriving from the different genetic backgrounds of the donor mice. Figure 2 shows the modifications over time in a single-cultured slice from an L7-GFPreln-/-F1/mouse. After 29 days in vitro, the mass of the GFP fluorescent PNs tends to spread from the center of the slice but the neurons do not migrate to form a layered structure. Figure 5 shows that in co-cultures the histology of the slice derived from a homozygous (reln-/-) mouse (Figure 5B-D) progressively changes to eventually become related to that from a heterozygous (reln+/-) mouse (Figure 5A).\n\nA: The cerebellar histology of a slice from an L7-GFPreln+/-F1/ mouse shows a cortical stratification that is similar to that of an early postnatal wild-type mouse in vivo. The PNs are stratified to form a PCL composed of several layers of these neurons. B: A single-cultured slice from an L7-GFPreln-/-F1/ mouse shows a large central mass of PNs. C-D: Exemplificative temporal evolution of a slice from an L7-GFPreln-/-F1/mouse co-cultured with slices from L7-GFPreln+/-F1/mice. The PNs are spread from the central mass (C) and try to form a multilayer PCL similar to that in A. Concentric circles in A and D are 100 μm spaced. Note that in B-D PNs have been stained for calb 28k and thus appear yellowish-orange for the superimposition of the green GFP signal and the red calb 28k fluorescence. Abbreviations: calb 28k = 28kD calbindin; CM = central mass; DIV = days in vitro; GFAP, Glial fibrillary acidic protein (red in A and green in B-D); GFP, green fluorescent protein; PCL = Purkinje cell layer; PNs = Purkinje neurons.\n\nVoronoi’s partition allowed for quantifying the dispersion of PNs in the presence or absence of Reelin. Starting from a set of points locating the position of the cell nuclei it was possible to obtain information on the order/disorder of the PN population (Figure 6). Polygon areas in single-cultured slices from reln+/- animals (Figure 6A-C and Figure 7A-C) are larger than those from reln-/- mice (Figure 6D-F and Figure 7A-C). Conversely, in co-cultures polygon areas in reln-/- slices (Figure 6G-I and Figure 7A-C) become larger than in single-cultured reln-/- slices, confirming a better dispersion of PNs in the presence of Reelin. RFav was not different in reln-/- slices under different culture conditions indicating that the geometry of the polygons was unchanged (Figure 7D). We have also plotted AD and RFH in X/Y diagrams to show the spatial behavior of the PNs in the three groups of cultures (Figure 7E) and established that in the co-cultures the Reelin provided by the reln+/- slices was sufficient to produce a measurable shift in the distribution of the PNs in reln-/- slices from the pattern observed when slices are cultivated singularly.\n\nConfocal images of the GFP-tagged PNs with superimposed Voronoi polygons (A, D, and G) that were generated and further elaborated as described in the Methods section and protocols.io. Images in B, E, and H show the initial elaboration of Voronoi polygons; those in C, F, and H show the last step of elaboration with the exclusion of the marginal polygons that are outside the convex hull. It can be seen that polygons are smaller and have a more homogeneous size in single cultured slices from L7-GFPreln-/-F1/ mice (D-F), become larger and have less homogeneous sizes in co-cultured slices from L7-GFPreln-/-F1/ mice (G-I), whereas slices from L7-GFPreln+/-F1/mice display larger polygons of quite homogeneous sizes. Black dots in A-B, D-E, and G-H are the centers of the PNs. They have been cleared in the subsequent elaboration (C, F, and I) to avoid interference with automated counting. Abbreviations: GFP, green fluorescent protein; PCL = Purkinje cell layer; PNs = Purkinje neurons.\n\nA-B: Descriptive statistics of the mean areas of Voronoi polygons. Note that there is little variability in the mean areas of polygons among singularly cultured slices obtained from reln-/- homozygous mice as PNs remain aggregated into a central mass deep to the cerebellar cortex (see Figures 1, 2, 5); in the two other groups of cultures values are more dispersed and this indicates the dispersion of the PNs to form the PCL that will be typical of the mature cortex. A: Raw data plotted without any adjustment; B: Cleaned data after removing the two outliers identified in the co-cultured slices from reln-/- homozygous mice with the ROUT method (Q = 1%). Error bars are 95% confidence interval. Data passed the Kolmogorov-Smirnov normality test. C: Ordinary one-way ANOVA [F(2, 20) = 8.966; P value = 0.0017] followed by Tukey’s multiple comparison test shows that in co-cultured slices from reln-/- homozygous mice the mean polygon area is larger than in single-cultured slices from animals with the same genetic background (mean ± 95% CI: 1,361 ± 385 μm2 versus 656 ± 195 μm2, adjusted P value = 0.0287) and becomes closer to that of polygons in slices of reln+/- heterozygous mice (mean ± 95% CI: 1,361 ± 385 μm2 versus 1,663 ± 576 μm2, adjusted P value = 0.4678). This observation confirms quantitatively the dispersion of the PNs in co-cultured slices from reln-/- homozygous mice that lack Reelin but are exposed to the protein produced ex vivo by the slices from reln+/- heterozygous mice. Also note the difference in mean areas of Voronoi polygons in single cultures of slices explanted from homozygous versus heterozygous mice (mean ± 95% CI: 56 ± 195 μm2 versus 1,663 ± 576 μm2, adjusted P value = 0.0014). n (number of slices from five different mice) = 8; * 0.05≤ adjusted P value >0.01; ** 0.001≤ adjusted P value >0.001. D: Brown-Forsythe [F* (2, 10.38) =11.41, P value = 0.0024] and Welch [W (2, 11.78) =11.94, P value = 0.0015) ANOVA tests of RFav. Since Voronoi polygons are convex, the average type of spatial occupation of the PNs is well-characterized by the RFav (mean circularity). In slices from single-cultured reln-/- homozygous mice the RFav of the Voronoi polygons is higher than that of the polygons in slices from co-cultured slices of the same genetic background (mean ± 95% CI: 0.6733 ± 0.007 versus 0.6515 ± 0.0149, adjusted P value = 0.0314) and single-cultured reln+/- heterozygous mice (mean ± 95% CI: 0.6733 ± 0.007 versus 0.6091 ± 0.0298, adjusted P value = 0.0082). On the other hand, the difference in RFav between single cultured slices from heterozygous mice and co-cultured slices from reln-/- homozygous mice is not statistically significant (mean ± 95% CI: 0.6091 ± 0.0298 versus 0.6515 ± 0.0149, adjusted P value = 0.0718). The RF of a circle is 1 while that of a line is 0. Therefore, our analysis confirms mathematically that in single-cultured slices from reln+/- heterozygous mice and in co-cultures of slices from reln-/- homozygous mice there is a tendency to the alignment of the PNs, whereas in single-cultured slices from mice that lack Reelin the population of the PNs displays a spatial occupation consistent with the formation of a mass of cells in the cerebellar white matter. E: X-Y diagram showing topographical information of the PN population in the three experimental groups of cerebellar slices under the different culturing conditions reported in the Materials and Methods section. The X-axis displays the values of AD. AD varies when the value of the intrinsic disorder (i.e., the heterogeneity of the Voronoi polygon areas) increases, and a given value of AD corresponds to a given value of intrinsic disorder for any cell population. The Y-axis displays the values of RFH that varies in parallel to geometric disorder, i.e., the homogeneity/inhomogeneity of the circularity of the Voronoi polygons. Both AD and RFH vary from 0 to 1. A highly ordered population is characterized by values of AD and RFH, respectively, corresponding to 0 and 126, this means that all the polygons have the same area and circularity. The AD and RFH values are typical of a highly ordered population (high RFH, low AD) when one analyzes the clustered population of the PNs forming the central mass in the single-cultured reln-/- slices. When the PNs align to eventually form a well-defined layer in the slices from reln+/- heterozygous mice, the RFH diminishes and becomes closer to that of a line (=0), whereas the AD increases because the Voronoi polygons are small where the PNs tend to be aligned, but larger in the other parts of the slice (see Figure 4A-C). Note that in the co-cultured slices from reln-/- mice, there is a shift towards the coordinates of the reln+/- heterozygous mice. Abbreviations: PNs = Purkinje neurons; PCL = Purkinje cell layer; RF = roundness factor; RFav = mean roundness factor; AD = area disorder; RFH = roundness factor homogeneity.\n\n\nDiscussion\n\nHere, not only we have been able to reduce the number of animals necessary to study ex vivo the effects of Reelin on cerebellar lamination, but also to avoid the use of the severe procedures that are necessary for in vivo longitudinal studies. Theoretically, our approach can be used for the study of the biological activities of any other brain-secreted protein, particularly if mutant and/or transgenic animals are available in which the protein under investigation is absent and thus it is possible to prepare co-cultures of the donor (normally expressing) and recipient (protein-lacking) slices. Several examples can be given to show the potential of our approach, a few of which are listed below. Remarkably, some of them refer to studies in Drosophila, a species that is easier to manipulate experimentally than mice and other mammals. For instance, the secreted neurotrophin Spätzle 3 was demonstrated to promote glial morphogenesis and neuronal survival and function in the fruitfly,33 and, in rescue experiments, it had these effects only over very short distances. On the other hand, it was recently demonstrated that Slit, an evolutionarily conserved protein essential for brain development, acts at a long range and does not require processing by extracellular proteases in Drosophila.34 Thus, our approach would be valuable to investigate the function of these two proteins in the mammalian brain, and, by plating slices at different distances, it could be useful to better establish their spatial range of action. Similarly, there is a growing interest in a better understanding of the function(s) of the Cyr61/CTGF/NOV (CCN) protein family in the nervous system.35 CNN proteins bind directly to integrins and heparan sulfate proteoglycans and trigger multiple intracellular signaling pathways. At the cellular level, these proteins regulate gene expression and cell survival, proliferation, differentiation, senescence, adhesion, and migration, but little is known about their function in neural development. Likewise, co-cultures would be useful in studying the secretion of mutated huntingtin, which leads to neuronal degeneration in Huntington disease,36 one of the most devastating neurodegenerative diseases. Our 3Rs approach could be primarily applied to neuroscience, although it is possible to envisage the preparation of slice cultures from organs such as the muscle, heart, liver, and solid tumors.\n\nWe have discussed in a previous publication the barriers for other potential end-users in the adoption of rodent ex vivo platforms in the field of neuroscience.17 In short, the main disadvantage of organotypic cultures lies in the disconnection of the explants from other areas of the brain with interruption of afferent and/or efferent pathways. Potential solutions to address/overcome these problems should be mainly sought in the reconstruction ex vivo of these connections by co-cultivating areas that are physiologically connected in vivo.37,38\n\nWe believe it is important that this or similar approaches are adopted by others, as they can be used in medium throughput screening experiments preliminary to (if necessary) true experimentation in vivo. They have several scientific benefits,29 such as the possibility to precisely control the experimental environment, pharmacologically manipulating the system with ease, the relative facility to perform longitudinal studies, the possibility to use several complementary techniques (genetic engineering, electrophysiology, immunocytochemistry) for biological characterization.\n\nAs partly discussed elsewhere previously,17 the potential of our approach in terms of animal reduction is remarkable as one can theoretically envisage reducing the number of experimental animals to at least one-fifth when aiming to characterize a single bioactive molecule.\n\n\nConclusions\n\nThis 3Rs approach is useful to study the effect of secreted biomolecules in a system modeling the in vivo condition but with remarkable benefits for animal reduction and refinement, avoiding the use of heavy surgery that is often necessary for the molecule(s) to reach the brain.",
"appendix": "Data availability\n\nFigshare: Voronoi analysis - Cultured Reln haplodeficient heterozygous mouse cerebellar slices, https://doi.org/10.6084/m9.figshare.21063616. 39\n\nThis project contains the following underlying data:\n\n- Original images and images elaborated for Voronoi analysis of cerebellar slices from postnatal day 5-7 Reln haplodeficient heterozygous hybrid mice (L7-GFPreln+/-F1/) cultured for 21 days in vitro.\n\n- Area, Perimeter, and Circularity of individual Voronoi polygons. Area Disorder (AD), Roundness Factor Homogeneity (RFH), and Mean Roundness Factor (RFav) of the Voronoi polygon population.\n\nFigshare: Voronoi analysis - Cultured Reln deficient homozygous mouse cerebellar slices, https://doi.org/10.6084/m9.figshare.21063517. 40\n\nThis project contains the following underlying data:\n\n- Original images and images elaborated for Voronoi analysis of cerebellar slices from postnatal day 5-7 Reln deficient homozygous hybrid mice (L7-GFPreln-/-F1/) cultured for 21 days in vitro.\n\n- Area, Perimeter, and Circularity of individual Voronoi polygons. Area Disorder (AD), Roundness Factor Homogeneity (RFH), and Mean Roundness Factor (RFav) of the Voronoi polygon population.\n\nFigshare: Voronoi analysis - Reln deficient homozygous mouse cerebellar slices co-cultured with Reln haplodeficient heterozygous mouse cerebellar slices, https://doi.org/10.6084/m9.figshare.21063280. 41\n\nThis project contains the following underlying data:\n\n- Original images and images elaborated for Voronoi analysis of cerebellar slices from postnatal day 5-7 Reln deficient homozygous hybrid mice (L7-GFPreln-/-F1/) co-cultured for 21 days in vitro in the presence of slices from Reln haplodeficient homozygous hybrid mice (L7-GFPreln+/-F1/).\n\n- Area, Perimeter, and Circularity of individual Voronoi polygons. Area Disorder (AD), Roundness Factor Homogeneity (RFH), and Mean Roundness Factor (RFav) of the Voronoi polygon population.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nFigshare: ARRIVE checklist for ‘Co-cultures of cerebellar slices from mice with different reelin genetic backgrounds as a model to study cortical lamination’, https://doi.org/10.6084/m9.figshare.21299211. 42\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nSchubert D, Herrera F, Cumming R, et al.: Neural cells secrete a unique repertoire of proteins. J. Neurochem. 2009 Apr; 109(2): 427–435. Epub 2009/02/10. eng. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFalconer DS: Two new mutants, ‘trembler’ and ‘reeler’, with neurological actions in the house mouse (Mus musculus L.). J. 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Publisher Full Text\n\nAlasia S, Cocito C, Merighi A, et al.: Real-time visualization of caspase-3 activation by fluorescence resonance energy transfer (FRET). Lossi L, Merighi A, editors. Neuronal Cell Death. New York:Humana Press/Springer Science+Business Media; 2015; pp. 99–114. Publisher Full Text\n\nLossi L, Castagna C, Merighi A:Neuronal cell death: an overview of its different forms in central and peripheral neurons.Lossi L, Merighi A, editors. Neuronal Cell Death. 1254 ed.New York:Springer;2015; pp. 1–18.\n\nMarcelpoil R, Usson Y: Methods for the study of cellular sociology: Voronoi diagrams and parametrization of the spatial relationships. J. Theor. Biol. 1992/02/07/; 154(3): 359–369. Publisher Full Text\n\nNawrocki AR, Scherer PE: Keynote review: the adipocyte as a drug discovery target. Drug Discov. Today. 9/15/2005; 10(18): 1219–1230.\n\nFaul F, Erdfelder E, Lang AG, Buchner A, et al.: G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav. Res. Methods. 2007 May; 39(2): 175–191. PubMed Abstract | Publisher Full Text\n\nLossi L, Alasia S, Salio C, et al.: Cell death and proliferation in acute slices and organotypic cultures of mammalian CNS. Prog. Neurobiol. 8/2009; 88(4): 221–245.\n\nUllrich C, Daschil N, Humpel C: Organotypic vibrosections: novel whole sagittal brain cultures. J. Neurosci. Meth. 9/30/2011; 201(1): 131–141. Publisher Full Text\n\nSchommer J, Schrag M, Nackenoff A, et al.: Method for organotypic tissue culture in the aged animal. MethodsX. 2017; 2017(4): 166–171.\n\nGanesh S, Utebay B, Heit J, et al.: Cellular sociology regulates the hierarchical spatial patterning and organization of cells in organisms. Open Biol. 2020; 10(12): 200300.\n\nCoutinho-Budd JC, Sheehan AE, Freeman MR: The secreted neurotrophin Spätzle 3 promotes glial morphogenesis and supports neuronal survival and function. Genes Dev. 2017 Oct 15; 31(20): 2023–2038. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCaipo L, González-Ramírez MC, Guzmán-Palma P, et al.: Slit neuronal secretion coordinates optic lobe morphogenesis in Drosophila. Dev. Biol. 2020 Feb 1; 458(1): 32–42. PubMed Abstract\n\nMalik AR, Liszewska E, Jaworski J: Matricellular proteins of the Cyr61/CTGF/NOV (CCN) family and the nervous system. Front. Cell. Neurosci. 2015; 9: 237. Epub 2015/07/15. eng. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTrajkovic K, Jeong H, Krainc D: Mutant Huntingtin Is Secreted via a Late Endosomal/Lysosomal Unconventional Secretory Pathway. J. Neurosci. 2017 Sep 13; 37(37): 9000–9012. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYamamoto N, Maruyama T, Uesaka N, et al.: Molecular mechanisms of thalamocortical axon targeting. Novartis Found. Symp. 2007; 288: 199–208. discussion -11, 76-81. PubMed Abstract\n\nCorner MA, Baker RE, van Pelt J , et al.: Compensatory physiological responses to chronic blockade of amino acid receptors during early development in spontaneously active organotypic cerebral cortex explants cultured in vitro. Prog. Brain Res. 2005; 147: 231–248. PubMed Abstract | Publisher Full Text\n\nMerighi A, Lossi L:Voronoi analysis - Cultured Reln haplodeficient heterozygous mouse cerebellar slices. figshare. [Dataset]. 2022. Publisher Full Text\n\nMerighi A, Lossi L:Voronoi analysis - Cultured Reln deficient homozygous mouse cerebellar slices. figshare. [Dataset]. 2022. Publisher Full Text\n\nMerighi A, Lossi L:Voronoi analysis - Reln deficient homozygous mouse cerebellar slices co-cultured with Reln haplodeficient heterozygous mouse cerebellar slices. figshare. [Dataset]. 2022. Publisher Full Text\n\nMerighi A: ARRIVE guideline checklist for Co-cultures of cerebellar slices from mice with different reelin genetic backgrounds as a model to study cortical lamination by Adalberto Merighi and Laura Lossi. figshare. Journal Contribution. 2022. Publisher Full Text"
}
|
[
{
"id": "153860",
"date": "03 Nov 2022",
"name": "Hector J. Caruncho",
"expertise": [
"Reviewer Expertise Neuropharmacology",
"Reelin neurobiology",
"Animal models",
"Mood and Psychotic disorders"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary of study: Hybrid mice were generated by crossing male heterozygous Reelin mutants with L7-GFP females, resulting in both homozygous and heterozygous Reeler hybrids with GFP-tagged Purkinje neurons. Cerebellum slices from both groups were cultured and co-cultured together. The morphology and clustering of cultured cells were compared and found differences to cell morphology and organization between homozygous Reeler mutant cultures versus co-cultures also including heterozygous Reeler tissue.\nStrengths and weaknesses:\nStrengths: Interesting original work. Low animal numbers needed. Relatively simple yet elegant combination of techniques. Thorough descriptions of methods to help readers apply to their own purposes/replication.\nWeaknesses: General: A bit strange that the conclusion is drawn pertaining to potential applications of cell cultures in general (I say that because although they’re not intended, it seems to speak to most forms of cell culture rather than specific to this technique). If this is a ground-breaking technique, it might be more valuable to show that it can be applied to more than one protein. Many proteins relate to cell survival, regulation of signaling, etc. as opposed to cell migration, so it’s a bit difficult to understand how this technique would benefit the study of other aspects of cell function. I suppose part of the issue for me is the absence of discussion of limitations to the model, so as I am imagining all sorts of limitations without the authors discussion or recognition of them, I’m left not understanding if/how the limitations would be explained. Some other limitations include: can you conclude that application of Reelin would resolve the layering deficits in homozygous Reelers through this model? I’m not understanding how the authors conclude cells originating from the homozygous slice show improved organization in co-cultures, as opposed to showing that amongst the co-culture, the cells originating from the heterozygous Reeler are the only cells showing altered organization because you a) can’t verify which slice they originate (both reported with the same protein, i.e. GFP, which can also be exchanged between cells); b) there’s no change from heterozygous and co-cultures, supporting the “Occam’s razor” hypothesis that it’s really a comparison of heterozygous cells against other heterozygous cells. Maybe it wasn’t clear enough how co-cultures are grown together to allow for differentiation.\nGeneral comments on:\n\nMethods: Good overall. My only concerns: Polygon selection and removal of the top polygon, which corresponds to the culmination of data (or all accounted for polygons). I’m not understanding why that information wouldn’t be valuable for comparing sets of polygons (I understand it’s included de facto in the sum of all selected polygons) but it would be good to show the amalgamations are similar across cultures (i.e. I would expect less stacking/layering of cells occurs in smaller montages of polygons compared to bigger ones corresponding to larger numbers of cells, which would impact nearest neighbour analyses etc.). Verification that the initial selection of cells is accurate is not done, and in fact is explained as being negligible. “Using the mouse, click above the center of each cell to generate the Voronoi polygons. Due to the thickness of the slice, it may be possible that two very close cells in the Z axis are not easily distinguished. This introduces an error that can be neglected considering that all slices are cut at the same initial thickness.” It isn’t clear why initial thickness of section would dictate how one would treat stacking of grown cells. The stacking isn’t uniform just because the initial slice was uniform (at least it very much appears there exists more stacking in the central mass relative to the periphery. Also, it matters entirely because those clicks define the cell sizes, which is one of the outputs for statistical comparisons.\nThe inability to verify which slice cells originate should be described/explained. Is it possible to use a secondary reporter to compare and contrast within co-cultures? What would it mean that you can’t verify if so?\n\nIs it true the imaging is done at the central mass? I had a difficult time understanding because there is also a section that states the coordinates images could be taken at. I’m very curious if there’s an impact of image location/bias involved. Is the origin selected by the researcher, are there methods for ensuring similarly sized clusters of cells are being imaged? Is it randomized? How many cells are removed in each? I found this comment particularly interesting: “It is possible to use several other Voronoi generators that can be found online as freeware or in dedicated programs.” They acknowledge the existence of other modeling systems, would be valuable to know if the results are similar., i.e. the impact of the modeling choice. Even a visual demonstration to compare the resulting polygons would be a powerful addition (to answer the obvious question about validity of Voronoi method, how important is accurate cell selection, is there an impact of user experience, etc.).\nData interpretation: I think my biggest concern is lack of description of limitations/how perceivable limitations might be overcome, and secondary, that the discussion and conclusion only includes the word Reelin once, in the first sentence…otherwise the paper is about animal welfare? If the focus is going to be about how to reduce animal sizes, more information should be provided about litter sizes, culling, survival of mutants, etc. and how litter survival might be a limitation for studying other proteins using this method (or not). More information would be required about how many cultures can be derived from a single animal (i.e. size of slice versus size of structure at age of collection, etc.) Either it’s about Reelin, which I think it should be, and I think is interesting, or it’s a methods paper, in which case I think it would be much more valuable to show positive results in at least 2 proteins of interest in a way that allows for comparing the cultures to really show the applications of this technique. I think it might be limited to studying proteins with a very specific subset of functions, so maybe choosing another protein with a vastly different function of Reelin would be a good choice to really highlight the value of this technique. Instead, I think re-writing the discussion and conclusion to focus on results about Reelin would be more appropriate. What can the authors infer about the possibility of Reelin application to modify Reelin-mediated deficits? What can the authors infer about Reelin’s function in regulating cell morphology, beyond simple layering/migration results? Are these results consistent with the in vivo known functions of Reelin? What does this mean? Would you expect there would be differences in non-Purkinje cells? What other sets of cells you can study with this technique? Are there basket cells, granular cells etc. in the culture that we can’t visualize? Why the cerebellum? Is there interaction between the various cells in culture (both PN to PN and PN to any other non-GFP cells)? How might you evaluate cell interactions using this model in the future? What other directions would you go? Just so much to talk about and instead we were told we can save an undetermined, unspecified number of animals…but to learn what? Instead of providing 2 highly specific proteins that could be studied with this method, why not provide a sweeping generalized set of proteins you might have interest in studying with this technique? Usually, the issue is people over-exclaim their success, but in this case, I think not enough effort is given to really dive into what this study indicates about Reelin or what else can be done with the method. If this method is so great, then there should be no shortage of things to tell the reader that you learned about Reelin in applying the technique, instead of how many fewer animals might be needed in future hypothetical studies.\nLanguage: Good language and writing. No considerable issues noted (grammar, spelling, awkward word choice, etc.).\nFigures and Tables: Very thorough and good quality figures and figure descriptions. No issues.\nStatistics: Only issue with stats described earlier: pertaining to non-randomized imaging location (coordinates in the dish essentially) leads to selection bias. Alternative suggestions would include: a) create a grid and take an average of all polygons in multiple grid boxes to get a variety of polygon origins within the analysis. Additionally, it would be valuable to demonstrate whether or not peripheral polygons are truly similar to the central mass related polygons, in other words, a within culture analysis would also be valuable (is there more or less homogeneity of cultures from Reelin homo- or heterozygous mice?). Combining a perceived selection bias with unconfirmed cell selection, the reader might reasonably be concerned the results aren’t the most meaningful or generalizable.\nEthics: No concerns.\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Yes\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "10163",
"date": "06 Oct 2023",
"name": "Adalberto Merighi",
"role": "Author Response",
"response": "Before responding point-to-point to the reviewers’ observations that as a whole were very useful and supportive to ameliorate our work, we allow ourselves to put beforehand here a brief history of the paper submission and its main purposes. We initially wrote this paper as a Brief Report in response to the NC3Rs center's call for papers written by the NC3Rs grantees to be published in their Gateway of F1000 Research. According to the call rules, papers were subjected to the Center’s check for their suitability for submission according to the mission of the organization. After this check, not only the paper was approved to be eligible for APC funding, but we were asked to expand it in the form of a full Method Paper, as it was then submitted to the journal. We believe this is the reason why it ended up displaying some mix between its focus on the 3Rs principles and the neurobiology issues that could be raised according to its results. We are grateful to the reviewers who spotted this primary fault of the original manuscript and we have done our best to correct it. Having said so, we allow ourselves to stress that some of the requests made by the referees (use of cultures from wild-type mice, extension of the study to other areas of the brain, block of Reelin ex vivo) would have indeed required to produce a significant additional amount of work that could be hardly considered within the NC3Rs framework. This is because the Reeler mouse is a suffering phenotype (at least according to Italian animal welfare regulations) and we were not in the position to ask for additional simply confirmative experiments using these mice. Namely, as we have discussed in the section of the Discussion of the revised paper entitled “Insights on Reelin function in Neurodevelopment” several other papers have been published in which the block of the protein function in vitro resulted in at least a partial rescue of the normal cerebellar phenotype, as we have shown here. Moreover, the study of other areas of the brain affected by the Reeler mutation was beyond our original purpose, and the use of the approach here proposed (as discussed in response to this specific comment below) would have required the generation of a specific mouse strain with some sort of useful fluorescent tagging of the cell population of putative interest. As all the above comments were surely aimed at strengthening the soundness of the method that we have proposed, we decided to pursue a different approach to validate the original Voronoi analysis and employed a series of spatial statistic tools that, up to now, are rarely used in neurobiology to analyze the dispersions of the Purkinje neurons in our cultures. Not only did these tools confirm the results of the Voronoi analysis, but gave interesting additional information on the mechanisms of migration of the Purkinje neurons during postnatal cerebellar development. Thus, we are confident that the reviewers will share our point of view and support the publication of the paper in its thoroughly revised form. Weaknesses: General: A bit strange that the conclusion is drawn pertaining to potential applications of cell cultures in general (I say that because although they’re not intended, it seems to speak to most forms of cell culture rather than specific to this technique). If this is a ground-breaking technique, it might be more valuable to show that it can be applied to more than one protein. Many proteins relate to cell survival, regulation of signaling, etc. as opposed to cell migration, so it’s a bit difficult to understand how this technique would benefit the study of other aspects of cell function. I suppose part of the issue for me is the absence of discussion of limitations to the model, so as I am imagining all sorts of limitations without the authors discussion or recognition of them, I’m left not understanding if/how the limitations would be explained. We thank the reviewers for these very useful observations. We have revised the paper by adding a thorough discussion of the limitations of the technique and trying to avoid a too strong generalization of its applicability. Some other limitations include: Can you conclude that application of Reelin would resolve the layering deficits in homozygous Reelers through this model? I’m not understanding how the authors conclude cells originating from the homozygous slice show improved organization in co-cultures, as opposed to showing that amongst the co-culture, the cells originating from the heterozygous Reeler are the only cells showing altered organization because you a) can’t verify which slice they originate (both reported with the same protein, i.e. GFP, which can also be exchanged between cells); b) there’s no change from heterozygous and co-cultures, supporting the “Occam’s razor” hypothesis that it’s really a comparison of heterozygous cells against other heterozygous cells. Maybe it wasn’t clear enough how co-cultures are grown together to allow for differentiation. We are sorry that we have not been able to clarify these issues in the original version of the paper. We believe that, from our observations, we can indeed conclude that the reelin secreted from the cerebellar granule cells in the slices from heterozygous mice (reelin haplodeficient) has a positive effect on the organization of the cerebellar cortex in the slices obtained from homozygous mice (lacking reelin). Our belief is based on the following: Faulty Reelin signaling in the cerebellum causes Purkinje neurons (PN) migration to be disrupted and, as a result, granule cell precursor (GCPs) proliferation to be diminished – for a recent review see [1]. Morphological observations in vivo have long ago demonstrated that the Reeler mouse, which is devoid of Reelin, displays an altered stratification of its cerebellar and cerebral cortices, as well as of other layered areas of the brain. Specifically in the cerebellum, these alterations affect the migration and correct positioning of the PNs that, in the homozygous reln-/- mouse, remain clustered together in a deep cellular mass embedded into the medullary body of the white matter [2]. Conversely, in reln+/- and reln+/+ mice the PNs migrate in an outward direction to eventually form a monolayer of cells between the molecular and granule cell layer of the mature cerebellar cortex, i.e. both genotypes display a normal cerebellar architecture, although we have recently demonstrated that there are very subtle differences in the position of the PNs between reln+/- and reln+/+ mice [3]. The effects of the PNs on the GCP proliferation are mediated by Sonic Hedgehog (reviewed in [4]) and we have subsequently demonstrated that the hypoplasia in the Reeler mouse cerebellum is consequent to a reduction of cortical size and cellularity, the latter being linked to quantitative differences in the extent of GCP proliferation and apoptosis between normal and Reeler mice [5]. The interactions between the PNs and the GCPs are thus quite complex: from one side the PNs stimulate the proliferation of GCPs and, from the other, the CGPs produce and release Reelin in the intercellular space, and the glycoprotein is essential for the correct positioning of the PNs. If we understood well the reviewers’ thoughts, they suggest that we cannot claim that “the cells originating from the homozygous slice show improved organization in co-cultures” as it is equally possible “that amongst the co-culture, the cells originating from the heterozygous Reeler are the only cells showing an altered organization” but this in total conflict with the above-reported literature. In addition, the reviewers believe that we are overinterpreting our findings because: We could not “verify which slice they originate (both reported with the same protein, i.e. GFP, which can also be exchanged between cells”. However, we never suggested that there was a migration of PNs from one slice to the other, and there are no pieces of evidence from previous studies that GFP is exchanged between cells in the L7 mouse. The PN-specific gene coding L7 or pcp2 (Purkinje cells specific protein-2) was first described in 1988 by two independent groups [6, 7], and since then it has been of paramount importance for genetic targeting of these neurons [8]. Anyway, even if one assumes that the GFP can be transferred between cerebellar neurons, the protein should preferentially reach the neurons of the cerebellar nuclei which are in contact with the PN axons, as the retrograde transsynaptic transfer occurs only when a fusion protein with a non-toxic fragment of tetanus toxin is used for genetic engineering/transfection, see e.g. [9]. “there’s no change from heterozygous and co-cultures, supporting the “Occam’s razor” hypothesis that it’s really a comparison of heterozygous cells against other heterozygous cells”. Although Occam’s razor is based on the idea that the simplest explanation is often the best one, we don’t see how the reviewers may conclude that we are simply comparing heterozygous (PN) cells between each other, since they derive from genotyped animals and no exchange of PNs occurs among slices. On the contrary, the simplest explanation of our findings is indeed the one put forward in the original paper. Yet, we fully agree with the referees that “it wasn’t clear enough how co-cultures are grown together to allow for differentiation” and we have amended the manuscript by better explaining how co-cultures were established and how they could influence each other by adding some supplementary information to the paper (Supplementary Material 1). General comments on: Methods: Good overall. My only concerns: Polygon selection and removal of the top polygon, which corresponds to the culmination of data (or all accounted for polygons). I’m not understanding why that information wouldn’t be valuable for comparing sets of polygons (I understand it’s included de facto in the sum of all selected polygons) but it would be good to show the amalgamations are similar across cultures (i.e. I would expect less stacking/layering of cells occurs in smaller montages of polygons compared to bigger ones corresponding to larger numbers of cells, which would impact nearest neighbour analyses etc.). The principle at the basis of Voronoi tessellation is that a plane can be divided into regions close to each of a given set of objects, in our case the centers of the GFP-tagged PNs. Cell centers are mathematically referred to as sites (or seeds or generators). For each site, there is a corresponding region, called a Voronoi cell (polygon), consisting of all points of the plane closer to that seed than to any other. In our case, PNs lay on a Euclidean plane (2D) and their centers form a discrete set of points. The marginal polygons must be excluded from analysis because one or two (when in the corners of the microscope image) of their sides are indeed extending to the infinite (i.e. they are OPEN polygons) as they are defined by the perimeter of the image and NOT by the existence of another site outside the microscopic field (See Fig. S3-1 in Supplementary Material 3). In other words, the software designs these polygons only because the image is a finite portion of the space and the marginal polygons do not derive from the algorithm at the basis of the tessellation. Similarly, one can explain the need to eliminate the polygons that are intersected by the convex hull (asterisks in Fig. S3-1). The convex hull of a finite set PP of points in the plane can be defined as the unique convex polygon whose vertices are points from PP and which contains all points of PP. It can be demonstrated that a Voronoi polygon is unbounded if and only if one of its points is on the convex hull (indicated by asterisks in the figure). As a corollary, the convex hull can be computed from the Voronoi diagram in linear time [10]. Being unbounded, the polygons intersecting the convex hull do not have a finite area and thus cannot the used in the analysis. We have tried to better explain these concepts in the revised paper and Supplementary Material 3. Additionally, in Supplementary Material 3 we have used a different Voronoi generator that automatically computes the convex hull (Fig. S3-2) and demonstrated that there are no statistically significant differences with our original procedure to determine the hull (Fig. S3-3). Verification that the initial selection of cells is accurate is not done, and in fact is explained as being negligible. “Using the mouse, click above the center of each cell to generate the Voronoi polygons. Due to the thickness of the slice, it may be possible that two very close cells in the Z axis are not easily distinguished. This introduces an error that can be neglected considering that all slices are cut at the same initial thickness.” It isn’t clear why initial thickness of section would dictate how one would treat stacking of grown cells. The stacking isn’t uniform just because the initial slice was uniform (at least it very much appears there exists more stacking in the central mass relative to the periphery. Also, it matters entirely because those clicks define the cell sizes, which is one of the outputs for statistical comparisons. Unfortunately, we have not been clear in explaining our point regarding the position of the GFP-tagged cells along the Z-axis of the section. We agree with the referees that stacking is not uniform, but what we signified in saying that selection errors were negligible was that if two or more cells are perfectly stacked one on top of the others we could visualize and take into consideration only the cells in the plane of focus as we used a 2D (and not a 3D) Voronoi analysis. To better clarify this point we have amended the text of the revised manuscript and added explanatory information in Supplementary Material 2. The inability to verify which slice cells originate should be described/explained. Is it possible to use a secondary reporter to compare and contrast within co-cultures? What would it mean that you can’t verify if so? If we understand well this comment signifies (also according to the comment above about the impossibility of verifying the origin of the cells as a consequence of a theoretical exchange of GFP from cell to cell) that we could not identify with certainty the phenotype of the GFP-tagged PNs in slices. We have substantially rebutted this possibility in responding to the previous comment. In addition, we don't see the need for a secondary reporter to compare and contrast within co-cultures. In the original paper, although not strictly necessary, we used calbindin 28k (a well-established marker of the PNs) to unambiguously prove the nature of the GFP-tagged neurons and we obtained a 100% coexistence of both tags (see e.g. Fig. 1 where the fluorescence of the positive neurons is yellow/orange for the sum of the green fluorescence of GFP and the red fluorescence of calbindin-immunostaining). This said, we believe is 100% positive that we could verify the origin of the cells in individual slices. To make this clearer, we have better explained how we have seeded the slices in the culture dish to allow for their unequivocal identification in the revised manuscript and Supplementary Material 1. Is it true the imaging is done at the central mass? I had a difficult time understanding because there is also a section that states the coordinates images could be taken at. I’m very curious if there’s an impact of image location/bias involved. Is the origin selected by the researcher, are there methods for ensuring similarly sized clusters of cells are being imaged? Is it randomized? How many cells are removed in each? Unfortunately, we have been unclear about these issues. We have added all the info about the above points in Supplementary Material 1 and Supplementary Material 4 (also in response to the comment below). I found this comment particularly interesting: “It is possible to use several other Voronoi generators that can be found online as freeware or in dedicated programs.” They acknowledge the existence of other modeling systems, would be valuable to know if the results are similar., i.e. the impact of the modeling choice. Even a visual demonstration to compare the resulting polygons would be a powerful addition (to answer the obvious question about validity of Voronoi method, how important is accurate cell selection, is there an impact of user experience, etc.). We found this comment particularly useful. We have briefly addressed this issue in the revised text and added a more detailed explanation in Supplementary Material 4. Data interpretation: I think my biggest concern is lack of description of limitations/how perceivable limitations might be overcome We have now described the limitations of the techniques in the main text and Supplementary Materials. and secondary, that the discussion and conclusion only includes the word Reelin once, in the first sentence…otherwise the paper is about animal welfare? If the focus is going to be about how to reduce animal sizes, more information should be provided about litter sizes, culling, survival of mutants, etc. and how litter survival might be a limitation for studying other proteins using this method (or not). More information would be required about how many cultures can be derived from a single animal (i.e. size of slice versus size of structure at age of collection, etc.) Either it’s about Reelin, which I think it should be, and I think is interesting, or it’s a methods paper, in which case I think it would be much more valuable to show positive results in at least 2 proteins of interest in a way that allows for comparing the cultures to really show the applications of this technique. I think it might be limited to studying proteins with a very specific subset of functions, so maybe choosing another protein with a vastly different function of Reelin would be a good choice to really highlight the value of this technique. Instead, I think re-writing the discussion and conclusion to focus on results about Reelin would be more appropriate. What can the authors infer about the possibility of Reelin application to modify Reelin-mediated deficits? What can the authors infer about Reelin’s function in regulating cell morphology, beyond simple layering/migration results? Are these results consistent with the in vivo known functions of Reelin? What does this mean? Would you expect there would be differences in non-Purkinje cells? What other sets of cells you can study with this technique? Are there basket cells, granular cells etc. in the culture that we can’t visualize? Why the cerebellum? Is there interaction between the various cells in culture (both PN to PN and PN to any other non-GFP cells)? How might you evaluate cell interactions using this model in the future? What other directions would you go? Just so much to talk about and instead we were told we can save an undetermined, unspecified number of animals…but to learn what? Instead of providing 2 highly specific proteins that could be studied with this method, why not provide a sweeping generalized set of proteins you might have interest in studying with this technique? Usually, the issue is people over-exclaim their success, but in this case, I think not enough effort is given to really dive into what this study indicates about Reelin or what else can be done with the method. If this method is so great, then there should be no shortage of things to tell the reader that you learned about Reelin in applying the technique, instead of how many fewer animals might be needed in future hypothetical studies. According to the comments above we have substantially rewritten the discussion that has now a section in which we take into consideration the significance of this study in terms of Reelin biology. Statistics: Only issue with stats described earlier: pertaining to non-randomized imaging location (coordinates in the dish essentially) leads to selection bias. Alternative suggestions would include: a) create a grid and take an average of all polygons in multiple grid boxes to get a variety of polygon origins within the analysis. Additionally, it would be valuable to demonstrate whether or not peripheral polygons are truly similar to the central mass-related polygons, in other words, a within-culture analysis would also be valuable (is there more or less homogeneity of cultures from Reelin homo- or heterozygous mice?). Combining a perceived selection bias with unconfirmed cell selection, the reader might reasonably be concerned the results aren’t the most meaningful or generalizable. We have clarified these points in response to some of the previous comments in particular in Supplementary Materials 1-4. We have also added a within-culture analysis by the use of several GIS tools. References (for both responses to reviewers) 1 Jossin, Y.: ‘Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation’, Biomolecules, 2020, 10, (6) 2 Mariani, J., Crepel, F., Mikoshiba, K., Changeux, J.P., and Sotelo, C.: ‘Anatomical, Physiological and Biochemical Studies of the Cerebellum from Reeler Mutant Mouse’, Philosophical Transactions of the Royal Society of London B: Biological Sciences, 1977, 281, (978), pp. 1-28 3 Magliaro, C., Cocito, C., Bagatella, S., Merighi, A., Ahluwalia, A., and Lossi, L.: ‘The number of Purkinje neurons and their topology in the cerebellar vermis of normal and reln haplodeficient mouse’, Ann Anat, 2016, 207, pp. 68-75 4 Ruiz i Altaba, A., Palma, V., and Dahmane, N.: ‘Hedgehog–GLI signaling and the growth of the brain’, Nature Reviews Neuroscience, 2002, 3, (1), pp. 24-33 5 Cocito, C., Merighi, A., Giacobini, M., and Lossi, L.: ‘Alterations of Cell Proliferation and Apoptosis in the Hypoplastic Reeler Cerebellum’, Frontiers in Cellular Neuroscience, 2016, 10, pp. 141 6 Oberdick, J., Levinthal, F., and Levinthal, C.: ‘A Purkinje cell differentiation marker shows a partial DNA sequence homology to the cellular sis/PDGF2 gene’, Neuron., 1988, 1, (5), pp. 367-376 7 Nordquist, D., Kozak, C., and Orr, H.: ‘cDNA cloning and characterization of three genes uniquely expressed in cerebellum by Purkinje neurons’, The Journal of Neuroscience, 1988, 8, (12), pp. 4780-4789 8 Sługocka, A., Wiaderkiewicz, J., and Barski, J.J.: ‘Genetic Targeting in Cerebellar Purkinje Cells: an Update’, Cerebellum, 2017, 16, (1), pp. 191-202 9 Maskos, U., Kissa, K., St Cloment, C., and Brûlet, P.: ‘Retrograde trans-synaptic transfer of green fluorescent protein allows the genetic mapping of neuronal circuits in transgenic mice’, Proc Natl Acad Sci U S A, 2002, 99, (15), pp. 10120-10125 10 Preparata, F.P., and Shamos, M.: ‘Computational Geometry: An Introduction’ (Springer New York, 1993. 1993) 11 Yoshiki, A., and Kusakabe, M.: ‘Cerebellar histogenesis as seen in identified cells of normal-reeler mouse chimeras’, Int.J Dev Biol., 1998, 42, (5), pp. 695-700 12 Schaefer, A., Poluch, S., and Juliano, S.: ‘Reelin is essential for neuronal migration but not for radial glial elongation in neonatal ferret cortex’, Dev Neurobiol, 2008, 68, (5), pp. 590-604 13 Hammond, V.E., So, E., Cate, H.S., Britto, J.M., Gunnersen, J.M., and Tan, S.S.: ‘Cortical layer development and orientation is modulated by relative contributions of reelin-negative and -positive neurons in mouse chimeras’, Cereb Cortex., 2010, 20, (9), pp. 2017-2026 14 Zhao, S., Chai, X., Bock, H.H., Brunne, B., Förster, E., and Frotscher, M.: ‘Rescue of the reeler phenotype in the dentate gyrus by wild-type coculture is mediated by lipoprotein receptors for Reelin and Disabled 1’, J Comp Neurol, 2006, 495, (1), pp. 1-9 15 D’Arcangelo, G., Nakajima, K., Miyata, T., Ogawa, M., Mikoshiba, K., and Curran, T.: ‘Reelin Is a Secreted Glycoprotein Recognized by the CR-50 Monoclonal Antibody’, The Journal of Neuroscience, 1997, 17, (1), pp. 23-31 16 Miyata, T., Nakajima, K., Aruga, J., Takahashi, S., Ikenaka, K., Mikoshiba, K., and Ogawa, M.: ‘Distribution of a reeler gene-related antigen in the developing cerebellum: An immunohistochemical study with an allogeneic antibody CR-50 on normal and reeler mice’, Journal of Comparative Neurology, 1996, 372, (2), pp. 215-228 17 Galli-Resta, L., Novelli, E., Kryger, Z., Jacobs, G.H., and Reese, B.E.: ‘Modelling the mosaic organization of rod and cone photoreceptors with a minimal-spacing rule’, European Journal of Neuroscience, 1999, 11, (4), pp. 1461-1469 18 Lagache, T., Lang, G., Sauvonnet, N., and Olivo-Marin, J.C.: ‘Analysis of the spatial organization of molecules with robust statistics’, PLoS One, 2013, 8, (12), pp. e80914 19 Kiskowski, M.A., Hancock, J.F., and Kenworthy, A.K.: ‘On the use of Ripley's K-function and its derivatives to analyze domain size’, Biophys J, 2009, 97, (4), pp. 1095-1103 20 Rahimi-Balaei, M., Bergen, H., Kong, J., and Marzban, H.: ‘Neuronal Migration During Development of the Cerebellum’, Frontiers in Cellular Neuroscience, 2018, 12 21 D'Arcangelo, G.: ‘Reelin in the Years: Controlling Neuronal Migration and Maturation in the Mammalian Brain’, Advances in Neuroscience, 2014, vol. 2014, Article ID 597395, 19 pages. doi:10.1155/2014/597395 22 Goffinet, A.M.: ‘The embryonic development of the cerebellum in normal and reeler mutant mice’, Anat Embryol (Berl), 1983, 168, (1), pp. 73-86 23 Mikoshiba, K., Nagaike, K., Kohsaka, S., Takamatsu, K., Aoki, E., and Tsukada, Y.: ‘Developmental studies on the cerebellum from reeler mutant mouse in vivo and in vitro’, Developmental Biology, 1980, 79, (1), pp. 64-80 24 Inoue, Y., Maeda, N., Kokubun, T., Takayama, C., Inoue, K., Terashima, T., and Mikoshiba, K.: ‘Architecture of Purkinje cells of the reeler mutant mouse observed by immunohistochemistry for the inositol 1,4,5-trisphosphate receptor protein P400’, Neuroscience Research, 1990, 8, (3), pp. 189-201 25 D'Arcangelo, G., Miao, G.G., Chen, S.C., Soares, H.D., Morgan, J.I., and Curran, T.: ‘A protein related to extracellular matrix proteins deleted in the mouse mutant reeler’, Nature, 1995, 374, (6524), pp. 719-723 26 Miyata, T., Nakajima, K., Mikoshiba, K., and Ogawa, M.: ‘Regulation of Purkinje Cell Alignment by Reelin as Revealed with CR-50 Antibody’, The Journal of Neuroscience, 1997, 17, (10), pp. 3599-3609 27 Shomer, N.H., Allen-Worthington, K.H., Hickman, D.L., Jonnalagadda, M., Newsome, J.T., Slate, A.R., Valentine, H., Williams, A.M., and Wilkinson, M.: ‘Review of Rodent Euthanasia Methods’, Journal of the American Association for Laboratory Animal Science, 2020, 59, (3), pp. 242-253"
}
]
},
{
"id": "153857",
"date": "18 Nov 2022",
"name": "Pascale Chavis",
"expertise": [
"Reviewer Expertise Pascale Chavis : Brain plasticity",
"Reelin neurobiology",
"Neuropsychiatric diseases. Thomas Boudier : Image processing",
"Image analysis."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary: The study reports the implementation of a co-culture method to analyze the effects of reelin and reduce animal use within the 3R framework. Hybrid mice were generated by crossing L7-GFP with heterozygous reeler to obtain GFP-tagged Purkinje neurons in different reelin backgrounds. Co-cultures of cerebellar slices from homozygous and heterozygous hybrids resulted in dispersion and morphology changes of GFP-tagged Purkinje neurons derived from slices bearing a homozygous background.\nGeneral: The main concern is about the general scope of the paper and whether it is about ethical use of animals in biological experiments and animal welfare or about reelin neurobiology in the 3R framework. Although the two former issues are not to be overlooked, they should be developed in the discussion rather than in the introduction, highlights and results.\nThe authors also state that this approach will allow the study of reelin effects on cortical lamination and that the method will also be applicable to investigate the function of other brain secreted proteins. They should show that this is indeed the case either in co-cultures of other cortices from reelin hybrids or in cerebellar co-cultures from mutants of different proteins.\n\nStrengths: The authors developed an elegant technique highly suited for longitudinal and dynamic studies, implemented in the 3Rs framework. They provide a very detailed and exhaustive description of the method to allow replication in other labs.\n\nMajor points: Methods: Voronoi analysis: The authors perform Voronoi analysis to analyze spatial organization of cells. Although they give references to support their work, the theoretical paper is dated from 1992. Since then, framework and tools to study spatial organization, based on robust spatial statistics such as F, G, H and K functions, have been developed (see Lagache et al., 20131 for example).\nThe overall method is also extremely manual, involving at least 4 different softwares, and the initial cell detection is purely manual, along with the Voronoi adjustment. The removal of Voronoi zones of cells touching edges is justified, but no explanation is given on why the authors chose to favor convex area hence removing some additional cells in their study.\nQuantitative analysis of PN migration: since slices expand with time (Figure 1), how is the center point precisely localized through different time points?\n\nData interpretation: In co-cultures, changes in the histology of reln-/- slices are interpreted as resulting from the effect of Reelin produced by reln+/- slices. However, there is no clear demonstration of this, as this could be due to another secreted factor. To answer this point, reelin blockade (function or binding, etc...) should be achieved. This experiment would also have the advantage to validate the statement made in the highlight that co-cultures are amenable to pharmacological intervention or other type of manipulation/treatment.\nIn the same line of thought, one can wonder whether reln-/- slices phenotypical improvement would be better achieved if the donor mice were reln+/+ instead of reln+/-? This would validate the method further and also give an indication about time and/or dose effect.\n\nStatistics: In Figure 7, what is the variable: does each point represent one culture? How many polygons are included in each point, this could actually be a bias in condition where GFP-PN survival decrease with time such as in the reln-/- group.\nPlease, indicate in legend samples size i.e. number of cultures/dishes used.\nIn 7B, the distribution in the single reln+/-, clearly shows 2 groups in Voronoi polygons areas. Could you comment? Moreover, this kind of distribution undermines the use of means as presented in 7C.\n\nFigures: Figures 1 and 5 are somehow overlapping. The paper would gain clarity by showing in different figures temporal modifications and histological characterization of single cultures and co-cultures (similar to Figure 2).\n\nMinor points: What is the age of the mice used for slice preparation? And why are mice euthanized using sodium pentobarbital prior brain slicing (protocols.io.6qpvr67bbvmk/v1)?\nWhat is the survival time of the single and co-cultures?\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Yes\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "10164",
"date": "06 Oct 2023",
"name": "Adalberto Merighi",
"role": "Author Response",
"response": "Before responding point-to-point to the reviewers’ observations that as a whole were very useful and supportive to ameliorate our work, we allow ourselves to put beforehand here a brief history of the paper submission and its main purposes. We initially wrote this paper as a Brief Report in response to the NC3Rs center's call for papers written by the NC3Rs grantees to be published in their Gateway of F1000 Research. According to the call rules, papers were subjected to the Center’s check for their suitability for submission according to the mission of the organization. After this check, not only the paper was approved to be eligible for APC funding, but we were asked to expand it in the form of a full Method Paper, as it was then submitted to the journal. We believe this is the reason why it ended up displaying some mix between its focus on the 3Rs principles and the neurobiology issues that could be raised according to its results. We are grateful to the reviewers who spotted this primary fault of the original manuscript and we have done our best to correct it. Having said so, we allow ourselves to stress that some of the requests made by the referees (use of cultures from wild-type mice, extension of the study to other areas of the brain, block of Reelin ex vivo) would have indeed required to produce a significant additional amount of work that could be hardly considered within the NC3Rs framework. This is because the Reeler mouse is a suffering phenotype (at least according to Italian animal welfare regulations) and we were not in the position to ask for additional simply confirmative experiments using these mice. Namely, as we have discussed in the section of the Discussion of the revised paper entitled “Insights on Reelin function in Neurodevelopment” several other papers have been published in which the block of the protein function in vitro resulted in at least a partial rescue of the normal cerebellar phenotype, as we have shown here. Moreover, the study of other areas of the brain affected by the Reeler mutation was beyond our original purpose, and the use of the approach here proposed (as discussed in response to this specific comment below) would have required the generation of a specific mouse strain with some sort of useful fluorescent tagging of the cell population of putative interest. As all the above comments were surely aimed at strengthening the soundness of the method that we have proposed, we decided to pursue a different approach to validate the original Voronoi analysis and employed a series of spatial statistic tools that, up to now, are rarely used in neurobiology to analyze the dispersions of the Purkinje neurons in our cultures. Not only did these tools confirm the results of the Voronoi analysis, but gave interesting additional information on the mechanisms of migration of the Purkinje neurons during postnatal cerebellar development. Thus, we are confident that the reviewers will share our point of view and support the publication of the paper in its thoroughly revised form. Summary: The study reports the implementation of a co-culture method to analyze the effects of reelin and reduce animal use within the 3R framework. Hybrid mice were generated by crossing L7-GFP with heterozygous reeler to obtain GFP-tagged Purkinje neurons in different reelin backgrounds. Co-cultures of cerebellar slices from homozygous and heterozygous hybrids resulted in dispersion and morphology changes of GFP-tagged Purkinje neurons derived from slices bearing a homozygous background. General: The main concern is about the general scope of the paper and whether it is about ethical use of animals in biological experiments and animal welfare or about reelin neurobiology in the 3R framework. Although the two former issues are not to be overlooked, they should be developed in the discussion rather than in the introduction, highlights and results. We fully understand this concern. A similar concern was also raised by Drs. Caruncho and Reive. The reason why the issues of the ethical use of animals in biological experiments and animal welfare have been developed in different parts of the manuscript other than the Discussion is to cope with the guidelines issued by the NC3Rs for Method papers. In response, we have fully revised the paper according to these observations as explained above in the response to the comments of the other two reviewers and in the preamble to our responses. The authors also state that this approach will allow the study of reelin effects on cortical lamination and that the method will also be applicable to investigate the function of other brain secreted proteins. They should show that this is indeed the case either in co-cultures of other cortices from reelin hybrids or in cerebellar co-cultures from mutants of different proteins. We agree with the reviewers that the experiments suggested would be indeed useful to confirm that our approach will permit studying 1. The effects of reelin in the other laminated areas of the brain or 2. The function of other secreted proteins. Yet, as regards the first issue, we have now thoroughly discussed previous experiments with approaches different from the one used here demonstrating the effects of Reelin on the lamination of the cerebral cortex. As regards the second issue, we have now softened our claims on the possible applications of our method to the study of other secreted brain proteins in another specific section of the discussion (Advantages and limitations of the organotypic culture approach to the study of neurodevelopment). We have also considered the issues raised here in a more thorough discussion of the strengths and weaknesses of our approach, as such a discussion was also suggested by Drs. Drs. Caruncho and Reive. We are confident that the reviewers would agree with us that the experiments suggested would require a large amount of work that could the the subject of another paper and well beyond the purpose of this Method Paper (that as mentioned in our prologue was sponsored by the NC3Rs and was prepared according to the guidelines for the NC3Rs gateway). Apart from this, there are several theoretical and practical limitations to the possibility of performing the experiments above (we have addressed this point in response to the first comment under “Data Interpretation”). That reelin produced by the cerebellar granule cells in slices from heterozygous or homozygous Reeler mice can diffuse in the culture medium was previously demonstrated after studies on chimeric mice and in Reeler cortical cultures. We have addressed this issue in the Discussion of the revised paper as follows: Although the structural effects of the Reeler mutation are well known, little work has been done on the possibility of modifying Reelin-mediated deficits in live cells. A study in the Reeler-normal chimeric mice has previously demonstrated that the morphology and position of the cerebellar neurons and glial cells are controlled by extracellular environments but not by their genotype [11]. Subsequent work has shown that the protein produced by cortical explants of reln+/+ or reln+/- mice co-cultured with a Reeler-like ferret dysplastic cortex was capable of at least partly rescuing neuronal migration in the ferret explant [12]. Other studies, were carried out in the cerebral cortex and hippocampus and led to similar conclusions. It was thus shown that cortical layer development and orientation are modulated by relative contributions of Reelin-negative and -positive neurons in mouse chimeras [13] and that the possibility to restore a normal phenotype in reln-/- slices co-cultured with wild-type slices was mediated via the Reelin receptors apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR) [14]. Our present observations are in full accord with these studies. A point left open for discussion regards the Reelin dosage necessary for the rescue of a normal phenotype in culture studies. In their chimeric mouse study, Yoshiki and Kusakabe qualitatively observed that only a few granule cells derived from a normal mouse were capable of promoting the alignment and the proper dendritic tree development of the PNs derived from the mutant. From their observations, these authors suggested that Reelin secreted from a single granule cell can affect the morphology of PNs in a wide area [11]. Our results quantitatively demonstrate that the Reelin produced by the slices obtained from haplodeficient mice is sufficient to restore the normal cerebellar phenotype. Therefore, our findings reinforce the idea that it may be possible to modify Reelin-mediated deficits through the experimental administration of the protein. Experiments have demonstrated that the medium obtained from cerebellar dissociated cultures from P5-8 normal mice as well as from cell extracts of the cultured cerebellum from these mice contained full-length Reelin [15]. These observations are fully in line with the demonstration that the protein is produced by the postmitotic granule cells of the deep external granular layer before they migrate to their final destination, the internal granular layer, where they lose Reelin immunoreactivity [16]. Strengths: The authors developed an elegant technique highly suited for longitudinal and dynamic studies, implemented in the 3Rs framework. They provide a very detailed and exhaustive description of the method to allow replication in other labs. Major points: Methods: Voronoi analysis: The authors perform Voronoi analysis to analyze spatial organization of cells. Although they give references to support their work, the theoretical paper is dated from 1992. Since then, framework and tools to study spatial organization, based on robust spatial statistics such as F, G, H and K functions, have been developed (see Lagache et al., 20131 for example). Frankly, we do not see why Voronoi's analysis should be hampered by its relative age. Voronoi tesselation has been and still is widely employed in the study of the spatial organization of many diverse types of neuronal (and other) cell populations [17]. The paper quoted by the reviewers uses a modified Ripley’s K function to define the clustered, dispersed, or uniform distribution of points (i.e. clathrin endocytotic sites) in the 2D space [18]. Ripley's K-, H-, and L-functions are used primarily to identify the clustering of proteins in membrane microdomains (as is indeed the case for Lagache’s paper). Using this approach, aggregation (or clustering) is identified if the average number of proteins within a distance r of another protein is statistically greater than that expected for a random distribution [19]. Kiskowski et al. emphasized that “it is not entirely clear how the function may be used to quantitatively determine the size of domains in which clustering occurs” and have widely discussed the limitations and potential of Ripley's K in real-life scenarios”[19]. In the case of this study, where indeed the main issue under investigation is the clustering of the PNs, which is very high in the reln-/- mice, one can raise reasonable doubts about the usefulness of applying Ripley's K in our conditions. Despite the above observations on the limitations of Ripley’s functions to modeling spatial clustering we have added a large bunch of new analyses based on the novel use of spatial statistics with ArcMap [geographical distribution tools (Central Feature, Mean Center, Median Center, Directional Distribution, and Standard Distance), pattern distribution tools (Average Nearest Neighbor, Getis-Ord General G, Ripley’s K function, and Global Moran’s I), and mapping clusters tools (Anselin Local Moran’s I, and Getis-Ord G*)] to compare their results with the conclusions that could be drawn solely from Voronoi analysis. As thoroughly discussed in the revised paper the two approaches yielded comparable results in support of our initial claims on the soundness of the method. The overall method is also extremely manual, involving at least 4 different softwares, and the initial cell detection is purely manual, along with the Voronoi adjustment. We have already at least partly addressed this comment in response to Drs. Caruncho and Reive observations (see Supplementary Material 4). In addition, we would like to stress here that the possibility of using an automated procedure is severely hampered by the extremely high compactness of the central mass of the PNs lying inside the cerebellar white matter. In other words, it seems to be very difficult to practically separate the individual PNs with a thresholding procedure based on color or gray histograms (see Fig. S4-2). In addition, the aforementioned paper by Lagache and collaborators uses a similar manual procedure for the initial detection of the regions of interest (ROIs) as reported in their Materials and Methods: “We first delimited cells’ contours by drawing polygonal Region of Interest (ROIs) with the Icy software [13] (http://icy.bioimageanalysis.org). We then used a wavelet-based detection method [28], implemented as a plugin Spot detector in Icy to extract the two-dimensional positions of putative endocytic spots at the cellular membrane…”. The removal of Voronoi zones of cells touching edges is justified, but no explanation is given on why the authors chose to favor convex area hence removing some additional cells in their study. We have addressed this comment also in response to similar observations made by Drs. Caruncho and Reive (see main text and Supplementary Material 3 and 4). Quantitative analysis of PN migration: since slices expand with time (Figure 1), how is the center point precisely localized through different time points? We believe that this comment applies to Figure 2 and thus refers to qualitative analysis. The center point was recorded using the memory system of the microscope stage at 4 DIV. Subsequent images were recorded using the memorized X-Y coordinates. Data interpretation: In co-cultures, changes in the histology of reln-/- slices are interpreted as resulting from the effect of Reelin produced by reln+/- slices. However, there is no clear demonstration of this, as this could be due to another secreted factor. To answer this point, reelin blockade (function or binding, etc...) should be achieved. This experiment would also have the advantage to validate the statement made in the highlight that co-cultures are amenable to pharmacological intervention or other type of manipulation/treatment. We agree that, theoretically, the changes in the histology of co-cultured reln-/- slice could be dependent on a different secreted factor. However, several published papers support our line of thought as we have discussed in the revised version of the paper (reported above). To our knowledge, no other molecules except Reelin and its downstream receptors and adaptor molecules have been demonstrated to be primarily responsible for the correct layered organization of the cerebellar cortex during postnatal development of altricial mammals, although the true mechanisms of PNs layering in the mature cerebellar cortex remain a matter of debate [20]. As authoritatively reviewed by Gabriella D’Arcangelo [21], the discoverer of Reelin and certainly one of the leading scientists in the field “In the cerebellum, Reelin is produced by granule cells in the external granule layer and is essential for the radial migration of the Purkinje neurons, which are born in the cerebellar ventricular zone and form at first a plate and then a single-cell layer. This assessment derives from a widespread analysis of cerebellar development in Reeler mice [2, 22-24], from Reelin gene and protein expression data [16, 25], and functional studies in organotypic cultures [26]”. We likewise agree that the blockade of Reelin would have the advantage of validating our statement that co-cultures are amenable to pharmacological or other types of manipulation. However, this would require a huge amount of additional work that is prone to several worries about its practicability (e.g. the effectiveness of Reelin-blocking antibodies -when available -to penetrate the entire thickness of a slice). In addition, much of the results that may be stemming from these efforts would be mainly confirmatory of previous observations. We have now discussed in our revision the previous literature on the block of the Reelin function in cultured cerebellar slices that demonstrates a long-distance effect of the molecule in vitro. In the same line of thought, one can wonder whether reln-/- slices phenotypical improvement would be better achieved if the donor mice were reln+/+ instead of reln+/-? This would validate the method further and also give an indication about time and/or dose effect. We agree with this observation in theory, but previously published observations on mouse chimeras [11] led to the conclusion that very little Reelin production could be sufficient to rescue the Reeler phenotype. In addition, our main goal was to validate the co-culture method that will be surely of good use to answer these questions in future work. Statistics: In Figure 7, what is the variable: does each point represent one culture? How many polygons are included in each point, this could actually be a bias in condition where GFP-PN survival decrease with time such as in the reln-/- group. The variable in the figure (now Figure 9) is a randomly chosen culture slice. The number of polygons included in each point is indicated in FigShare uploaded Excel files (.xlsx or .csv). Inspection of these files shows that the number of polygons remains very high in single cultured reln-/- slices despite survival decrease thus excluding a bias. Please, indicate in legend samples size i.e. number of cultures/dishes used. Done In 7B, the distribution in the single reln+/-, clearly shows 2 groups in Voronoi polygons areas. Could you comment? Moreover, this kind of distribution undermines the use of means as presented in 7C. The existence of two groups of Voronoi polygon areas is explained by the layering of the cortex in the slices from heterozygous mice. We respectfully disagree with the observation that this kind of distribution undermines the use of the means in the now Figure 7C as 1. Analysis was supported by inferential statistics and 2. Results from ArcMap GIS analysis where the tessellations of images only included the hexagons with PNs inside (see Figures 6 and 10 in main text and Figs. S64-15 in Supplementary Material 6) led to fully comparable results as shown and discussed in the revised version of the paper. Figures: Figures 1 and 5 are somehow overlapping. The paper would gain clarity by showing in different figures temporal modifications and histological characterization of single cultures and co-cultures (similar to Figure 2). In response, we have deleted panels A and B in the original Figure 1. In addition, we have shown other images of the cultures to better demonstrate their histological appearance (Fig. 10A-C) and Figure S2. Minor points: What is the age of the mice used for slice preparation? And why are mice euthanized using sodium pentobarbital prior brain slicing (protocols.io.6qpvr67bbvmk/v1)? The mice were 5 days old. We have added this information to the revised paper. They were euthanized with sodium pentobarbital (SP) as routinely done in our laboratory. Injectable barbiturates are acceptable for use in mouse fetuses and neonates according to the AVMA GUIDELINES FOR THE EUTHANASIA OF ANIMALS: 2020 EDITION, whereas decapitation and cervical dislocation are acceptable with conditions according to the guidelines. In addition, a recent publication [27] has reviewed the effects of SP (and other euthanasia methods) on cells and tissues as well as on different analytes without finding adverse effects of SP versus decapitation and/or cervical dislocation in the brain. Therefore we prefer to use SP also following the recommendations of our Department’s Ethical Committee. What is the survival time of the single and co-cultures? The survival time was 30 days at maximum. We have added this information to the revised paper. References (for both responses to reviewers) 1 Jossin, Y.: ‘Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation’, Biomolecules, 2020, 10, (6) 2 Mariani, J., Crepel, F., Mikoshiba, K., Changeux, J.P., and Sotelo, C.: ‘Anatomical, Physiological and Biochemical Studies of the Cerebellum from Reeler Mutant Mouse’, Philosophical Transactions of the Royal Society of London B: Biological Sciences, 1977, 281, (978), pp. 1-28 3 Magliaro, C., Cocito, C., Bagatella, S., Merighi, A., Ahluwalia, A., and Lossi, L.: ‘The number of Purkinje neurons and their topology in the cerebellar vermis of normal and reln haplodeficient mouse’, Ann Anat, 2016, 207, pp. 68-75 4 Ruiz i Altaba, A., Palma, V., and Dahmane, N.: ‘Hedgehog–GLI signaling and the growth of the brain’, Nature Reviews Neuroscience, 2002, 3, (1), pp. 24-33 5 Cocito, C., Merighi, A., Giacobini, M., and Lossi, L.: ‘Alterations of Cell Proliferation and Apoptosis in the Hypoplastic Reeler Cerebellum’, Frontiers in Cellular Neuroscience, 2016, 10, pp. 141 6 Oberdick, J., Levinthal, F., and Levinthal, C.: ‘A Purkinje cell differentiation marker shows a partial DNA sequence homology to the cellular sis/PDGF2 gene’, Neuron., 1988, 1, (5), pp. 367-376 7 Nordquist, D., Kozak, C., and Orr, H.: ‘cDNA cloning and characterization of three genes uniquely expressed in cerebellum by Purkinje neurons’, The Journal of Neuroscience, 1988, 8, (12), pp. 4780-4789 8 Sługocka, A., Wiaderkiewicz, J., and Barski, J.J.: ‘Genetic Targeting in Cerebellar Purkinje Cells: an Update’, Cerebellum, 2017, 16, (1), pp. 191-202 9 Maskos, U., Kissa, K., St Cloment, C., and Brûlet, P.: ‘Retrograde trans-synaptic transfer of green fluorescent protein allows the genetic mapping of neuronal circuits in transgenic mice’, Proc Natl Acad Sci U S A, 2002, 99, (15), pp. 10120-10125 10 Preparata, F.P., and Shamos, M.: ‘Computational Geometry: An Introduction’ (Springer New York, 1993. 1993) 11 Yoshiki, A., and Kusakabe, M.: ‘Cerebellar histogenesis as seen in identified cells of normal-reeler mouse chimeras’, Int.J Dev Biol., 1998, 42, (5), pp. 695-700 12 Schaefer, A., Poluch, S., and Juliano, S.: ‘Reelin is essential for neuronal migration but not for radial glial elongation in neonatal ferret cortex’, Dev Neurobiol, 2008, 68, (5), pp. 590-604 13 Hammond, V.E., So, E., Cate, H.S., Britto, J.M., Gunnersen, J.M., and Tan, S.S.: ‘Cortical layer development and orientation is modulated by relative contributions of reelin-negative and -positive neurons in mouse chimeras’, Cereb Cortex., 2010, 20, (9), pp. 2017-2026 14 Zhao, S., Chai, X., Bock, H.H., Brunne, B., Förster, E., and Frotscher, M.: ‘Rescue of the reeler phenotype in the dentate gyrus by wild-type coculture is mediated by lipoprotein receptors for Reelin and Disabled 1’, J Comp Neurol, 2006, 495, (1), pp. 1-9 15 D’Arcangelo, G., Nakajima, K., Miyata, T., Ogawa, M., Mikoshiba, K., and Curran, T.: ‘Reelin Is a Secreted Glycoprotein Recognized by the CR-50 Monoclonal Antibody’, The Journal of Neuroscience, 1997, 17, (1), pp. 23-31 16 Miyata, T., Nakajima, K., Aruga, J., Takahashi, S., Ikenaka, K., Mikoshiba, K., and Ogawa, M.: ‘Distribution of a reeler gene-related antigen in the developing cerebellum: An immunohistochemical study with an allogeneic antibody CR-50 on normal and reeler mice’, Journal of Comparative Neurology, 1996, 372, (2), pp. 215-228 17 Galli-Resta, L., Novelli, E., Kryger, Z., Jacobs, G.H., and Reese, B.E.: ‘Modelling the mosaic organization of rod and cone photoreceptors with a minimal-spacing rule’, European Journal of Neuroscience, 1999, 11, (4), pp. 1461-1469 18 Lagache, T., Lang, G., Sauvonnet, N., and Olivo-Marin, J.C.: ‘Analysis of the spatial organization of molecules with robust statistics’, PLoS One, 2013, 8, (12), pp. e80914 19 Kiskowski, M.A., Hancock, J.F., and Kenworthy, A.K.: ‘On the use of Ripley's K-function and its derivatives to analyze domain size’, Biophys J, 2009, 97, (4), pp. 1095-1103 20 Rahimi-Balaei, M., Bergen, H., Kong, J., and Marzban, H.: ‘Neuronal Migration During Development of the Cerebellum’, Frontiers in Cellular Neuroscience, 2018, 12 21 D'Arcangelo, G.: ‘Reelin in the Years: Controlling Neuronal Migration and Maturation in the Mammalian Brain’, Advances in Neuroscience, 2014, vol. 2014, Article ID 597395, 19 pages. doi:10.1155/2014/597395 22 Goffinet, A.M.: ‘The embryonic development of the cerebellum in normal and reeler mutant mice’, Anat Embryol (Berl), 1983, 168, (1), pp. 73-86 23 Mikoshiba, K., Nagaike, K., Kohsaka, S., Takamatsu, K., Aoki, E., and Tsukada, Y.: ‘Developmental studies on the cerebellum from reeler mutant mouse in vivo and in vitro’, Developmental Biology, 1980, 79, (1), pp. 64-80 24 Inoue, Y., Maeda, N., Kokubun, T., Takayama, C., Inoue, K., Terashima, T., and Mikoshiba, K.: ‘Architecture of Purkinje cells of the reeler mutant mouse observed by immunohistochemistry for the inositol 1,4,5-trisphosphate receptor protein P400’, Neuroscience Research, 1990, 8, (3), pp. 189-201 25 D'Arcangelo, G., Miao, G.G., Chen, S.C., Soares, H.D., Morgan, J.I., and Curran, T.: ‘A protein related to extracellular matrix proteins deleted in the mouse mutant reeler’, Nature, 1995, 374, (6524), pp. 719-723 26 Miyata, T., Nakajima, K., Mikoshiba, K., and Ogawa, M.: ‘Regulation of Purkinje Cell Alignment by Reelin as Revealed with CR-50 Antibody’, The Journal of Neuroscience, 1997, 17, (10), pp. 3599-3609 27 Shomer, N.H., Allen-Worthington, K.H., Hickman, D.L., Jonnalagadda, M., Newsome, J.T., Slate, A.R., Valentine, H., Williams, A.M., and Wilkinson, M.: ‘Review of Rodent Euthanasia Methods’, Journal of the American Association for Laboratory Animal Science, 2020, 59, (3), pp. 242-253"
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https://f1000research.com/articles/11-1183
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https://f1000research.com/articles/12-1254/v1
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02 Oct 23
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{
"type": "Case Report",
"title": "Case Report: Medial prefrontal syndrome in a coup de sabre scleroderma carrier",
"authors": [
"Ciro Sanguino-Caneva",
"Carlos Carrillo-Chapman",
"Melissa Luque-Llano",
"Valmore Bermúdez",
"Jose Vargas-Manotas",
"Ciro Sanguino-Caneva",
"Carlos Carrillo-Chapman",
"Melissa Luque-Llano",
"Valmore Bermúdez"
],
"abstract": "Introduction: Linear scleroderma en coup de sabre is a subtype of scleroderma hallmarked by cutaneous and extracutaneous manifestations in which neurological symptoms can be a predominant feature of this condition.\nCase presentation: We report a case of a previously healthy 47-year-old male who developed neuropsychiatric symptoms and right-sided cephalalgia for two months. Clinical examination revealed a right frontoparietal cutaneous lesion and neurological findings suggesting a medial prefrontal syndrome. The neuroimaging evaluation identified scalp and bone thinning adjacent to the skin lesion and cortical-subcortical white matter hyperintensity due to vasogenic oedema at the right frontal and parietal region. A biopsy from the affected area revealed reactive gliosis.\nConclusion: To our knowledge, this is the first linear scleroderma en coup de sabre report associated with a neurological involvement typical of a medial prefrontal syndrome. This case highlights the importance of clinical acuity in recognising atypical phenotypes within the spectrum of this uncommon disease.",
"keywords": [
"Localized Scleroderma",
"Linear Scleroderma en coup de sabre",
"Morphea",
"Neurologic involvement",
"Neurologic manifestations",
"prefrontal syndrome"
],
"content": "Introduction\n\nScleroderma is an immune-mediated and chronic connective tissue disease typified by a pathogenic triad encompassing vasculopathy due to endothelial dysfunction, dysregulation of innate and adaptive immunity, and progressive tissue fibrosis affecting the skin and multiple internal organs.1 This entity has traditionally been classified into systemic and localised forms.2 Systemic scleroderma, or systemic sclerosis (SS), can manifest at any age, mainly in adults. Like most autoimmune disorders, prevalence is higher in females.3 The SS epidemiological behaviour is notably variable due to its rarity, the broad clinical symptoms spectrum, the changing diagnostic criteria, and evolving classifications. These features complicate a comparative analysis plausibility across studies and an accurate prevalence trends estimation.4 In this vein, a recent meta-analysis encompassing 82 studies5 revealed that 83.9% of the world's countries had not reported systemic scleroderma epidemiological data. This study projected a global incidence of 8.64 affected individuals per 100,000 persons annually (range: 1.78 to 23.57). The prevalence was calculated as 18.87 per 100,000 (range: 1.55–25.28), approximating 1.47 million (range: 0.12–1.97 million) affected individuals globally. Incidence and prevalence were higher in females, adults, and high-income countries.5\n\nLocalised scleroderma (LS), or morphea, is delineated by skin lesions and involvement of underlying tissues (e.g., fascia, subcutaneous cellular tissue). Based on the extent and depth of fibrotic changes, LS is classified into limited, generalised, deep, mixed, and linear subtypes.6 LS incidence ranges from 0.3 to 3 per 100,000 individuals/year, affecting children and adults equally.7 Although it is primarily seen as a skin-limited disease, certain subtypes exhibit extracutaneous manifestations, including musculoskeletal (myositis, fasciitis, arthritis), central nervous system (headache, migraine, seizures, epilepsy), and ocular (uveitis) involvements.8 LS encompasses forms leading to progressive facial hemiatrophy (Parry-Romberg Syndrome) and those affecting facial and cranial regions without facial hemiatrophy (linear scleroderma en coup de sabre, LSCS), the latter initially described by Addison in 1854.6 In this sense, band-like sclerotic lesions located on the face and usually extended to the head, skin atrophy groove formation, underlying tissue changes, localised alopecia, and occasional changes in skin pigmentation are the typical presentation of LSCS. Though rare, neurological involvement has been described as epileptic seizures, cephalalgia, focal neurological deficits, and neuropsychiatric symptoms.9 Given the rarity of LSCS and the uncommon coexistence of neurological manifestations beyond epileptic seizures, we detail a case of LSCS associated with clinical neurological features compatible with a medial prefrontal syndrome.\n\n\nCase presentation\n\nA 47-year-old professional truck driver, right-handed Hispanic male consulted our neurology department because of a 2-month history of behavioural changes. As reported by his spouse, these changes included apathy, anhedonia, abulia, decreased sociability, reduced spontaneous speech progressing towards mutism, irritability, and emotional lability. In addition, the patient refers to a right-pulsatile hemicranial headache with moderate intensity. There was no significant personal or familial past medical history. Initial physical examination revealed a sclerotic, depressed band with skin atrophy and alopecia extending from the forehead to the right parietal region. After inquiring with family members, this lesion progressed for over two years (Figure 1). Neurological examination demonstrated spatial disorientation, reduced spontaneous speech, decreased spontaneous motor activity, and reduced task-directed behaviours. Dysphoria was evident, but there were no speech or mnesic function disturbances. On the Montreal Cognitive Assessment (MoCA) scale, he scored 15/30, indicating impairments in executive function, cognitive flexibility, and mathematical reasoning. Cranial nerve examination, motor evaluation, sensory assessment, coordination, and gait were all within normal limits. The rest of the physical examination was unremarkable.\n\nLaboratory tests showed elevated erythrocyte sedimentation rate (ESR): 24 mm/h (reference range: 0.0–15.0 mm/h), raised C-reactive protein (CRP): 32.50 mg/l (reference range: 0.00–10.00 mg/l), and decreased vitamin B12 levels: 140.8 pg/ml (reference range: 174.0–878.0 pg/ml). Blood analysis, kidney and liver function, ionogram, glucose levels, coagulation tests, veneral disease research laboratory (VDRL), ELISA HIV, tumor markers (prostate antigen, CA 19-9, alpha-fetoprotein, carcinoembryonic antigen), vitamin B1, folic acid, and autoimmune profile (anti-nuclear antibodies (ANA), anti-double stranded DNA antibodies (Anti-dsDNA), anti–Sjögren's-syndrome-related antigen A antibodies (AntiRo/SSA), anti–Sjögren's-syndrome-related antigen B antibodies (AntiLA/SSB), anti-Smith antibodies (Anti-SM), anti-ribonucleoprotein antibodies (Anti-RNP), antiphospholipid IgG and IgM, serum complement C3, C4, lupus russell viper anticoagulant venom test) were all within normal ranges.\n\nCerebrospinal fluid (CSF) macroscopic analysis showed a clear, transparent pH of 8 liquid. The cellular count was 0.003 cells/ul (leukocytes: 0–2 xc, erythrocytes: 0–3 xc), with 20% in polymorphonuclear cells, 80% in mononuclear cells and no bacteria observed at the microscope observation. CSF chemical analysis exhibited a glucose concentration of 74 mg/dl, 21.5 mg/dl proteins, and negative results for India ink and gram stains. Moreover, potassium hydroxide (KOH) test and culture stains showed no evidence of microorganisms.\n\nNon-contrast and contrast-enhanced brain magnetic resonance imaging (MRI) revealed right frontal epicranial tissues and diploë thinning, a subcortical and deep white matter increased T2 signal, suggestive of vasogenic edema at the right cingulate gyrus, superior frontal gyrus, supramarginal gyrus and superior temporal gyrus. Underlying the high T2 area of vasogenic edema, there was a focal lesion which exhibited a low signal on the echo gradient sequence due to calcification at the right superior frontal gyrus with slight gadolinium lesional enhancement (Figure 2).\n\nAn eccentric hypointensity is evident, corresponding to the lesion area. (B) Vasogenic edema is observed with a central hypointense lesion adjacent to the temporal horn of the right lateral ventricle. (C) The lesion shows low signal in the Gradient Echo sequence and (D) homogeneous enhancement in the T1-weighted sequence following gadolinium administration.\n\nThe patient was hospitalised for further evaluation. General measures were implemented, including gastroprotection, thromboprophylaxis, and analgesia for the headache, and he was started on antiepileptic medication Valproic Acid 500 mg every 8 hours for seizure prevention and Sertraline 50 mg daily for mood management. Given the non-specific findings on MRI and the differential diagnosis considering a neoplastic lesion, it was decided to further the diagnostic workup with an electroencephalogram, spectroscopy analysis and scheduled for a stereotactic biopsy.\n\nLesions spectroscopy of the described revealed no elevated choline peaks and preserved n-acetyl-aspartate levels. On the eighth day of admission, the patient underwent a stereotactic biopsy. Post-procedure, the patient was transferred to an intermediate care unit for neurological monitoring and initiated on corticosteroid therapy with Dexamethasone 4 mg IV every 8 hours.\n\nA follow-up non-contrast MRI of the brain, taken 24 hours post-surgery, showed minimal bleeding at the biopsy site and no evidence of vasogenic oedema progression compared to the initial neuroimaging assessment. Clinical examination remains unchanged from the evaluation at admission.\n\nLesional stereotactic biopsy showed normal-looking neurons, reactive gliosis areas, acute and chronic inflammatory infiltrates, and no evidence of microorganisms, granulomas, or malignancy at cerebral parenchyma. Immunohistochemical markers showed positivity for glial fibrillary protein (GFAP) and S-100 in the reactive astrocytes.\n\nOn the eleventh day post-admission, the patient experienced a sudden episode of retrosternal pain, dyspnea, desaturation, hypotension, and bradycardia, culminating in cardiac arrest. Despite immediately initiating basic and advanced cardiopulmonary resuscitation measures, the patient could not be resuscitated and was pronounced deceased.\n\n\nDiscussion\n\nLS, or morphea, is a rare immunoinflammatory disorder of the connective tissue affecting both adults and children,2 with a clear sex predominance in women with a 2–4:1 ratio.7 LS incidence ranges between 0.3 and 3 cases per 100,000 individuals annually,4 and although it occurs across all ethnicities, the White population exhibits the highest prevalence, followed by Latin American and other Hispanic-related groups.7\n\nLSCS, also known as frontoparietal linear morphea or en coup de sabre scleroderma, is a rare variant of LS affecting the skin and bone in the frontoparietal region.10 LSCS is a very rare condition; most of the scientific literature indicates that it only accounts for 2–4% of linear scleroderma cases in adults, contrasting to the fourth-fold increase in LSCS prevalence in children with 3–17%.11 Based on an extensive and systematic literature review in Scopus, Web of Science, PubMed and Google Scholar, fewer than 100 case reports have been published on adult-onset LSCS,12–14 with only one case reported in Colombia.15 In Table 1 and Table 2, we present the case reports, cases series, and systematics reviews of patients with neurological manifestations identified during our literature search. Indeed, after this extensive search, we did not identify any studies specifically detailing the mediofrontal syndrome as a neuropsychiatric manifestation of neurological involvement in LSCS; thus, to our knowledge, this is the first report related to this association. In this regard, the accumulation of descriptive evidence from clinical case reports has enlightened previously considered an atypical manifestation, nervous system involvement in scleroderma is now increasingly recognised. Headache and seizures are the most frequently reported neurological manifestations in LSCS.16\n\n* This systematic review included patients with Parry-Romberg Syndrome.\n\nThe underlying pathophysiology of linear scleroderma remains only partially understood. It is believed to involve various factors, including genetics, environmental influences (such as trauma and infections), and disruptions in the immune system, primarily characterised by increased cytokine production. Based on current evidence, the pathophysiological process of morphea can be divided into three distinct phases: 1. early inflammatory, 2. sclerotic/fibrotic, and 3. late atrophic.34 In LSCS, both clinical and histopathological findings suggest a complex interaction between the vasculature and the immune system. Like SS, CD4 T lymphocytes appear to be associated with the fibrotic changes in these lesions. Initially, TH1 and TH17 inflammatory pathways predominate and later, fibrotic changes are believed to arise due to a shift in these inflammatory pathways, with a TH2 response dominance.35 Eventually, atrophy occurs, characterised by epidermal thickness, blood vessels, and inflammatory cell loss.34\n\nLSCS typically presents as a solitary, linear, fibrous plaque that affects the skin and muscle, depressing the underlying bone and resembling the strike of a sabre – hence its name.10 Many authors consider extracutaneous manifestations of localised scleroderma extremely rare, with only approximately 20% of patients developing them. Among these manifestations, arthritis, uveitis, and epileptic seizures are predominantly observed, with neurological manifestations being the most frequent among them.22\n\nOur patient exhibited atypical features and manifestations. One was a medial frontal syndrome as an initial clinical feature. According to the systematic review published by Amaral et al.,16 the most common neurological manifestations in linear scleroderma are epileptic seizures, affecting 41% of patients, followed by headaches in 18.8%. Only 1–3% exhibited cognitive decline and behavioural changes.\n\nAdditionally, another uncommon feature of our patient was his male gender. In the report by Taniguchi et al.,36 out of 16 cases of LSCS, only three were male, and none exhibited neurological manifestations. Among the 13 females, only five presented neurological manifestations, including headaches and abnormal findings in the electroencephalogram, akin to the observations reported by Amaral et al.16 None displayed behavioural or cognitive alterations.\n\nRegarding complementary studies, abnormal neuroimaging findings exist in approximately 84% of patients. In a case report and literature review by Kister et al., only 11% of patients had normal brain MRIs. The remainder exhibited at least one T2 hyperintense lesion, primarily in the subcortical white matter and the corpus callosum, basal ganglia, and brainstem. These lesions were ipsilateral to the skin lesion in 88% of the patients. The predominance of these ipsilateral lesions to the skin manifestation suggests a potential pathogenic correlation between cerebral damage and the dermatological lesion, though the exact mechanism remains a topic of debate and investigation.22\n\nOn the other hand, it is relevant to consider that while a significant proportion of patients may exhibit abnormal brain MRI, not all of them experience overt clinical symptoms. This phenomenon underscores the need for regular neurological and radiological monitoring, allowing for early patient intervention in those who might develop complications. Some of these findings were identified during our patient evaluation, notably in subcortical and deep white matter hyperintensities ipsilateral to the skin lesion.\n\nRegarding treatment, management guidelines recommend systemic therapy for localised scleroderma. Methotrexate, either as monotherapy or combined with corticosteroids, is suggested as a first-line treatment.37,38 Additionally, positive outcomes with mycophenolate and tocilizumab have been reported in other publications.39 Our patient received corticosteroid treatment consistent with descriptions in other case reports and as recommended in clinical practice guidelines. However, we could not monitor the treatment response and clinical progress due to the patient's demise from a non-neurological complication. Nevertheless, the follow-up imaging did not reveal the progression of the lesions noted in subsequent MRI scans.\n\nWritten informed consent for publication of their clinical details and clinical images was obtained from the patient's relative.",
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PubMed Abstract | Publisher Full Text\n\nInfante-Valenzuela A, Camara-Lemarroy CR, Delgado-Garcia G, et al.: Steroid-responsive headache in scleroderma en coup de sabre. Acta Neurol. Belg. 2017 Mar; 117(1): 405–407. Epub 2016 Jul 18. PubMed Abstract | Publisher Full Text\n\nDoolittle DA, Lehman VT, Schwartz KM, et al.: CNS imaging findings associated with Parry-Romberg syndrome and en coup de sabre: correlation to dermatologic and neurologic abnormalities. Neuroradiology. 2015 Jan; 57(1): 21–34. Epub 2014 Oct 11. PubMed Abstract | Publisher Full Text\n\nAppenzeller S, Montenegro MA, Dertkigil SS, et al.: Neuroimaging findings in scleroderma en coup de sabre. Neurology. 2004 May 11; 62(9): 1585–1589. PubMed Abstract | Publisher Full Text\n\nLis-Święty A, Brzezińska-Wcisło L, Arasiewicz H: Neurological abnormalities in localized scleroderma of the face and head: a case series study for evaluation of imaging findings and clinical course. Int. J. Neurosci. 2017 Sep; 127(9): 835–839. Epub 2016 Oct 26. PubMed Abstract | Publisher Full Text\n\nHixon AM, Christensen E, Hamilton R, et al.: Epilepsy in Parry-Romberg syndrome and linear scleroderma en coup de sabre: Case series and systematic review including 140 patients. Epilepsy Behav. 2021 Aug; 121(Pt A): 108068. Epub 2021 May 28. PubMed Abstract | Publisher Full Text\n\nPapara C, De Luca DA, Bieber K, et al.: Morphea: The 2023 update. Front Med (Lausanne). 2023 Feb 13; 10: 1108623. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKurzinski K, Torok KS: Cytokine profiles in localized scleroderma and relationship to clinical features. Cytokine. 2011 Aug; 55(2): 157–164. Epub 2011 May 4. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTaniguchi T, Asano Y, Tamaki Z, et al.: Histological features of localized scleroderma 'en coup de sabre': a study of 16 cases. J. Eur. Acad. Dermatol. Venereol. 2014 Dec; 28(12): 1805–1810. Epub 2013 Oct 10. PubMed Abstract | Publisher Full Text\n\nAsano Y, Fujimoto M, Ishikawa O, et al.: Diagnostic criteria, severity classification and guidelines of localized scleroderma. J. Dermatol. 2018 Jul; 45(7): 755–780. Epub 2018 Apr 23. PubMed Abstract | Publisher Full Text\n\nKnobler R, Moinzadeh P, Hunzelmann N, et al.: European Dermatology Forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 1: localized scleroderma, systemic sclerosis and overlap syndromes. J. Eur. Acad. Dermatol. Venereol. 2017 Sep; 31(9): 1401–1424. Epub 2017 Aug 9. PubMed Abstract | Publisher Full Text\n\nMertens JS, Marsman D, van de Kerkhof PC , et al.: Use of Mycophenolate Mofetil in Patients with Severe Localized Scleroderma Resistant or Intolerant to Methotrexate. Acta Derm. Venereol. 2016 May; 96(4): 510–513. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "211349",
"date": "25 Oct 2023",
"name": "Cornelia Drees",
"expertise": [
"Reviewer Expertise Neurology",
"epilepsy",
"publication on Parry-Romberg syndrome"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors present a case with clinical features of linear scleroderma (LS) presenting with behavioral symptoms that can be seen with a medial prefrontal syndrome. However, the presentation as described does not contain details or test results that would have confirmed an association of his LS and his psychiatric manifestations. While a connection is conceivable, in this case it is circumstantial.\n\nRe. Sufficient detail in history/exam/testing: Changes associated with scleroderma are often insidious and develop over a long time - just like the scar - and therefore a 2-month history of behavioral changes should be clarified. Was the behavior change never noted or was it just worse in the last 2-months before he presented, or did he have seizures (focal seizures arising from the right frontal or temporal region which do not need to have motor features) related to the lesions which changed his behavior more abruptly, possibly as a postictal effect? It was not mentioned how much alcohol the patient consumed and whether there was a h/o alcoholism (esp in light of the low vit B12 level). Thyroid function tests are not listed, though thyroid disorders would be a much more common reason for behavioral changes. Furthermore, a psychiatric assessment is not mentioned to determine whether there may have been a psychiatric component, such as depression. Regarding the MRI, I doubt that there is vasogenic edema as there is no compression of the adjacent sulci or ventricle and no response to treatment with steroids. Typically, there is not much or any edema in brain lesions associated with LS, rather gliosis (however, vasogenic edema would be expected for a neoplastic process). Lastly, and importantly, there was no functional test mentioned that looked at the impact of the lesion in the right frontal lobe (e.g. EEG showing right frontal slowing or PET showing metabolic abnormalities in that area), therefore I believe the authors cannot assume or maintain that the the lesion which is relatively small and the behavior are connected.\n\nRe. sufficient discussion of findings: I believe the patient has LS, but I think the authors have not not proven a causal relationship of behavior and the right frontal lesion by missing crucial historical findings, lab results and tests. At this point it is an association of features that may or may not be related which does not justify the claim that this is the first case of LS with a medial prefrontal syndrome.\nI do not think that the Table 2 is valid unless the authors take care to sort out which cases are repeated in each of the systematic reviews and case series - as especially the systematic reviews accumulate the same cases from the literature. As far as I can tell the authors haven't done this, yet. Table 1 is also not valid as it stands because it lists and counts the same case twice under \"Seizure\" (17) and another case twice under \"Cranial nerve involvement\" (26) - this may be an oversight or warrants explanation.\n\nRe. sufficient detail for other practitioners: I think the case and the pictures of scalp and MRI could be used for a discussion of LS with intracranial involvement, as well as a general discussion of neurological findings in these cases.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": []
},
{
"id": "223944",
"date": "28 Feb 2024",
"name": "Daniel H. Glaser",
"expertise": [
"Reviewer Expertise Pediatric Rheumatology",
"Craniofacial Scleroderma"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis care report attempts to add to the literature in providing description of a novel CNS manifestation of craniofacial scleroderma. The authors present a single adult male with significant behavioral alterations, who is concurrently noted to have skin lesions consistent with craniofacial subset of localized scleroderma (encoup de sabre phenotype). Cognitive, laboratory, and imaging investigations identify significant cognitive difficulties and a markedly abnormal brain MRI. Although the patient unexpectedly expired in the hospital, the authors note that this was likely unrelated to his initial presentation.\nUnfortunately, multiple portions of the case presentation lack sufficient detail to directly conclude that the reported symptoms were related to the purported diagnosis. In addition, there are multiple content issues that undermine confidence in the report and should be further addressed by the authors.\nCase History and Details\nElevated inflammatory markers are very uncommon in localized scleroderma, so clarification on why present in this patient, as well as additional laboratory trends would be appreciated. Vitamin B12 level was noted to be low, but unclear why this was not addressed in the discussion. Authors note EEG was obtained, but no report of results is provided; this needs to be addressed Lab results refer to “lupus russell anticoagulant venom test”; this terminology is incorrect and should be either “dilute Russell viper venom time” or “Russell viper venom time”.\nBackground and Discussion\nAuthors assert that “medial frontal syndrome was initial clinical feature”, though they report that his lesion had been present for at least two years in the case presentation. In the discussion, reference 4 is cited as a source for localized scleroderma incidence but that reference refers to systemic sclerosis incidence. Extracutaneous manifestations occurring with incidence of 20% is not particularly rare. Directly connecting the patient’s cognitive symptoms with the lesions is difficult, as the patient did not survive long enough for treatment response measurements. Exploration of localization of lesions in context of the patient’s symptoms would have strengthened this assertion given the global deficits reported in the context of relative focal lesions. Additional discussion of neuroimaging findings in other patients to contextualize this patient’s findings would also be helpful for readers to understand significance of results. Use of reference 22 source from brain MRI abnormality frequency in Discussion is inappropriate; that study was only examining patients with symptomatic lesions. Studies with unselected cohorts would be more appropriate. In those, symptomatic lesions are uncommon (<10%) and are likely more reflective of general epidemiologic data. In table 1, reference 17 is counted twice in “Seizure”. Reference 26 is counted twice in “Cranial Nerve Involvement”. This needs to be addressed or corrected. In table 2, reference 33 is a systematic review of 137 cases AND a case series of 3 new cases, so unclear why not included in Table 1. This needs to be addressed or corrected. In table 2, reference 16 includes in its systematic review cases lists in Table (ie. references 22 and 23). This is misleading to the reader who will think that a greater number of unique cases exist in the literature than are actually present.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1254
|
https://f1000research.com/articles/12-42/v1
|
11 Jan 23
|
{
"type": "Research Article",
"title": "Risk of mental disorders and malnutrition in elderly COVID-19 survivors: An observational study",
"authors": [
"Ria Maria Theresa",
"Marlina Dewiastuti",
"Sri Rahayu Ningsih",
"Lisa Safira",
"Ria Maria Theresa",
"Sri Rahayu Ningsih",
"Lisa Safira"
],
"abstract": "Background: The incidence rate of COVID-19 is around 11-15% in the elderly. The case fatality rate (CFR) of COVID-19 in the elderly is around 8.9% and increases with age. The risk of mental disorders and malnutrition is increased in COVID-19 survivors. Continuous inflammatory conditions result in a state of hypercatabolism that can disrupt brain neuroendocrine and protein consumption for the formation of acute-phase reactant proteins. Mental disorders and malnutrition can lead to fragility. The aim of this study was to assess the risk of mental disorders and malnutrition in elderly survivors of COVID-19. Methods: This research was a cross-sectional study. The results of the research on age, disease symptoms, and comorbidities have proven that they are risk factors for mental disorders and malnutrition in elderly COVID-19 survivors. This study used total sampling and included 100 study subjects. The research was conducted in Depok for two months; data was collected directly through shared questionnaires and direct anthropometric measurements. The questionnaires used were the SRQ-20 tool for mental disorder screening and MNA for malnutrition screening. Results: The risk factors for mental disorders were age over 70 years old OR 3 (CI 1.0-8.8), severe COVID-19 symptoms OR 4.5 (CI 1.2-16.17), and multi-comorbidity OR 2.3 (CI 0.6-8.8). The risk factors for malnutrition were age higher than 70 years old OR 2.5 (CI 0.8-7.9), moderate COVID-19 symptoms OR 6.3 (CI 2.0-19.81), and multi-comorbidity OR 6.6 (CI 1.5-28.5). Conclusions: Those infected with COVID-19 have a risk of mental disorders and malnutrition, especially in geriatrics, and this risk increases with age.",
"keywords": [
"COVID-19",
"elderly",
"survivors",
"mental disorders",
"malnutrition"
],
"content": "Introduction\n\nThe Coronavirus disease 2019 (COVID-19) is currently a worldwide pandemic. The morbidity and mortality rates are still increasing, especially in developing countries such as Indonesia. More than one million Indonesians suffer from COVID-19. Data from several studies indicate high morbidity and mortality rates in the elderly population. The incidence rate of COVID-19 in the population is around 11-17%, while the case fatality rate (CFR) is around 8.9% and increases with age.1–5\n\nThe elderly population has an immunosenescence state, a condition that causes disturbances in both innate and adaptive immune systems. COVID-19 in the elderly results in a continuous inflammatory response, causing the clinical symptoms of COVID-19 in the elderly to often be more severe and the mortality rate to be high.6\n\nSurvivors of COVID-19 have an increased risk of psychiatric disorders. About 20% of COVID-19 survivors will experience mental disorders. The most common clinical manifestations are depression, anxiety, and sleep disturbances.6–10\n\nMental disorders increase along with the increasing age of COVID-19 survivors. The pathogenesis of psychiatric disorders in COVID-19 survivors is a continuous inflammatory state that can result in disturbances in neuroendocrine, neuroimmune, and nervous structures.11–15\n\nA total of 52.7% of the elderly population who were infected by COVID-19 suffers from malnutrition. This is due to the fact that most elderly people who suffered from COVID-19 have multiple comorbidities. In addition, the inflammatory reaction causes high catabolism, causing high protein consumption for the formation of acute phase reactants. The expression of angiotensin-2 receptor (ACE-2) in the gastrointestinal tract is high which causes symptoms of nausea, vomiting, diarrhea, and reduced appetite to increase in the elderly. The ongoing inflammatory reaction that occurs in the elderly results in a higher risk of malnutrition even when they have survived COVID-19.16–20\n\nThe risk of mental disorders and malnutrition in elderly COVID-19 survivors can lead to fragility. The fragility of elderly COVID-19 survivors increases hospitalization rates and mortality (Figure 1).17,21–25\n\nThe aim of this study was to investigate the risk of mental disorders and malnutrition in elderly COVID-19 survivors.\n\n\nMethods\n\nThis study was approved by the UPN Veteran Jakarta Ethical Clearance Committee (Protocol number: 455/X/2021/KEPK) after due consultation, consent letters had been provided by the researchers to all respondents.\n\nThis research was a cross-sectional study conducted in Depok, Indonesia. The research sampled 100 people (male = 52, female = 48) using total sampling. Data were collected by interview and direct data collection within three months of respondents being infected with COVID-19. The data was taken from the elderly population of Depok who had been infected with COVID-19 between May-July 2021. Inclusion criteria were the population of people over 60 years old and diagnosed with COVID-19 who was undergoing treatment in a hospital or quarantine at home, while exclusion criteria were the population who had been diagnosed with mental disorders. Medical conditions such as dementia or other cognitive disorders were not previously evaluated in the study.\n\nThe outcome variables of this study were the risk of mental disorders and malnutrition. Both variables were categorized as having risks and having no risks. The independent variable in the study was age, measured since the respondent's birth. Another variable was the degree of severity of COVID-19; the severity of the disease was characterized as mild, moderate, and severe and whether there were concomitant diseases or not. The three variables were observed and tested using a logistic regression test. Insignificant variable expenditure cause a change in odds ratio (OR); if the OR change is more than 10% then the variable is a confounder variable and must be included in the model. Other potential confounders not observed in the study were economic status, a history of previous mental disorders.\n\nData were collected from questionnaires and anthropometric measurements. Questionnaire interviews were conducted by trained interviewers (RM). Interviews and data collection took 20-30 minutes per participant. Responses to questionnaires were inputted into electronic data. Before the data was collected, interrater reliability was carried out.\n\nSociodemographic information and health conditions obtained in this study included age, occupation, availability of caregivers, already received vaccinations, symptoms of COVID-19, and comorbidities. Data on comorbidities was obtained from self-reports.\n\nAnthropometric measurements included measurements of height, weight, and body mass index. Measurement of body mass index was calculated based on the weight in kilograms divided by height in meters squared.\n\nThe data was cleaned after collection. Incomplete questionnaire data at the time of collection was re-confirmed with the study respondents.\n\nThe mental disorder questionnaire was based on the SRQ-20 questionnaire. There were 20 questions that were asked by direct interview. Obtaining a value of more than or equal to 8 meant the respondent had a risk of mental disorders. This questionnaire is a screening questionnaire that has been tested for validity and reliability and a diagnostic test with 88% sensitivity for mental disorder screening.26–28\n\nThe malnutrition questionnaire used a mini nutritional assessment (MNA) questionnaire, conducted directly with interviews and direct body index measurements. Obtaining a value less than 11 was considered possible malnutrition. The MNA questionnaire is a questionnaire commonly used for malnutrition screening in the elderly. This questionnaire has been conducted with validity and reliability tests and diagnostic tests with a sensitivity of 96%.29,30\n\nStatistical analysis was performed with the Statistical Package for Social Sciences (SPSS). Significance was determined with an alpha value of <0.05. Descriptive analysis was conducted to look at demographic data such as gender, occupation, care during COVID-19, availability of caregivers, and vaccination status. Variables such as age, the severity of disease, and comorbidities were assessed using a Chi-square test. A logistic regression test was conducted to determine the factors that influence mental disorders and malnutrition with a multivariate model.\n\n\nResults\n\nThis study invited 158 participants; 56 participants refused and did not respond the questionnaire. Two had missing data on the dependent variable and could not be contacted for confirmation of research data. A total of 100 participants were studied (Figure 2).\n\nA total of 100 respondents were tested based on baseline characteristics; p-values were over 0.05, so it can be concluded that there was no significant differences in the characteristics of respondents. The variable of availability of caregivers or nurses while being infected with COVID-19 for those who have a disorder did not show any significant differences; this is because the number of respondents who were outpatients is small.\n\nAs seen in Table 1, there was no difference in the occurrence of mental disorders between sexes; men and women had almost the same percentages. There was no difference in the occurrence of mental disorders between the different professions, nor was there a difference in the occurrence of mental disorders between those with caregivers and those without. Regarding treatment, a difference was observed because most of the elderly population infected with COVID-19 are likely to receive treatment in hospitals.\n\nThe characteristics of the malnourished group also showed there was no difference in baseline characteristics (gender, profession, caregiver, income, vaccinated status), where the characteristics of the respondents in patients who had malnutrition and those who did not suffer from malnutrition were homogeneous.\n\nIn Table 2 there are no differences between gender, profession, and availability of caregivers’ effect on the risk of malnutrition. However, there was a difference between treatment during COVID-19 infection and the risk of malnutrition; this may be because most elderly people infected with COVID-19 get treatment in hospitals.\n\nBased on the results in Tables 3 and 4, the variables of age, symptoms, and comorbidities were included in the multivariate analysis, both for mental disorders and malnutrition disorders.\n\nTable 3 shows there was a relationship between increased age and the risk of mental disorders. There was also a relationship between the severity of COVID-19 symptoms and the number of comorbidities with the risk of mental disorders.\n\nTable 4 shows a relationship between increasing age and the risk of malnutrition. There was also a relationship between the severity of COVID-19 symptoms and the number of comorbidities with the risk of.\n\nBased on the results of the multiple logistic regression analysis in Table 5, the factors that influenced mental disorders were age and symptoms. People older than 70 years had a three-time greater risk of experiencing mental disorders than the elderly aged between 60-70 years old, after controlling for symptoms and comorbidities variables at a 95% confidence interval (CI) between 1,071 to 8,83. The elderly with severe COVID-19 symptoms were at a 4.5-time greater risk of experiencing mental disorders compared to the elderly with mild symptoms, after controlling for age and comorbidities variables at a 95% confidence level between 1.23 to 16.71.\n\nBased on the results of multivariate analysis, malnutrition disorders were influenced by symptom variables and comorbidities. Elderly people with more than one comorbidity had a 6.6-time greater risk of experiencing malnutrition after controlling for symptoms and age variables at a 95% confidence level, between 1.56 to 28.57.\n\n\nDiscussion\n\nOne-third of the post-COVID-19 population experience mental disorders; 40% of patients will experience depression, and the rest will experience symptoms such as anxiety, and delirium.10,11,23,31-33 Between 43-70% of COVID-19 survivors experience psychological disorders. Several studies say this is related to the degree of disease, age, and comorbidities. However, several studies have stated that mental disorders are not related to this, especially in the elderly.5,6,14,15\n\nThe older the age, the higher the risk for mental disorders will be. Based on the results of our study, it was found that as age increased, the risk of mental disorders in the elderly after COVID-19 infection increased by 2.5 times according to the results of the study in Tables 3 and 5.16\n\nCOVID-19 infection predisposes to mental disorders, which are induced by cytokine bodies and hyperinflammatory states.10,11 Therefore, it can cause disruption of the blood-brain barrier and ultimately inflammation of the nervous system. In the elderly, there is a susceptibility to inflammation.17 Hyper-inflammatory conditions affect the severity of COVID-19 disease; the severity of COVID-19 disease will increase the risk of post-infection mental disorders. In addition, comorbidity in the elderly is often multi-comorbid.17 The number of comorbidities increases the risk of mental disorders.23,32,34 Table 3 shows that there is a relationship between age, the degree of disease severity, and comorbidities that increase the risk of mental disorders in the elderly after COVID-19 infection. The degree of severe illness leads to a 4.5 times higher risk of mental disorders and multi comorbidities lead to a 2.3 times higher risk of experiencing mental disorders.34\n\nMalnutrition is a nutritional disorder that has an unfavorable impact, especially on the elderly. The incidence of malnutrition in the elderly infected with COVID-19 is higher than in the general population. The pathomechanism of malnutrition is an acute inflammatory state causing high body protein consumption, and less lean body mass in the elderly, which continues to decrease with increasing age so that elderly people often lose weight due to acute inflammation. The infection of SARS-CoV-2 in the gastrointestinal system of the elderly is greater, so elderly people who are infected with COVID-19 often experience severe gastrointestinal disorders. Other factors can also influence malnutrition: the severity of COVID-19 infection increases the risk of malnutrition as 32.3% of the elderly infected with COVID-19 will continue to be malnourished 30 days after infection. Comorbidity in the elderly is also related to the incidence of malnutrition, which is related to chronic inflammation that leads to acute exacerbations causing a hyperinflammatory state so that catabolism increases and muscle mass is used.10,12,18,19,35,36\n\nBased on the results of the study, it was found that older age, degree of disease severity, and comorbidities were associated with the risk of malnutrition in the elderly after COVID-19. Increasing age increased the risk of malnutrition by 2.5 times. The severity of the disease also increased the risk of malnutrition, although in this study it was shown that people with the moderate disease had the highest risk of malnutrition, which was 6.3 times higher, while people with severe degree disease had 4.4 times risk of malnutrition. In some studies, 32.3% of patients suffering from malnutrition during treatment still experienced malnutrition on day 30, meaning about 70% experienced an improvement in their condition. In this study, multi-comorbidities led to 6.6 times higher risk of malnutrition, more comorbidities, and increased susceptibility in the elderly as seen in Table 6.\n\n\nConclusions\n\nAge, COVID-19 symptoms and the presence of disease comorbidities are risk factors for mental disorders and malnutrition in COVID-19 elderly survivors. The older the age, the more severe the symptoms of COVID-19; the number of comorbidities also increased the risk of mental disorders and malnutrition.\n\nEvaluation of mental health and nutritional status in elderly COVID-19 survivors needs to be carried out regularly to avoid vulnerabilities which will negatively impact the quality of life of elderly people.\n\nThe limitations of this study are the total sampling approach. In addition, in this study some variable confounders couldn’t be strictly controlled. Variable confounders that can affect the results include mental disorders that have previously been experienced or have had previous symptoms.\n\n\nData availability\n\nFigshare: Risk of mental disorders and malnutrition in elderly COVID-19 survivors, https://doi.org/10.6084/m9.figshare.19588519.v2.37\n\nThis project contains the following underlying data:\n\n- response from 100 respondents in Covid-19 Survivor.csv\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nKaryono DR, Wicaksana AL: Current prevalence, characteristics, and comorbidities of patients with COVID-19 in Indonesia. J. Community Empower Heal. 2020; 3(2): 77. Publisher Full Text\n\nAzwar MK, Setiati S, Rizka A, et al.: Clinical Profile of Elderly Patients with COVID-19 hospitalised in Indonesia’s National General Hospital. Acta Med. Indones. 2020; 52(3): 199–205. PubMed Abstract\n\nWang L, He W, Yu X, et al.: Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company’s public news and information.2020; (January).\n\nBurgaña Agoües A, Serra Gallego M, Hernández Resa R, et al.: Risk Factors for COVID-19 Morbidity and Mortality in Institutionalised Elderly People. Int. J. Environ. Res. Public Health. 2021; 18(19). PubMed Abstract | Publisher Full Text\n\nGoldstein JR, Lee RD: Demographic perspectives on the mortality of COVID-19 and other epidemics. Proc. Natl. Acad. Sci. U. S. A. 2020; 117(36): 22035–22041. PubMed Abstract | Publisher Full Text\n\nTrecarichi EM, Mazzitelli M, Serapide F, et al.: Clinical characteristics and predictors of mortality associated with COVID-19 in elderly patients from a long-term care facility. Sci. Rep. 2020; 10(1): 20834–20837. PubMed Abstract | Publisher Full Text\n\nAhmed H, Patel K, Greenwood DC, et al.: Long-term clinical outcomes in survivors of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronavirus outbreaks after hospitalisation or ICU admission: A systematic review and meta-analysis. J. Rehabil. Med. 2020; 52(5): 0. Publisher Full Text\n\nFerreira W, Olegário L, Chaves RM, et al.: Mental Health and COVID-19 Infection: Moara Rodrigues Costa1, Systematic Review in Human Cross-Michelly Farias Rocha3, Sectional Studies Gabriela Carvalho Jurema Abstract. iMedPub Journals. Published online 2020; 1–7. Publisher Full Text\n\nStein AMB: Coronavirus disease 2019 (COVID-19): Psychiatric illness. Wolters Kluwer. 2020; 2019: 1–31.Reference Source\n\nTaquet M, Luciano S, Geddes JR, et al.: Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA. Lancet Psychiatry. 2021; 8(2): 130–140. PubMed Abstract | Publisher Full Text\n\nMo GH, Wang ZX, Chen XS, et al.: The prognosis and prevention measures for mental health in COVID-19 patients: Through the experience of SARS. Biopsychosoc. Med. 2020; 14(1): 1–6. 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Nutr. 2020; 74(6): 871–875. PubMed Abstract | Publisher Full Text\n\nSagarra-Romero L, Viñas-Barros A: COVID-19: Short and long-term effects of hospitalization on muscular weakness in the elderly. Int. J. Environ. Res. Public Health. 2020; 17(23): 1–12. PubMed Abstract | Publisher Full Text\n\nSavage M, Dooley L, Waldron T, et al.: Malnutrition risk post COVID-19 infection on a care of the elderly rehab ward. Clin Nutr ESPEN. 2020; 40(July 2016): 610–611. Publisher Full Text\n\nRothenberg E: Coronavirus disease 19 from the perspective of ageing with focus on nutritional status and nutrition management—a narrative review. Nutrients. 2021; 13(4). PubMed Abstract | Publisher Full Text\n\nCuerda C, Sánchez López I, Gil Martínez C, et al.: Impact of COVID-19 in nutritional and functional status of survivors admitted in intensive care units during the first outbreak. Preliminary results of the NUTRICOVID study. Clin. Nutr. 2021; (xxxx). PubMed Abstract | Publisher Full Text\n\nChang SF, Lin HC, Cheng CL: The Relationship of Frailty and Hospitalization Among Older People: Evidence From a Meta-Analysis. J. Nurs. Scholarsh. 2018; 50(4): 383–391. PubMed Abstract | Publisher Full Text\n\nBergeron CD, Boolani A, Jansen EC, et al.: Practical Solutions to Address COVID-19-Related Mental and Physical Health Challenges Among Low-Income Older Adults. Front Public Heal. 2021; 9(July): 1–8. PubMed Abstract | Publisher Full Text\n\nWahyuhadi J, Efendi F, Al Farabi MJ, et al.: Association of stigma with mental health and quality of life among Indonesian COVID-19 survivors. PLoS One. 2022; 17(2 February): e0264218–e0264213. PubMed Abstract | Publisher Full Text\n\nAli AM, Kunugi H: Approaches to nutritional screening in patients with coronavirus disease 2019 (Covid-19). Int. J. Environ. Res. Public Health. 2021; 18(5): 1–15. PubMed Abstract | Publisher Full Text\n\nHoldoway A: Nutritional management of patients during and after COVID-19 illness. Br. J. Community Nurs. 2020; 25: S6–S10. PubMed Abstract | Publisher Full Text\n\nScholte P: Chapter 6 Psychometric properties and longitudinal validation of the Self-Reporting Questionnaire (SRQ-20) in a Rwandan community setting: a validation study. Ment. Heal. War-Affected Popul. 2013; 91–111.\n\nChipimo PJ, Fylkesnes K: Comparative Validity of Screening Instruments for Mental Distress in Zambia. Clin. Pract. Epidemiol. Ment. Health. 2010; 6(1): 4–15. PubMed Abstract | Publisher Full Text\n\nde Graaff AM , Cuijpers P, Leeflang M, et al.: A systematic review and meta-analysis of diagnostic test accuracy studies of self-report screening instruments for common mental disorders in Arabic-speaking adults. Glob. Ment. Heal. 2021; 8: e43. PubMed Abstract | Publisher Full Text\n\nArulmohi M, Vinayagamoorthy V, Dongre AR: Physical Violence Against Doctors: A Content Analysis from Online Indian Newspapers. Indian J. Community Med. 2017; 42(1): 147–150. Publisher Full Text\n\nGuigoz Y, Vellas B: Nutritional Assessment in Older Adults: MNA® 25 years of a Screening Tool & a Reference Standard for Care and Research; What Next?. J. Nutr. Heal. Aging. 2021; 25(4): 528–583. PubMed Abstract | Publisher Full Text\n\nMenges D, Ballouz T, Anagnostopoulos A, et al.: Burden of post-COVID-19 syndrome and implications for healthcare service planning: A population-based cohort study. PLoS One. 2021; 16(7 July): e0254523. PubMed Abstract | Publisher Full Text\n\nTaquet M, Geddes JR, Husain M, et al.: 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry. 2021; 8(5): 416–427. PubMed Abstract | Publisher Full Text\n\nDamayanthi HDWT, Prabani KIP: Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID- 19. The COVID-19 resource centre is hosted on Elsevier Connect, the company’ s public news and information.2020; (January).\n\nGrolli RE, Eduarda M, Mingoti D, et al.: Impact of COVID-19 in the Mental Health in Elderly: Psychological and Biological Updates.Published online 2021.\n\nLiu K, Chen Y, Lin R, et al.: Clinical features of COVID-19 in elderly patients: A comparison with young and middle-aged patients. J. Infect. 2020; 80(6): e14–e18. PubMed Abstract | Publisher Full Text\n\nQuilliot D, Gérard M, Bonsack O, et al.: Impact of severe SARS-CoV-2 infection on nutritional status and subjective functional loss in a prospective cohort of COVID-19.\n\nTheresa RM, Dewiastuti M, Ningsih SR, et al.: RISK OF MENTAL DISORDERS AND MALNUTRITION IN ELDERLY COVID-19 SURVIVOR. figshare. Dataset.2022. Publisher Full Text"
}
|
[
{
"id": "164467",
"date": "02 May 2023",
"name": "Mirasari Putri",
"expertise": [
"Reviewer Expertise Nutrition-Immunology-Biomolecular"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbstract\nMethod: Write the time of this research conducted\n\nWrite down the significant comorbidities that play a role in mental disorders and malnutrition based on the findings in this study.\nIntroduction:\nIt should provide evidence gaps to highlight unanswered questions in this study and how this study will contribute to filling the gap.\n\nHighlight the originality and novelty of this study.\nMethod:\nWas it true that there were 100 elderly people affected by Covid in May-July 2021 throughout Depok? Explain further what is meant by the total sample in this study.\n\nWhy was malnutrition in the elderly before being diagnosed with Covid not excluded in this study? Malnutrition is one risk factor in the elderly with or without Covid. How can authors ensure that the patients' malnutrition is because of Covid, not because they have had it before?\n\nParagraph 2, line 2 adds a reference for mental disorder categorization.\n\nParagraph 2, line 4 adds the reference for Covid severity.\n\nWrite the number of ethical approval.\n\nParagraph 1, line 2 add the reference for mental disorder categorized and explain the method briefly\n\nExplain whether the patients who are used as subjects were patients who experienced Covid for the first time, have been exposed to it more than once, or were all taken as subjects.\nResult:\nExplain further about the comorbidities presented in tables 3 and 4. In more than 1 comorbidity, which comorbidities are the high risk factors for mental disorder and malnutrition in your research?\n\nParagraph 10: which table represents multivariate analysis? Please write it.\n\nIn the table note, write the statistical method used and the total number of respondents.\n\nDiscussion:\n\nParagraph 3: Explain in more detail the mechanism of hyperinflammation and cytokines in infections associated with the nervous system, which are at risk of causing mental disorders\n\nParagraph 3: Explain in more detail about the multiple comorbidities that can increase the risk of mental disorders concerning the comorbidities found in your research and also the mechanism\n\nParagraph 4: the authors explained that gastrointestinal factors are one of the causes of malnutrition in the elderly with Covid. Did the authors investigate these gastrointestinal factors? If yes, the results can be written in the results section. Because this is something that can confirm the mechanism of malnutrition in the elderly with Covid\n\nParagraph 5: Discuss why the risk of malnutrition in Covid patients with moderate symptoms was higher than those with severe ones.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "9786",
"date": "02 Oct 2023",
"name": "Ria Maria Theresa",
"role": "Author Response",
"response": "Abstract : There is no cachexia and no cancer Introduction: 1. Malnutrition in elderly will worsen health status in any situation. 2. No studies have assesed malnutrition in elderly covid patients. Method: 1. Pasien was diagnosed covid-19 by hospital data from Depok hospital, using total sampling of hospital data. 2. The malnourished patient was excluded in this study. We are sure that from this study, the sample was not diagnosed malnourished based on hospital data (BMI and by mini nutritional assessment from hospital data when patients were hospitalized). 3.Paragraph 2, line 2 adds a reference for mental disorder categorization: Stein AMB: Coronavirus disease 2019 (COVID-19): Psychiatric illness. Wolters Kluwer. 2020; 2019: 1–31. 4.Paragraph 2, line 4 adds the reference for Covid severity: Azwar MK, Setiati S, Rizka A, et al.: Clinical Profile of Elderly Patients with COVID-19 hospitalised in Indonesia’s National General Hospital. Acta Med. Indones. 2020; 52(3): 199–205 5.Write the number of ethical approval: 455/X/2021/KEPK 6. The sudden changes situation during the covid 19 had an impact on difficulty adapting and this situation had impact on mental health of elderly. Reference for mental health disorder categorized are DSM V and ICD XI 7. in this study, inclusion criteria were the population og people over 60 years old and diagnosed for the first time exposure by covid 19. Result: 1. Comorbidity in this study was hypertension, diabetes mellitus, and cardiovascular disease (coronary arterial disease or cerebrovascular disease). We dont study comordities that lead to mental disorders. 2. Table 5 and 6 Discussion: 1. COVID-19 infection predisposes to mental disorders induced by cytokine bodies and hyperinflammatory states. Therefore, it can cause disruption of the blood-brain barrier and ultimately inflammation of the nervous system. In the elderly, there is a susceptibility to inflammation. Hyper-inflammatory conditions affect the severity of COVID-19; the severity of COVID-19 will increase the risk of post-infection mental disorders. In addition, comorbidity in the elderly is often multi-comorbid. The number of comorbidities increases the risk of mental disorders. Table 3 shows that there is a relationship between age, the degree of disease severity, and comorbidities that increase the risk of mental disorders in the elderly after COVID-19 infection. The degree of severe illness leads to a 4.5 times higher risk of mental disorders and multi-comorbidities lead to a 2.3 times higher risk of experiencing mental disorders. Interferon-gamma related to hyperinflammatory condition increase during covid-19 infection can affect brain function. it is well-known that chronic accumulation of cytokines causes neuronal damage 2. Other factors like glucose level, hypertension, and other comorbidities increase the severity of the disease. Immune signatures correlated with diseases trajectory to sequalae 3. In this study, there is no evaluation on gastrointestinal symptoms during hospitalization 4. Decrease appetite, digestive disturbances, increased metabolism, longer duration of illness in moderate patients."
}
]
},
{
"id": "186579",
"date": "31 Jul 2023",
"name": "Tusawar Iftikhar Ahmad",
"expertise": [
"Reviewer Expertise Health Economics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nFeedback for improving the quality of the manuscript:\nIn the abstract, include statistics on the incidence and case fatality rate (CFR) of COVID-19 in the elderly within the context of Indonesia.\n\nIn the abstract, present the findings related to Odds Ratios in the following format: for example, provide the numeric value of the OR (p-value = 0.00; CI = 1.0-8.8).\n\nIn Figure 1, the visualization of the sequence depicting the risk of mental disorders and malnutrition in elderly COVID-19 survivors is unclear. Please clarify the directions of the arrows and sequence of the text boxes to provide a more coherent understanding.\n\nPlease provide a statistical justification for the adequacy of the sample size (n = 100) and its implications for the generalizability of the findings.\n\nThe current study lacks a clear presentation of its theoretical underpinnings. Please include a section to address this aspect.\n\nThe research gap is not specifically identified. Consider highlighting the specific gap that this study aims to address.\n\nProvide a brief description of the study area (Depok, Indonesia), including cartographic presentation, demography, socioeconomic dynamics, etc.\n\nThe paper mentions the use of the SRQ-20 and the MNA questionnaires to assess mental disorder and malnutrition, respectively. Please add a brief description of the structures of both questionnaires in the paper.\n\nPlease specify the sampling technique employed to collect the data.\n\nInclude a description, along with a mathematical expression, explaining the relevance of using multiple logistic regression as the estimation technique for this research.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-42
|
https://f1000research.com/articles/12-836/v1
|
17 Jul 23
|
{
"type": "Research Article",
"title": "Active adults have thicker peripheral muscles and diaphragm: A cross-sectional study",
"authors": [
"Aishwarya Shetty",
"Baskaran Chandrasekaran",
"Koustubh Kamath",
"Sneha Ravichandran",
"Rajagopal Kadavigere",
"Leena R David",
"Banumathe Karuppaya",
"Guruprasad Vijayasarathi",
"Suresh Sugumar",
"Aishwarya Shetty",
"Baskaran Chandrasekaran",
"Koustubh Kamath",
"Sneha Ravichandran",
"Rajagopal Kadavigere",
"Leena R David",
"Banumathe Karuppaya"
],
"abstract": "Background: The association between exercise and muscle build-up is a long-run connection. Whereas limited physical activity doesn't do well with muscle build-up. But how much is that difference in muscle thickness between different levels of physical activity? Aim: To understand this we conducted a cross-sectional study to associate physical activity and sitting time with the muscle thickness of the lower limb and diaphragm. Methods: The research's participants ranged in age from 18 to 35. Out of 91 patients, 30 were found to smoke routinely and 6 had a drinking history after questions concerning lifestyle factors including smoking and drinking were questioned. In terms of occupation, 74.7% of people had an occupation and 25% were unemployed. We acquired ultrasonography for the quadriceps (rectus femoris and vastus intermedialis), soleus muscle, and diaphragm. Participants were divided into groups according to their self-reported levels of physical activity and sitting time based on IPAQ scores. Results: We found that the lower limb muscles have shown statistically significant differences between vigorous physical activity (VPA) and lower physical activity (LPA). We found that the quadriceps muscle(rectus femoris and vastus intermedialis) thickness was 1.3 cm in LPA whereas 2.8 cm in VPA with (p=<0.001) soleus muscle thickness being 1 cm in LPA and 2.2 cm. Conclusions: Physical activity levels are found to be positively related to the peripheral muscle thickness VPA (p=<0.001). Physical activity levels are found to be positively related to peripheral muscle thickness.",
"keywords": [
"Sedentary behavior",
"Muscle thickness",
"Diaphragm",
"Physical activity",
"Ultrasonography"
],
"content": "Introduction\n\nPhysical activity (PA) (any bodily movement produced by skeletal muscles that require energy expenditure) is crucial for potential health benefits and protection against chronic diseases.1 Insufficient physical activity and sedentary behavior (SB) (any waking behavior characterized by an energy expenditure of 1.5 metabolic equivalents (METS) or less while sitting or reclining) are now associated with an increased risk of cardiometabolic disease and cancer.2 Experimental studies have administered several interventions to address the increasing burden of physical inactivity and SB. However, observational studies have established a relationship between PA and SB, with the health risks remaining still unclear, as there could be health risks associated with SB.3\n\nMuscle mass and strength are predictors of performance enhancement and ability to work in adults and mobility functions in the elderly population. Furthermore, peripheral muscle mass and strength are associated with chronic diseases like sarcopenia which is a major risk and early mortality. Though anecdotal evidence claims a bidirectional relationship between physical inactivity and peripheral muscle strength or thickness, observational studies establishing the relationship are lacking. In young, healthy people, there is a substantial correlation between overall muscular strength and higher-intensity PA, and age-related reductions in muscle size and strength have been seen to coincide with lower activity levels.4–6 According to our knowledge,3 a person’s level of moderate to vigorous physical activity (MVPA) is associated with broader benefits including improved cardiorespiratory fitness and total work capacity, but not directly to muscle growth and strength.4,7 The evidence regarding the relationship between levels of PA and the peripheral muscle (soleus, gastrocnemius, and diaphragm) is still debatable using an ultrasonogram.\n\nWe hypothesized that: 1) there is a possible change in the muscle thickness and strength of individuals engaged in some PA compared to a sedentary lifestyle, and 2) a change in the thickness of muscles changes as age progresses.8 Hence we aimed to relate various dimensions of PA and sitting time with the diaphragm & lower limb muscle thickness.\n\n\nMethods\n\nThis study was a prospective single-centered randomized crossover trial conducted between January 2022 to November 2022 in the Department of Radio-diagnosis and Imaging, Kasturba medical hospital, Manipal, India. Institutional Ethics Committee, KH (IEC2: 125/2022) and Clinical Trial Registry of India (CTRI/2022/10/046187) https://ctri.nic.in/Clinicaltrials/rmaindet.php?trialid=72850&EncHid=34225.86311&modid=1&compid=19 approved the study. Figure 1 depicts this methodology.\n\nWe recruited the potential participants from the patients who were waiting for the radiological screening from the radiological department of the multidisciplinary teaching hospital. The written consent was obtained from the participants. The participants were first screened for the exclusion factors like recent trauma, orthopedic interventions, bed-ridden, paralyzed, osteoarthritis, and other chronic diseases of the heart and lungs which can hamper the diaphragm thickness. Hence, we included both male and female patients aged 18 – 35 years old for the following study.\n\nSelf-reported PA was assessed using Short International Physical Activity Questionnaire (S-IPAQ) for young and middle-aged adults. The questionnaire evaluates the amount of time (frequency and duration) spent engaging in activities of vigorous, moderate intensity, walking, and sitting over the course of the previous seven days. The vigorous, moderate, and walking intensities were quantified as 8, 4, and 3.3 metabolic equivalents (METS).\n\nSample size calculation\n\nWe required 91 samples to achieve a moderate correlation (r1 > 0.4) at an alpha level of 95% and an 80% strength. The algorithm for determining the cumulative correlation coefficient distribution is used in all analyses.9\n\nThe lower limb muscles measured in this study were the soleus and quadricep muscle (rectus femoris and vastus intermedialis) in both limbs. For measuring the diaphragm, the patient was laid supine and measured at both inhalation and exhalation using the M Mode ultrasonography. The measurement pattern is depicted in Figure 2\n\nA – Soleus, B – Quadriceps (rectus femoris and vastus intermedialis), C – Diaphragm inhalation, D – Diaphragm exhalation.\n\nWe used the ultrasound machine with linear and curvilinear transducers for the following study. All patients had to be screened for their anterior quadriceps, soleus, and diaphragm measurements.\n\nThe anterior thigh muscle of all subjects will be measured using a 13MHz linear array probe. The B-model ultrasound was used to identify the anterior quadriceps muscle. The patient will be placed in a supine posture with their knees extended and their feet in a neutral position. The distance that lies between the anterior fascia of the rectus femoris muscle (RF) and the posterior fascia of the vastus intermedius muscle will be evaluated to calculate the anterior thigh muscle thickness (TMT). An axial cross-sectional image of the anterior quadricep muscle is obtained of both limbs and recorded.10\n\n• To measure the soleus:\n\nAn ultrasound with a 13MHz linear probe was used on distal 1/3 of the calf length which was used to obtain soleus muscle imaging. The B-model ultrasound was used to identify the soleus muscle. Participants were oriented in a prone position, knees outstretched and 0° dorsiflexion of the ankle or knees bent at 30°, and ankle dorsiflexion at 0° in the prone position with a pillow underneath. To keep track of muscle movement, the ultrasound device was switched to M-mode to trace motion.11\n\n• To measure the diaphragm:\n\nThe chest wall was aligned perpendicularly with a 13-MHz linear array transducer. Using M-mode, the diaphragmatic thickness was determined. Tdi, ee (Diaphragmatic thickness at end-expiration) and Tdi, pi (peak inspiration) measurements were already taken on consecutive breaths, which were seen in a single M-mode image. The diaphragmatic thickness was measured before normal inhalation and after complete exhalation.\n\nThe thickness of the diaphragm for each experiment has been recorded.12,13\n\n\nResults\n\nThe study included 91 patients aged 18 to 35 years with N = 78 male subjects with mean age and standard deviation of 27.954 years ± 4.67 and N = 13 females with mean age and standard deviation of 27.978 years ± 4.67\n\nThe research’s participants ranged in age from 18 to 35. Out of 91 patients, 30 were found to regularly smoke, and six had drinking habits after questions regarding lifestyle characteristics including smoking and drinking were asked. In terms of occupation, 74.7% of people had an occupation and 25% were unemployed. The following data is shown in Table 1.\n\nThe participants were divided into three distinct categories: low (n = 6), intermediate (n = 46), and high METS score (n = 39, 42.85%). The results showed that the low METS score was 500.66 minutes per week, the moderate METS score was 1969.69 minutes per week, and the high METS score was 4408.17 minutes per week.\n\nBased on the PA and IPAQ scores, we divided patients into low, moderate, and high PA. When we compared the muscle thickness with the PA, we found the following results. The left and right quadriceps values (rectus femoris and vastus intermedialis) were significantly increased as PA increased. The mean values were 1.3 cm for LPA, 1.7 cm for moderate PA, and 2.8 cm for VPA. Similarly, in the right and left soleus muscle thicknesses, the values increased from 1 cm for LPA to 1.56 cm for moderate PA and 2.2 cm for VPA. The diaphragm thickness showed an increase with PA ranging from 0.19 mm for LPA, 0.25 mm in moderate PA to 0.29 mm for VPA in full inhalation, compared to 0.18 mm, 0.23 mm, and 0.27 mm respectively for exhalation.\n\nWe found that the association between PA and muscle thickness was significant in the lower limb muscles, with a p-value lower than 0.01. The diaphragm thickness showed a positive association with PA but was not statistically significant, as the p-value were 0.35 for inhalation and 0.17 for exhalation. The data are presented in Table 2. The Pearson correlation results for lower limb muscle thickness with the PA levels are depicted in Figure 3. All the graphs depict a positive correlation between muscle thickness and PA (Figure 3).\n\nEven if physical activity was based on patients’ self-report, the occupation made a difference. Desk-based workers mostly lead a sedentary lifestyle hence their PA level was comparatively lower than those who had an active lifestyle.14 In the majority of the studies, unemployment is detrimental to health behavior.14 Furthermore, it is believed that both the physical and social environments play an important role. In addition, Owen et al. reported that adult participation in PA was influenced by a range of personal, social, and environmental factors and those individual-level variables such as socioeconomic status and perceived self-efficacy demonstrated the strongest association with PA behavior (sitting time, workout time).14,15\n\n\nDiscussion\n\nOur study aimed to look for the possible relationship between muscle thickness and various levels of PA. According to our research concept, the research was focused on a few factors, including age, appropriate muscles for this investigation, and potential repercussions.16\n\nA total of 91 patients were included in our study, of which six were sorted into the LPA, N = 46 for moderate PA, and N = 39 for VPA; these make about 7% of the participants perform LPA, 50% with moderate PA, and 43% with VPA. Previous studies that have considered a larger population in India have found that around 54% of the total sample they had were physically inactive, and 14% had high PA.17 Internationally, around 15.8% of the people in East and Southeast Asia are physically inactive.18\n\nIn our study, we observed that the soleus muscle thickness was 1 cm in LPA and 2.2 cm in VPA (p = 0.001), while the quadriceps muscle thickness (rectus femoris and vastus intermedialis) was 1.3 cm in LPA and 2.8 cm in VPA. The diaphragm thickness was 0.19 cm in LPA and 0.29 (p = 0.358) in PA. A study by Schoenfeld observed the difference in the muscle thickness for low versus high resistance exercises and found that the high resistance exercises were improving the quadriceps muscle thickness by 9.5%.19 This supports our results that show that increased PA improves muscle thickness.\n\nThe study conducted by Silva et al. in 2010 observed that Asians have lower skeletal muscle mass as compared to African Americans, Whites, and Hispanics.20 The muscle thickness that we measured in our study without considering the PA level was 1.78 cm and 1.79 cm for the right and left quadriceps (rectus femoris and vastus intermedialis) respectively, and 1.55 cm and 1.56 cm for the right and left soleus muscles respectively.\n\nThe reason for selecting the quadriceps, soleus in the lower limb, and the diaphragm for the study were that many researchers have found that there is a change in muscle thickness as age progresses, and it differs with sex as well. In 2010 Katsuo Fujiwara et al. reported that compared to their contemporaries in their 20s, men and women who were at least 60 years old had significantly thinner gastrocnemius muscles. With regards to the soleus, neither sex’s age group showed any appreciable changes in soleus thickness. For the gastrocnemius but not the soleus, muscle thickness decreased more from age 40 to 79. These findings support the idea that the gastrocnemius deteriorates and atrophies more rapidly than the soleus. One of the variables that contribute to a decline in muscle strength is aging. Age generally results in a loss of muscle mass and strength.8 According to previoys studies, men’s skeletal muscle degradation is correlated with age at about 27 years of age.12 With this clause, we have restricted our study age group to between 18-35 years. The diaphragm muscle thickness showed much less changes during inhalation and exhalation, which showed a negative association between inhalation and exhalation values. Enright et al. discovered that In healthy people, the dimensions of the diaphragm can be increased by weight training. The effect of inspiratory muscle training (IMT) on diaphragm thickness has not been previously reported in healthy people.21 In Enright et al.’s study the group demonstrated an increase in diaphragm thickness. This increase in diaphragm thickness may result in increased inspiratory muscle efficiency or improved pulmonary mechanics, or both.\n\nIn this study, we focused on the lower limb muscles and diaphragm to get a prospective idea of the relationship of these muscles with PA. When humans are physically active, the lower body is most engaged in these activities. PA could be as simple as walking or running. Most likely, the lower body muscles are active while the breathing pattern changes simultaneously, therefore the diaphragm is engaged too. Recent studies have shown and proved that diaphragm muscle thickness changes with increased PA, e.g. weight training.21 In addition, quadriceps, soleus, and gastrocnemius muscles show the greatest activation during the quiet standing posture, These muscles are also vigorously activated in the stance phase of walking to maintain the standing posture and generate forces for propulsion.\n\nWith all these factors as constants and variables, our study shows that with an increase in PA, there is a significant increase in the quadriceps (rectus femoris and vastus intermedialis), soleus muscle and diaphragm thicknesses, with mean values of 1.3 cm, 1.78 cm and 2.8 cm in LPA, moderate PA and VPA respectively for the quadriceps muscle (rectus femoris and vastus intermedialis); 1 cm, 1.56 cm and 2.2 cm for soleus, and 0.19 mm, 0.25 mm and 0.29 mm for the diaphragm, with increasing PA levels from LPA to moderate PA to VPA respectively. The changes in the lower limbs showed statistically significant results.\n\n\nConclusions\n\nPeripheral muscle thickness has been found to positively correlate with physical activity levels. However future trials should further expand the association with the objectively measured PA levels.\n\nDue to the fact that the PA measures utilized in the study were self-reported, there is a risk of recalling bias and response bias. Instead of employing a self-reported questionnaire, future studies could use objectively assessed PA.\n\nUsing IPAQ, which provides subjective measurement, we were able to determine the patients’ PA parameters in the current study. Due to observational studies’ use of self-perceived PA, which is frequently unjustified, our comprehension of the association between PA and muscle thickness currently is still unclear. This calls for additional studies employing objectively measured PA.\n\nThe nature of the cross-sectional approach used in the research made it difficult to determine the actual link between PA and changes in muscle thickness. If one adopts this approach, one might have a better grasp of how lifestyle factors affect individual muscle strength. Future research should look into these lifestyle choices and take them into account since they can have an impact on these results. Understanding how PA and lifestyle choices affect muscular strength requires studies that demonstrate associations between changes in muscle thickness and PA.",
"appendix": "Data availability\n\nHarvard Dataverse: Active adults have thicker peripheral muscles and diaphragm: a cross-sectional study, https://doi.org/10.7910/DVN/MVFLMY.\n\nThis project contains the following underlying data:\n\n- Aishwarya data sheet.xlsx\n\n\nReferences\n\nWarburton DER: Health benefits of physical activity: the evidence. Can. Med. Assoc. J. 2006 Mar 14; 174(6): 801–809. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMansoubi M, Pearson N, Clemes SA, et al.: Energy expenditure during common sitting and standing tasks: examining the 1.5 MET definition of sedentary behaviour. BMC Public Health. 2015 Dec 29; 15(1): 516. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSpirduso W, Etnier J: Day Theme: Weil-Being, Quality of Life, and Cognitive Function Plenary Keynotes PHYSICAL ACTIVITY, WELLBEING, AND QUALITY OF LIFE THROUGH THE LIFESPAN PHYSICAL ACTIVITY IN THE PREVENTION OE DEMENTIA. J. Aging Phys. Act. 2012; 20: S7–S101. Publisher Full Text\n\nRostron ZP, Green RA, Kingsley M, et al.: Associations Between Measures of Physical Activity and Muscle Size and Strength: A Systematic Review. Arch. Rehabil. Res. Clin. Transl. 2021 Jun; 3(2): 100124. PubMed Abstract | Publisher Full Text\n\nLeblanc A, Taylor BA, Thompson PD, et al.: Relationships between physical activity and muscular strength among healthy adults across the lifespan. Springerplus. 2015 Dec 28; 4(1): 557. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKalyani RR, Corriere M, Ferrucci L: Age-related and disease-related muscle loss: the effect of diabetes, obesity, and other diseases. Lancet Diabetes Endocrinol. 2014 Oct; 2(10): 819–829. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRostron ZP, Green RA, Kingsley M, et al.: Associations Between Measures of Physical Activity and Muscle Size and Strength: A Systematic Review. Arch. Rehabil. Res. Clin. Transl. 2021 Jun; 3(2): 100124. Publisher Full Text\n\nFujiwara K, Asai H, Toyama H, et al.: Changes in muscle thickness of gastrocnemius and soleus associated with age and sex. Aging Clin. Exp. Res. 2010 Feb; 22(1): 24–30. Publisher Full Text\n\nBujang MA, Baharum N: Sample Size Guideline for Correlation Analysis. World J. Soc. Sci. Res. 2016 Mar 10; 3(1): 37. Publisher Full Text\n\nTakahashi Y, Fujino Y, Miura K, et al.: Intra- and inter-rater reliability of rectus femoris muscle thickness measured using ultrasonography in healthy individuals. Ultrasound J. 2021 Dec 15; 13(1): 21. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFujiwara K, Asai H, Toyama H, et al.: Changes in muscle thickness of gastrocnemius and soleus associated with age and sex. Aging Clin. Exp. Res. 2010 Feb 25; 22(1): 24–30. Publisher Full Text\n\nBoussuges A, Rives S, Finance J, et al.: Ultrasound Assessment of Diaphragm Thickness and Thickening: Reference Values and Limits of Normality When in a Seated Position. Front. Med. (Lausanne). 2021 Oct 27; 8. Publisher Full Text\n\nGoligher EC, Laghi F, Detsky ME, et al.: Measuring diaphragm thickness with ultrasound in mechanically ventilated patients: feasibility, reproducibility and validity. Intensive Care Med. 2015 Apr 19; 41(4): 642–649. PubMed Abstract | Publisher Full Text\n\nMacassa G, Ahmadi N, Alfredsson J, et al.: Employment status and differences in physical activity behavior during times of economic hardship: results of a population-based study. Int. J. Med. Sci. Public Health. 2016; 5(1): 102. Publisher Full Text\n\nVan Domelen DR, Koster A, Caserotti P, et al.: Employment and Physical Activity in the U.S. Am. J. Prev. Med. 2011 Aug; 41(2): 136–145. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIkezoe T, Mori N, Nakamura M, et al.: Age-related muscle atrophy in the lower extremities and daily physical activity in elderly women. Arch. Gerontol. Geriatr. 2011 Sep; 53(2): e153–e157. Publisher Full Text\n\nAnjana RM, Pradeepa R, Das AK, et al.: Physical activity and inactivity patterns in India – results from the ICMR-INDIAB study (Phase-1) [ICMR-INDIAB-5]. Int. J. Behav. Nutr. Phys. Act. 2014 Dec 26; 11(1): 26. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGuthold R, Stevens GA, Riley LM, et al.: Worldwide trends in insufficient physical activity from 2001 to 2016: a pooled analysis of 358 population-based surveys with 1·9 million participants. Lancet Glob. Health. 2018 Oct; 6(10): e1077–e1086. PubMed Abstract | Publisher Full Text\n\nSchoenfeld BJ, Peterson MD, Ogborn D, et al.: Effects of Low- vs. High-Load Resistance Training on Muscle Strength and Hypertrophy in Well-Trained Men. J. Strength Cond. Res. 2015 Oct; 29(10): 2954–2963. Publisher Full Text\n\nSilva AM, Shen W, Heo M, et al.: Ethnicity-related skeletal muscle differences across the lifespan. Am. J. Hum. Biol. 2010 Jan; 22(1): 76–82. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEnright SJ, Unnitham VB, Heward C, et al.: Effect of high-intensity inspiratory muscle training on lung volumes, diaphragm thickness, and exercise capacity in subjects who are healthy. Phys. Ther. 2006; 86(3): 345–354. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "188229",
"date": "25 Aug 2023",
"name": "Ranganath Gangavelli",
"expertise": [
"Reviewer Expertise Musculoskeletal Health",
"Mobilization",
"Pain."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI appreciate the author's efforts in conducting this study. It is interesting to study the impact of physical activity and its impact on muscle thickness. The Introduction is well structured. However, there are a few aspects that need serious consideration.\nThe study is reported as a cross-sectional design in the Abstract. However, in the Methods section of the Manuscript, it is mentioned as a randomized crossover design approved by the Institutional Ethics Committee. Further, the trial was registered as an interventional study in CTRI. Please justify the discrepancy. However, no medical/ therapeutic intervention was reported in the manuscript except for diagnostic investigation.\n\nThe hypothesis statement is not clear. The muscle Strength measures are never reported in the manuscript. Are the thickness measures equated to strength? The word \"change\" is confusing. Are the authors measuring the change in this study? Which of the three designs mentioned earlier is adopted in the study and is used to test the hypothesis? Or is it a cohort study to determine the \"change\" in the thickness of muscles as age progresses in an individual, as stated in the 2nd hypothesis? However, only a single timepoint for thickness measure was reported in the manuscript.\n\nRegarding participants: Please justify the reason for recruiting the Patients while the data could be collected from asymptomatic volunteers with self-reported physical activity levels. Could the underlying health condition (not stated in the manuscript) influence the data? Details/reports of provisional or final diagnoses will help interpret the data.\n\nThe procedure is expressed in the future tense.\n\nThe ankle's position while measuring the soleus's thickness is repetitive.\n\nPlease justify obtaining the data on smoking and alcohol use. It is not discussed.\n\nThe expression of the result is inconsistent.\n\nThe reported diaphragm thickness is quite less than earlier reports 1. Please discuss the reasons for the difference in recording. The population seems to be the same.\n\nGrammar and spelling checks are required in the Results and Discussion sections.\n\nBody Mass Index, along with Physical activity level, may have an impact on the thickness measures. Please report if the data is available.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "10197",
"date": "06 Oct 2023",
"name": "suresh sukumar",
"role": "Author Response",
"response": "We are grateful for the comments and suggestions.We have tried to incorporate the changes and have justified for the same. The study is reported as a cross-sectional design in the Abstract. However, in the Methods section of the Manuscript, it is mentioned as a randomized crossover design approved by the Institutional Ethics Committee. Further, the trial was registered as an interventional study in CTRI. Please justify the discrepancy. However, no medical/ therapeutic intervention was reported in the manuscript except for diagnostic investigation. The study is an observational study to see the changes within the muscles with respect to physical activity. Since the study includes various procedures and activity we have mentioned it as interventional study. Furthermore the RCT design changes shall be made. The hypothesis statement is not clear. The muscle Strength measures are never reported in the manuscript. Are the thickness measures equated to strength? The word \"change\" is confusing. Are the authors measuring the change in this study? Which of the three designs mentioned earlier is adopted in the study and is used to test the hypothesis? Or is it a cohort study to determine the \"change\" in the thickness of muscles as age progresses in an individual, as stated in the 2nd hypothesis? However, only a single timepoint for thickness measure was reported in the manuscript. The muscle strength measurements are not mentioned here but instead we have measured the thickness. Also Muscle strength depends on muscle quality as well as muscle quantity (e.g. muscle volume including muscle thickness). To simplify the word change here we have measured the muscle thickness of a physically active individual and sedentary lifestyle individual to see the changes in the muscle thickness with respect to physical activity. It’s a combination of cross sectional and interventional study since we have taken a period of 7 days for the measurement of muscle which would be considered a short span of time to be determined as cohort study. Regarding participants: Please justify the reason for recruiting the Patients while the data could be collected from asymptomatic volunteers with self-reported physical activity levels. Could the underlying health condition (not stated in the manuscript) influence the data? Details/reports of provisional or final diagnoses will help interpret the data. We have chosen the patients from the KMC hospital as it was more feasible to collect data from them. Also after screening the patient we have excluded patients with recent trauma, orthopedic interventions, bedridden, paralyzed, osteoarthritis, and other chronic diseases of the heart and lungs which can hamper the muscle thickness. The procedure is expressed in the future tense. Apologies for the inconvenience. Corrections shall be done. The ankle's position while measuring the soleus's thickness is repetitive Corrections shall be done. Please justify obtaining the data on smoking and alcohol use. It is not discussed. The motive of obtaining the smoking and alcohol consumption details was basically to see if it hampers the change in the muscle thickness of an individual. The expression of the result is inconsistent. We shall work on that and improvise it. The reported diaphragm thickness is quite less than earlier reports 1. Please discuss the reasons for the difference in recording. The population seems to be the same The measurement may vary with patients, the inspiration and expiration rate may change too since it’s a self- reported study minor differences can occur. Grammar and spelling checks are required in the Results and Discussion sections. Definitely changes will be made. Body Mass Index, along with Physical activity level, may have an impact on the thickness measures. Please report if the data is available. Unfortunately we haven’t taken the body mass index data with PA."
}
]
},
{
"id": "194233",
"date": "30 Aug 2023",
"name": "Małgorzata Pałac",
"expertise": [
"Reviewer Expertise Respiratory muscle ultrasonography",
"Physiotherapy",
"Shear wave elastography"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI appreciate the work on this interesting and inspiring study. The article analyzes the muscles thickness of the lower limb and diaphragm with the level of physical activity. The study included a considerable number of participants. However, the article needs improvement.\n1. Inaccurate information in methodology.\nNot clear breathing maneuver during the diaphragm measurement:\n“Using M-mode, the diaphragmatic thickness was determined. Tdi, ee (Diaphragmatic thickness at end-expiration) and Tdi, pi (peak inspiration) measurements were already taken on consecutive breaths, which were seen in a single M-mode image. The diaphragmatic thickness was measured before normal inhalation and after complete exhalation.” (methods)\nIn the first sentence diaphragm thickness was measured at the end-expiration and in peak inspiration. In the second sentence diaphragm thickness was measured before normal inhalation and after complete exhalation. It is not clear which information is true.\nSecondly, no information was provided about where exactly the thickness measurements were taken from the images of muscles. This is not clear in Fig. 2.\n\nWas the only one value collected from each photo? It would be better to describe it in the methodology section.\n\n“The chest wall was aligned perpendicularly with a 13-MHz linear array transducer.”\n\nIs the diaphragm definitely measured by a linear probe?\n\nMoreover, it would be appropriate to add information about the subjects' BMI.\n\nThe results include information about smoking and drinking alcohol. The method lacks information on how the data was collected.\n\nIncorporating the interpretation of correlation results into the methodology and subsequently discussing them in the results and discussion sections is valuable. This approach contributes to a more accurate and insightful analysis of the results.\n\n“To measure the quadriceps” section is described in the subchapter. \"To measure the soleus and diaphragm\" is listed as sub-items in the subchapter to “measure the quadriceps section”. It is better to divide all descriptions to subchapters. The information from “muscle thickness” subsection in the methodology seem to be redundant.\nIt is important to provide sufficient details of methods to allow replication and analysis by others.\n2. The introduction and discussion contains interesting information, but it is good to confirm it with a citation. The information then looks more reliable, e.g.\n“Muscle mass and strength are predictors of performance enhancement and ability to work in adults and mobility functions in the elderly population.” (introduction)\n\n“Furthermore, peripheral muscle mass and strength are associated with chronic diseases like sarcopenia which is a major risk and early mortality”. (introduction)\n\n“The reason for selecting the quadriceps, soleus in the lower limb, and the diaphragm for the study were that many researchers have found that there is a change in muscle thickness as age progresses, and it differs with sex as well.” (discussion)\n\nThe sentence seems intended to explain why these particular muscles were selected for analysis. If that was the aim, what is missing is the citation indicating that these particular muscles change in thickness with age.\n3. In introduction there is sentence: “Experimental studies have administered several interventions to address the increasing burden of physical inactivity and SB.”\n\nUnfortunately, this information was not given in article.\n4. The hypotheses are interesting, but they do not fully align with the research in this article.\n5. \"Anecdotal evidence\" that are not scientifically proven should not be described, e.g.:\n“Though anecdotal evidence claims a bidirectional relationship between physical inactivity and peripheral muscle strength or thickness, observational studies establishing the relationship are lacking.” (introduction) If research has been done on this subject but not published, it is worth mentioning it. If not, it may be better to add this kind of suggestion in the discussion (if needed).\n6. It is a very excellent idea to add a flow diagram regarding the qualification stage of participants. Unfortunately, the flow diagram needs improvement. It might look more aesthetically pleasing if the shape and size of the elements were unified.\nIn the flow diagram, the initial number of participants was 91, which is the same as the final number. Is it the same number for sure? Below \"patients screened\", \"bedridden patients not screened for the study\" is mentioned. This suggests that some people were excluded for this reason. However, the number of people excluded from the study for this reason was not reported. I think that in the flow chart it is worth specifying the initial number of people at the top. Then, the number of those excluded due to the exclusion criterion (as listed in the methodology: recent trauma, orthopedic interventions, bedridden, paralyzed, osteoarthritis, and other chronic diseases of the heart and lung).\n7. The instruments need to be better characterized, with the manufacturer, city, state (if applicable), and country of manufacture, including the programs for data analysis used.\n8. Some photos could have a better quality (Fig. 2) and not be cropped. I suggest transferring images to a computer, then choosing a clearly visible image. It would look better.\n9. English in some places need improvement, e.g.\n“The study included 91 patients aged 18 to 35 years with N = 78 male subjects with mean age and standard deviation of 27.954 years 4.67 and N = 13 females with mean age and standard deviation of 27.978 years 4.67.” (results)\n\n“According to previoys studies, men’s skeletal muscle degradation is correlated with age at about 27 years of age. With this clause, we have restricted our study age group to between 18-35 years.” (discussion)\nIn these sentences authors should choose “age” or “years”.\nAdditionally, if a standard deviation is given for the age, it is sufficient for the average number of ages to be rounded to the nearest whole number (maximum of one decimal place). It looks more readable.\n\nMoreover, in some sentences it says the \"diaphragm thickness\", in others the \"diaphragm muscle thickness\" (discussion). The diaphragm thickness is sufficient.\nConsidering this I recommend to send the manuscript to a fluent English-speaking person and ask them to correct the linguistic aspect of the manuscript.\n10. Some information is redundant or repeated:\nThe number and age of participants are repeated twice in the results section (3 lines apart).\nTo simplify and not repeat the information, the first sentences from the results section can be placed in the baseline characteristic section.\nSecondly, I don't see the purpose of providing employment information. Maybe it would be a good idea if the results were divided into two groups to show different correlations between employed and unemployed people. In the context of this work, perhaps a better question would be: Does the daily work performed by the participants involve physical or office work?\n\nThirdly, results given in the table are repeated in the text. This is not advisable. Moreover, several results from the text do not coincide with the results from the tables.\n11. Table 1 needs improvement.\nI would suggest changing the title of the table, e.g. Patients characteristics.\n\nAlso, remove the occupation information.\n\nSome values are given to a whole number, some to 1 decimal place, some to 2 decimal places, others with 3 decimal places. This should be standardized.\n\nThere is a lack of explanation of abbreviations in the tables. Some of them are explained in the text it would be clearer to the reader if they were also placed below the table (the same as MET was explained).\n12. Some of the sentences in the article are incorrect or stylistically/grammatically wrong which sometimes makes them seem unclear e.g.\n\n“Out of 91 patients, 30 were found to regularly smoke, and six had drinking habits after questions regarding lifestyle characteristics including smoking and drinking were asked.” (results)\n\n“This increase in diaphragm thickness may result in increased inspiratory muscle efficiency or improved pulmonary mechanics, or both.” (discussion)\n\n“Recent studies have shown and proved that diaphragm muscle thickness changes with increased PA, e.g. weight training.” (discussion)\nJust use one shown or proved.\n“We required 91 samples to achieve a moderate correlation (r1 > 0.4) at an alpha level of 95% and an 80% strength.”\nIs it certain that the version \"rl\" is the correct one?\n“With all these factors as constants and variables, our study shows that with an increase in PA, there is a significant increase in the quadriceps (…).” (discussion)\nThe sentence is misleading. Muscle thickness was not studied with increasing physical activity. It was written in a better form in the conclusions: “Peripheral muscle thickness has been found to positively correlate with physical activity levels.”\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "10199",
"date": "06 Oct 2023",
"name": "suresh sukumar",
"role": "Author Response",
"response": "We are grateful for the comments and suggestions provided. we have tried to incorporate the changes and justified the same. Inaccurate information in methodology. Not clear breathing manoeuvre during the diaphragm measurement: In the first sentence diaphragm thickness was measured at the end-expiration and in peak inspiration. In the second sentence diaphragm thickness was measured before normal inhalation and after complete exhalation. It is not clear which information is true. the diaphragmatic thickness was determined as the distance between the diaphragmatic pleura and the peritoneum at end-expiration (Tdi,ee) and peak inspiration (Tdi,pi). To be more specific we have mentioned as before normal inspiration. Was the only one value collected from each photo? It would be better to describe it in the methodology section. Yes only one value was measured – inspiration and expiration values. “The chest wall was aligned perpendicularly with a 13-MHz linear array transducer.” Is the diaphragm definitely measured by a linear probe? Yes a high frequency linear probe is used for better resolution and a wide field of view. Moreover, it would be appropriate to add information about the subjects' BMI. Unfortunately we haven’t collected the body mass index data . The results include information about smoking and drinking alcohol. The method lacks information on how the data was collected. The data was collected while the patient had to fill out the questionnaire. To measure the quadriceps” section is described in the subchapter. \"To measure the soleus and diaphragm\" is listed as sub-items in the subchapter to “measure the quadriceps section”. It is better to divide all descriptions to subchapters. The information from “muscle thickness” subsection in the methodology seem to be redundant. The changes shall be done as instructed. The introduction and discussion contains interesting information, but it is good to confirm it with a citation. The information then looks more reliable, Definitely we’ll work on that. . \"Anecdotal evidence\" that are not scientifically proven should not be described, e.g.: “Though anecdotal evidence claims a bidirectional relationship between physical inactivity and peripheral muscle strength or thickness, observational studies establishing the relationship are lacking.” (introduction) If research has been done on this subject but not published, it is worth mentioning it. If not, it may be better to add this kind of suggestion in the discussion (if needed). Sure will do the changes. In the flow diagram, the initial number of participants was 91, which is the same as the final number. Is it the same number for sure? Below \"patients screened\", \"bedridden patients not screened for the study\" is mentioned. This suggests that some people were excluded for this reason. However, the number of people excluded from the study for this reason was not reported. I think that in the flow chart it is worth specifying the initial number of people at the top. Then, the number of those excluded due to the exclusion criterion (as listed in the methodology: recent trauma, orthopedic interventions, bedridden, paralyzed, osteoarthritis, and other chronic diseases of the heart and lung). Yes we screened 91 excluding the bed ridden patients and the procedure was focused on these patients. But I shall add the initial number in the beginning . English in some places need improvement, e.g. “The study included 91 patients aged 18 to 35 years with N = 78 male subjects with mean age and standard deviation of 27.954 years 4.67 and N = 13 females with mean age and standard deviation of 27.978 years 4.67.” (results) “According to previoys studies, men’s skeletal muscle degradation is correlated with age at about 27 years of age. With this clause, we have restricted our study age group to between 18-35 years.” (discussion) The study comprised 91 individuals between the ages of 18 and 35. There were 78 male subjects (mean age, standard deviation, 27.954 years) and 13 female subjects (mean age, standard deviation, 27.978 years). Previous research has shown that men's skeletal muscle deterioration starts to increase at the age of 27. This provision limits the study age range to those between the ages of 18 and 35. Secondly, I don't see the purpose of providing employment information. Maybe it would be a good idea if the results were divided into two groups to show different correlations between employed and unemployed people. In the context of this work, perhaps a better question would be: Does the daily work performed by the participants involve physical or office work? The occupation data was only collected to have a brief understanding about patient’s PA and sedentary lifestyle. Some of the sentences in the article are incorrect or stylistically/grammatically wrong which sometimes makes them seem unclear e.g. “Out of 91 patients, 30 were found to regularly smoke, and six had drinking habits after questions regarding lifestyle characteristics including smoking and drinking were asked.” (results) “This increase in diaphragm thickness may result in increased inspiratory muscle efficiency or improved pulmonary mechanics, or both.” (discussion) “Recent studies have shown and proved that diaphragm muscle thickness changes with increased PA, e.g. weight training.” (discussion) Corrections : In responses to inquiries on lifestyle factors including drinking and smoking, it was discovered that 30 of the 91 patients smoked frequently and 6 had drinking habits. (results) The rise in diaphragm thickness might lead to improved pulmonary mechanics, enhanced inspiratory muscle efficiency, or even both. (discussion) \"Recent research has shown that diaphragm thickness changes with increased PA, such as weight training.\" (discussion)"
}
]
}
] | 1
|
https://f1000research.com/articles/12-836
|
https://f1000research.com/articles/11-1329/v1
|
16 Nov 22
|
{
"type": "Research Article",
"title": "Survival status and predictors of mortality among mechanically ventilated COVID-19 patients in Addis Ababa COVID-19 Care Centers, Ethiopia: A survival analysis",
"authors": [
"Girma Nega",
"Migbar Sibhat",
"Altayework Mekonnen",
"Tesfaye Techane",
"Altayework Mekonnen",
"Tesfaye Techane"
],
"abstract": "Background: The COVID-19 pandemic has caused stress on the health care system of many countries worldwide. To accommodate the growing number of critically ill patients requiring mechanical ventilation, hospitals expanded and tried to meet overwhelming demands. Despite this, outcomes of patients after mechanical ventilation were devastating, with high mortality rates. Therefore, this study investigated the survival status and predictors of mortality among mechanically ventilated COVID-19 patients. Methods: A retrospective cohort study was applied on the patient charts of 496 critically ill and mechanically ventilated COVID-19 patients at intensive care units of Addis Ababa COVID-19 Care Centers from September 2020 to October 2021. Data were collected using a data extraction checklist and entered into Epi data manager. Then, data were transferred to STATA V-14 for cleaning and analysis. The cox-proportional hazard regression model was used for analysis. Covariates with p-value ≤0.20 in the bivariate analysis were fitted to multivariate analysis after the model fitness test. Finally, statistical significance was decided at p-value <0.05, and hazard ratios were used to determine the strength of associations. Results: Of the 496 patients, 63.3% had died. The incidence rate of mortality was 56.7 (95% CI: 50.80, 63.37) per 1,000 person-days of observation, with 5534 person-day observations recorded. Advanced age (>60 years old) (adjusted hazard ratio (AHR)=1.86; 95% CI: 1.09, 3.15) and being invasively ventilated (AHR=2.02; 95% CI: 1.25, 3.26) were associated with increased risk of mortality. Furthermore, presence of diabetes (AHR=1.50; 95% CI: 1.09, 2.08), shock (AHR=1.99; 95% CI: 1.12, 3.52), and delirium (AHR=1.60; 95% CI: 1.05, 2.44) were significantly associated with increased mortality. Conclusions: Clear directions are needed in the recommendation of non-invasive versus invasive ventilation, especially among elderly patients. The controversy of when to intubate (early versus late) needs to be clarified as well. Early detection and prompt management of shock is paramount.",
"keywords": [
"Mechanical ventilator",
"COVID-19",
"Mortality",
"predictors",
"Ethiopia"
],
"content": "Introduction\n\nCoronavirus disease 2019 (COVID-19), a contagious disease caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) (One), imposed public health challenges within a short period.1 Over the past two years, the COVID-19 pandemic caused stress on the health care system of many countries in the world. Hospitals were overcrowded, and many lives were lost worldwide. As of 29th June 2022, about 545.2 million confirmed COVID-19 cases were reported globally, of which 6,334,728 have died, and around 12 billion people received vaccination (One).\n\nIn the first few months of the pandemic, 13.8% of the total confirmed cases were severe, and 5% were critically ill.1 Severe respiratory failure was reported as the most common cause of death.2 According to the International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) report, the world's largest database, of all confirmed COVID-19 cases, 20% required intensive care unit (ICU) or highly dependent unit (HDU) admission during their illness.3\n\nThe mechanism of COVID-19 infection remains puzzling yet. It is hypothesized that it may affect the pulmonary, cardiac, nervous, hepatic, renal and the coagulation system.4–6 COVID-19 can lead to different health consequences, including cardiomyopathy, shock, acute coronary syndrome, lung fibrosis, myocarditis, acute kidney injury, thromboembolism and arrhythmias.4–7\n\nBecause of acute respiratory distress syndrome (ARDS) and diffuse parenchyma injury, about 60-90% of patients admitted to the ICU demand respiratory support with mechanical ventilators.8–10 Mechanical ventilation (MV) is the medical term for artificial ventilation where machines are used to assist or replace spontaneous breathing either invasively or non-invasively. Invasive mechanical ventilation (IMV) is a method of ventilation that involves inserting a plastic/metal tube into the patient's airway. IMV is performed in the ICU or emergency room to meet the patient's oxygen demands. Conversely, non-invasive ventilation (NIV) is breathing support administered through a face mask, nasal mask, or a helmet without tracheal intubation.11–13\n\nIn the earliest stages of the pandemic, early intubation was encouraged over NIV due to the fear of increased viral transmission from aerosolization.14,15 Lately, almost all studies conducted to investigate the outcome of mechanically ventilated patients reported devastating figures (mortality rate as high as 97%). Nonetheless, the proportion of mortality was even higher among invasively ventilated patients,16–18 and NIV was associated with a significant survival benefit.19–21 On the other hand, it was hypothesized that COVID-19 might not cause classic ARDS that question the use of mechanical ventilation in such patients.22,23\n\nHealthcare interventions undertaken in the initial times of the pandemic in line with community mobilization and considerable government commitment played a significant role to limit the number of new cases and deaths due to COVID-19. The pandemic resulted in remarkable economic crisis, especially in low and middle-income countries. This damage is estimated to take years to recover.24\n\nThe number of incident cases, severity of the disease, and fatality rate in Ethiopia were lower than in the rest of the world in the earliest periods. Nonetheless, the COVID-19 infectivity, severity, and fatality rate have reached to peak after then. At present, it imposes an additional impact on the country's overburdened healthcare and socio-economic issues.25 Therefore, in this study, we aimed to assess survival status and predictors of mortality of mechanically ventilated COVID-19 patients admitted to the ICU settings.\n\n\nMethods\n\nA retrospective cohort study was employed. Recordings of patients admitted to the ICU settings of the COVID-19 Care Centers in Addis Ababa, Ethiopia starting from September 2020 to October 2021 were reviewed retrospectively. There were three major COVID-19 Care Centers in Addis Ababa. Despite considerable resource delimitations, Millennium COVID-19 Care Center (MCCC) was recognized as an organized and relatively well-equipped COVID-19 care center compared to other centers countrywide. The center is the largest COVID-19 treatment center in the country, with a capacity of greater than 1,000 admission beds. It serves patients with confirmed mild, moderate, and critically ill COVID-19 infection in different treatment units, including outpatient departments, emergency service, wards, HDU, and ICU service (>40 ICU beds). Until November 2021, an overall 6,211 patients were admitted to the center. Of those, 1,537 were diagnosed with severe and critical illness, demanding ICU services. Among those who were admitted to the ICU settings of MCCC, 722 were admitted to the ICU from September 2020 to October 2021. Data collection was conducted from January 23, 2022, to March 07, 2022. We have taken efforts to minimize potential sources of bias by setting and following thoroughly predetermined research plans, performing analysis by different team members independently, and receiving critics and reviews from external peers. The study was reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting observational studies.26\n\nAll COVID-19 infected patients admitted to the ICU and received mechanical ventilation support at Addis Ababa COVID-19 care centers were the source population. The study population included recordings of all patients admitted to the ICU and received respiratory support with a mechanical ventilator at the Millennium COVID-19 Care Center from September 2020 to October 2021. The lists of medical records were obtained from the COVID-19 registry and the liaison office reports. Recordings of patients deceased in the therapeutic center were considered events, whereas recordings of patients who discharged alive, weaned off from mechanical ventilator, and transferred out, were considered censored cases. Patient recordings with complete information were included in the study. The details of participant recruitment procedures were described in the flowchart (Figure 1).\n\nICU, intensive care unit.\n\nAn event was considered when a patient died while on mechanical ventilation. Time to event or censor refers to the time to occurrence of an event (death) or other outcomes measured from ICU admission to the date that the event or censor occurred. Censored were those cases discharged alive from the ICU, transferred to other institutions, or weaned off to mechanical ventilators. Mechanical ventilation refers to providing artificial respiratory support using a ventilator machine either invasively (IMV) or non-invasively (NIV). The follow-up was started when the patient was put on a mechanical ventilator for respiratory support and ended when the patient was weaned off from a machine, transferred out from ICU while on MV, or died while receiving MV support, and was measured in days.\n\nThe data extraction checklist was developed from the WHO COVID-19 guideline, mechanical ventilation protocols, and related literature.27,28 Before the actual study, recordings of all ICU mechanically ventilated patients were roughly reviewed (extracted) to identify the study subjects using medical record numbers (MRN) obtained from the ICU admission and discharge registration book. Then, all charts that fulfilled the inclusion criteria were reviewed, and relevant data were extracted. The data extraction tool comprised socio-demographic, disease-related, ventilator-related, and management-related variables. Data collectors and supervisors were recruited and trained on the data collection requirements. The checklist was pretested on 5%25 of randomly selected charts at MCCC to check its clarity and consistency. Accordingly, variables not recorded in the patient recordings were excluded from the extraction checklist. The pretest data was not included in the actual analysis. During data collection, each filled checklist was crosschecked and revised daily by the investigator for completeness. Hence, incomplete tools and missing information were managed at the spot during the data collection procedure by cross-checking and communicating with the data collector at the end of each day.\n\nAfter completion of data collection, the data was coded and entered into EpiData Manager 4.4.2.1 and exported to Stata 14 (an open-access alternative that can perform an equivalent function is Rstudio) for data cleaning and analysis. Then, an exploratory analysis was conducted to determine the level of missing values, influential outliers, and data distribution. The data were described using frequency tables, percentages, graphs, and means with standard deviations or medians with interquartile ranges based on the nature of data. A Kaplan-Meier curve was constructed to compare survival differences and to estimate the median survival time. Life tables were used to estimate cumulative probabilities of death at different time intervals.\n\nBivariate analysis was conducted using the Cox-proportional hazard model to determine the association between each independent variable with the outcome variable (death). Accordingly, variables with a p-value of ≤0.20 were considered for further analysis (multivariate analysis) to identify the net effect of each variable on mortality. The proportional hazard model assumption was checked using a global test (Schoenfeld residuals) (p=0.877). Besides, model fitness was checked using Cox-Snell residuals, and the graph showed the model fits the data well (Figure 2). Finally, statistical significance was declared at p≤0.05, and the strength of associations was summarized using an adjusted hazard ratio (AHR) with 95% confidence intervals.\n\nThe study was conducted after granting ethical approval (Reference=PM23/799; dated 06/12/2021) from the Saint Paul’s Hospital Millennium Medical College institutional review board (IRB). After approval, the IRB provided a waiver of patient consent since the study was conducted by chart review. Accordingly, permission for data collection was received from hospital directors on behalf of patients to get full access to patient recordings. Data coding and aggregate reporting were used so that names and other personal identifiers were not stated throughout the study process to ensure anonymity and confidentiality.\n\n\nResults\n\nOverall, 722 COVID-19 infected patients were admitted to ICU settings in the Millennium COVID-19 care center from September 2020 to October 2021. Consequently, 496 (n=496) mechanically ventilated patients with complete records were incorporated for analysis.\n\nThe study finding showed that more than 70% (350/496) of study participants were male. On the other hand, 79% of male patients and 60% of female patients died in the ICU. The mean age of participants was 59 years (SD=14.5), and only one-fourth of the study subjects were below the age of 50 years. The proportion of death was 41.5% (59/142) among patients below 50 years of age. In contrast, about 80% (n=200) of patients aged 65 years and over died during the follow-up period (Table 1).\n\nAbbreviations: SD, standard deviation; IQR, inter quartile range; Sx, symptom; SPO2, oxygen saturation; PIP, peak inspiratory pressure; PEEP, positive end expiratory pressure; FiO2, fraction of inspired oxygen; MV, mechanical ventilator; WBC, white blood cell; Cr, creatinine.\n\nBased on the findings, more than 55% (276/496) of patients were admitted to the center after seven days of symptom onset. The median time from symptom onset to hospital admission was eight days (IQR=3). Drastically, more than 75% of the cases were found to be hypoalbuminemic (<3.25g/dl) with a mean albumin level of 2.38g/dl (SD=1.32) at admission (Table 2). The findings also revealed that 314 patients had at least one chronic medical illness, of which 78.7% (247/314) have died. Conversely, 36.8% (67/182) of patients who did not have any chronic illness ended up with death due to COVID-19 infection. Diabetes mellitus (DM) (47%, n=496) and hypertension (HTN) (43%, n=496) were the most frequently recorded comorbidities. The proportion of death was much higher among those having DM (84.5%, n=233) and HTN (81.3%, 214) compared to patients who were free of DM (44.5%, n=263) and HTN (49.6%, n=282) (Table 2).\n\nAbbreviations: DM, diabetes mellitus; HTN, hypertension; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; HIV/AIDS, human immunodeficiency virus/acquired immune deficiency syndrome.\n\nAfter commencing artificial ventilation, patients remain on a mechanical ventilator for a median of 10 days (IQR=7). In-line with this, more than 55% (174/314) of deaths were recorded within the first 10 days of MV initiation (Table 1). According to the study result, 315 (63.5%) patients were intubated. Pressure regulated volume control (PRVC) was the most widely used (63.5%, n=315) mode of ventilation for intubated patients. An overall 181 (36.5%) patients were ventilated only with the non-invasive method of ventilation, of which 29 (16%) died. In opposition, 285 (90.5%, n=315) deaths were recorded among patients who received invasive ventilator support. The study results also showed that 71.8% (356/496) of study subjects developed ICU complications. All 496 (100%) study subjects took antibiotics, steroid therapy, and thromboprophylaxis (Table 3).\n\nAbbreviations: NIV, non-invasive ventilation; IV, invasive ventilation; PRVC, pressure regulated volume control; PCV, pressure control ventilation; VCV, volume control ventilation; CPAP, continuous positive airway pressure; AKI, acute kidney injury; HAI, hospital-acquired infections.\n\nThe Kaplan-Meier survival curve decreases stepwise and crosses the survival function at a survival probability of 0.5 (50%) (Figure 3).\n\nThe overall mortality rate among mechanically ventilated COVID-19 patients was 63.3% (95% CI: 59.1, 67.6). Among 182 (36.7%) patients who were considered censored, 170 (93.4%) patients were weaned off from mechanical ventilators, and the rest 12 (6.6%) were transferred to other institutions. The total person-time observation was 5534 person-days. The incidence rate of mortality among mechanically ventilated COVID-19 infected patients was 56.7 (95% CI: 50.80, 63.37) per 1000 person-days of observation. The median survival time was found to be 13 days (95% CI: 8.0, 18.0). Thus, 50% of participants could remain on mechanical ventilation for up to 13 days of follow-up. The cumulative probabilities of mortality at the end of 7, 14, 21, and 28 days were 0.24, 0.72, 0.95, and 0.98 consecutively (Table 4).\n\nAfter determining the nature of the data, the Kaplan-Meier curve and life tables were used for data description. Then, a log-rank statistic test was used to compare the survival difference between groups. Afterward, a bivariate analysis was conducted, and variables to be included in the final model for multivariable analysis were identified. Accordingly, patient's age, comorbidities, shock, albumin, peak inspiratory pressure (PIP), positive end expiratory pressure (PEEP), DM, chronic kidney disease (CKD), chronic obstructive pulmonary diseases (COPD), method of ventilation, coagulopathy, acute kidney injury (AKI) and delirium after admission were transferred for further analysis. However, sepsis, length of stay on MV, electrolyte level, and smoking status were excluded since they violate the proportional hazard assumptions with the value of less than 0.05 during the Schoenfield residual test.\n\nIn the multivariable analysis, advanced age, invasive ventilation, DM, delirium, and shock were found to be independent predictors of mortality among mechanically ventilated COVID-19 infected patients at a 95% confidence level (Table 5).\n\n* Statistically significant at a 95% uncertainty interval in the multivariable analysis.\n\nAbbreviations: CHR, crude hazard ratio; AHR, adjusted hazard ratio; CI, confidence interval; DM, diabetes mellitus; HTN, hypertension; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; PEEP, positive end-expiratory pressure; PIP, peak inspiratory pressure; AKI, acute kidney injury; ICU, intensive care unit.\n\n\nDiscussion\n\nThis study was conducted to determine survival status and predictors of mortality among COVID-19 patients who were mechanically ventilated. The incidence rate of mortality among mechanically ventilated COVID-19 patients was 56.7 (95% CI: 50.80, 63.37) per 1000 person-days of observation. The median survival time was found to be 13 days (95% CI: 8.0, 18.0). Older age (>60yrs), having DM, shock, and delirium while on MV were reported as predictors of mortality among mechanically ventilated COVID-19 patients. Moreover, being invasively ventilated was significantly associated with an increased mortality.\n\nThe overall mortality rate among mechanically ventilated COVID-19 patients was 63.3% (95% CI: 59.1, 67.6). The incidence rate of mortality among COVID-19 patients was 56.7 (95% CI: 50.80, 63.37) per 1000 person-days of observation with a total of 5534 person-day observations. This finding was much higher than reports of previous studies conducted in Belgium, 55%,13 Norway, 21%,29 Singapore, 9.1%,24 Kuwait, 45.6%,30 and Saudi Arabia, 32.1%.31 The possible rationale might be that previous studies used a small sample size and included mild and moderate cases,13,30,32 unlike the current study, which considered only critically ill patients. Besides, a significant delay in admission after symptom onset and shorter duration of stay on a mechanical ventilator (median=10 days) in our study could inflate the mortality rate compared to earlier studies13,31 since literature evidenced an inverse relationship between the length of stay and chance of mortality.19,33 Furthermore, the difference in the level of readiness to halt the pandemic would also result in this discrepancy. ICU services require intensive resources in terms of equipment, medications, skilled professionals, space, and time, which is challenging for developing nations like Ethiopia. Here in Ethiopia, medical supplies, including lifesaving medications, were scarce.25,34\n\nConversely, a study conducted in Pakistan reported a higher ICU mortality rate (77%).19 The possible justification could be that the Pakistan study was conducted in the earliest waves of the pandemic, where countries lack readiness and inconsistent management protocols that might significantly influence patient outcomes. Furthermore, a shorter duration of follow-up and a small sample size applied can contribute to this discrepancy.19\n\nPatients aged above 60 years were 1.86 times at an increased hazard of death compared to their counterparts (AHR=1.86; 95% CI: 1.09, 3.15). This finding was conformable with reports of several studies conducted abroad.19,29,31,32,35,36 The possible justification could be physiological responses decline with advanced age, which weakens host defense in acute infections resulting in an increased risk of complications and adverse health outcomes.37 On the contrary, previous studies suggested that elders have increased differential gene expression for an inflammatory condition, with a reduction in type I interferon beta. This is because the innate host response to viral infections is stronger in elders than in younger age groups.38\n\nFurthermore, the hazard of death among diabetic patients was 50% (AHR=1.50; 95% CI: 1.09, 2.08) higher than those who were not diagnosed with DM. Results of former studies conducted in Brazil and Norway were in agreement with this finding.29,39,40 This is because diabetic patients have immune suppression that makes them susceptible to severe infections. Hence, the COVID-19 virus might rapidly replicate and invade the lung parenchyma easily. Moreover, this immune-compromised state can expose patients to superimposed infections such as hospital-acquired or superimposed pneumonia and sepsis.40 Diabetic patients also have elevated levels of pro-inflammatory markers.40\n\nThe hazard of death was two-folds higher among invasively ventilated (intubated) patients compared to their counterparts (AHR=2.02; 95% CI: 1.25, 3.26). This was in line with previous study findings.19,20,32,39,41 This can be multifactorial. First, in most scenarios, intubation is considered if NIV is unsuccessful, which could increase the chance of refractory hypoxia.42 Second, intubated patients were highly prone to ventilator-associated complications, including pneumothorax, ventilator-associated pneumonia, increased risk of sepsis, and sedation inadequacy or excess.43 Third, unlike those non-invasively ventilated, intubated patients can not complain of any discomfort or inconvenience such as pain and are solely dependent on the skill and commitment of health personnel. Previous studies also agreed that more than half of patients who fulfilled intubation criteria survived with just NIV and avoided invasive ventilation, whereas clinical outcomes and mortality among invasively ventilated patients were devastating.20,41\n\nAdditionally, a diagnosis of shock while on artificial ventilation also showed a statistically significant association with mortality of critically ill COVID-19 patients. Mechanically ventilated patients who developed shock had a twofold (AHR=1.99; 95% CI: 1.12, 3.52) increased risk of death due to critical COVID-19 illnesses compared to their counterparts. We could not find any research that reported the effect of shock on the mortality of COVID-19 patients who needed MV support. The scientific rationale could be that shock can result in hypoperfusion and hypoxemia. To add fire to the chaff, the pressure support (specially PEEP) can compromise tissue perfusion by indirectly counteracting venous return and cardiac output,44–46 making shock management arduous. As a result, hypoperfusion of vital organs could lead to multi-organ failure and hypo-function, thus, ending up in death.\n\nOn the other hand, the risk of death among patients who developed delirium in the ICU compared to their counterparts was 60% higher (AHR=1.60; 95% CI: 1.05, 2.44). This might be due to the effect of delirium on patient-ventilator interaction. Patients with delirium usually have asynchrony, especially during NIV support. Furthermore, delirious patients would fight with the ventilator machine, which could increase peak airway pressure. Sequentially, this will lead to an increased risk of pulmonary barotrauma (pneumothorax). On the other hand, delirious patients require an extra dose of sedation to maintain synchrony, exposing them to unintended drug adverse effects and an unrousable state. Consequently, all these factors can deteriorate the patient's condition and result in death.\n\nThe study considered censored observations. Besides, in addition to baseline information, follow-up data were used to estimate patient characteristics, which enabled a more accurate investigation of the effects of these variables. Conversely, this study also has its limitations. First, there was considerable delay in ICU admission and mechanical ventilation support from symptom onset. Hence, there might be an overestimation of the mortality rate. Second, we did not evaluate the effect of some important variables such as procalcitonin, troponin, serum ferritin, d-dimer, lactate dehydrogenase, and interleukin-6 that showed statistically significant association in the previous studies conducted abroad due to lack of access for these laboratory tests.\n\n\nConclusions\n\nThe study finding showed a high incidence of mortality among critically ill COVID-19 patients who were supported with mechanical ventilators. Older age (>60 years), invasive means of mechanical ventilation, having DM, and ICU complications such as shock and delirium were independent predictors of death among mechanically ventilated COVID-19 patients. Clear directions are needed in the recommendation of non-invasive versus invasive ventilation, especially among elderly patients. The controversy of when to intubate (early versus late intubation dilemma) needs to be clarified as well. Early detection and prompt management of shock is paramount, especially considering that most intubated patients develop shock immediately after intubation and are due to sepsis.",
"appendix": "Data availability\n\nFigshare: DATASET for Survival status and predictors of mortality among mechanically ventilated COVID-19 patients in Addis Ababa COVID-19 Care Centers, Ethiopia. https://doi.org/10.6084/m9.figshare.21126178. 47\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nFigshare: STROBE checklist for ‘Survival status and predictors of mortality among mechanically ventilated COVID-19 patients in Addis Ababa COVID-19 Care Centers, Ethiopia’. https://doi.org/10.6084/m9.figshare.20870908. 26\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgments\n\nThe authors would like to thank data collectors, supervisors, hospital staff, and administrators for their unreserved efforts and commitment. The authors also appreciated Saint Paul’s Hospital Millennium Medical College for chasing this chance and covering the data collection costs.\n\n\nReferences\n\nNovel Coronavirus Pneumonia Emergency Response Epidemiology: The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China. Zhonghua liu xing bing xue za zhi= Zhonghua liuxingbingxue zazhi. 2020; 41(2): 145.\n\nBerlin DA, Gulick RM, Martinez FJ: Severe covid-19. N. Engl. J. Med. 2020; 383(25): 2451–2460. Publisher Full Text\n\nWinck J, Scala R: Non-invasive respiratory support paths in hospitalized patients with COVID-19: Proposal of an algorithm. Pulmonology. 2021; 27: 305–312. PubMed Abstract | Publisher Full Text\n\nWiersinga WJ, Rhodes A, Cheng AC, et al.: Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020; 324(8): 782–793. 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Infect. 2020: 148.\n\nGuo W, Li M, Dong Y, et al.: Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab. Res. Rev. 2020; 36(7): e3319.\n\nSivaloganathan AA, Nasim-Mohi M, Brown MM, et al.: Noninvasive ventilation for COVID-19-associated acute hypoxaemic respiratory failure: experience from a single centre. Br. J. Anaesth. 2020; 125(4): e368–e371. PubMed Abstract | Publisher Full Text\n\nTu Y, Yang P, Zhou Y, et al.: Risk factors for mortality of critically ill patients with COVID-19 receiving invasive ventilation. Int. J. Med. Sci. 2021; 18(5): 1198–1206. PubMed Abstract | Publisher Full Text\n\nHaribhai S, Mahboobi SK:Ventilator Complications. StatPearls. Treasure Island FL: © 2022:StatPearls Publishing LLC; 2022.\n\nZhou L, Cai G, Xu Z, et al.: High positive end expiratory pressure levels affect hemodynamics in elderly patients with hypertension admitted to the intensive care unit: a prospective cohort study. BMC Pulm. Med. 2019; 19(1): 1–9.\n\nCournand A, Motley HL, Werko L, et al.: Physiological studies of the effects of intermittent positive pressure breathing on cardiac output in man. American Journal of Physiology-Legacy Content. 1947; 152(1): 162–174. PubMed Abstract | Publisher Full Text\n\nPinsky MR: The hemodynamic consequences of mechanical ventilation: an evolving story. Intensive Care Med. 1997; 23(5): 493–503. PubMed Abstract | Publisher Full Text\n\nSibhat M:DATASET for Survival status and predictors of mortality among mechanically ventilated COVID-19 patients in Addis Ababa COVID-19 Care Centers, Ethiopia. figshare. [Dataset].2022. Publisher Full Text"
}
|
[
{
"id": "191979",
"date": "14 Aug 2023",
"name": "Fadi Aljamaan",
"expertise": [
"Reviewer Expertise Critical care"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nPlease remove the methodology and statistical details from the abstract.\n\nPlease use medical term that are more professional and international, for example (invasively ventilated) should use (on mechanical ventilation)\n\nThere is no need to describe intubation procedure and mechanical ventilation in the introduction, that’s waste of attention of the audience.\n\n“We have taken efforts to minimize potential sources of bias by setting and following thoroughly predetermined research plans, performing analysis by different team members independently, and receiving critics and reviews from external peers” would you please clarify this sentence, as I don’t understand where were the potential sources of bias exactly especially in data collection.\n\nWould you please clarify how did you treat those who were weaned from MV and discharged to ward but died before discharge from hospital?\n\nPlease refer to the appropriate table in the results section. Table 1 doesn’t have the results texted in the first paragraph of the results section.\n\nPlease label P value as P value not significance.\n\nWhat is the value of Table 3 compared to table 5 , you can merge them together please.\n\nWhat is the importance of Table 4 in relation to your study of outcomes in mechanically ventilated patients with COVID-19??\n\nIs table 5 bivariate or multivariate?\n\nPlease submit data about the patient who were mechanically ventilated, whether their disease was more severe and affected their mortality rather than the MV itself.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10298",
"date": "06 Oct 2023",
"name": "Migbar Sibhat",
"role": "Author Response",
"response": "Manuscript title: Survival status and predictors of mortality among mechanically ventilated COVID-19 patients in Addis Ababa COVID-19 Care Centers, Ethiopia: A survival analysis Thank you for the opportunity to submit a revised version of our manuscript for consideration for publication. We appreciate the thoughtful and constructive comments of the reviewer and have revised our manuscript accordingly. Detailed responses to each of the comments or questions raised by the respected reviewer are presented below. We have indicated the text changes that have been made and the line number on the tracked changes manuscript at which our changes can be found. Reviewer #1 Reflections: 1. Comment#1: “Please remove the methodology and statistical details from the abstract.” Author’s response: We tried to shorten the methods section of the abstract part as much as possible. However, as per the journal’s guidelines, the abstract section should include a succinct description of the methods. Hence, we prefer to shorten it. 2. Comment#2: “Please use the medical terms that are more professional and international, for example (invasively ventilated) should use (on mechanical ventilation).” Author’s response: Thank you for the suggestion. Mechanical ventilation can be applied in two different ways: invasively vs. non-invasively. Our study includes patients who received mechanical ventilation support with intubation (either via endotracheal intubation or tracheostomy) or without intubation (via CPAP or BiPAP). Patients who received respiratory support by intubation were termed as invasively ventilated whereas patients who received ventilatory support by providing positive pressure without intubation were referred to as non-invasively ventilated. This definition is internationally acceptable and is already presented in the introduction section of the main manuscript (Lines 24-28). Hence, “on mechanical ventilation” represents both “invasive” & non-invasive” ventilation, and thus, it could not be used as an exact replacement for “invasively ventilated”. Therefore, we prefer to keep it as it is. 3. Comment#3: “There is no need to describe the intubation procedure and mechanical ventilation in the introduction, that’s a waste of attention of the audience.” Author’s response: Well! It could be simple to remove those statements. However, since the study population comprised of patients who received respiratory support by the mechanical ventilator (both invasively/intubated and non-invasively/without intubation), it’s essential to create a clear notion of mechanical ventilation, why, and how it’s applied so that readers could easily understand and interpret the study findings. Together with stating the problem, one of the purposes of the introduction section is to provide a general overview and familiarize them with the topic under investigation. Without knowing what mechanical ventilation is, the audience could not understand the study findings. 4. Comment#4: “We have made efforts to minimize potential sources of bias by setting and following thoroughly predetermined research plans, performing analysis by different team members independently, and receiving critics and reviews from external peers” Would you please clarify this sentence, as I don’t understand where were the potential sources of bias exactly especially in data collection.” Author’s response: This statement was mainly to minimize biases that could arise during data analysis. However, regarding the data collection, different techniques including pretest, data collector training, supervision, daily and on-spot cross-checking were applied. Besides, checklists with incomplete records were excluded to maintain data quality. It was already described in detail in the main manuscript file (please refer to Lines 100-108). 5. Comment#5: “Would you please clarify how you treat those who were weaned from MV and discharged to the ward but died before discharge from the hospital?” Author’s response: Initially, at the proposal stage, we planned to include them in the study and count them as cases (only if readmitted to ICU since mechanical ventilation could not be provided in the wards in our set-up). Nevertheless, during data collection, we did not have such records and we removed this statement from the manuscript file. Be reminded that patients who died in the hospital (even in the ICU) without receiving mechanical ventilator support were not counted as events. Because all samples in the study should be exposed to mechanical ventilator support. 6. Comment#6: “Please refer to the appropriate table in the results section. Table 1 doesn’t have the results texted in the first paragraph of the results section.” Author’s response: Well appreciated! We made the required changes in the main text. Findings for continuous variables were provided as supplementary files separately and cited accordingly (see Lines 145-150). 7. Comment#7: “Please label P value as P value not significance.” Author’s response: Thanks again. We amended the issue as directed (Table 5). 8. Comment#8: “What is the value of Table 3 compared to Table 5, you can merge them please.” Author’s Response: Table 3 is just a description table. It shows the distribution /crosstab output/ of management-related variables only. Conversely, Table 5 presents the regression analysis findings, and it contains variables included in the Cox model (which fulfilled the variable selection criteria). Table 5 consists of sociodemographic variables, comorbidities, mechanical ventilator parameters, and laboratory findings. Contrarily, Table 3 presents mechanical ventilator parameters, laboratory findings, and clinical characteristics. Therefore, the two tables are distinct, and thus, cannot be merged. 9. Comment#9: “What is the importance of Table 4 concerning your study of outcomes in mechanically ventilated patients with COVID-19?” Author’s response: One of the study objectives was to determine the incidence of mortality among mechanically ventilated critically ill COVID-19 patients. Incidence was expressed in cumulative incidence at a certain time interval and overall incidence density rate. Hence, Table 4 presents incidence rates of mortality at specific time intervals, which was one of the study objectives. Thus, it’s essential to address one of the study objectives. 10. Comment#10: “Is table 5 bivariate or multivariate?” Author’s Response: Table 5 displays variables that were included in the Cox regression model. In short, Table 5 is a multivariable output. It mainly presents multivariable outputs in which all variables in the final model were presented. Presenting only variables associated with the multivariable analysis could be inappropriate since variables that form the final model should be presented. Otherwise, one could not understand how many variables were incorporated for adjustment. We presented the crude estimates to make the table more informative and self-explanatory, such that readers will not question why and which variables were included in the final model for confounder adjustment. It provides better detail. To conclude, the table footnote shows crude (bivariable) and adjusted (multivariable) outputs. It should not be a question at all since every researcher understands that crude (CHR) implies before adjustment (bivariable) and adjusted (AHR) implies multivariable output. 11. Comment#11: “Please submit data about the patients who were mechanically ventilated, whether their disease was more severe and affected their mortality rather than the MV itself” Author’s response: That’s great. All the patients included in the study were either severely or critically ill and needed mechanical ventilator support. From the beginning, patients with mild to moderate illnesses without respiratory distress and who did not require ventilatory support could not be incorporated in this study. Therefore, COVID-19 severity could not be considered as a covariate. To be included in the study, all patients should have severe respiratory distress requiring artificial ventilation by mechanical ventilation with or without intubation. Conversely, existing literature documented a huge variation in patients’ mortality rate with intubation and without intubation. During the worst times of the pandemic, clinicians were in the intubate vs. not-intubate dilemma despite the intubation criteria met (invasive vs. non-invasive ventilation dilemma). Besides, several literature reported that the mode and method of mechanical ventilation are essential for the success of ventilatory support. Since mechanical ventilation support was one exposure variable in our study, we assessed the method of MV as an exposure variable. Consequently, it’s mandatory to assess the effect of the method of MV itself on patient mortality. We apologize if any of our responses seem offensive or if we used strong tones. If any exist, we want to declare that none of them were intentional! We just have full of appreciation and gratitude for the comments received so far! Thank you in advance."
}
]
}
] | 1
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https://f1000research.com/articles/11-1329
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https://f1000research.com/articles/12-841/v1
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18 Jul 23
|
{
"type": "Research Article",
"title": "Immune system and tumor microenvironment in early-stage breast cancer: different mechanisms for early recurrence after mastectomy and chemotherapy on ductal and lobular types",
"authors": [
"Andreas Andrianto",
"I Ketut Sudiana",
"Desak Gede Agung Suprabawati",
"Hari Basuki Notobroto",
"Andreas Andrianto",
"Desak Gede Agung Suprabawati",
"Hari Basuki Notobroto"
],
"abstract": "Background: The most common type of breast cancer is the ductal type (IDC), followed by lobular type (ILC). Surgery is the main therapy for early-stage breast cancer. Adjuvant chemotherapy might be given to those at high risk of recurrence. Recurrence is still possible after mastectomy and chemotherapy and most often occurs in the first two years. We aimed to determine the mechanisms in early local recurrence in both types. Methods: We used an observational method with a cross-sectional study design. The samples were patients with early-stage IDC and ILC, who underwent modified radical mastectomy (MRM) and got adjuvant chemotherapy with taxan and anthracycline base, and experienced recurrence in the first two years after surgery. The materials in this study were paraffin blocks from surgical specimens; we examined vimentin, α-SMA and MMP1, PDGF and CD95 by immunohistochemistry (IHC). Data analysis was done using OpenEpi 3.0.1 and EZR. We used pathway analysis with linear regression. Results: There were 25 samples with local recurrence and 25 samples without recurrence in the ductal type group. The lobular type group consisted of six subjects without recurrence and seven with recurrence. There were significant differences in the expression of vimentin (p = 0.000 and 0.021, respectively), PDGF (p = 0.000 and 0.002) and CD95 (p = 0.000 and 0.045) in ductal and lobular cancer types, respectively. MMP1 (p = 0.000) and α-SMA (p = 0.000) only showed a significant difference in the ductal type. The pathway analysis showed that in the ductal type, the mechanism of recurrence was enabled by two factors: α-SMA and CD95. Meanwhile, for the lobular type, the recurrence mechanism was through the CD95 pathway. Conclusions: Local recurrence in early-stage IDC and ILC had different mechanisms. These findings are expected to make cancer treatment in both types more focused and efficient.",
"keywords": [
"Ductal Carcinoma",
"Lobular Carcinoma",
"Local Recurrence",
"Early Breast Carcinoma"
],
"content": "Introduction\n\nMetastasis in breast cancer occurs when cancer cells can migrate and survive against the body's defense mechanisms.1 These cancer cells must be able to change the structure of their cytoskeleton and the surrounding extracellular matrix to support the migration process and avoid the apoptotic process to survive and metastasize, by producing proteins to protect themselves and changing signaling pathways so that the apoptotic process does not occur.2\n\nBreast cancer is still a major health problem both in the world and in Indonesia. In Indonesia, the highest incidence of cancer in women is breast cancer, which is 42.1 per 100,000 population, with an average death rate of 17 per 100,000 population.3 The two most common histological types are 80% invasive ductal carcinoma (IDC), followed by 15% invasive lobular carcinoma (ILC).4 Which type shows the better prognosis is still controversial.5 Local recurrence and distant metastases after surgery are more common in the ILC type.6 The high number of metastases in the ILC type is due to its nature, which tends to be multicentric and can invade the stroma without causing excessive stromal reactions, making it difficult for anatomic pathologists to determine the radicality of surgery.7,8\n\nTwo surgical procedures that are often performed on breast cancer are breast conserving surgery (BCS) and modified radical mastectomy (MRM).9 BCS is a wide excision procedure of the tumor accompanied by procedures in the ipsilateral axilla (level I and II axillary dissection or sentinel node dissection).10 MRM is a procedure for removing the tumor and the skin over the tumor, all breast glands, accompanied by axillary dissection which is carried out simultaneously.11 After MRM procedure, recurrence and metastases are still common even though the entire breast has been removed, even after adjuvant chemotherapy.12\n\nThe most critical time for local recurrence in both types of histology is the first two years after the primary surgery.13,14 The choice of management of local recurrence after a BCS procedure is re-excision or salvage mastectomy,13 but the decision on which procedure to choose is still being debated because of the high rate of post-re-excision metastases.15 Until now, the management of local recurrence after MRM has not been standardized, i.e., whether re-excision can be carried out or treated in a setting like stage IV.13,16\n\nSurgery for residual breast cancer is thought to cause shedding of tumor cells into the bloodstream and lymph nodes.17 Surgery will also suppress cellular mediated immunity (CMI) so that cancer cells are more aggressive and go through metastasis more easily.18 Surgery for breast cancer that has experienced metastases can also reduce the distant anti-angiogenic effect so that it can trigger new metastatic foci in distant organs.17,19 Surgery and chemotherapy can increase the formation of reactive oxygen species (ROS), which in turn can protect cancer cells from apoptosis through the “anti-ROS” mechanism by Nuclear Factor Kappa Beta (NF-kB). In addition, low ROS levels can turn cancer cells into cancer stem cells (CSC) via the twist signaling pathway.20\n\nTo survive and metastasize, cancer cells are also capable of changing their nature to become immortal (stemness) and capable of invasion/migration. Through the epithelial to mesenchymal transition (EMT) mechanism, cancer cells can change from an epithelial phenotype to a more mobile mesenchymal phenotype.21 One of the factors that makes cancer stem cells (CSCs) immortal is their ability to avoid apoptosis triggered by the body’s immune system, namely by increasing the expression of CD95 which has an apoptotic function and triggers cancer stemness.22\n\nThe occurrence of EMT in cancer cells is indicated by the increased expression of mesenchymal markers: vimentin, n-cadherin, and fibronectin. There is also a decrease in the expression of epithelial markers such as: e-cadherin, cytokeratin, claudin.23,24 Cancer cells that have undergone the EMT process could migrate and metastasize through a mechanism that can convert normal fibroblast cells into cancer associated fibroblasts (CAF) via the Platelet Derived Growth Factor (PDGF) pathway.25 CAF alters the structure and shape of fibroblasts to better support the metastatic process. The formation of CAFs can be identified by the increased expression of α-SMA which correlates with EMT events.23,26,27 In addition, CAF can issue signals to induce matrix metalloproteinase (MMP) formation to degrade the extra cellular matrix so that the path for cancer cells to migrate becomes easier. MMP is a proteolytic enzyme that regulates the microenvironment around cells and its expression is always increased in cancer.28 There are more than 21 types of MMPs, and in breast cancer the MMP expression that increases is MMP1.29\n\nThis study was conducted to explain the differences in local recurrence mechanisms of ductal and lobular invasive breast carcinoma after mastectomy and chemotherapy. This study compared the expression of vimentin, α-SMA, MT-MMP1, PDGF and CD95 in the two types of breast cancer to assess which factors play a greater role in the process of local recurrence in each type of breast cancer.\n\nBefore study began, this research obtained ethical approval from the Research Ethics Committee of the Faculty of Medicine, State University of Jember with number 1.537/H25.1.11/KE/2021. The first author works as surgical oncologist at Dr. Koesnadi General Hospital (RSDK) Bondowoso, East Java, Indonesia. The research samples were taken at RSDK which belongs to the network of the Faculty of Medicine, Jember State University, where first author also teaches; therefore ethical approval was granted out by the ethics commission of Jember State University that acts as in-charge university. Currently, the first author is following a doctoral program at Airlangga University, East Java, Indonesia, so for the author's affiliation use Airlangga University, Surabaya. The co-authors are promotors and co-promotors for disertation and they all are lecturers of Airlangga University. All patients whose sample took part in this study, after receiving an explanation about the study, signed a consent form to participate. If the patient died, the consent form is signed by their child or the patient’s next of kin.\n\n\nMethods\n\nThe research design used was analytic observational study with a cross-sectional study design. The subjects were patients with early-stage IDC and ILC (stages I and II), who had undergone MRM between January 2014 - December 2019 (five years) and received chemotherapy using a taxane and anthracycline base regimen, and experienced local recurrence within two years after surgery. All were operations performed by the first author. We obtained data from medical records in the surgical department of Dr H Koesnadi Bondowoso General Hospital, East Java, Indonesia (RSDK). The research subjects were divided into two groups for each type: a group with local recurrence and a group without local recurrence. The number of samples for IDC was 25 samples for each group. Determining the number of sample size based on the minimum number of samples needed for regression analysis The sampling technique for each ductal groups was simple random sampling. For ILC, number of samples was total subject who meet the inclusion and exclusion. This research was conducted at the RSUD Dr. Koesnadi General Hospital and Bhayangkara Hospital, East Java-Indonesia. The inclusion and exclusion criteria were as follows:\n\n1. Inclusion criteria\n\na. Patients with early stage lobular and ductal invasive breast cancer (early breast cancer) with locoregional recurrence after MRM and who have received chemotherapy for taxan and anthracycline base six times with an interval of three weeks (one series).\n\nb. There was an anatomic pathology examination report which includes:\n\n• Histological type\n\n• Grades\n\n• Radicality\n\n• Regional lymph node metastases\n\nc. There was a complete medical record of the patient including:\n\n• Patient's identity and age\n\n• Patient's hormonal status\n\n• Date of surgery and time of recurrence\n\n• Timing and type of chemotherapy regimen\n\n2. Exclusion criteria\n\na. The patient had received radiation therapy before.\n\nb. There was malignancy in other organs.\n\nc. The results of the pathological examination stated that the edges of the resection were not tumor-free, coincided or less than 1 cm.\n\nd. The paraffin block was damaged and could not be used.\n\ne. Paraffin blocks for surgical specimens could not be examined by immunohistochemistry because of poor fixation.\n\nBlock paraffin derived from the MRM operation specimen was cut to a thickness of 4 μm and then heated at 600°C for one hour. After that, deparaffinization was carried out three times using xylene solution for 3 minutes each. Furthermore, rehydration was carried out using 100%, 96%, and 70% ethanol. After rehydration, wash with water for 3 minutes. Peroxidase blockade was performed using 0.5% H2O2 for 30 minutes in methanol, then water cleansing for 5 minutes. Before and after peroxidase blockade, washing was carried out using pH 7.4 phosphate-buffer saline (PBS). Monoclonal antibodies used in this study were the Mouse anti-Human Monoclonal Antibody from MyBioSource. Each variable expression was assessed by looking at the number of cells that gave a positive reaction to the antibody. Calculations were performed at ten different fields of view using 400× magnification light microscope and the average was calculated. Data processing was performed using EZR and Openepi 3.0. bivariate analysis used the Chi-square test or Fisher’s exact test. The statistical value considered significant was p<0.05.\n\n\nResults\n\nThe research selected 50 patients with early-stage ductal type breast cancer and 13 patients with lobular type. The ductal type was divided into two groups: the first group comprised 25 patients who had local recurrence in the first two years and a control group of 25 patients who did not had local recurrence. In the lobular type group, the division was also carried out with the number of patients who had local recurrence, amounting to seven patients, and those who did not had local recurrence, comprising six patients. Statistical test result showed there was no significance diference based on age, lymphnode metastasis, tumor grade and hormonal status on ductal type breast cancer (Table 1 and Table 2).\n\nBefore we carried out statistical tests, we tested for normality and homogeneity of data distribution. For data that were not normally distributed, the statistical test used was a non-parametric Mann-Whitney test, while for data which had a normal distribution, we used a parametric independent t test.\n\nBased on Table 3, there was a significant difference in vimentin expression between the group that experienced recurrence and the group that did not experience recurrence, where for the ductal type p=0.000 and for the lobular type p=0.021.\n\n* Mann-Whitney test.\n\n** Independent t-test.\n\nAccording to the test results, there was a significant difference in PDGF expression between the group that experienced recurrence and the group that did not experience recurrence in both types of breast cancer, where for the ductal type p=0.000 and for the lobular type p=0.002 (Table 4).\n\n* Mann-Whitney test.\n\n** Independent t-test.\n\nAccording to the results of the tests performed, a significant difference in MMP1 expression was only found between the recurrence and non-recurrence groups in the ductal type group (p=0.000), while in the lobular type there was no significant difference in MMP1 expression in the non- recurrence group compared to the recurrence group (p=0.102) (Table 5).\n\n* Mann-Whitney test.\n\n** Independent t-test.\n\nBased on the results for α-SMA expression, a significant difference was found in α-SMA expression in the ductal type (p=0.000) while in the lobular type there was no significant difference (p=0.063) (Table 6).\n\n* Mann-Whitney test.\n\nAccording to the results of the tests conducted, there was a significant difference in CD95 expression between the group that experienced recurrence and the group that did not experience recurrence for both cancer types, where for the ductal type p=0.000 and for the lobular type (p=0.045) (Table 7).\n\n* Mann-Whitney test.\n\nTo analyze the recurrence mechanism, we performed pathway analysis. The results of the pathway analysis for the ductal type breast cancer are presented in Figure 1, and for lobular type in Figure 2.\n\nSolid arrow: there is correlation; dotted arrow: there is no correlation.\n\nSolid arrow: there is correlation; dotted arrow: there is no correlation.\n\nBased on these results, it was found that the recurrence mechanism in the early-stage ductal type breast cancer after mastectomy and chemotherapy was different from that of the lobular type. In the ductal type, the recurrence mechanism goes through two ways, namely through the pathway that affects the extra cellular structure of cancer cells (via the α-SMA pathway) and through the suppression of the body's immune cells (via the CD95 pathway). For the lobular type, the recurrence mechanism of this study was only through the CD95 pathway. The recurrence mechanism in the lobular type can elucidate why in the lobular type it is not very clear that changes in the extra cellular matrix in cancer cells will ultimately make it difficult to determine the outer edge of the tumor.\n\n\nDiscussion\n\nTumor microenvironment (TME) has long been a topic of research to determine the biological properties of tumor cells themselves and is one of the main factors in the process of tumor growth, metastases, and resistance to chemotherapy.30 Many studies have mentioned that there is a two-way communication between tumor cells and TME which allows tumor cells to avoid the body's defense system, survive after chemotherapy and can spread to other places.31\n\nThe main point in the process of recurrence and the occurrence of chemotherapy drug resistance is the occurrence of epithelial to mesenchymal transition (EMT), which can be detected using mesenchymal markers, including vimentin, N-cadherin, and fibronectin. Vimentin is the main component that makes up the cell skeleton (cytoskeleton). Also, vimentin acts as a protein forming the cell skeleton and plays a role in the process of cell motility. Vimentin expression is positive in cells that are actively dividing. Increased vimentin expression is associated with more aggressive tumor cell properties, increased ability to metastasize and poorer prognosis.32 The actin structure of the cytoskeleton is a crucial element in the process of protrusion and cell migration, so that the intermediate cytoskeleton filament, especially vimentin, also plays a role in the process of adhesion and cell spread.33 In addition, vimentin can protect cells against exposure to stress.34\n\nAbnormal vimentin expression is found in some types of cancer such as primary epithelial cancer or metastasis. Recent studies have found that vimentin also plays a role in the EMT process of breast cancer, resulting in a decrease in genes associated with invasion and such basal phenotypes.35 Excessive expression of this compound correlates with poor prognosis in breast cancer patients. In addition, high vimentin levels are significantly associated with the spread and survival of breast cancer cells, allowing recurrence cancer cases.36 This is in line with research by Yamashita in 2013, who stated that vimentin levels are associated with poor prognosis in recurrence breast cancer.37 In addition, research conducted by Winter in 2021 showed an increase in vimentin activating the AKT pathway, which plays a role in increased breast cancer cell proliferation and invasion.38\n\nBased on the results of statistical tests conducted in this study, there were significant differences in vimentin expression between groups that had recurrence events and those who did not in the ductal type (p=0.000) and lobular type groups (p=0.021). This result is in line with research conducted by Wang, 2020, who found that vimentin overexpression was found in ductal type breast cancer cells.39 This is due to the synergy between vimentin and LAP3, where LAP3 expression can increase vimentin expression.39 In addition, the relationship between the two can also be significant because vimentin plays an important role in promoting the migration and invasion of breast cancer cells by LAP3.40 Research conducted by Vora, 2009 also showed similar results, namely recurrence breast cancer patients having higher vimentin levels compared to non-recurrence breast cancer, both in lobular and ductal breast cancer types.41 A study conducted by Rodrigez stated that vimentin expression in non-basal-like tumors was lower than that in basal-like tumors (p<0.001). Basal-like tumors correlate with poor prognosis and tend to recur, and vimentin expression in tumor cells correlates with recurrence.42 Different result were obtained in a study conducted by Seshadri in 1996. This study stated that there is no significant association between vimentin expression and the risk of recurrence or death from breast cancer. In the same study, the authors also explained that vimentin plays a greater role only in tumors with negative hormone receptors.43\n\nIn our study, there was a significant difference in MMP1 expression between the non-recurrence group and the recurrence group in the ductal type (p=0.000), while for the lobular type there was no significant difference (p=0.102). According to a study conducted by Del Caszar, increased expression of MMP1 is obtained especially in ductal type breast cancer when compared to other types of breast cancer (mucinous and lobular).44 A study conducted by Shen et al. also mentioned that increased MMP1 expression in invasive breast cancer is correlated with the occurrence of resistance to chemotherapy drugs (multi-drug resistance).45 In addition to causing chemoresistance, increased MMP1 expression is also correlated with the occurrence of resistance to hormonal therapy.46 Another study also stated that increased MMP1 expression in breast cancer is correlated with recurrence and metastasis so that MMP1 can be used as a prognostic factor in breast cancer.47\n\nAt the time of EMT in breast cancer, cancer cells induce increased PDGF expression through the TGF-β pathway. In normal cells, TGF-β functions to control homeostasis, maintaining the body's defense system and plays a role in the wound healing process. When cells are in a pre-malignant state, TGF-β plays a role in suppressing tumor growth directly, for example through apoptosis activation or indirectly by controlling the stroma around the cells (e.g.: suppressing the inflammatory process). When the cell has become malignant and EMT has occurred, the cell can deactivate the ability of TGF-β to suppress tumor growth, so that what becomes dominant is the function of TGF-β as a trigger for tumor progression.48\n\nCancer cells that have gone through EMT will make TGF-β produce cytokines that are pro-tumorigenic, including ILEI (Interleukin-like EMT-inducer), HGF (hepatocyte growth factor), EGF (epidermal growth factor) and PDGF (platelet-derived growth factor).49 PDGF is a pro-angiogenic factor that plays a role in several solid tumor growth processes by paracrine and autocrine means. The signal derived from PDGF will make the tumor cells become more aggressive (autocrine), stimulate angiogenesis (paracrine) and turn normal fibroblasts into cancer-associated fibroblasts (CAF). Furthermore, the CAF will activate transcription factors (among others: SNAIL, SLUG) which can convert epithelial progenitor cells into mesenchymal progenitor cells. All these processes will result in more cells experiencing EMT, and a “loop signaling” allows cancer cells to multiply and progress.50\n\nCAF is the most abundant component found in the tumor microenvironment. In malignancy, CAF will determine the progress of tumor cells through regulating nutrition for tumor cells, re-shaping the extracellular matrix so that cancer cells can invade more easily, suppressing the body's defense system so that cancer cells are not destroyed by immune cells, and regulating extra and intra-cellular signals so that cancer cells can survive chemotherapy.51 CAF has several markers including: α-SMA, FAP, integrin β1/CD29; where α-SMA is the most widely used marker for CAF.52\n\nIn this study, significant differences were found for PDGF expression between the non-recurrence group and the recurrence group, both for the ductal type (p=0.000) and the lobular group (p=0.002). These results are the same as studies conducted by Jansson which stated that PDGF expression is correlated with the occurrence of early recurrence in breast cancer.53 Another study conducted by Chou stated that breast cancer patients who get taxane chemotherapy tend to experience chemoresistance if they get over expression of PDGF.54 Another study stated that if PDGF expression in breast cancer patients is inhibited, it increases the effectiveness of hormonal therapy in patients with positive hormonal receptors.55\n\nThe expression α-SMA in this study showed that for ductal type breast cancer there was a significant difference between the non-recurrence group and the recurrence group (p=0.000). These results are the same as research by Bonneau which stated that α-SMA (CAF) expression correlates with recurrence and metastasis in luminal (ductal) type breast cancer.56 In lobular breast cancer, α-SMA expression was not significantly different between the non-recurrence group and the recurrence group (p=0.063). These results were found since in lobular type breast cancer, there are no severe TME changes compared to the ductal type.44 Recurrence that occurs in lobular type breast cancer often occurs due to a non-radical margin of operation because changes in the structure of the TME are not very clear, making it difficult for surgeons and pathologists to determine the outer boundary of the tumor.57\n\nBreast cancer cells that are still present when the patient undergoes therapy (surgery, chemotherapy, or radiotherapy) is in a dormant condition. While in dormant conditions, cancer cells adjust to new micro-environment conditions, try to survive chemotherapy and radiation, and adapt to avoid the body's defense mechanisms.58\n\nAn important phase for cancer cells to come out of a dormant situation is when the breast cancer cells can change from an epithelial phenotype to mesenchymal phenotype (EMT). The EMT process makes cancer cells convert pro-apoptotic factors into non-apoptotic, so that the cells become immortal and have cancer stemness properties. When cancer cells are already in such a condition, they will be more resistant to multi-drug chemotherapy, more aggressive and likely to recur.59\n\nOne of the pro-apoptotic factors that play an important role in controlling cancer cell growth is CD95. Activation of CD95 by cancer cells activates the death-inducing signaling complex (DISC) via the Fas-associated protein with death domain (FADD), caspase-8 and caspase-10 pathways.60 When EMT occurs or if it is continuously stimulated, CD95 can change its nature from pro-apoptotic factor to non-apoptotic factor.61 EMT and chronic stimulation of CD95 will make cancer cells secrete interferon type I (IFNα or IFNβ) which will interact with its receptors (IFNAR1 and IFNAR2). This interaction activates the signal transducer and activator of transcription 1 (STAT1) and causes STAT1-promoting cancer stemness.62\n\nThe results of this study showed that there was a significant difference in CD95 expression between the group that experienced recurrence and did not experience recurrence in the Ductal type (p=0.000) and lobular type (p=0.045). Similar results were also mentioned by Pellegrino, reporting that CD95 expression is one of the risk factors for breast cancer recurrence.63\n\nLocal recurrence mechanism in ductal type breast cancer\n\nThe results of pathway analysis in ductal type recurrence breast cancer in this study showed a significant influence between vimentin expression and MMP1 expression (p=0.000) and had a strong correlation between the two (β=0.611). These results are in line with research conducted by Stallings-Mann, 2012, on Rac1b cells, showing that vimentin induces an increase in MMP1 expression.64\n\nVimentin expression also had an influence on PDGF expression (p=0.000) and had a strong correlation coefficient (β=0.670). This result is in accordance with the findings of research conducted by Paulin, 2022, which stated that the occurrence of EMT (with vimentin markers) affects several growth factors, including PDGF, through the binding of basic protein heterodimers, leucine-zipper (bZIP), either Jun (c-Jun, JunB, JunD), Fos (cFos, FosB, Fra1 and Fra2), ATF (ATF-1, ATF-2)/CREB, or homodimers from Jun/Jun.65\n\nPDGF in this study also showed a significant effect on α-SMA expression (p=0.000) with a moderate correlation (β=0.592). Similar results were also shown in previous research by Valgeirsdóttir, 1998. The study also added that activation of the PDGF receptor causes reorganization of vimentin through the associated fibroblast cancer pathway of which α-SMA is a marker.66\n\nThe expression of α-SMA in this study had an influence on the occurrence of recurrence in ductal type breast cancer (p=0.000) with a moderate correlation (β=0.592). These results are in line with a study conducted by Bonneau which stated that CAF correlates with the occurrence of recurrence in early-stage ductal type breast cancer.56 Another study conducted by Risom also stated that changes in the structure and composition of the stroma of cancer cells due to CAF activation causes cancer cells to become more aggressive and increase the risk of recurrence.67\n\nThe occurrence of recurrence in this study was also influenced by EMT which resulted in the body's defense mechanism impairment. Pathway analysis in this study showed that EMT influenced CD95 (p=0.000) with a correlation value of β=0.592 (moderate correlation). Furthermore, CD95 expression significantly influenced the occurrence of recurrence (p=0.000). In a previous study, Guégan also mentioned the same thing, reporting that CD95 expression correlated with recurrence and resistance to chemotherapy in ductal type breast cancer.68\n\nLocal recurrence mechanism in lobular type breast cancer\n\nFor lobular type breast cancer, in this study the occurrence of recurrence was influenced by the failure of the body's defense mechanism to destroy cancer cells. The TME in this study did not have a significant influence on the occurrence of recurrence. Research conducted by Van der Sangen concluded that TME in lobular type breast cancer affects the occurrence of recurrence if the surgery performed is not radical.69\n\nThe EMT process that occurs in lobular breast cancer makes CD95 a significant non-apoptotic factor (p=0.000) and has a moderate correlation coefficient (β=0.467). These changes give cancer cells properties like those of cancer stem cells and make them immortal.62 This is evidenced by this study, which shows that CD95 affects the occurrence of recurrence (p=0.001) and has a very strong correlation (β=0.802). The nature of cancer cells that become immortal will make the cancer cells resistant to chemotherapy and cause recurrence. These results are similar to a study by Wilson which stated that lobular type breast cancer is more resistant to chemotherapy when compared to ductal type breast cancer.70\n\nAccording on the results of observations and statistical analysis, it was found that the number of cells expressing vimentin, MMP1, and PDGF in ductal type cancers was different from the lobular type cases that underwent local recurrence after mastectomy and adjuvant chemotherapy. Meanwhile, we found no difference in α-SMA and CD95. Besides that, the local recurrence mechanism in the ductal type of early-stage breast cancer is different from that of the lobular type. In the ductal type, the mechanism of recurrence happens through two pathways: through pathways that affect the tumor microenvironment and through pathways that affect the body's defense mechanisms. Whereas for lobular breast cancer, the local recurrence mechanism is only through pathways that affect the body's defense mechanisms. Finally, author realize that breast cancer cases are very heterogeneous; the heterogenicities of the sample and the small number of samples were weakness in this study.",
"appendix": "Data availability\n\nFigshare: RAW Data for surgical specimens subjected to immunohistochemical examination using monoclonal antibodies against vimentin, α-SMA and MT-MMP1, PDGF and CD95, https://doi.org/10.6084/m9.figshare.22817513.v1. 71\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication)\n\n\nAcknowledgement\n\nThis article is part of a dissertation.\n\n\nReferences\n\nLu L, Dong J, Wang L, et al.: Activation of STAT3 and Bcl-2 and reduction of reactive oxygen species (ROS) promote radioresistance in breast cancer and overcome of radioresistance with niclosamide. Oncogenes. 2018; 37(39): 5292–5304. Publisher Full Text\n\nSarmiento-Salinas F, Delgado-Magallon A, Montes-Alvarado J, et al.: Breast cancer subtypes present a differential production of reactive oxygen species (ROS) and susceptibility to antioxidant treatment. Front. Oncol. 2019; 9(jun): 480. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nSeshadri R, Raymond WA, Leong AS, et al.: Vimentin expression is not associated with poor prognosis in breast cancer. Int. J. Cancer. 1996; 67(3): 353–356. Publisher Full Text\n\ndel Casar JM , González-Reyes S, González LO, et al.: Expression of metalloproteases and their inhibitors in different histological types of breast cancer. J. Cancer Res. Clin. Oncol. 2010; 136(6): 811–819. PubMed Abstract | Publisher Full Text\n\nShen CJ, Kuo YL, Chen CC, et al.: MMP1 expression is activated by Slug and enhances multi-drug resistance (MDR) in breast cancer. PLoS One. 2017; 12(3): e0174487. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKim HW, Park JE, Baek M, et al.: Matrix Metalloproteinase-1 (MMP1) Upregulation through Promoter Hypomethylation Enhances Tamoxifen Resistance in Breast Cancer. Cancers. 2022; 14(5). 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nBadrinath N, Yoo SY: Recent Advances in Cancer Stem Cell-Targeted Immunotherapy. Cancers. 2019; 11(3): 310. Publisher Full Text\n\nScott FL, Stec B, Pop C, et al.: The Fas-FADD death domain complex structure unravels signalling by receptor clustering. Nature. 2009; 457(7232): 1019–1022. PubMed Abstract | Publisher Full Text | Free Full Text\n\nQadir AS, Stults AM, Murmann AE, et al.: The mechanism of how CD95/Fas activates the Type I IFN/STAT1 axis, driving cancer stemness in breast cancer. Sci. Rep. 2020; 10(1310): 1–14. Publisher Full Text\n\nZhu M, Li S, Cao X, et al.: The STAT family: Key transcription factors mediating crosstalk between cancer stem cells and tumor immune microenvironment. Semin. Cancer Biol. 2023; 88: 18–31. Academic Press. PubMed Abstract | Publisher Full Text\n\nPellegrino B, Hlavata Z, Migali C, et al.: Luminal Breast Cancer: Risk of Recurrence and Tumor-Associated Immune Suppression. Molecular Diagnosis and Therapy. 2021; 25(4): 409–424. Adis. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStallings-Mann ML, Waldmann J, Zhang Y, et al.: Matrix Metalloproteinase Induction of Rac1b, a Key Effector of Lung Cancer Progression. Sci. Transl. Med. 2012; 4(142): 142ra95–142ra95. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPaulin D, Lilienbaum A, Kardjian S, et al.: Vimentin: Regulation and pathogenesis. Biochimie. 2022; 197: 96–112. Publisher Full Text\n\nValgeirsdóttir S, Claesson-Welsh L, Bongcam-Rudloff E, et al.: PDGF induces reorganization of vimentin filaments. J. Cell Sci. 1998; 111(Pt 14): 1973–1980. PubMed Abstract | Publisher Full Text\n\nRisom T, Glass DR, Averbukh I, et al.: Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma. Cell. 2022; 185(2): 299–310.e18. 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}
|
[
{
"id": "205648",
"date": "22 Sep 2023",
"name": "Sumadi Lukman Anwar",
"expertise": [
"Reviewer Expertise Breast cancer",
"hnscc",
"molecular cancer"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe study provides new insights in the different expression of some proteins between ductal and lobular breast carcinomas. However, there are some rooms for improvement:\nIn the methods: please provide antibody clones used in the study and the company so that other researchers can repeat the experiments. The incubation time, temperature, and processing during the IHC should be provided.\n\nImmunohistochemistry could be interpreted by pathologists. In this study, image analysis should be explained more details, calculation of the images, statistical analysis should be explained\n\nIn the methods, pathway analysis should be explained in more detail, which software or enrichment analysis that has been used and how to develop the pathway.\n\nIn the conclusion (abstract), the authors should explain more in the different mechanisms of lobular and ductal carcinomas and which cancer treatment that can be modified according to this study\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "10286",
"date": "06 Oct 2023",
"name": "Andreas Andrianto",
"role": "Author Response",
"response": "Immunohistochemistry (IHC) Staining and Assessment Block paraffin derived from the MRM operation specimen was cut to a thickness of 4 µm and then heated at 600°C for one hour. After that, deparaffinization was carried out 3 times using xylene solution for 3 minutes each. Furthermore, rehydration was carried out using 100%, 96%, and 70% ethanol. After rehydration, wash with water for 3 minutes. Peroxidase blockade was performed using 0.5% H2O2 in thirty minutes of methanol, then water cleansing for 5 minutes. Before and after peroxidase blockade, washing was carried out using pH 7.4 Phosphate-buffer saline (PBS). Immunohistochemical staining was carried out on all tumor samples to identify vimentin, α-SMA, PDGF, MMP1, CD95 protein expression. The antibodies used for the study were Mouse anti-human Monoclonal Antibody from MyBioSource with the catalog number: MBS475544 vimentin), MBS2507725 (PDGF), MBS476188 (MMP1), MBS266274 (α-SMA ) and MBS10754069 (CD95). ). The antibodies were optimized at a concentration of 1:600, diluted in phosphate-buffered saline (PBS) with bovine serum albumin (BSA), and then incubated with the tumor sections for 30 minutes at room temperature. The slides obtained were subjected to evaluation and analysis by quantifying the number of cells exhibiting a positive response to each specific antibody. This assessment was conducted using a light microscope set at a magnification of 400x. The calculation was conducted across ten fields of view, after which the average number of positive cells per field of view was determined. A statistical analysis was conducted in order to ascertain the disparities between the group that experienced recurrence and the group that did not experience recurrence. The statistical test employed in this study is the mean difference test. Prior to doing pathway analysis, it is customary to perform a normality test and homogeneity test, which are subsequently followed by a logistic regression test. The data processing program utilized is OpenEpi version 3.0, along with the free statistical software EZR, which is built upon R-command. The statistical value that is considered significant is <0.05 Conclusion The processes of local recurrence in early-stage IDC and ILC exhibit distinct characteristics. The tumor microenvironment (TME) and the immune system are both critical factors in determining the likelihood of recurrence in IDC, while in ILC, the immune system plays a crucial role in determining the likelihood of recurrence. The results of this study indicate that there is merit in exploring the augmentation of the patient's immune system as a viable approach for the treatment of cancer."
}
]
},
{
"id": "205651",
"date": "26 Sep 2023",
"name": "Kristanto Yuli Yarso",
"expertise": [
"Reviewer Expertise molecular biology",
"tumor microenvironment",
"breast cancer"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nPlease explain abbreviations when first used: IDC, ILC, SMA, MMP1, PDGF.\n\nWhen you chose cancer recurrence as entry point and followed retrospectively then obtained many predicting factors from MRM tissue - this should be put as case control design.\n\nNo need to discuss about BCS, since all your subjects were mastectomy patients.\n\nNo need to explain data distribution analysis since it is standard procedure, just present data in \"mean\" whenever it has normal distribution and \"median\" when it has no normal distribution.\n\nMore subjects would be more appropriate.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "10302",
"date": "06 Oct 2023",
"name": "Andreas Andrianto",
"role": "Author Response",
"response": "I express my gratitude for dedicating your time to evaluate the content of my manuscript. 1. The explanation of abbreviations in the main text has been revised to accommodate the restricted character limitation in the abstract. 2. The study design has been revised in accordance with the recommendations provided by the reviewers. 3. The explanation regarding BCS has been omitted. 4. We appreciate your input, and we have made the necessary revisions. 5. We have added it to the conclusions and suggestions section"
}
]
}
] | 1
|
https://f1000research.com/articles/12-841
|
https://f1000research.com/articles/12-810/v1
|
11 Jul 23
|
{
"type": "Data Note",
"title": "The identification of high-performing antibodies for Apolipoprotein E for use in Western Blot and immunoprecipitation",
"authors": [
"Riham Ayoubi",
"Kathleen Southern",
"Carl Laflamme",
"NeuroSGC/YCharOS collaborative group",
"Riham Ayoubi",
"Kathleen Southern"
],
"abstract": "Apolipoprotein E is a secreted protein involved in mediating lipid distribution and metabolism among cells of specific tissues. The dysregulation of Apolipoprotein E can disturb cholesterol homeostasis, resulting in several diseases, including cardiovascular disease and Alzheimer’s disease. The therapeutic potential of Apolipoprotein E against these diseases demonstrates the importance of providing high-quality antibodies for this protein to the scientific community. In this study, we characterized fourteen Apolipoprotein E commercial antibodies for Western Blot and immunoprecipitation, using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.",
"keywords": [
"Uniprot ID P02649",
"APOE",
"Apolipoprotein E",
"antibody characterization",
"antibody validation",
"Western Blot",
"immunoprecipitation"
],
"content": "Introduction\n\nApolipoprotein E, or APOE, is a 299 amino acid transcribed and secreted to regulate lipid homeostasis by controlling the uptake of cholesterol and lipoproteins via receptor-mediated endocytosis.1,2 Three major isoforms of APOE exist, apoE4, apoE3, and apoE2.1 Despite only differing by single amino acid substitutions, their functionalities are altered at both the cellular and molecular levels.1 Accordingly, the binding affinity of APOE to its ligand, the LDL receptor (LDLR), varies depending on the isoform.2 ApoE3 and apoE4 bind to LDLR with high affinity while apoE2 binds with low affinity.3\n\nAssociation studies have demonstrated apoE4 to be a genetic risk factor for cardiovascular disease, as it can cause high levels of circulating cholesterol, in the form of LDL as well as a genetic risk factor for late-onset Alzheimer’s disease.4–7 The critical role of APOE in health and disease highlights the need for additional research into the protein’s mechanism of action and potential for therapeutic strategies.8 Mechanistic studies would be greatly facilitated with the availability of validated and high-quality antibodies.\n\nHere, we compared the performance of a range of commercially-available antibodies for Apolipoprotein E and validated several antibodies for Western Blot and immunoprecipitation, enabling biochemical and cellular assessment of Apolipoprotein E properties and function.\n\n\nResults and discussion\n\nOur standard protocol involves comparing readouts from wild-type (WT) and knockout (KO) cells.9–11 The first step was to identify a cell line(s) that expresses sufficient levels of Apolipoprotein E to generate a measurable signal. To this end, we examined the DepMap transcriptomics database to identify all cell lines that express the target at levels greater than 2.5 log2 (transcripts per million “TPM” + 1), which we have found to be a suitable cut-off (Cancer Dependency Map Portal, RRID:SCR_017655). Commercially available HAP1 cells expressed the APOE transcript at RNA levels above the average range of cancer cells analyzed. Parental and APOE knockout HAP1 cells were obtained from Horizon Discovery (Table 1).\n\nApolipoprotein E is predicted to be a secreted protein. Accordingly, we collected concentrated culture media from both WT and APOE KO cells and used the conditioned media to probe the performance of the antibodies (Table 2) side-by-side by Western Blot and immunoprecipitation.10,11 The profiles of the tested antibodies are shown in Figures 1 and 2.\n\n* Monoclonal antibody.\n\n** Recombinant antibody.\n\nHAP1 WT and APOE KO were cultured in serum free media. Media were collected, concentrated, and 30 μg of protein were processed for Western Blot with the indicated Apolipoprotein E antibodies. The Ponceau stained transfers of each blot are shown. Antibody dilutions were chosen according to the recommendations of the antibody supplier. Exceptions were given for antibodies 13366**,18254-1-AP and 66830-1-Ig* which were titrated to 1/500, 1/200 and 1/200, respectively, as the signals were too weak when following the supplier’s recommendations. Antibody dilution used: GTX635889* at 1/200, GTX635891* at 1/200, ab52607** at 1/1000, ab51015** at 1/1000, ab1907* at 1/1000, 13366** at 1/500, ARP54283 at 1/1000, 701241** at 1/200, MA5-41148** at 1/1000, MA5-15852* at 1/1000, MAB41441* at 1/200, NB110-60531* at 1/200, 18254-1-AP at 1/200, 66830-1-Ig* at 1/200. Apolipoprotein E predicted band size: 36 kDa. *Monoclonal antibody, **Recombinant antibody.\n\nImmunoprecipitation was performed on 0.9 mg concentrated culture media from HAP1 WT, and using 2.0 μg of the indicated Apolipoprotein E antibodies pre-coupled to protein G or protein A magnetic beads. Samples were washed and processed for Western Blot with the indicated Apolipoprotein E antibody. Antibody 13366** was used at 1/500 for all Western Blots. The Ponceau stained transfers of each blot are shown. SM=3% starting material; UB=3% unbound fraction; IP=immunoprecipitate; HC=heavy chain; *Monoclonal antibody, **Recombinant antibody.\n\nIn conclusion, we have screened Apolipoprotein E commercial antibodies by Western Blot and immunoprecipitation and identified several high-quality antibodies under our standardized experimental conditions. The underlying data was previously uploaded to an open access repository, Zenodo.12,13\n\n\nMethods\n\nAll Apolipoprotein E antibodies are listed in Table 2, together with their corresponding Research Resource Identifiers (RRID), to ensure the antibodies are cited properly.14 Peroxidase-conjugated goat anti-mouse and anti-rabbit antibodies are from Thermo Fisher Scientific (cat. number 65-6520 and 62-6120).\n\nHAP1 WT and APOE KO cell lines used are listed in Table 1, together with their corresponding RRID, to ensure the cell lines are cited properly.15 Cells were cultured in DMEM high-glucose (GE Healthcare cat. number SH30081.01) containing 10% fetal bovine serum (Wisent, cat. number 080450), 2 mM L-glutamate (Wisent cat. number 609065), 100 IU penicillin and 100 μg/mL streptomycin (Wisent cat. number 450201). Cells were starved in DMEM high-glucose containing L-glutamate and penicillin/streptomycin.\n\nHAP1 cells WT and APOE KO were washed 3× with PBS 1× and starved for ~18 hrs. Culture media were collected and centrifuged for 10 min at 500× g to eliminate cells and larger contaminants, then for 10 min at 4500× g to eliminate smaller contaminants. Culture media were concentrated by centrifuging at 4000× g for 30 min using Amicon Ultra-15 Centrifugal Filter Units with a membrane NMWL of 10 kDa (MilliporeSigma cat. number UFC901024).\n\nWestern Blots were performed as described in our standard operating procedure.16 Midi precast 4-20% Tris-Glycine polyacrylamide gels from Thermo Fisher Scientific (cat. number WXP42012BOX) were used and proteins were transferred on nitrocellulose membranes. Proteins on the blots were visualized with Ponceau S staining (Thermo Fisher Scientific, cat. number BP103-10) which is scanned to show together with individual Western Blot. Blots were blocked with 5% milk for 1 hr, and antibodies were incubated overnight at 4°C with 5% bovine serum albumin (BSA) (Wisent, cat. number 800-095) in TBS with 0.1% Tween 20 (TBST) (Cell Signaling Technology, cat. number 9997). Following three washes with TBST, the peroxidase conjugated secondary antibody was incubated at a dilution of ~0.2 μg/mL in TBST with 5% milk for 1 hr at room temperature followed by three washes with TBST. Membranes were incubated with Pierce ECL from Thermo Fisher Scientific (cat. number 32106) or with Clarity Western ECL Substrate from Bio-Rad (cat. number 1705061) prior to detection with the iBright™ CL1500 Imaging System from Thermo Fisher Scientific (cat. number A44240).\n\nImmunoprecipitation was performed as described in our standard operating procedure.17 Antibody-bead conjugates were prepared by adding 2 μg or 20 μL of antibody at an unknown concentration to 500 μL of Pierce IP Lysis Buffer from Thermo Fisher Scientific (cat. number 87788) in a 1.5 mL microcentrifuge tube, together with 30 μL of Dynabeads protein G - (for Mouse and rat antibodies) and protein A - (for rabbit antibodies) from Thermo Fisher Scientific (cat. number 10003D and 10002D, respectively). Pierce IP Lysis Buffer (25 mM Tris-HCl pH 7.4, 150 mM NaCl, 1 mM EDTA, 1% NP-40 and 5% glycerol) was supplemented with the Halt Protease Inhibitor Cocktail 100X from Thermo Fisher Scientific (cat. number 78446) at a final concentration of 1×. Tubes were rocked for ~1 hr at 4°C followed by two washes to remove unbound antibodies. Starved HAP1 WT culture media were concentrated as described above. 0.6 mL aliquots at 1.5 mg/L of protein were incubated with an antibody-bead conjugate for ~1 hr at 4°C. The unbound fractions were collected, and beads were subsequently washed three times with 1.0 mL of IP Lysis Buffer and processed for SDS-PAGE and Western Blot on precast midi 4-20% Tris-Glycine polyacrylamide gels. Prot-A: HRP (MilliporeSigma, cat. number P8651) was used as a secondary detection system at a concentration 0.4 μg/mL.",
"appendix": "Data availability\n\nZenodo: Antibody Characterization Report for Apolipoprotein E, https://doi.org/10.5281/zenodo.7249055. 12\n\nZenodo: Dataset for the Apolipoprotein E antibody screening study, https://doi.org/10.5281/zenodo.7802875. 13\n\n\nAcknowledgment\n\nWe’d like to thank the NeuroSGC/YCharOS collaborative group for their important contribution to the creation of an open scientific ecosystem of antibody manufacturers and knockout cell line suppliers as well as the development of community-agreed protocols. Members of the group can be found below.\n\nNeuroSGC/YCharOS collaborative group: Riham Ayoubi, Aled M. Edwards, Carl Laflamme, Peter S. McPherson, Chetan Raina and Kathleen Southern.\n\nThank you to the Structural Genomics Consortium, a registered charity (no. 1097737), for your support on this project. The Structural Genomics Consortium receives funding from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Genome Canada through Ontario Genomics Institute (grant no. OGI-196), the EU and EFPIA through the Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN grant no. 875510), Janssen, Merck KGaA (also known as EMD in Canada and the United States), Pfizer and Takeda.\n\nAn earlier version of this article can be found on Zenodo (doi: 10.5281/zenodo.7249055).\n\n\nReferences\n\nMahley RW, Rall SC Jr: Apolipoprotein E: far more than a lipid transport protein. Annu. Rev. Genomics Hum. Genet. 2000; 1: 507–537. PubMed Abstract | Publisher Full Text\n\nMann KM, Thorngate FE, Katoh-Fukui Y, et al.: Independent effects of APOE on cholesterol metabolism and brain Abeta levels in an Alzheimer disease mouse model. Hum. Mol. Genet. 2004; 13(17): 1959–1968. PubMed Abstract | Publisher Full Text\n\nYamamoto T, Choi HW, Ryan RO: Apolipoprotein E isoform-specific binding to the low-density lipoprotein receptor. Anal. Biochem. 2008; 372(2): 222–226. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMenzel H, Kladetzky R, Assmann G: Apolipoprotein E polymorphism and coronary artery disease. Arteriosclerosis. 1983; 3(4): 310–315. Publisher Full Text\n\nStengård JH, Zerba KE, Pekkanen J, et al.: Apolipoprotein E polymorphism predicts death from coronary heart disease in a longitudinal study of elderly Finnish men. Circulation. 1995; 91(2): 265–269. Publisher Full Text\n\nCorder EH, Saunders AM, Strittmatter WJ, et al.: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993; 261(5123): 921–923. PubMed Abstract | Publisher Full Text\n\nStrittmatter WJ, Saunders AM, Schmechel D, et al.: Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. 1993; 90(5): 1977–1981. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, et al.: Absolute 10-year risk of dementia by age, sex and APOE genotype: a population-based cohort study. CMAJ. 2018; 190(35): E1033–E1041. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLaflamme C, McKeever PM, Kumar R, et al.: Implementation of an antibody characterization procedure and application to the major ALS/FTD disease gene C9ORF72. elife. 2019; 8: 8. Publisher Full Text\n\nAyoubi R, Southern K, Laflamme C, et al.: The identification of high-performing antibodies for Midkine for use in Western blot and immunoprecipitation [version 1; peer review: awaiting peer review]. F1000Res. 2023; 2023(12): 148.\n\nAyoubi R, Southern K, Laflamme C, et al.: The identification of high-performing antibodies for Secreted frizzled-related protein 1 (sFRP-1) for use in Western Blot and immunoprecipitation [version 1; peer review: awaiting peer review]. F1000Res. 2023; 12: 291. Publisher Full Text\n\nAyoubi R, McPherson PS, Laflamme C: Antibody Characterization Report for Apolipoprotein E.2022. Publisher Full Text\n\nLaflamme C: Dataset for the Apolipoprotein E antibody screning study. [Data set]. Zenodo. 2023. Publisher Full Text\n\nBandrowski A, Pairish M, Eckmann P, et al.: The Antibody Registry: ten years of registering antibodies. Nucleic Acids Res. 2023; 51(D1): D358–D367. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBairoch A: The Cellosaurus, a Cell-Line Knowledge Resource. J. Biomol. Tech. 2018; 29(2): 25–38. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAyoubi R, McPherson PS, Laflamme C: Antibody Screening by Immunoblot.2021. Publisher Full Text\n\nAyoubi R, Fotouhi M, McPherson P, et al.: Antibody screening by Immunoprecitation.2021. Publisher Full Text"
}
|
[
{
"id": "186248",
"date": "19 Jul 2023",
"name": "Leonard Kritharides",
"expertise": [
"Reviewer Expertise Cell biology and biochemistry of apo E"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have compared and validated commercially available apolipoprotein E antibodies for detection by Western blotting and immunoprecipitation using HAP1 cells with and without apoE expression.The resource is helpful and could be improved by addressing the following:\nProvide a summary and conclusion commenting on which antibodies are recommended for either Western Blotting or Immunoprecipitation.\n\nApoE can be cleaved generating a C-terminal and a N-terminal peptide. The current work does not investigate whether the antibodies tested detect these cleavage products. Please state the immunogenic region to which the antibodies are raised in table 2.\n\nPlease add details about species specificity to Table 2. If all detect human apoE please make this explicit.\n\nCellular apoE exists as non-glycosylated and glycosylated isoforms, and secreted apoE is variably but predominantly glycosylated (refs 1-3). The authors have only shown detection of secreted apoE. It would be helpful to show the ability of the antibodies to detect cellular apoE glycoforms. This will also indicate whether the antibodies display non-specific binding to other cellular proteins.\n\nProvide full name for HAP1 before abbreviation is used.\n\nWhat is the apoE genotype of the HAP1 cell line they have used?\n\nIs the rationale for creating the dataset(s) clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": [
{
"c_id": "9942",
"date": "04 Aug 2023",
"name": "Kathleen Southern",
"role": "Author Response",
"response": "Thank you to Leonard Kritharides and Maaike Kcokx for your extensive review of this article. We appreciate your constructive feedback and will be submitting a new version of the manuscript, to include several of your suggestions that are within the scope of this study. Unfortunately, we cannot comment or conclude on which antibodies to select for Western Blot and Immunoprecipitation. Previously discussed on the FAQ section of the YCharOS gateway page, we have found that, for the most part, scientists interested in our reports have the expertise to interpret the antibody characterization data. Moreover, as the antibodies are tested under one specific set of conditions, the scoring/recommendation would be valid only under the precise experimental setup and cell line used. That said, YCharOS reports serve as an invaluable guide pointing scientists to select the appropriate antibodies for their experimental needs. As per your second and third points, a column will be added to Table 2 in the newly submitted version of the manuscript to include the immunogenic regions of the commercial antibodies that were tested. We also included a statement in the Antibodies sub-section of the Methods section stating that all antibodies tested were reactive against Human ApoE antigen. As a follow up to your fourth point, our workflow consists of testing antibodies on culture media for secreted proteins - allowing the identification of antibodies with high selectivity for the corresponding protein. We believe our data can be used to inform scientists on the best antibodies to purchase to identify intracellular ApoE. We leave it to experts in the field to optimize antibodies for their own experimental conditions. For the final suggestion, we have included in Table 1 that the ApoE KO cell line is derived from a 16bp deletion of ApoE."
}
]
}
] | 1
|
https://f1000research.com/articles/12-810
|
https://f1000research.com/articles/12-1250/v1
|
29 Sep 23
|
{
"type": "Case Study",
"title": "War damages compensation: a case study on Ukraine",
"authors": [
"Iryna Izarova",
"Yuliia Hartman",
"Silviu Nate",
"Yuliia Hartman",
"Silviu Nate"
],
"abstract": "Russia's illegal, brazen and cynical full-scale invasion of Ukraine began on February 24th, 2022, and is still ongoing at the time of this research (July 2023). The damages incurred by Ukraine and its citizens during the years of occupation of the territories and the war are calculated in millions, although it is difficult to definitively determine both the methodology and specific numbers. To restore justice, it seems much more important to define a fair, transparent, and understandable procedure for compensating the losses suffered by citizens and businesses as a result of these events. This is especially important in the context of the need to implement the goals of sustainable development, in particular, ensuring equal access to justice for all. The article is devoted to these and related issues. To determine the procedure for compensating losses and damages caused by the war, we first determined what exactly can be compensated and who can apply for compensation. These and other factors determine the peculiarities of the procedure for the restoration of rights and compensation for damage caused by the war in Ukraine. In searching for an answer to the researched question, we analyzed the current legislation of Ukraine and draft laws proposed to regulate relations related to compensation for damages. We also conducted a comprehensive analysis of concepts such as losses, damages, compensation, reparations, and reimbursement as defined in national legislation and international treaties. The generalization of the case law of national courts (more than 200 analyzed decisions of the courts of the first and appeal and cassation instances for the period from February 20, 2014 to March 1, 2023, examples of which are presented in the study) indicates the presence of various approaches of compensation for damage, in understanding how to restore the violated rights of citizens.",
"keywords": [
"reimbursement for damage",
"war damages compensation",
"war in Ukraine",
"settlement of disputes",
"transitional justice"
],
"content": "Introduction\n\n\n\n«Difficult questions include who is included among the victims to be compensated, how much compensation is to be rewarded, what kinds of harm are to be covered, how harm is to be quantified, how different kinds of harm are to be compared and compensated and how compensation is to be distributed».1\n\nThe tragedies of the war in Ukraine did not pass by anyone, at the same time, everyone’s situation is unique: different rights were violated, therefore, the damages that were incurred should be differentiated according to certain criteria.\n\nUkraine is obliged to provide victims with effective remedies (provide effective remedies to victims), namely to provide victims with equal access to effective judicial protection, as well as to other legal remedies, including access to administrative bodies and other bodies, as well as mechanisms, conditions and procedures in accordance with national legislation, which was defined by the UN in Basic Principles and Guidelines on the Right to a Remedy and Reparation for Victims of Gross Violations of International Human Rights Law and Serious Violations of International Humanitarian Law 2005.2\n\nResolution of the Council of Europe3 is foreseen (18) to create an international framework for compensating for any harm, loss, or injury caused. To realize this task, it was proposed the creation of an international register of damage, in cooperation with Ukraine and the EU member states aimed to keep records pertaining to evidence and claims regarding damage, loss, or injury suffered by individuals and entities, both natural and legal, in Ukraine (19.2). An international compensation commission was chosen as an option to examine and make decisions on the claims that have been submitted and documented through the registry. The second goal is to keep an indemnification fund that would disburse compensation awards to claimants who have successfully proven their claims (19.3). The main and the most interesting issue is how to incorporate the proposed ideas within the existing mechanisms of damage compensation according to the national laws of Ukraine.\n\nThis is especially important in the context of the need to implement the goals of sustainable development, in particular, ensuring equal access to justice for all. Goal 16 For Sustainable Development4 emphasize the importance of robust and peaceful institutions that operate to guarantee equal access to justice for all individuals within inclusive and harmonious societies. Accomplishing this task amidst formidable obstacles such as the pandemic and the ongoing war in Ukraine was exceptionally challenging. Though Ukraine made some necessary steps forward5 and considering mechanisms of war damage compensation should continue to keep introducing it.6\n\nIn general, the principles underlying schemes for compensating victims of war are enshrined in international humanitarian law and international human rights law. These principles concern the protection and assistance of victims of armed conflict and the recognition of their right to compensation for damages incurred.\n\nThe compensation for damages can be realized in different ways and in different areas. Financial compensation for material damages: affected Ukrainian citizens could claim financial compensation for their homes, properties, and property destroyed during the conflict. Affected Ukrainian citizens who have lost their jobs or suffered economic losses due to the conflict could apply for emergency financial aid, economic reconstruction and revitalization programmes and other forms of support to restore their sources of income. Medical and psychological assistance: persons who suffered from violent crimes during hostilities could seek medical and psychological assistance to recover their mental and physical health. Social aid and protection of children’s rights: orphaned children and other vulnerable people could apply for social aid and protection of children’s rights to rebuild their lives and ensure they are not at risk of exploitation or abuse. Humanitarian assistance and protection of refugees: Ukrainian citizens who have had to take refuge in other areas of Ukraine or Europe could apply for humanitarian assistance and protection of refugees to provide shelter, food, water and different basic needs.\n\nHaving drawn attention to the above, in this article, we focus on the issues of compensation for the damage caused by Russia’s invasion of Ukraine, taking into account the specifics of other types of assistance to victims (such as medical, psychological, etc.), which are the subject of research in other fields of science.\n\nThe draft law proposed in March 2022 defined compensation for damaged and destroyed real estate during the war [1]. This does not mean that other types of losses caused by the war will not be compensated, but the purpose of this draft law was to define a simplified procedure for the restoration of rights, but at least other options for the restoration of violated rights will not be in the same conditions - simply and quickly.\n\nIn today’s difficult conditions of war and mass destruction, it is extremely important to ensure the achievement of the appropriate level of satisfaction of public expectations, when citizens suffering from war will receive fair compensation for their losses. Transitional justice is a complex phenomenon that has already existed on the territory of Ukraine over time since the temporary occupation of the territory of the East and Crimea,7–11 which allows the introduction of flexible tools for restoring justice in post-war conditions.\n\nAs rightly emphasized in the Secretary General’s of United Nations report, published in August 2004, on the rule of law and transitional justice, in the conditions of massive violations of human rights, states are obliged to act not only against criminals, but also on behalf of victims - including by providing compensation, appropriate programs to compensate victims for the damage caused can to be an effective and operational complement by offering tangible remedies, fostering reconciliation, and reinstating victims’ confidence in the state, thereby acknowledging the valuable role of tribunals and truth commissions.12 As stated in the last report, “designing and implementing inclusive, context-specific and victim-centered transitional justice processes”13 is exactly the result we should strive for.\n\nThe experience of other countries clearly demonstrates the importance and urgency of providing a comprehensive approach to the settlement of the issue of compensation for the losses of the civilian population in war conditions, not limited to the introduction of separate procedures for the compensation of costs for the losses of this or that property.\n\nIn particular, the Main Legal Department of the Verkhovna Rada of Ukraine drew attention to the unreasonableness of limiting only compensation for damaged and destroyed immovable property, the correct remark about the selectivity of the mechanism cannot also be applied to all objects of civil rights provided for by the current legislation (Chapter 3 of the Civil Code).14\n\nWe firmly believe, and our research will substantiate this standpoint, that the diverse array of losses endured by Ukrainian citizens and legal entities necessitates the pursuit of an effective and comprehensive mechanism for compensating damages. This mechanism should serve as an umbrella procedure encompassing the restoration of both property and non-property rights that were violated during the war and occupation.\n\nWe have to mention that in Ukraine, the institute of reimbursement of damages exists (‘vidshkoduvannia’), provided by Chapter 82 of the Civil Code of Ukraine, Articles 280, 515, 602, 1072, etc. In the meantime, the draft law on compensation consists of the other term, used in Ukrainian legislation in other ways.15\n\nThe ways of protecting civil rights and interests include compensation for damages and other methods of reimbursement (‘vidshkoduvannia’) for property damage prescribed by Article 16 of the Civil Code of Ukraine. According to Article 22 of the Civil Code of Ukraine, a person who has suffered damages as a result of a violation of their civil right has the right to compensation; damages are: 1) losses experienced by an individual due to the destruction or harm to an object, along with the expenses incurred or to be incurred in order to rectify the infringement of their rights (real damages); 2) the potential earnings that an individual would have received under normal circumstances had their rights not been violated (forgotten benefit).\n\nHowever, the concept of ‘compensation’ regarding compensation for property damage does not contain its definition or features. This definition is contained in the Law of Ukraine “On Copyright and Related Rights”,16 in which it uses as well as definition “reimbursement”, but has some peculiarities.\n\nThe term “compensation” is also used in the Commercial Code of Ukraine,17 the context of reimbursement of expenses for the purchase of machinery and equipment (Article 16, paragraph 2. The state may make compensations or additional payments to agricultural producers for agricultural products sold by them to the state).\n\nAt the same time, Article 152 contains provisions regarding the right of a business entity that carries out economic activity to demand compensation for damage caused to its natural resources by other entities. Part 1 of Article 225 of the Commercial Code contains provisions on possible material compensation for moral damage in cases provided for by law, which are part of the damages subject to compensation by a person who committed an economic offense. In a similar context, the concept is also used to determine the rights to compensation and reimbursement for losses to foreign investors (Article 397 of the Commercial Code of Ukraine).\n\nProbably, the question of the correct application of the institutions of civil law and commercial law also lies in the realm of defining these two branches of law and the debates that take place in academic circles,18–21 and may also be related to real problems of practical application since a separate branch of commercial courts operates in Ukraine.22\n\nParadoxically, in Latin, the term “reimbursement” (‘vidshkoduvannia’) sounds like compensatio. It is also worth noting that the UN documents refer primarily to reparations.1\n\nAs stated by the UN in the document Basic Principles and Guidelines on the Right to a Remedy and Reparation for Victims of Gross Violations of International Human Rights Law and Serious Violations of International Humanitarian Law 2005, in accordance with national legislation and international law, victims must be provided with full and effective compensation, which includes the following forms: restitution, compensation, rehabilitation, satisfaction and guarantees of non-repetition,2 namely:\n\n‘Restitution should, whenever possible, restore the victim to the original situation before the gross violations of international human rights law or serious violations of international humanitarian law occurred. Restitution includes, as appropriate: restoration of liberty, enjoyment of human rights, identity, family life and citizenship, return to one’s place of residence, restoration of employment and return of property’ (authors’ italics).\n\nAmong the specified forms is compensation,2 which in content corresponds to reimbursement for damage under the legislation of Ukraine - this is compensation for any economically assessed damage, depending on the severity of the infringement and specific circumstances of each situation, that arise as a consequence of severe transgressions of international law, human rights, and significant breaches of international humanitarian law, such as: (a) Physical or psychological harm; (b) Foregone prospects, including employment, education, and social advantages; (c) Material losses and diminished income, including loss of future earning capacity; (d) Non-monetary harm; (e) Costs necessary for legal or expert aid, medications, medical services, as well as psychological and social support. Rehabilitation should encompass medical and psychological treatment, as well as legal and social assistance.\n\nAt the same time, science expresses different views on the possibilities of applying these institutions: as noted by Larry May, restitution is the return to the rightful owner of what was lost or taken, and reparation is the restoration in proper condition of what was damaged. Restitution and reparation have the same root, restoration, which itself is a type of correction or compensation (rectification or compensation). But each term emphasizes different aspects of the idea of recovery. May argues that when transitional justice is achieved, as opposed to ordinary compensatory justice, sometimes the person who caused harm is not the only one who has a duty to restore.23\n\nThe question of the content of the concept is of great importance, since the appeal to the court with a demand for the protection of the right and the chosen method of protection of this right must comply with the current legislation, in particular, the main codified act regulating property and non-property relations - the Civil Code of Ukraine.\n\nQuestions regarding specific objects, losses, which are compensated under the specified Law, are dictated primarily by the desire to restore the rights of citizens who were left without a home, without a roof over their heads [2]. At the same time, any expenses that may have been caused by it should be reimbursed, otherwise, society’s expectations will not be fully met.\n\nHow to explain why the damaged house and not the car or other things are subject to compensation? Which are of interest to their owner. A house and an apartment are objects of property rights, like everything else; at the same time, it is precisely the aspect of their importance for the owner that should be decisive for assessing the value of compensation for expenses (photos, children’s personal clothes, etc.).\n\nAt the same time, in the conditions of war and transitional justice, it is not the fact of monetary compensation for losses that is important, but sometimes the very fact of recognizing these losses. Reparations may encompass non-financial aspects, as highlighted in the UN report,1 such as reinstating victims’ legal rights, implementing victim rehabilitation programs, and adopting symbolic actions like official apologies, monuments, and commemorative ceremonies.\n\nThe absence of effective loss compensation mechanisms can lead to unexpected consequences, the experience of other countries of the world24–26 confirms the need to introduce transparent and clear procedures, a defined procedure for compensation and a list of types of damage that are subject to them.\n\nThe looting of art objects by the Soviet Union and attempts to justify it are known to the whole world,24 which should attract the special attention of scientists, primarily because one of the declared goals of the war is the destruction of the Ukrainian people and their culture, so in this case it is not about precious art objects as such, but about, in particular, objects of Ukrainian culture and art, decisive for the history and identity of the Ukrainian people [3].\n\nIt is worth paying special attention to the procedure for compensation for damage caused to the health and life of the Ukrainian and civilian population in general during the war. In particular, as emphasized25 in a study of the Iraq and Afghanistan wars, the military paid out benefits to civilians for “accidental” injury, death, and/or property damage in order to “win” the hearts and minds of the population. The author reasonably concludes that while cash payments may alleviate short-term economic needs, the lack of legal accountability is problematic because it may contribute to increased impunity for combatant soldiers.26 Therefore, not in every case of damage, compensation can be determined precisely in monetary terms.\n\nAs the UN report rightly points out, restoration of property rights, or simply compensation when this cannot be done, is a common problem, especially when done through massive government programs. Challenging inquiries arise regarding who is among the victims who should receive compensation, how much compensation should be paid, what types of damage are covered, how to quantify damage, how different types of damage are compared and compensated, and how compensation is to be distributed.1\n\nSimultaneously, one year has elapsed since the commencement of Russia’s active hostilities, yet no mechanisms have been developed to compensate losses or indemnify those who have suffered due to the war. In Ukraine, only the matter of compensating costs for the temporary accommodation (stay) of internally displaced persons remains regulated.27 Persons who offered free accommodation to internally displaced individuals in Ukraine are eligible for this compensation, alongside employers who hired such individuals during the period of martial law in the country, and are entitled to reimbursement for their payment costs.28\n\nThe examples of other countries make it necessary to carry out a more careful analysis of the possibilities of pre-trial or other alternative settlement of disputes related to the compensation of damage caused to citizens en masse [4]. Since this article does not analyze these issues in detail in view of the scope and goals of the research, it is important to emphasize the perspective of this direction for further research.\n\nIn particular, it is worth recalling that, according to the report, states should, among other things, make efforts to develop procedures that would allow groups of victims to submit claims for reparations and receive reparations, if appropriate.2\n\nSeparate discussions are taking place in scientific circles regarding the compensation of ecological losses in Ukraine.29 The experience of settling disputes on violation of the environmental rights of citizens and compensation for losses is quite demonstrative. In this regard, the UN Compensation Commission is a unique model of responsibility and compensation for environmental damage, which provided a legal process that cataloged, assessed and awarded funds to pay for the clean-up and restoration of damaged soil, water, coastal ecosystems and other damage caused by the war in the Persian Gulf 1990-1991 years.30 The UNCC Environmental Program emphasizes the importance of an innovative approach to post-war justice.31 The Commission adapted the traditional bilateral compensation commission model, which highlights the accountability of states for environmental harm during armed conflicts and underscores the advantages that can be derived from engaging in multilateral efforts and sustaining long-term commitments towards environmental restoration.32\n\nAmong the issues that should be included in the circle of objects of compensation for damage caused by the war, the issue of relocation and return to the place of residence. As quite rightly noted in the literature, the issue of displacement during war is important, as we can see from the analysis of Ukrainian courts decisions, the results of which we present below, many displaced persons are in a legal limbo, without recognition and compensation. We also endorse the entitlement to return as recognized by customary international law, which obligates states to facilitate voluntary repatriation and provide restitution.2 Facilitation entails refraining from obstructing or impeding the return process, preventing acts of retaliation or discrimination, and addressing the underlying causes of displacement. Restitution encompasses the restoration of property, compensation for both material and non-monetary harm, as well as measures promoting reintegration, reconciliation, and the implementation of effective return models. The study appropriately underscores the importance of determining the temporal aspect, the conditions for return, and addressing ongoing crises within the legal framework governing forced displacement.33\n\nIn our opinion, it is not necessary to generalize the approaches to the definition of compensation as compensation for the costs of accommodation of internally displaced persons or for payment of employment, which are carried out by citizens voluntarily and on their own conviction, and compensation for damage caused by war, from which citizens suffer regardless of their will.\n\nIt is worth quoting here from the report that “no form of compensation is likely to satisfy the victims. Instead, as a complement to the proceedings of criminal tribunals and truth commissions, well-designed combinations of reparations measures are usually required.” As practice shows, the judges of the Yugoslavian and Rwandan tribunals recognized and suggested that the United Nations consider the possibility of creating a special reparations mechanism that would function alongside the tribunals.1\n\nAccordingly, the variety of losses suffered by citizens of Ukraine and legal entities prompts the search for an effective and multifaceted mechanism of reimbursement for damage, in the order of which various methods of legal protection can be applied, not only those provided for by the Civil Code of Ukraine, but also those referred to in UN reports - restoration of victims’ legal rights, victim rehabilitation programs and symbolic measures such as official apologies, monuments and commemorative ceremonies. One cannot and should not underestimate the attention and respect for the memory of the victims and losses suffered by the people of Ukraine and any other people from the burdens of the war, which cannot be compensated with money alone. At the same time, complex measures of recognition will perform another important function, a preventive one, with the aim of preventing possible similar conflicts in the future.\n\nThe main compensation procedure can be an umbrella procedure, within which the restoration of both property and non-property rights that were violated during the war and occupation will be carried out. At the same time, the application for compensation must be guaranteed for the loss of any objects of civil rights provided for by the current legislation, and not a list defined by law or in another order.\n\nThis study argues that the limitation or selective approach to determining the objects of compensation or expenses that are subject to reimbursement is incorrect and also violates basic human rights. The compensation mechanism should provide for a simplified and transparent version of the procedure for restoring the rights to housing, for resuming work, everything that ensures the possibility of a person’s normal life. At the same time, there should remain a real prospect of applying for the restoration of rights that have been violated in the person’s opinion, in particular, copyrights, or any others that cannot be classified as top priorities.\n\nIn this case, the actions that caused the violation of rights should be decisive - this is war and actions directly related to it (military actions, terrorist acts, sabotage caused by armed aggression). This will make it possible to clearly separate the actions and efforts aimed at restoring justice after the war, the expenditure of compensation funds.\n\nWhat is the basis of the appeal and the reason for the violation of the right - war or occupation? Military actions or any actions during war? On the territory of all of Ukraine or on the territory of hostilities? The draft law on compensation of expenses states that it is about losses “as a result of hostilities, acts of terrorism, sabotage caused by the armed aggression of the Russian Federation against Ukraine”.34 Analyzing court decisions reveals that the primary basis for compensation claims is Russia’s active armed aggression against Ukraine, which includes the occupation of certain Ukrainian territories, engagement in hostilities, acts of terrorism, and other related consequences that serve as valid grounds for such claims. On the other hand, the word “war” is not used either in judicial practice as a basis for going to court, or in national legal acts, that was discovered during the research of court decisions and national legislation, respectively.\n\nAs it was mentioned in Basic Principles and Guidelines on the Right to a Remedy and Reparation for Victims of Gross Violations of International Human Rights Law and Serious Violations of International Humanitarian Law 2005,2 for compensation, the damage must be the result of gross violations of international law, human rights, and serious violations of international humanitarian law.\n\nAll these features make it necessary to return to the main question - which procedure should be used in case of incurring costs during wartime - reimbursement for damage or compensation? After all, in accordance with the Civil Code, reimbursement for damage is preceded by the determination of the composition of the civil offense, namely, who caused the damage, their illegal behaviour (action or inaction), the result and the cause-and-effect relationship between them.14 At the same time, illegal behaviour is behaviour that does not meet the requirements of the law, entails a violation (reduction, limitation) of the property rights (goods) and legitimate interests of another person. In the conditions of war, it may not be so easy.\n\nIn order to prove the presence of damages, it is important to establish a causal relationship between the illegal behavior of the violator and the damages. The condition of responsibility for an offense is the fault of the person who caused the damage, that is, the guilty action is failure to perform, refusal to perform, or improper performance of obligations. The creditor, demanding reimbursement for damages, must prove the first three conditions of liability, in particular, the fact of the debtor’s illegal behavior, the amount of damages, and causation. The debtor’s guilt in the violation is presumed and cannot be proved by the creditor. Absence of fault is subject to proof by the person causing the damage.\n\nAt the same time, determining the procedure for reimbursement of expenses incurred in connection with the actions described in the law does not require compliance with such procedure and determination of the entire composition of the offense, since the law defines the conditions under which such reimbursement is paid.14\n\nThe main method of protection of violated rights, provided for by the civil legislation of Ukraine, is reimbursement for the damage caused by the court procedure. In order to receive at least some satisfaction for the property and moral damage caused by the Russian Federation, which is certainly not able to fully end all the mental suffering of the persons who suffered from the act of armed aggression, the victims are applying to the court with claims for reimbursement for moral and property damage, caused by the armed aggression of the Russian Federation against Ukraine.14\n\nIn connection with the ongoing full-scale invasion of the Russian Federation in Ukraine and realizing how much damage, both property and moral, has been caused during this time,35 one can absolutely predict that the judicial system will experience a boom in claims for reimbursement.\n\nThis suggests that, in some cases, the compensation mechanism should be used to compensate war victims, so that in the process of restoring their rights, even greater trauma is not caused (for example, unjustified length of waiting for compensation, which is quite real in the case of judicial order of reimbursement).\n\nThe amount of compensation is also a question. According to the Basic Rules of the UN [5],2 compensation must be provided for any economically evaluated harm that is suitable and commensurate with the gravity of the transgression and the specific circumstances of each individual case. This compensation should encompass lost prospects and the loss of potential earnings. States bear the responsibility to offer compensation to victims for acts or omissions attributable to the state itself, which amount to gross violations of international law, human rights, or severe breaches of international humanitarian law. However, there are known cases when national commissions significantly overestimated the amount of losses for real losses, and this led to a jump in economic growth.34\n\nBriefly summarizing, it is worth noting that efforts should be made by the war-affected state to implement a comprehensive compensation mechanism for reparations for victims of war, military operations, as well as including, but not limited to, ways of protecting rights provided for by national law, as well as special legislation on compensation for losses to war victims (non-property satisfaction measures for victims).\n\nAs regards the compensation plan for Ukraine, a coordinated strategy should be formulated to ensure that the Ukrainian citizens affected by the conflict with Russia receive the necessary help and assistance. This strategy should include the following:\n\n‐ Identification and registration of all persons affected by the conflict: it is essential to identify and register all persons affected, including those who have fled or lost their jobs or property. Such data should be centralized in a register of victims of war to facilitate the provision of aid and assistance.\n\n‐ Assessment of the needs of the victims of war: to be able to provide adequate help and assistance, it is crucial to assess the individual needs of the victims of war. This assessment should include medical, psychological, social and economic needs.\n\n‐ Providing appropriate assistance and help: based on the assessment of the needs of the victims of war, proper assistance and aid should be provided. This could include financial support, training programmes, medical and psychological assistance, social protection and humanitarian aid.\n\n‐ Implementation of a system for compensating the victims of war: The Government of Ukraine should implement a system of compensation for the victims of war to ensure that they receive adequate compensation for their material and economic losses.\n\n‐ Collaboration with international organizations: Ukraine should work with international organizations such as the European Union, the United Nations and the Organization for Security and Cooperation in Europe to receive financial and technical support in providing aid and assistance to victims of war.\n\n‐ Promoting a culture of reconciliation: To overcome the traumas of war and build a stronger and more united society, it is vital to encourage a culture of reconciliation and solidarity. This could include promoting intercommunity dialogue and cultural and educational exchanges between different ethnic groups in Ukraine.\n\nIt should be emphasized that the Ukrainian Government and the legislative power are actively working on the implementation of points of this generalized strategy.15 Some of them (for example, implementation of a system for compensating the victims of war and collaboration with international organization in some aspects of compensation) are discussed in more detail in this article.\n\n\nWho can apply for compensation (reimbursement)?\n\n\n\n«The purpose of compensation is to put the injured party in the same financial position they would have been in if the loss had not occurred. This compensation can include compensation for out-of-pocket expenses, lost income, pain and suffering, and other types of damages» [6].2\n\nA fundamental question is who can apply for compensation if they believe their rights have been violated and costs can be reimbursed or compensated. An important issue is the protection of foreign investors, whose activities are crucial to the reconstruction of the state after the war.35 From a practical perspective, the experience of Ukrainian legal entities and individual entrepreneurs in protecting rights violated during war can be helpful. However, the Ukrainian legal field does not yet have a compensation mechanism for damages caused by armed aggression to business entities. Therefore, the only way for these entities to obtain reimbursement is to go to court.17 Since the beginning of the full-scale invasion, according to the data obtained on the web portal of the Unified State Register of Court Decisions, more than 100 business representatives (which, compared to the scale of destruction, is actually a small number) have applied to commercial courts with claims against the Russian Federation for damages caused to their property by enemy bombing, rocket and artillery fire. This has resulted in the destruction of both movable and immovable property and occupation, which has made it impossible to access the property and remove movable property while preserving its integrity. In addition to real losses, reimbursement is also available for lost profits due to the inability to carry out economic activities, especially due to occupation and destruction of property used for conducting such activities. Although, as a general rule, there is a presumption of the defendant’s fault in these cases, the plaintiffs (business entities) must substantiate their claims by indicating the circumstances under which their rights were violated and providing appropriate evidence to support the amount of damages to be recovered. This approach allows the business to receive the maximum possible amount of reimbursement proportional to the total amount of losses suffered (both real losses and lost profits) [7].\n\nThe conducted generalization shows that several categories can be distinguished among the natural persons who applied to the courts with claims for reimbursement for damages caused as a result of the armed aggression of the Russian Federation against Ukraine. The first category consists of persons who have the status of a participant in hostilities and participated in the anti-terrorist operation (ATO) and/or the Joint Forces Operation (JFO). Often, among such persons, those who were in captivity apply for reimbursement, which, of course, has a painful impact on the mental health of these defenders. We should not forget about physical injuries caused by combat wounds, which usually lead to a person receiving disability - such damage is also compensated by the courts at the expense of moral damages [8]. As judicial practice currently only knows cases of appeals for reimbursement by persons who participated in anti-terrorist operations, but there are still no examples of appeals with claims by persons who came to the defense of Ukraine at the beginning of a full-scale war (and an extremely large number of such appeals is expected). Then, in support of their demands, the participants of the ATO/JFO indicate, in addition to the circumstances of their captivity and the performance of combat missions, that after the beginning of the armed aggression of the Russian Federation against Ukraine, their general morale deteriorated, and their mental suffering intensified [9]. Similar examples of actions by participants in hostilities for reimbursement for moral damages can be seen in other court decisions (in 2022 [10] [11], and earlier, starting from 2016 [12]). It should be noted that judicial practice is moving towards the satisfaction of such claims.\n\nThe next category of plaintiffs that should be singled out are family members of those killed as a result of the armed aggression of the Russian Federation. A characteristic feature of this category of plaintiffs is that individuals seek reimbursement for moral damages related to the death of a family member, both on their own behalf and in the interests of minors, since in many cases, this deceased family member is the father of a minor child. In particular, the person applying to the court is the wife of the deceased, who acts on her own behalf and in the interests of her minor child and applies for reimbursement for moral damages from the Russian Federation. The basis for the lawsuits in this particular case is that the husband of the plaintiff and the father of her minor child, who was called up for military service as part of the Armed Forces of Ukraine, directly participated in the defense of the independence, sovereignty, and territorial integrity of Ukraine and died while performing a combat mission. The consequence of this and the damage caused is that due to the loss of her husband and the father of her child, the plaintiff experiences continuous, unrelenting mental pain and suffering, has lost peace of mind, constantly feels insecure and disappointed, and the child, left without a father, will never have the opportunity to feel the necessary parental love and attention for full development [13].\n\nAdult children also file lawsuits for moral damages in connection with the death of one of their parents caused by armed aggression. Thus, in the mentioned cases, the plaintiffs, adult children, indicate that in connection with the death of one of their parents, they suffered moral damage, which consists of the fact that after learning about their parent’s death, they experienced strong emotional stress and a sense of mental pain from the awareness of the irreversibility of the loss of a loved one. Most of the plaintiffs were minors at the time of the death of one of their parents (mostly the father was a military serviceman), so they noted the loss of life orientations since, usually, the parental figure plays a significant role in the formation of a child’s personality and their upbringing. As a result of the loss, the minors had their usual way of life radically changed, and a depressed state was observed, which collectively caused them severe moral suffering. The courts satisfied such lawsuits, recognizing the Russian Federation as the cause and the sole culprit [14].\n\nAs an example of lawsuits regarding reimbursement for moral damage caused by the death of a family member, one can also cite the filing of such a lawsuit by one of the parents who lost a child - in the case cited as an example, the plaintiff filed a claim for reimbursement for moral damage caused in connection with the death of his son, who served in the Armed Forces of Ukraine and died while performing a combat mission. As a result of the death of his son, the plaintiff suffered moral damage, which consisted in the fact that he lost the meaning of life, suffered severe emotional stress, unrelenting mental pain and suffering, which will accompany him throughout his life [15].\n\nAnother category of plaintiffs in cases of reimbursement for moral and property damage are internally displaced persons who suffered damage to both property and moral well-being arising from the armed aggression carried out by the Russian Federation against Ukraine. The moral damage caused to internally displaced persons consists, for the most part, in the fact that, as a result of the occupation, these persons experience unbearable mental suffering due to the loss of housing, have lost the hope of returning home, a settled life, the opportunity to plan their lives, free communication with friends and relatives. In particular, due to the influence of Russian propaganda in the temporarily occupied territories, they are forced to deal with adaptation issues in a new place, which causes them severe stress and nervous breakdowns. They also suffer from a sense of longing for their native home, detachment from home, and the loss of the opportunity to pursue their previous activities and businesses [16]. In such cases, as experience shows, the court usually rules in favor of the injured person.\n\nAmong the cases on the reimbursement of moral damage, in which the plaintiffs are internally displaced persons, the cases based on the claims of persons who survived the occupation stand out especially in terms of their content. They impress with the detailing of the justification for the infliction of moral damage and the presentation of all the circumstances that the plaintiff had to experience during the occupation. The decision of the Bilotserkiv District Court of the Kyiv Region dated January 10, 2023 in case No. 357/9325/22 is telling, in which the court detailed all the circumstances of the case, which were referred to by the plaintiff, a resident of Mariupol, Donetsk Region. The plaintiff saw the beginning of a full-scale war in her native Mariupol and was under occupation for about a month. She described in detail the air raids and bombing of the city, the constant hiding in the basement of her own house, the difficulties of obtaining water and food, the lack of the possibility of performing basic hygiene procedures, being cut off from information, the destruction of the city, her way out of the occupied territory and the difficulty of passing the occupying checkpoints, and as well as her emotional experiences, fears and moral and physical suffering [17]. All these physical and moral sufferings were assessed by the plaintiff as moral damage caused to her by the Russian Federation and the court, agreeing with her arguments, satisfied the claims. In our opinion, such a clear statement of the circumstances of the case and the details provided by the plaintiffs are extremely important for making a decision on the satisfaction of the claims, especially when it comes to such a claim as reimbursement for moral damage, as shown by the analysis of judicial practice in this category of cases.\n\nIn this case, the applicant estimated the moral damage caused to her in the amount of UAH 1,000,000. While this assessment is not uncommon in judicial practice, it should be noted that this amount is unreasonable. In the majority of cases, plaintiffs determine the amount of moral damage in the hryvnia equivalent of 60,000 euros, which is determined according to the official exchange rate of the NBU as of the day of filing the claim (this amount, as of the time of the investigation, exceeds UAH 1,000,000). This technique is consistent with the practice of determining the amount of reimbursement for moral damage, which is reflected in the decisions of the ECHR [18]. Ukrainian courts consider these decisions as a source of law36 and form their national law enforcement practice accordingly. If the monetary value of the moral damage exceeds the amount established by judicial practice, and there is no corresponding evidence to support such an amount, the court may partially satisfy such claims, to the extent that corresponds to the practice of the ECHR [19].\n\nThe category of internally displaced persons can be conditionally divided into two subgroups - these are internally displaced persons who acquired this status before the start of a full-scale invasion on February 24, 2022, and, accordingly, after. Therefore, court cases initiated by internally displaced persons can also be divided into two groups, which are characterized by different approaches to determining the amount of damage caused, as well as the origin of funds and property, at the expense of which reimbursement should be made.\n\nIn this regard, cases where plaintiffs also specified the origin of the property from which reimbursement should be made are interesting. Specifically, some plaintiffs requested reimbursement for damages caused by money obtained from forcibly seized property rights of the Russian Federation and its residents, or any other property belonging to the Russian Federation and located on the territory of Ukraine [20]. Regarding applications by internally displaced persons filed before February 24, 2022, a fairly straightforward formulation of the claim has been established, consisting of a specific amount of funds to be collected and the type of damage for which reimbursement is sought. However, the origin of the funds to be collected is not determined by the plaintiffs.\n\nHowever, in such cases, the courts require sufficient evidence to confirm that the objects of property rights of the Russian Federation and its residents, or any other property of the Russian Federation, have been properly confiscated in Ukraine in accordance with the procedure established by law, and that the funds obtained from such confiscation can be used to compensate the moral damage caused to the plaintiffs. Unfortunately, such evidence is often not provided to the courts. The issue of forced alienation of objects of property rights of the Russian Federation and its residents on the territory of Ukraine or abroad is still subject to appropriate legal regulation and requires the adoption of appropriate decisions by state authorities [21]. Ukraine has confirmed this obligation in the resolution of the Cabinet of Ministers of Ukraine No. 326 dated March 20, 2022, “On approval of the Procedure for determining damage and losses caused to Ukraine as a result of the armed aggression of the Russian Federation”.37 Therefore, based on the aforementioned considerations and legal groundlessness, the courts refuse to grant this part of the claim.\n\nRegarding the property damage caused to internally displaced persons, in the analyzed case law, it is possible to distinguish between property damage caused by lost profits and real property damage caused by the loss of property (real damages). The lost profit can include the calculation of the cost of renting an apartment for the period during which the territory on which the property is located was under the occupation of the Russian Federation [22]. Additionally, plaintiffs include the deprivation of their right to use and dispose of the property, which is located in the temporarily occupied territory, belonging to them by the right of ownership, as a lost benefit in property damage [23]. The amount of property damage is measured using such indicators as costs associated with the forced rental of housing in the controlled territory of Ukraine, forced costs for housing maintenance (payment of communal services), etc. [24]. At the same time, the courts note that existing international and national normative legal acts do not contain provisions on the emergence of a temporarily displaced person’s right to reimbursement for the moral suffering suffered by them due to such displacement from the aggressor state [25]. We are of the opinion (and have already noted this in our research) that this approach of the courts is incorrect, and such damage should also be subject to reimbursement since the key factor in the displacement of a person is compulsion, which is connected with occupation, hostilities, terrorist acts, etc., that is, it is committed against the will of a person, which means that it causes them suffering.\n\nBased on the analysis of judicial practice, there were cases where plaintiffs claimed compensation for property damage resulting from the armed aggression of the Russian Federation against Ukraine in the form of lost income due to forced displacement related to the occupation of part of Ukraine’s territory. The calculation of lost income due to forced displacement is determined from the moment of temporary occupation until the filing of the lawsuit by adding the annual average earnings of the specific position held by the internally displaced person before the forced displacement [26].\n\nRegarding the real property damage, which is connected with the loss of property, internally displaced persons state in their lawsuits that their property was lost due to hostilities, terrorist acts, sabotage caused by the armed aggression of the Russian Federation, which violates the laws and customs of war. Accordingly, they ask the court to establish the legal fact of such destruction and oblige the Russian Federation to compensate for the damage caused. This should also include cases of non-fulfilment of contracts for the purchase and sale of property rights to immovable property located in the temporarily occupied territories of the Donetsk and Luhansk regions (TOT), which were not completed due to the armed aggression of the Russian Federation against Ukraine. According to such contracts, the seller-developer was obliged to complete and transfer ownership of the home to the buyer-plaintiff. Such situations occurred in 2014, when Russia began its aggression against Ukraine by occupying Crimea and the Donetsk and Luhansk regions. It is clear that at that time no property was built under such contracts and no one returned any money to the buyers, so the buyers demanded reimbursement for the damages caused by Russia in court [27].\n\nWe should also not forget about property damage in the form of the loss of movable property, which became especially relevant with the beginning of the full-scale invasion and mass robberies of Ukrainian homes by Russian servicemen. For example, in one case, the plaintiff stated that Russian servicemen robbed her apartment with particular disdain, cynicism, and cruelty. They destroyed all the furniture, appliances, and other things in the apartment and also stole her car. However, in many cases, as in this case, it is impossible to assess the value of all the stolen property due to the Russian occupation. Therefore, the plaintiff asked for reimbursement for the damage caused by the theft of only the car, assessing its value based on the publicly available information about the value of a car of the same model [28]. Among the movable property that was lost by internally displaced persons as a result of hostilities and occupation, personal belongings are also mentioned, which, although they do not have great property value, their sentimental value cannot be determined from the point of view of the significance of these things for such persons. These things carry memories and personal history. The practice is that the loss and/or destruction of things that are sacred to their owner is assessed by the plaintiffs themselves as moral damage caused to them, and the courts agree with this assessment.\n\nIn cases of reimbursement for moral damage caused as a result of Russia’s armed aggression against Ukraine, it is worth highlighting another category of plaintiffs such as ordinary citizens of Ukraine. These individuals justify their legal claim by stating that since the beginning of the armed aggression of the Russian Federation against Ukraine, they have suffered mental distress, their well-being has deteriorated, and their vitality has decreased. This is due to daily news about the death and injury of people, explosions and destruction of buildings, taking and torturing hostages in the war zone, witnessing funeral processions for the fallen defenders of Ukraine, and awareness of the scale of destruction of the economy and ecological disaster in the territories where the hostilities took place. Courts usually reject such claims due to the lack of evidence of actual moral damage, apart from the plaintiffs’ generalized statements [29]. However, in practice, there are sometimes cases where courts make a positive decision under such circumstances [30]. In such cases, it is important not only to establish the fact of armed aggression against Ukraine, which in itself causes mental suffering to every conscious citizen, but also to confirm such suffering and its specific manifestations in each individual situation.\n\n\nWho is responsible for compensation?\n\n\n\n«16. States should endeavour to establish national programmes for reparation and other assistance to victims in the event that the parties liable for the harm suffered are unable or unwilling to meet their obligations».2\n\nGiven that states bear the responsibility of safeguarding the rights of their citizens, encompassing the rights to life, physical well-being, and property, the allocation of accountability for inaction, and subsequently the state’s obligation to finance reparation initiatives, can be significantly burdensome. While states should ideally hold the individuals directly responsible for the wrongful harm liable for restitution, if this proves unfeasible or inadequate in achieving the goal of reparation, then the state itself assumes responsibility. This means that taxpayers, and perhaps their future generations, must bear the burden of recovery.38\n\nRussia is responsible for the damage caused during the war with Ukraine. Relevant international regulations that can be applied in this situation include the Hague Convention on the Laws and Customs of Land Warfare of 1907,39 the Geneva Convention for the Treatment of Prisoners of War of 194940 and Additional Protocol I to the Geneva Convention of 1977.41 They set international standards on the treatment of civilians, prisoners of war and civil property during armed conflicts.\n\nUkraine could also invoke the provisions of the Convention on the Protection of Human Rights and Fundamental Freedoms, which provides for the right to life, the right to respect for private and family life and the property right.42 These rights were violated during the war, and Russia is obliged to provide adequate compensation.\n\nBased on the generalization of Ukrainian judicial practices, it can be observed that in the majority of cases, the defendant is the Russian Federation. The plaintiffs address their claims for reimbursement either to the Russian Federation, or to the Russian Federation in the person of the Embassy of the Russian Federation in Ukraine or the Ministry of Justice of the Russian Federation. The plaintiffs justify the Russian Federation’s defendant status by stating that it is responsible for violating the rights and freedoms of citizens of Ukraine, including the personal rights of the plaintiffs, as a result of its armed aggression and occupation of Ukrainian territory. Therefore, the Russian Federation is the entity charged with the obligation to reimburse for the damages caused by these actions.\n\nHowever, from the perspective of international law, the question arises regarding the legality of prosecuting the Russian Federation as a foreign state. According to the general rule established by the Vienna Convention on Diplomatic Relations of April 18, 1961,43 to which Ukraine is a party, foreign states are entitled to judicial immunity, which means that they cannot be subjected to the legal authority of the courts in a different state without their explicit or tacit consent. Thus, each sovereign state can only participate in a court case in another state with its consent expressed through authorized persons. This position was also stated in the decision of the Supreme Court dated September 1, 2021, in case No. 754/10080/19 [31]. Therefore, the usual practice of Ukrainian courts, in accordance with the Regulation on Diplomatic Missions and Consular Institutions of Foreign Countries in Ukraine, approved by the Decree of the President of Ukraine No. 198/93 of June 10, 1993,44 is to send a letter through the Ministry of Foreign Affairs of Ukraine to the Embassy of the Russian Federation requesting consent to consider the case and granting the Russian Federation the procedural status of the defendant in the case. It should be noted that letters of this nature were typically sent several times as the Russian side did not reply due to its non-recognition of its acts of armed aggression, the illegal annexation of the Autonomous Republic of Crimea, and the occupation of the eastern regions of Ukraine. Such ignoring is regarded by the courts as giving the defendant tacit consent to participate in the case by its actions, as provided by the Law of Ukraine “On International Private Law”.45\n\nIn addition, the courts take into account the violations of international law committed by the Russian Federation. The courts believe that the Russian Federation, by violating the UN Charter,46 the Universal Declaration of Human Rights,47 the Budapest Memorandum (paragraphs 1 and 2),48 the Helsinki Final Act of the Conference on Security and Cooperation in Europe dated August 1, 1975,49 as well as the agreements concluded between Ukraine and Russia, including those related to the Ukrainian-Russian state border, has exceeded its sovereign rights, which are guaranteed by Article 2 of the UN Charter. Therefore, the Russian Federation is considered an aggressor state according to the normative acts adopted by Ukraine, and is therefore not entitled to judicial immunity.\n\nJurisprudence regarding the absence of judicial immunity in the Russian Federation and the legality of its prosecution by Ukrainian courts had been developing in the direction described above until the Supreme Court formulated a new conclusion regarding the judicial immunity of the Russian Federation in the case of reimbursement for damage caused by the aggressor state in 2022 [32].\n\nThe Supreme Court referred to the European Convention on the Immunities of States, adopted by the Council of Europe on May 16, 1972, and the UN Convention on the Jurisdictional Immunities of States and their Property, adopted by resolution 59/38 of the General Assembly on December 2, 2004, which reflect the evolving trajectory of international law, acknowledging that foreign states have certain limitations on claiming immunity in civil proceedings. The court concluded that a state cannot invoke immunity in cases involving harm to health or life if such harm is wholly or partially caused within the territory of the court’s state and if the person responsible for the harm was present in the court’s state at that time. The Supreme Court further highlights the principle of “equality among equals” in terms of power and jurisdiction, which necessitates mutual recognition of sovereignty among nations. Since the Russian Federation denies the sovereignty of Ukraine and engages in aggressive warfare against it, there is no obligation to respect and uphold the sovereignty of Ukraine.\n\nThe court reached the determination that, given the continuous and extensive armed aggression perpetrated by the Russian Federation against Ukraine, which flagrantly infringes upon its sovereignty, it is presently unsuitable to seek the consent of the Russian Federation to participate as a defendant in such cases. Halting the proceedings to secure the Russian Federation’s consent would result in an unjustifiable delay in the case’s adjudication, thus failing to serve the best interests of the plaintiff in terms of safeguarding their rights effectively.\n\nAs a consequence of the unprovoked and extensive act of armed aggression by the Russian Federation against Ukraine, along with numerous acts of genocide perpetrated against the Ukrainian people, the Russian Federation will no longer be eligible to invoke judicial immunity. Consequently, Ukrainian courts are empowered to consider and resolve cases seeking reimbursement for damages arising from such acts of aggression. The Supreme Court asserts that the aggressor country, in question, did not operate within the boundaries of its sovereign right to self-defense but instead deliberately violated all sovereign rights of Ukraine while conducting its actions on Ukrainian territory. Hence, the Russian Federation unequivocally forfeits the privilege of utilizing judicial immunity in this specific category of cases [33].\n\nThe analyzed court decisions revealed cases where, prior to the formulation of the Supreme Court’s aforementioned positions [34] the courts denied claims for reimbursement for damages caused by the Russian Federation’s armed aggression against Ukraine. This was due to an incorrect interpretation of the judicial immunity of the Russian Federation, which was mistakenly considered absolute without taking into consideration the evolution of international law50 and the specifics of cases related to reimbursement for damages. Such cases allow exceptions under which a foreign state can be prosecuted. The courts also misinterpreted the tacit consent of a foreign state to participate in the legal process.51\n\nIn particular, some court decisions noted that “despite the temporary occupation of Ukrainian territories resulting from the armed aggression of the Russian Federation, it remains unchanged that the Russian Federation, as a sovereign state, cannot be a party to a case in a general jurisdiction court of Ukraine without its explicit or implied consent expressed through its authorized entities or officials.” The courts considered the potential ramifications, including the non-recognition and non-enforcement of Ukrainian national court decisions by the Russian Federation [35]. The evident outcome of such refusals was an appeal, and later a cassation appeal, of court decisions, resulting in the plaintiffs’ demands still being subject to satisfaction [36].\n\nThe Unified State Register of Court Decisions contains cases of reimbursement for damage caused by the armed aggression of the Russian Federation against Ukraine, in which the defendant is not only the Russian Federation as a foreign state, but also the Embassy of the Russian Federation in Ukraine, represented by the Ministry of Justice of the Russian Federation, and JSC “Sberbank”, which was later renamed to JSC “International Reserve Bank” and thus became jointly liable with the Russian Federation for reimbursement. However, there is a lack of consistency in judicial practice regarding whether JSC “International Reserve Bank” can be recognized as a proper defendant in these cases. In case No. 215/294/21, for example, the court ruled that there was no legal basis for collecting moral damages from the Bank as the plaintiff failed to provide evidence of which actions of the Bank caused damage and violated their rights. The court concluded that the entire burden of reimbursement rests solely on the Russian Federation, as the sole guilty party [37]. We agree with such conclusions as establishing guilt and a causal relationship between the subject’s actions and the damage is necessary to establish the subject’s obligation to compensate for the damage caused. Although some courts recognize JSC “International Reserve Bank” as a proper defendant [38], such conclusions are later found to be erroneous during the appeal process [39].\n\nEnsuring the unity of judicial practice and observance of human rights is an important task. The generalization of the national judicial practice during the 9 years of the armed aggression of the Russian Federation against Ukraine - from 2014 to 2022 - indicates the presence of a basic practical framework, in particular, in the justification by the courts of the motives from which they proceed when making a decision. This observation concerns both courts of first instance and appeals courts, and, of course, the Supreme Court, which, in fact, forms the unity of judicial practice and the application of legal norms by courts.\n\nIn the motivational part of the court decision, the courts paid considerable attention to justifying the legality of the participation of the Russian Federation as a party in civil proceedings and its recognition as a proper defendant due to the presence of its judicial immunity. Although, after the Supreme Court formulated its legal position regarding the lack of judicial immunity of the Russian Federation [40] in the studied category of cases, this necessity disappeared. We have investigated in detail this issue and the motives from which the courts proceeded both in the period from February 20, 2014 to February 24, 2022, in the first two phases of the armed aggression of the Russian Federation against Ukraine, and after the full-scale invasion that began on February 24, 2022, and continues to this day. However, for research purposes, it is important to find out what other arguments the courts use to strengthen their position when satisfying or refusing to satisfy claims.\n\nFirst of all, it is important to ascertain a cause-and-effect relationship between the actions of the defendant (in our case, the Russian Federation) and the damage that was caused, whether moral or property, for the success of the claim. Courts during the trial are obliged to fully, comprehensively and impartially investigate all available evidence in the case in order to establish this cause-and-effect relationship, and therefore the validity of the satisfaction of the claims. Therefore, before the courts when considering cases of reimbursement for damage caused as a result of the armed aggression of the Russian Federation against Ukraine, the primary task is to establish the relationship between the armed aggression of the Russian Federation and the damage that was caused.\n\nWhen satisfying claims for reimbursement for moral and property damage caused as a result of the armed aggression of the Russian Federation against Ukraine, the courts proceed from this.\n\nAccording to Part 4 of Article 2 of the Law of Ukraine “On the Legal Status of the Temporarily Occupied Territory of Ukraine,” the responsibility for any material or non-material harm inflicted upon Ukraine due to the armed aggression by the Russian Federation lies with the Russian Federation, in accordance with the principles and standards of international law [41].52 Part 6 of Article 5 of the same law corresponds to the above-mentioned norm, which is also referred to by the courts in their decisions. The statement asserts that the responsibility for compensating for both tangible and intangible harm incurred due to the temporary occupation falls entirely on the Russian Federation, acting as the occupying nation, in relation to the state of Ukraine, legal entities, public associations, Ukrainian citizens, foreigners, and stateless individuals.53\n\nThe courts also refer to the Resolution of the Verkhovna Rada of Ukraine No. 145-VIII, dated February 4, 2015, “On Ukraine’s recognition of the jurisdiction of the International Criminal Court regarding the commission of crimes against humanity and war crimes by high-ranking officials of the Russian Federation and leaders of the terrorist organizations “DPR” and “LPR” which led to particularly grave consequences and the mass murder of Ukrainian citizens” when forming the motivational part of the decision. This resolution states that since February 20, 2014, the armed aggression of the Russian Federation against Ukraine has been ongoing, and the terrorist fighters supported by it have occupied part of the Donetsk and Luhansk regions of Ukraine and annexed the Autonomous Republic of Crimea and the city of Sevastopol, which are part of the territory of the independent and sovereign state of Ukraine. The resolution also highlights that numerous Ukrainian citizen, including children, have lost their lives, while thousands have sustained injuries. Moreover, the resolution emphasizes the extensive destruction of the entire region’s infrastructure, and the displacement of hundreds of thousands of citizens from their homes. The courts refer to this resolution to establish the background and context of the armed aggression and to emphasize the gravity of the consequences of the actions of the Russian Federation.54\n\nThe courts have used normative legal acts to support the assertion that the Russian Federation has been committing armed aggression against Ukraine since 2014. This reasoning has been repeatedly upheld in court decisions that have awarded damages in cases related to full-scale invasion [42]. As a result, the courts now routinely refer to the Russian Federation’s aggression against Ukraine as a well-established and generally recognized fact. There is no longer a need for a detailed description of the legal acts that confirm this, as the international legal community and Ukrainian judicial practice have both recognized Russia’s aggression against Ukraine.\n\nThe motivational part of court decisions related to reimbursement for damage caused by the Russian Federation’s armed aggression against Ukraine has evolved with the onset of the war and the expansion of both national and international legal frameworks. Specifically, recent decisions have included references to a resolution adopted by the Verkhovna Rada of Ukraine on April 14, 2022, which recognizes the actions of the Russian Armed Forces and political and military leadership as genocide against the Ukrainian people. This resolution was passed in response to the ongoing armed aggression by Russia against Ukraine, which began on February 24, 2022.55\n\nFurthermore, courts have cited the resolution on the termination of the Russian Federation’s membership in the Council of Europe as evidence in their decisions [43]. This resolution affirms that the Russian Federation’s aggression against Ukraine is a grave violation of its obligations under Article 3 of the Charter of the Council of Europe.\n\nWhen substantiating the size and necessity of reimbursement for moral damage caused, courts have cited the decision of the European Court of Human Rights in the case of “Luizidou v. Republic of Turkey” [44]. This case involved the illegal occupation of the northern part of Cyprus by the Turkish Armed Forces, where the applicant was born and lived. The Court ruled that the Republic of Turkey was obliged to pay compensation to the applicant, including for moral suffering resulting from the occupation. The Court found that the applicant had suffered psychological harm, including forced relocation from her home, an inability to live in the occupied territory, and a feeling of fear and helplessness. This decision has been used as a precedent for determining reimbursement for moral damage caused in cases related to the Russian Federation’s armed aggression against Ukraine.\n\nWhen determining the amount of reimbursement for moral damage caused to the applicant, Ukrainian courts rely on the amount of claims that have been granted in similar disputes considered by the European Court of Human Rights. For instance, in the case of “Luizidou v. Republic of Turkey” [45], the European Court of Human Rights ruled that the Republic of Turkey had to pay the applicant compensation in the amount of 20,000 Cypriot pounds. At the time of the dispute in the European Court of Human Rights, which was prior to the introduction of the euro, the European Union used the exchange rate of 0.585274 Cypriot Pounds to 1 Euro [46].\n\nIn addition, when addressing this matter, courts take into consideration relevant rulings by the European Court of Human Rights in cases such as “Khachukayeva v. Russia (23/04/2009)” [47], “Sagayeva and Others v. Russia (08/12/2015)” [48], “Islamova v. Russia (30/04/2015)” [49], and “Sultygov and Others v. Russia (09/10/2014)” [50].\n\nIn addition, under international law, Ukraine can claim compensation for damage caused by Russia under the principle of international state responsibility. Such damage should include material damage, moral damage to the loss of human life, the victims’ physical and psychological suffering, and the destruction of civil property.\n\nAs of today, Ukraine is actively working on collecting the evidence base for future trials to hold Russia accountable for what it has done, including the recovery of compensation, as well as legal mechanisms for creating special courts and addressing already existing international courts. In today’s conditions, these issues are extremely important and promising for further research.\n\nOn the other hand, next to the question of determining the procedure for bringing the perpetrator to justice for the damage caused and the obligation to compensate for it, the question of exactly by what means this damage can be compensated arises. One of the options for sources of compensation, which is discussed in society, is “frozen” funds and other property of Russia and its citizens in Western countries. However, this issue also should to be studied additionally and has researching perspective for future works.\n\n\nConclusion\n\nThe diversity of losses suffered by Ukrainian citizens and legal entities during the aggression of the Russian Federation since 2014 necessitates the search for an effective and multi-option mechanism for compensating damages. In our opinion, such a mechanism should be a comprehensive ‘umbrella’ procedure that provides opportunities for the swift and cost-effective consideration of claims for reimbursement for various types of damage and losses in different categories of cases. As the analysis of existing approaches and the generalization of judicial practice show, there are specific issues regarding reimbursement for material and moral damages, depending on the composition of the case.\n\nThe generalization of judicial practice in cases of reimbursement for damage caused as a result of Russia’s armed aggression against Ukraine has allowed the identification of categories of persons who have applied or are continuing to apply for the protection of their rights that were violated by the war, including family members of deceased persons (most often military personnel), participating military personnel in hostilities, and internally displaced persons. It has become evident that the plaintiffs, as well as the Ukrainian courts, maintain a united and firm position by naming the Russian federation as the defendant in this category of cases. The main demands that are unanimously put forward to the aggressor state are reimbursement for moral and material damages. However, despite the well-defined position of the overwhelming majority of courts, including the Supreme Court, there are cases where courts of appeal and cassation review decisions based on complaints from injured persons due to incorrect application of the law by courts of first instance.\n\nThe impact of the European Court of Human Rights’ practice on national judicial practice and the unity of approaches that have emerged since 2014 indicate the grounds for the introduction of simplified procedures for determining compensation and its recovery, particularly in cases of moral damage caused by armed aggression against Ukraine. More accessible and unified procedures will also aim to relieve claimants of exhausting court proceedings and additional stress. The fact of armed aggression by the Russian federation against Ukraine is rightfully considered universally recognized, meaning that it does not require further evidence, which creates additional opportunities for simplifying and improving the protection procedures of the affected parties.\n\nThe adopted resolution of the Council of Europe provides significant impetus for further searching and implementing mechanisms for compensation for the losses suffered, as well as for the establishment of a register of losses. The resolution establishes specific guidelines that must be considered when formulating and implementing procedures for compensating the damages resulting from military actions. However, at the same time, the issue of compensating for the damage caused by the occupation of Ukrainian territory since 2014 should not be overlooked, and it also needs to find a proper place in the mechanism that ensures equal access to justice for all who have suffered.\n\nThe fact that decisions have been made to recover funds from the Russian Federation government means that it will be necessary to search for property and means of recovery, which will be a challenging process. This may be the aim of further studies.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReferences\n\nUNHCR: Report of the Secretary-General of the United Nations “The rule of law and transitional justice in conflict and post conflict societies”.2004. Reference Source\n\nOHCHR: Basic principles and guidelines on the right to a remedy and reparation for victims of gross violations of international human rights law and serious violations of International Humanitarian Law.2005. Reference Source\n\nParliamentary Assembly of the Council of Europe: Resolution of Parliamentary Assembly of the Council of Europe ‘Legal and human rights aspects of the Russian Federation’s aggression against Ukraine’.2023. Reference Source\n\nThe Global Goals For Sustainable Development: 2015. 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Publisher Full Text\n\nThe Law of Ukraine ‘On the Peculiarities of State Policy to Ensure State Sovereignty of Ukraine in the Temporarily Occupied Territories in Donetsk and Luhansk Oblasts’ No. 2268-VIII.18 January 2018.\n\nThe Law of Ukraine ‘On Ensuring the Rights and Freedoms of Citizens and the Legal Regime in the Temporarily Occupied Territory of Ukraine’, No. 1207-VII, VVR 2014, no. 26.15 April 2014; p. 892.\n\nThe Resolution of the Verkhovna Rada of Ukraine ‘On the Statement of the Verkhovna Rada of Ukraine “On the recognition by Ukraine of the jurisdiction of the International Criminal Court…’ No. 145 VIII.4 February 2015.\n\nThe Resolution of the Verkhovna Rada of Ukraine ‘On the statement of the Verkhovna Rada of Ukraine ‘On the commission of genocide by the Russian Federation in Ukraine’.14 April 2022.\n\n\nFootnotes\n\n1 The bill on compensation of expenses was introduced in 2022 by the President of Ukraine. Available at: https://itd.rada.gov.ua/billInfo/Bills/Card/39283. It was adopted by the Verkhovna Rada of Ukraine on February 23, 2023. Available at: https://zakon.rada.gov.ua/laws/show/2923-20#Text. On March 17, 2023 the Law was signed by the President of Ukraine and is entering into force.\n\n2 Even the loss of real estate should be assessed more comprehensively, taking into account the destruction of the surrounding infrastructure, see Al-Harithy H., Lessons in Post-War Reconstruction: Case Studies from Lebanon in the Aftermath of the 2006 War, Lessons in Post-War Reconstr.: Case Stud. from Leban. in the Aftermath of the 2006 War, Lessons in Post-War Reconstruction: Case Studies from Lebanon in the Aftermath of the 2006 War (Taylor and Francis, 2010), https://doi.org/10.4324/9780203851524.\n\n3 Regarding the specifics of the known experience, cultural objects took a prominent place in reparations, which is now interesting to rethink through the prism of property rights. Between 1919 and 1945, there were two contrasting cases where the legal status of cultural objects changed through reparations mechanisms. See details Perrot X., ‘Cultural objects in the reparation for war damages, 1919 and 1945, restitutio in integrum (restoration to original condition), compensation and fungibility’, Revue Historique de Droit Francais et Etranger 84, no. 1 (2006): 47–69.\n\n4 It concerns the environmental rights of citizens, in particular see the case in more detail Jobin P., ‘The Economy of Compensation and Struggle for Reparation: The Case of Formosa Plastics in Taiwan’, in Rethinking Post-Disaster Recovery: Socio-Anthropological Perspectives on Repair. Environments (Taylor and Francis, 2021), 25–48, https://doi.org/10.4324/9781003184782-3.\n\n5 Compensation of damages refers to the monetary compensation awarded to a person or entity as a result of losses or harm they have suffered as a result of a breach of contract or tort (civil wrong).\n\n6 Compensation of damages refers to the monetary compensation awarded to a person or entity as a result of losses or harm they have suffered as a result of a breach of contract or tort (civil wrong). The purpose of compensation is to put the injured party in the same financial position they would have been in if the loss had not occurred. This compensation can include compensation for out-of-pocket expenses, lost income, pain and suffering, and other types of damages.\n\n7 See more details in the Decision of the Commercial Court of the Kyiv region dated January 30, 2023 in case No. 911/2065/22 (Available at: https://reyestr.court.gov.ua/Review/108985076), the Decision of the Commercial Court of the Kharkiv region dated October 18, 2022 in case No. 922/916/22 (Available at: https://reyestr.court.gov.ua/Review/106939659), the Decision of the Commercial Court of the Kyiv City dated December 6, 2022 in case No. 914/1552/22 (Available at: https://reyestr.court.gov.ua/Review/107702941).\n\n8 The Decision of the Baryshiv District Court of the Kyiv Region dated November 11, 2019 in case No. 355/1030/19. Available at: https://reyestr.court.gov.ua/Review/85591782.\n\n9 The Decision of the Dovhyntsiv District Court of the city of Kryvyi Rih, Dnipropetrovsk region in case No. 211/3600/20. Available at: https://reyestr.court.gov.ua/Review/103890683.\n\n10 The Decision of the Khmelnytskyi City and District Court of the Khmelnytskyi Region dated September 12, 2022 in case No. 686/21759/21. Available at: https://reyestr.court.gov.ua/Review/107478121.\n\n11 The Decision of the Central City District Court of Kryvyi Rih, Dnipropetrovsk Region dated September 22, 2022 in case No. 216/3586/21. Available at: https://reyestr.court.gov.ua/Review/106871522.\n\n12 The Decision of the Yarmoline District Court of the Khmelnytskyi Region dated December 14, 2016 in case No. 689/1880/16-ц. Available at: https://reyestr.court.gov.ua/Review/63701174.\n\n13 The Decision of the Leninsky District Court of Kirovohrad of December 4, 2018 in case No. 405/6702/18. Available at: https://reyestr.court.gov.ua/Review/78297243. Similar cases of filing claims for reimbursement for moral damages by plaintiffs who are family members of persons killed as a result of armed aggression against the Russian Federation can be traced in the vast majority of investigated cases to the Decision of the Uzhhorod City District Court of Zakarpattia Oblast dated February 2, 2021 in case No. 308/9708/19, the Decision of Zhovtnevy of the District Court of Kryvyi Rih from June 21, 2022 in case No. 212/4039/21 (Available at: https://reyestr.court.gov.ua/Review/104854655), the Decision of the Khmelnytskyi City and District Court of the Khmelnytskyi Region dated November 13, 2018 in case No. 686/21800/18 (Available at: https://reyestr.court.gov.ua/Review/77861694).\n\n14 The Decision of the Terniv district court of the city of Kryvyi Rih, Dnipropetrovsk region, dated June 8, 2022, in case No. 215/294/21. Available at: https://reyestr.court.gov.ua/Review/104683338.\n\n15 The Decision of the Saksagan District Court of Kryvyi Rih, Dnipropetrovsk Region dated May 18, 2022 in case No. 214/5601/21. Available at: https://reyestr.court.gov.ua/Review/104420460. Similar claims and circumstances of the case are contained in the Decision of the Brovary City and District Court of the Kyiv Region dated September 5, 2017 in case No. 361/2955/17 (Available at: https://reyestr.court.gov.ua/Review/69248932), the Decision of the Derazhnyan district court of the Khmelnytsky region dated December 21, 2017 in case No. 673/1550/17 (Available at: https://reyestr.court.gov.ua/Review/71328444), the Decision of the Rivne city court of the Rivne region dated November 30, 2018 in case No. 569/18381/18 (Available at: https://reyestr.court.gov.ua/Review/78434066). Courts usually decide such cases in favor of the plaintiffs.\n\n16 The Decision of the Starobil district court of the Luhansk region dated December 27, 2018 in case No. 431/4115/18. Available at: https://reyestr.court.gov.ua/Review/78392525. Similar cases and justifications are given in other decisions of national courts, in particular, in the Decision of the Supreme Court as part of the panel of judges of the First Judicial Chamber of the Cassation Civil Court dated May 18, 2022 in case No. 428/11673/19, the Decision of the Central City District Court of of Kryvyi Rih, Dnipropetrovsk region from October 12, 2022 in case No. 216/1907/22 (Available at: https://reyestr.court.gov.ua/Review/106996083), the Decisions of the Khmelnytskyi City and District Court of July 25, 2022 in case No. 686/30265/21 (Available at: https://reyestr.court.gov.ua/Review/106416818).\n\n17 The Decision of the European Court of Human Rights in the case of Louisidou v. Republic of Turkey (28/07/1998). Available at: https://hudoc.echr.coe.int/ukr#{“tabview”:[“document”],“itemid”:[“001-58201”]}.\n\n18 The Decision of the Bilotserkiv District Court of the Kyiv Region dated January 10, 2023 in case No. 357/9325/22. Available at: https://reyestr.court.gov.ua/Review/108371522.\n\n19 The Decision of the Central City District Court of Kryvyi Rih, Dnipropetrovsk Region dated April 9, 2021 in case No. 216/4601/20. Available at: https://reyestr.court.gov.ua/Review/96315393.\n\n20 The Decision of the Ivano-Frankivsk City Court of the Ivano-Frankivsk Region dated July 26, 2022 in case No. 344/5555/22. Available at: https://reyestr.court.gov.ua/Review/105546152.\n\n21 The Decision of the Ivano-Frankivsk City Court of the Ivano-Frankivsk Region dated July 26, 2022 in case No. 344/5555/22. Available at: https://reyestr.court.gov.ua/Review/105546152. The same conclusions are contained in the Resolution of the Grand Chamber of the Supreme Court dated May 12, 2022 in case No. 635/6172/17. Available at: https://reyestr.court.gov.ua/Review/104728593.\n\n22 See, in particular, the Decision of the Starobil district court of Luhansk region dated December 27, 2018 in case No. 431/4115/18. Available at: https://reyestr.court.gov.ua/Review/78392525.\n\n23 Such cases are found in the Decision of the Holosiivsky District Court of the city of Kyiv dated August 23, 2016 in case No. 752/7929/16-ц (Available at: https://reyestr.court.gov.ua/Review/61275011), the Decision of the Primorsky District Court of Odesa from July 5, 2019 in case No. 522/20396/18 (Available at: https://reyestr.court.gov.ua/Review/82831857).\n\n24 The Decision of the Sosniv District Court of Cherkasy dated October 21, 2022 in case No. 712/10119/20. Available at: https://reyestr.court.gov.ua/Review/107043791.\n\n25 The Decision of the Zhovtenevyy District Court of Kryvyi Rih dated December 19, 2022 in case No. 212/3718/22. Available at: https://reyestr.court.gov.ua/Review/108199195.\n\n26 The Decision of the Dnipro District Court of Cherkasy dated March 27, 2019 in case No. 711/17/19. Available at: https://reyestr.court.gov.ua/Review/81024789.\n\n27 The Decision of the Slovyanskyi City and District Court of the Donetsk Region dated February 8, 2023 in case No. 243/2585/22. Available at: https://reyestr.court.gov.ua/Review/108839812.\n\n28 The Decision of the Vinnytsia City Court of the Vinnytsia Region dated January 24, 2023 in case No. 127/12775/22. Available at: https://reyestr.court.gov.ua/Review/108672416.\n\n29 The Decision of the Darnytsky District Court of Kyiv dated October 4, 2022 in case No. 753/15426/20. Available at: https://reyestr.court.gov.ua/Review/106915823.\n\n30 The Decision of the Holosiivsky District Court of the city of Kyiv dated June 25, 2019 in case No. 752/11085/19. Available at: https://reyestr.court.gov.ua/Review/82615042.\n\n31 The Resolution of the Supreme Court dated September 1, 2021 in case No. 754/10080/19. Available at: https://reyestr.court.gov.ua/Review/99425886.\n\n32 The Resolution of the Supreme Court as part of the panel of judges of the Third Judicial Chamber of the Civil Court of Cassation dated April 14, 2022 in case No. 308/9708/19. Available at: https://reyestr.court.gov.ua/Review/104086064.\n\n33 The Resolution of the Supreme Court as part of the panel of judges of the Third Judicial Chamber of the Civil Court of Cassation dated April 14, 2022 in case No. 308/9708/19. Available at: https://reyestr.court.gov.ua/Review/104086064.\n\n34 See more details in the Resolution of the Supreme Court dated April 14, 2022 in case No. 308/9708/19 (Available at: https://reyestr.court.gov.ua/Review/104086064) and in the Resolution of the Supreme Court dated September 1, 2021 in case No. 754/10080/19 (Available at: https://reyestr.court.gov.ua/Review/99425886).\n\n35 The Decision of the Uzhgorod City and District Court of the Zakarpatskyy Region dated February 2, 2021 in case No. 308/9708/19. Available at: https://reyestr.court.gov.ua/Review/94815876. For identical reasons, the Prydniprovskyi District Court of Cherkasy in the Decision of March 27, 2019 in case No. 711/17/19 also refused to satisfy the claim for damages.\n\n36 It is about the Resolution of the Civil Court of Cassation of the Supreme Court dated May 13, 2020 in case No. 711/17/19 and the Resolution of the Civil Court of Cassation of the Supreme Court dated April 14, 2022 in case 308/9708/19.\n\n37 The Decision of the Terniv district court of the city of Kryvyi Rih, Dnipropetrovsk region, dated June 8, 2022, in case No. 215/294/21. Available at: https://reyestr.court.gov.ua/Review/104683338.\n\n38 The Decision of the Saksagan District Court of Kryvyi Rih, Dnipropetrovsk Region dated May 18, 2022 in case No. 214/5601/21. Available at: https://reyestr.court.gov.ua/Review/104420460.\n\n39 The Resolution of the Dnipro Court of Appeal dated December 20, 2022 in case No. 217/5601/21. Available at: https://reyestr.court.gov.ua/Review/107988495.\n\n40 The Resolution of the Supreme Court as part of the panel of judges of the Third Judicial Chamber of the Civil Court of Cassation dated April 14, 2022 in case No. 308/9708/19. Available at: https://reyestr.court.gov.ua/Review/104086064.\n\n41 Now this Law has lost its validity on the basis of the Law of Ukraine ‘On Amendments to Certain Laws of Ukraine Regarding the Regulation of the Legal Regime in the Temporarily Occupied Territory’ dated April 21, 2022 No. 2217-IX. Available at: https://zakon.rada.gov.ua/laws/show/2217-20#Text).\n\n42 This is, among others, the Decision of the Starobil district court of the Luhansk region dated December 27, 2018 in case No. 431/4115/18, the Decision of the Holosiiv district court of the city of Kyiv dated August 23, 2016 in case No. 752/7929/16-ц, the Decision Ivano-Frankivsk City Court of Ivano-Frankivsk Region dated February 7, 2017 in case No. 344/15673/16-ц (Available at: https://reyestr.court.gov.ua/Review/64694889).\n\n43 The Resolution of the Supreme Court as part of the panel of judges of the Third Judicial Chamber of the Civil Court of Cassation dated April 14, 2022 in case No. 308/9708/19. Available at: https://reyestr.court.gov.ua/Review/104086064. References are made to the specified legal acts, in particular, in the Resolution of the Supreme Court of May 18, 2022 in case No. 428/11673/19 (Available at: https://reyestr.court.gov.ua/Review/104635313), the Decision of the Dovgyntsivsky District Court of the city of Kryvyi Rih, Dnipropetrovsk Region in case No. 211/3600/20, the Decision of the Oktyabrskyi District Court of Poltava City dated February 7, 2023 in case No. 554/10776/22 (Available at: https://reyestr.court.gov.ua/Review/109225780).\n\n44 The Decision of the European Court of Human Rights in the case of Louisidou v. Republic of Turkey (28/07/1998). Available at: https://hudoc.echr.coe.int/ukr#{“tabview”:[“document”],“itemid”:[“001-58201”]}.\n\n45 The Decision of the European Court of Human Rights in the case of Louisidou v. Republic of Turkey (28/07/1998). Available at: https://hudoc.echr.coe.int/ukr#{“tabview”:[“document”],“itemid”:[“001-58201”]}.\n\n46 The Decision of the European Court of Human Rights in the case of Louisidou v. Republic of Turkey (28/07/1998). Available at: https://hudoc.echr.coe.int/ukr#{“tabview”:[“document”],“itemid”:[“001-58201”]}. The use of this Decision of the European Court of Human Rights was observed in the Decision of the Dovgyntsiv District Court of the city of Kryvyi Rih, Dnipropetrovsk Region in case No. 211/3600/20, the Decision of the Starobil District Court of Luhansk Region dated December 27, 2018 in Case No. 431/4115/18, the Decision of Leninskyi Kirovograd District Court dated December 4, 2018 in case No. 405/6702/18, the Decision of the Holosiivskyi District Court of the city of Kyiv dated August 23, 2016 in case No. 752/7929/16-ц, the Decision of the Khmelnytskyi City District Court dated July 21, 2022 in case No. 686/26852/21. It should be noted that this list of cases is not exhaustive.\n\n47 The Decision of the European Court of Human Rights in the case of Khachukayev v. Russia (23/04/2009). Available at: https://hudoc.echr.coe.int/ukr#{“fulltext”:[“Khachukayev”],“itemid”:[“001-92369”]}.\n\n48 The Decision of the European Court of Human Rights in the case of Sagayeva and Others v. Russia (08/12/2015). Available at: https://hudoc.echr.coe.int/fre#{“itemid”:[“001-160943”]}.\n\n49 The Decision of the European Court of Human Rights in the case of Islamova v. Russia (30/04/2015). Available at: https://hudoc.echr.coe.int/ukr#{“tabview”:[“document”],“itemid”:[“001-154025”]}.\n\n50 The Decision of the European Court of Human Rights in the case of Sultygov and Others v. Russia (09/10/2014). Available at: https://hudoc.echr.coe.int/ukr#{“tabview”:[“document”],“itemid”:[“001-146775”]}."
}
|
[
{
"id": "211327",
"date": "08 Nov 2023",
"name": "Mohamad Albakjaji",
"expertise": [
"Reviewer Expertise International Environmental Law"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe topic is very interesting. It will be the basis for additional research in the future. It will also be a starting point for the mechanisms that will determine how to compensate victims of Gross Violations of International Human Rights Law and Serious Violations of International Humanitarian Law.\nHowever, the reviewer would like to provide feedback in order to make the research of greater academic and practical value.\nIn the introduction, the Author stated that: Resolution of the Council of Europe3 is foreseen (18) to create an international framework for compensating for any harm, loss, or injury caused. To realize this task, it was proposed the creation of an international register of damage, in cooperation with Ukraine and the EU member states aimed to keep records pertaining to evidence and claims regarding damage, loss, or injury suffered by individuals and entities, both natural and legal, in Ukraine.\nIn this point, the author should mention the international mechanisms which is needed to implement such resolutions. As we may know, adopting rules and resolutions are not enough to resolve the dilemma. Such European resolutions will not be effective if it is not adopted at the international level, or at least clear mechanisms for compensation are globally established.\nThe authors stated that: As stated by the UN in the document Basic Principles and Guidelines on the Right to a Remedy and Reparation for Victims of Gross Violations of International Human Rights Law and Serious Violations of International Humanitarian Law 2005…etc\nHere, there is no discussion of the mechanisms used at the international level through which affected countries can oblige aggressor countries to pay compensation for damages.\nYes, it is true that international law and international humanitarian law stipulate, ‘Restitution should, whenever possible, restore the victim to the original situation before the gross violations of international human rights law or serious violations of international humanitarian law occurred. Restitution includes, as appropriate: restoration of liberty, enjoyment of human rights, identity, family life and citizenship, return to one’s place of residence, restoration of employment and return of property’ (authors’ italics) Also, the authors stated that: In particular, it is worth recalling that, according to the report, states should, among other things, make efforts to develop procedures that would allow groups of victims to submit claims for reparations and receive reparations, if appropriate.\n\nThe authors mentioned that countries must not only prosecute criminals, but must provide fair compensation to the victims as well. However, the author did not mention what methods of compensation should be resorted to at the international level. For example, the authors mentioned that the concept of compensation is mentioned in the Ukrainian Civil Code, Commercial Code, Property Rights, and other local laws. But the author did not address the concept of compensation and its elements in accordance with international law. This is very important because the conflict between Russia and Ukraine is an issue that crosses the internal borders of countries, and therefore international mechanisms must be resorted to understand how to compensate for damages.\nWho can apply for compensation (reimbursement)?\nThe author stated that, the Ukrainian legal field does not yet have a compensation mechanism for damages caused by armed aggression to business entities. So as long as the local legal frameworks do not have yet a compensation mechanism, so it is so important to discuss the mechanisms victims may use internationally. The authors should discuss it.\nAlthough the writer mentioned most of the categories of plaintiffs who are entitled to compensation, the article needs a deep analysis regarding the rights of these categories and whether they will be able, in practical terms, to obtain fair compensation\nWe also find that the article lacks in-depth analysis. The article is a descriptive enumeration of the categories of people who are entitled to compensation. It would have been better to write using both descriptive and analytical methods. For example, when the categories entitled to compensation were determined, the possibility of obtaining this right from a practical standpoint was not discussed, and what are the difficulties that those seeking compensation will face in obtaining compensation, whether these difficulties are related to legal challenges or the lack of competent institutions to assess damages or determine the amount of damage. Which affects every person or group\nWho is responsible for compensation?\nIn general, this issue has been discussed from a theoretical perspective only. It has been determined how the Ukrainian government will approach the Russian government for compensation. The foundations of liability were also discussed, such as harmful action, damage, and causal relationship.\nBut it would also have been better for the writer to discuss the issue of forcing Russia to pay compensation, what international legal frameworks can be used to demand Russia to pay compensation, and how effective such means are. All of these points must be discussed in order to have a complete picture of all the issues related to the extent of Russia’s responsibility for war damage and how to demand it to pay compensation, etc\nTo make the research stronger, the researchers need to clarify what are the grounds Ukraine may relay on when claiming for compensation. They need to conduct acritical analysis of the main rules used for this purpose. I suggest here to study the international rules specially the main conventions that Russia breaches. Also, the international warfare rules, and the roles of the international criminal course, and the international court of justice in this process should be studied.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes\n\nIs the case presented with sufficient detail to be useful for teaching or other practitioners? Yes",
"responses": []
},
{
"id": "221690",
"date": "22 Nov 2023",
"name": "Oksana Kaplina",
"expertise": [
"Reviewer Expertise War damages",
"criminal procedure",
"prosecution",
"tribunals"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article I evaluated is devoted to the important and complex topic of compensation for the damage caused by the war in Ukraine. First of all, I want to emphasize that the authors have well worked out the prerequisites of the study, emphasizing important details, such as the limitations of alternative methods of compensation in Ukraine, researching different concepts of compensation and their international definitions, which is extremely important for their application in the Ukrainian reality.\nIt is worth noting the commendable citation of various literature that is relevant for this study - international and national legal acts, research by domestic and foreign authors, as well as a significant amount of judicial practice, which determines the applied nature of the study.\nUnfortunately, the article lacks a statistical representation of the results of the analysis of court decisions, in particular, the quantitative indicators of the affected persons in the percentage ratio. Such details would help the reader better understand the discussed issues. However, despite this, the article has a comprehensive approach, a logical division into parts, and a consistent presentation of the material.\nAnother minor shortcoming is the lack of due attention to the extent of the damage caused and their monetary value, being limited only to the determination of the amounts to be recovered due to the moral damage caused to the victims. In my opinion, this is a fairly important criterion, especially for the victims themselves. However, taking into account the fact that the article is aimed at a research analysis of the legal aspects of compensation, and not its economic content, such omissions did not affect the overall quality of the article.\nThe authors have highlighted enough key issues of compensation for damage that it is appropriate to discuss them in one article. However, in my opinion, researchers should consider in more detail the question of assigning responsibility to the state, which has a positive duty to protect its citizens and population. This issue may become promising for further research.\nIn the article, the authors indicated several areas for further research, which remained unexplained due to the limitations of the scope of the article and the set goals. I agree that this study will be incomplete without further work in these directions.\nIt is also worth noting that the research methodology corresponds to the selected type of publication on the F1000Research platform.\nConclusions are clearly presented and correspond to all intermediate conclusions that were made during the study and do not contradict the main part. The tasks set at the beginning of the article have been achieved.\nThis article may be useful to other researchers in search of answers to questions related to compensation for damage caused by armed aggression, and its practical part may be important in the development of appropriate compensation mechanisms by authorized persons. Also, this article has the potential to become a new turn in the scientific discussion on the existing problems of reparations and post-war reconstruction of Ukraine.\nTaking into account all the above-mentioned points and despite minor shortcomings, I believe that the article deserves to be approved, and there is no need for revision.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes\n\nIs the case presented with sufficient detail to be useful for teaching or other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1250
|
https://f1000research.com/articles/12-863/v1
|
20 Jul 23
|
{
"type": "Systematic Review",
"title": "The post-award effort of managing and reporting on funded research: a scoping review",
"authors": [
"Ksenia Crane",
"Amanda Blatch-Jones",
"Kathryn Fackrell",
"Amanda Blatch-Jones",
"Kathryn Fackrell"
],
"abstract": "Introduction: Reporting is a mechanism for funding organisations to monitor and manage the progress, outputs, outcomes, and impacts of the research they fund. Inconsistent approaches to reporting and post-award management, and a growing demand for research information, can lead to perception of unnecessary administrative effort that impacts on decision-making and research activity. Identifying this effort, and what stakeholders see as unmet need for improvement, is crucial if funders and Higher Education Institutions (HEIs) are to streamline their practices and provide better support with reporting activities. In this review, we summarise the processes in post-award management, compare current practices, and explore the purpose of collecting information on funded research. We also identify areas where unnecessary effort is perceived and improvement is needed, using previously reported solutions to inform recommendations for funders and HEIs. Methods: We conducted a scoping review of the relevant research and grey literature. Electronic searches of databases, and manual searches of journals and funder websites, resulted in inclusion of 52 records and 11 websites. Information on HEI and funder post-award management processes was extracted, catalogued, and summarised to inform discussion. Results: Post-award management is a complex process that serves many purposes but requires considerable effort, particularly in the set up and reporting of research. Perceptions of unnecessary effort stem from inefficiencies in compliance, data management and reporting approaches, and there is evidence of needed improvement in mechanisms of administrative support, research impact assessment, monitoring, and evaluation. Solutions should focus on integrating digital systems to reduce duplication, streamlining reporting methods, and improving administrative resources in HEIs. Conclusions: Funders and HEIs should work together to support a more efficient post-award management process. The value of research information, and how it is collected and used, can be improved by aligning practices and addressing the specific issues highlighted in this review.",
"keywords": [
"Post-award management",
"grant management",
"monitoring and reporting",
"compliance",
"assurance",
"research funding",
"research bureaucracy",
"research impact assessment"
],
"content": "Introduction\n\nThe availability of research funds is declining and is subject to tighter compliance, performance, and fiscal controls.1 As funders are under more pressure to monitor and account for the research they fund, the effort of ‘post-award management’ is also increasing and affecting the productivity and culture in academic research.2–5\n\nPost-award management, also frequently known as ‘compliance’,6 ‘grant management’,7 and ‘monitoring and reporting’,8 involves reporting to funders on award-related activities, and is how funders oversee the progress, outputs, outcomes, and impacts of the research they fund. The effort involved can be considerable, and having administrative support is therefore important to avoid hindrance to research and spending too much time on grant-related administrative activity.9 Where adequate support is lacking however, too many compliance and reporting requirements can lead to faculty burden9 and the feeling of ‘pressure’ among early career researchers.10 Despite this, practices in post-award management have been rarely explored by the research community, and resources related to funding and ‘grantsmanship’ remain focused on pre-award areas, such as applications and peer review.11\n\nThe disruptive effect of the pandemic on research has led to renewed focus on academic support and removing administrative barriers to mechanisms of funding and research delivery.12,13 In the United Kingdom, plans for reducing ‘research bureaucracy’ include making changes to practices that now crucially involve post-award management, and organisations are asked to streamline how they collect and share information to reduce duplication and delay in research.14 While there is evidence that funders are indeed making changes to reduce administrative burden in practices, these still mostly focus on pre-award processes (e.g., shorter funding applications and contracts),15–17 while post-award management remains an area of few visible changes. Funders and Higher Education Institutions (HEIs) must therefore show they are addressing their post-award processes and comparing their practices, involving other institutions and sponsors in making decisions (e.g., on methods of information collection), and explaining to researchers why information is asked for, and how it is used.14\n\nAs strategic changes occur in this space,18–20 they should be supported by better understanding of the tasks and effort that go into post-award management. The value of the process needs to be clarified to the research community,21 and so should the roles that funders and HEIs play in supporting more efficient methods of research reporting. The aim of this review was therefore to understand the current position and landscape of post-award management; catalogue and summarise the different activities involved; and explore the purpose of information collection in research. An additional aim was to compare how funders currently approach post-award management, identify any unnecessary effort or need for improvement, and to use evidence of previous solutions to inform recommendations for both funders and HEIs.\n\n\nMethods\n\nThe review followed the unpublished protocol of the authors and is based on the PRISMA-ScR and JBI methodological and reporting frameworks for scoping reviews.22,23\n\nTo find and describe relevant literature, the broad definition of ‘post-award management’ was used and refers to any process – funder or HEI – that is relevant to the receiving of funds, set up, management, monitoring, and reporting of an ‘externally’ funded research award (i.e., an award obtained outside of HEIs, such as from public funders or charities). Processes can include any type of request for information (e.g., financial report, progress report, recruitment updates) made by funders or other external organisations and stakeholders (e.g., government departments) to inform on the status, outputs, outcomes or impacts of a research award. They can also include any processes associated with the curating of award data (e.g., management of award data within HEIs or use of data by funders for evaluations and impact assessments). Processes are considered ‘post-award’ from when the decision to fund has been made (e.g., issue of the Notice of Award) and include any that are carried out during project set-up (e.g., HEI approvals), research delivery (e.g., progress reporting), award close-out (e.g., end of grant reports) and after the award is completed (e.g., tracking of long-term outcomes and impacts).\n\nTo be included in the review, records had to be written in English, be accessible in full text or PDF format and describe any process(es) relevant to post-award management and reporting, as per the definition above. Records were excluded if they broadly referenced to post-award management without detail on the processes involved, or if they were out of the study scope (e.g., focusing on financial management of research awards or frameworks for research impact assessment). Eligible records could be peer-reviewed publications, grey literature (e.g., blogs, reports), presentations, or websites and no limit was placed on the publication date, status, or country to capture as much of the literature as possible in what we expected to be a sparsely explored area of research.\n\nAll authors were involved in developing the electronic database search strategy used to identify relevant literature on post-award management and reporting of funded research.\n\nTo test the initial search term and keyword combinations, limited searches were conducted in Embase and Medline by the lead author (KC) to check the availability and relevance of titles and abstracts. Since combining all the search terms returned no results in either database, the search strategy had to be refined, whereby multiple separate single-term searches were conducted (Table 1) and the results of each search were screened separately. This process was followed by searches using search term/keyword combinations to narrow searches where possible (as shown in Table 1) and these results were also screened.\n\nSearches are shown in the order they were conducted, and each line represents a separate search, the results of which were separately screened.\n\nFull literature searches were undertaken in relevant electronic databases, namely Embase, Medline, Pubmed, Web of Science and Google Scholar. Additionally, manual searches of the content tables of key journals (determined using the interquartile rule for outliers) were conducted to find relevant articles published in the last year (2022-23). Initial searches were conducted in March 2022 and the final manual searches were conducted in March 2023.\n\nIn addition to electronic and manual searches, the websites of 11 funding organisations (listed in Table 2) were reviewed to obtain information on current funder approaches to post-award management. The funders (listed in Table 2) were chosen to incorporate a range of geographical regions, funder sizes and monitoring and reporting approaches. The websites were reviewed between March and October 2022, with updated review in February 2023. The dates the websites were accessed and links to the web pages searched are shown in Table 2.\n\nRelevant web links include funders’ homepages and pages dedicated to award management, monitoring, and reporting. Where available, links to reporting content (including downloadable templates) are also included.\n\nRecords identified through database and manual searches were exported with citation, titles, and abstracts into Endnote 20 (Clarivate, UK) and duplicates removed. Records were divided into two groups to screen titles and abstracts against the eligibility criteria. Each group was independently screened by two authors (AJBJ and KF), with the lead author (KC) screening all records. Any disagreements between authors regarding the decision to include or exclude were resolved through discussion until consensus was reached. Full texts were retrieved for all records that were agreed to be included at this stage. Where full texts could not be retrieved, access to full texts was requested from the University of Southampton Library Services. Two authors (KC and AJBJ) screened all the full texts of records, and if agreement to include or exclude was not reached the third author (KF) was consulted to arbitrate.\n\nA structured data extraction form was created in Microsoft Excel and piloted using five eligible records. Following team discussions, the form was revised before formal extraction began. The lead author extracted the data for each record. Extraction fields (shown in Box 1) included: (i) study identifiers, (ii) study characteristics, (iii) details on post-award management processes, (iv) descriptions of unnecessary effort or need for improvement, and (v) descriptions of any previous solutions or recommendations from authors.\n\nHEI=Higher Education Institution.\n\n\n\nAn additional data extraction form was created for information on the current post-award management practices of funders, as obtained from their websites. The lead author extracted data from 11 websites in total, with the relevance of all information checked by all authors. The extraction fields are shown in Box 1.\n\nExtracted information on specific processes, requirements and tasks was analysed thematically, whereby similar processes were categorised and the resulting categories represented the main components of the post-award management processes. Each category was then ordered according to its frequency in the literature (i.e., the number of citing records) to give an idea of the effort involved. In adaptation of a method used by Glonti et al. to explore the roles and tasks of journal reviewers,24 extracted information relating to the purpose of post-award management was collated and used to compose common purpose-related statements (“The purpose of post-award management is …”). To do this, all relevant information was extracted into a Microsoft Excel spreadsheet by KC. Subsequently, information was coded into common statements and similar statements were categorised into overarching themes and ordered by frequency, again based on the number of citing records. Finally, extracted information relating to unnecessary effort or need for improvement in post-award management was summarised for each publication and thematically categorised according to the component of post-award management (e.g., research impact assessment) the information was relevant to. This information, along with any information on previous solutions or authors’ recommendations, was used to inform broad recommendations for funders and HEIs.\n\nThe information obtained from funder websites was extracted into and collated in Microsoft Excel and used to draw out the main points of variation in how funders approach post-award management. This included comparison of reporting requirements and the frequency of reporting, use of digital systems for award management, funder policies, resources and evidence of support.\n\n\nResults\n\nThe search strategy is depicted in Figure 1. Database searches yielded 2731 eligible records. Duplicate records were removed, and of the remaining 2117 records, 1926 records were excluded through title and abstract screening for not having met our eligibility criteria. Following full text screening of the remaining 191 records, a further 144 records were excluded (due to being too broad (n=38), out of the scope (n=100), or the full texts could not be retrieved (n=6)), which left 47 records to be included in data extraction. Manual searches identified a further 5 eligible records, giving a total of 52 records that were ultimately included in the review.\n\nJust over half of the records on post-award management and reporting consisted of primary research studies and reviews (27 records; 51%). Research included mixed-methods studies, observational studies, case studies, evaluations (prospective and retrospective), needs assessments and computational models. The remaining 25 records (48%) were non-research (e.g., opinion pieces and blogs) and included reports and pilots of funding programmes and grant management systems. Where research fields were specified, most were related to health and clinical research (19; 37%), with less represented fields including agricultural and life sciences (2; 4%), social research (1; 2%), the arts (1; 2%) and the study of research administration (1; 2%). The remaining records were deemed widely generalisable, as they were not aimed at any specific research field or type of research funding (24; 46%). Records were predominantly from the USA (21; 40%) and the United Kingdom (18; 35%), followed by Europe (3; 6%), Africa (3; 6%), South Asia (3; 6%) and the Middle East (1; 2%).\n\nAll records described processes relevant to post-award management; however, there was significant variation in the terminology used by authors (Box 2), with most frequent terms including ‘grant management’, ‘monitoring’, and ‘monitoring and reporting’. In terms of the organisational level, half of the records (26; 50%) focused ‘externally’ and described the tasks and information requirements (e.g., progress reports) that funders or other sponsors external to HEIs request on funded awards. In contrast, only 10 records (19%) focussed on the HEI side of the process by describing the administrative and technical operations involved in the internal set up of awards (e.g., financial approvals, staff hiring) and the tasks related to compliance and assurance reporting (e.g., data management, preparing audit reports). In almost a third of the records (16; 30%), authors explored both the funder and HEI sides of the process, describing mechanisms relevant to both.\n\nSquare brackets ([]) indicate the possible variations in terms.\n\nAdministration of awards\n\nAssurance [reporting and monitoring]\n\nAward management [process]\n\nCompliance [and reporting]\n\nGrant administration\n\nGrant monitoring, tracking and reporting\n\nGrantee reporting\n\nGrantmaking practices\n\nGrants and awards management\n\nGrant[s] management\n\nGrants management and reporting\n\nGrants program monitoring and evaluation\n\nGrant[s] reporting\n\nIn-grant implementation\n\nIn-grant management\n\nManagement of external research funds\n\nManagement of [grants/awards] and reporting\n\nMonitoring\n\nMonitoring and closeout\n\nMonitoring and [outcome] evaluation\n\nMonitoring and reporting\n\nMonitoring compliance\n\nOngoing assessment\n\nPost-administration requests\n\nPost-award administration\n\nPost-award grant[s] management\n\nPost-award management\n\nPost-award monitoring\n\nPost-award monitoring and reporting\n\nPost-award phase\n\nPost-award processes\n\nPost-award research activities\n\nProject management\n\nProject reporting process\n\nProject tracking management\n\nReporting [process]\n\nReporting and research impact assessment\n\nResearch assessment of progress criteria based on reported output\n\nResearch contracts reporting\n\nResearch management\n\nResearch reporting\n\nScientific reporting\n\nTracking individual projects\n\nTable 3 includes a summary of the 52 records and the key information extracted from each record. In line with eligibility criteria, all records provided information on post-award management processes. The majority (44 papers; 85%) also referred to the types of stakeholders involved, of which 30 different types were identified and the ‘researcher/principal investigator’ was the most frequently mentioned (20 publications; 38%). Twenty-eight records (54%) also provided information on digital systems used by funders and HEIs to support award management and reporting; in these, we captured 36 systems/initiatives in total.\n\nAsterisk (*) denotes an unpublished report obtained with permission from the National Institute for Health and Care Research (NIHR) Coordinating Centre.\n\nTo help simplify the complex process of post-award management and gauge the level of effort that may be involved (particularly from HEIs and researchers), the processes, tasks and reporting requirements extracted from records were catalogued into 14 categories representing the main components of the post-award management process (see Table 4). Based on the number of records, the top five categories where processes were mentioned included: Award-set up, compliance and close-out, Financial management and financial reporting, Progress reporting, End-of-grant reporting, and Digital tracking of outputs, outcomes, and impacts.\n\nExtracted information on processes, tasks, and information requirements is categorised and shown in a descending order of frequency (according to the number of citing records). Responsibilities for the below are not limited to researchers but aim to capture the responsibilities of other staff involved in coordinating the post-award management process.\n\nBased on the number of tasks and requirements involved, and their frequency in the literature, we found that for HEIs most of the post-award effort is likely around the set up and close-out of research awards, including the different considerations and approvals steps associated with these stages. Table 4 presents the processes, tasks and information requirements that could be involved, of which 27 items were related just to Award set up, compliance, and close-out. As an example, some of these are tasks related to providing ‘assurance’ to funders,14,25 and include due diligence, internal auditing, and reviewing award Terms and Conditions (T&Cs). Others include considerations for funder policies, such as compliance with Open Access of study data, governance, and record retention. Financial management and financial reporting also involve many tasks (17 items; Table 4) required for funder assurance,25 and these include monitoring award balances, managing Payroll, reporting expenditure for contracted services, and producing financial statements.\n\nReporting is another major focus of post-award effort, based on all the information that may be required for Progress and End-of-Grant reporting (Table 4). We found 22 items associated with Progress reporting which refer to specific information requirements for report contents (such as the ‘project goals and objectives’, the ‘overall progress’, ‘milestones and deliverables’, and ‘changes to work plan’) and 15 items associated with End-of-grant reporting (Table 4), which notably include content such as a ‘Plain English summary’, an ‘impact statement’, and ‘post-grant plans’. Some information, such as ‘outputs’, ‘achievements’, and ‘Intellectual Property’, can be requested in both types of report and can also be required for Digital tracking of outputs, outcomes, and impacts (Table 4) on research platforms such as Researchfish.26 Of note, other categories of reporting that add to the overall effort for researchers include In-person and informal reporting (6 items) and Performance reporting (5 items) (Table 4). The former may apply to any project and typically involve researchers presenting their progress to programme officers during site visits, or delivering additional information to funders (e.g., on impact activities) via surveys or interviews. Performance reporting on the other hand is more specific to research involving participants (e.g., clinical trials) and involves the reporting of participant data, such as enrolment and recruitment figures, as well as the outputs and outcomes of these studies (e.g., in compliance with funder clinical trial transparency policies).27\n\nIn an effort to better understand the value of post-award management and reporting, and why organisations may need to request information from researchers and HEIs throughout and beyond the award period, relevant information from records was collated into common purpose-related statements (i.e., “The purpose of post-award management is …”) (Table 5). In total, 57 common purpose-related statements were written from collation of data and then thematically grouped into 14 categories of purpose (Table 5) and arranged in a descending order of frequency (based on the number of citing records). Based on this analysis, the most common reasons for needing a post-award management process were: Research impact assessment (14 records) (e.g., “To understand what works in research and leads to impact”), Compliance (12 records) (e.g., “To comply with local legislation and the institutional rules that govern research”), Accountability to sponsors, volunteers and the public (12 records) (e.g., “To satisfy project sponsors and commissioners”), Funder programme development and planning (10 records) (e.g., “For funders to identify gaps where future funding may be needed”), and Ensuring responsible research conduct (9 records) (e.g., “To maintain integrity and ethics in research”). Less common but notable reasons included Securing future funding for researchers (8 records) (e.g., “To maintain funding support and advocate for the need for further research”) and Promoting and protecting the reputations of institutions and researchers (6 records) (e.g., “To promote the profiles of projects and researchers”).\n\nPurpose-related statements (n=57) reflecting the common reasons for needing post-award management and reporting in research. Each statement is based on the information collated from records, with the contributing references indicated. Categories of statements relating to a common purpose are shown in a descending order of frequency (based on the number of referencing publications).\n\nTo identify which specific area(s) of post-award management and reporting may be creating perception of unnecessary effort or need for improvement through solutions/interventions (e.g., new methods of information collection, administrative support), relevant information was extracted from publications and summarised in Table 6.\n\nSummary of findings from publications describing areas of post-award management and reporting where processes, or the research culture associated with these, create perception of unnecessary effort or need for improvement (n=28). Proposed solutions to the issues are summarised and include examples of previously implemented solutions or the recommendations of authors. HEI = Higher Education Institution.\n\n\n\n• Described issues (Perceptions of unnecessary effort or need for improvement)\n\n• Proposed solutions (previous specific solutions or recommendations)\n\n\n\n• HEI research administrators (RAs) report facing significant administrative workload and a stressful environment when managing research grants, updating policies, and supporting researchers through the grant lifecycle.\n\n• Some research administrators report not feeling appreciated and respected by their colleagues, who may be unaware of their true contributions to research and as such may hinder them from doing their jobs to support research activities.\n\n• Differences in professions, negative stereotyping and diverse backgrounds can challenge relationships between RAs and researchers, creating burden for both.\n\n• Failure to communicate and interact beyond work, and a lack of confidence in mutual input, contribute to unhealthy relationships between RAs and researchers, impacting on overall research collaboration and funding success.\n\n\n\n• Researchers and RAs should cultivate healthy and respectful working relationships to effectively manage all aspects of grant administration by tolerating differences in opinions, being aware of individual contributions, and being open to new ideas.\n\n• Effective working relationships can be facilitated by nurturing mutual respect and trust, communication, and collaboration.\n\n\n\n• In the United States, over $85 million a year was at one time found to be spent on administrative activities related to research.\n\n• Most researchers report that the administrative burden of grant management has increased over the years, and principal investigators now devote almost half their time to indirect research activities.\n\n• Submission of grant progress reports is considered the biggest source of administrative burden for researchers, even more so than grant proposal submission.\n\n• Knowledge of and compliance with federal agency and local HEI policies, procedures and systems all contribute to the time and effort researchers must commit to grant management instead of research.\n\n• The distribution of administrative burden is not equal, with those in public HEIs and medical schools shown to be disproportionately affected.\n\n\n\n• HEIs and sponsoring agencies should streamline and co-ordinate grant management processes to help reduce burden for researchers and administrative staff.\n\n• A better balance of administrative workload would allow researchers to commit more time to active research, without compromising on accountability and compliance.\n\n• HEI department heads should re-assign some of the administrative work currently placed on researchers and find additional support resources to free up more valuable time for research.\n\n\n\n• There are numerous reports that faculty members feel overwhelmed by the administrative burden and the many policies in research, and are looking for more HEI support with grant-related activities.\n\n\n\n• The University of Michigan’s PART-E program (a research administration onboarding and training program) serves as an example of how simply helping new research staff be aware of and understand the internal administrative resources and post-award functions available to them can help reduce faculty burden and make grant management a more positive process.\n\n• An effective onboarding programme would need to go beyond basic orientation and would benefit most from regular in-person sessions, which would encourage the building connections and a more positive overall research culture.\n\n\n\n• HEIs lacking the administrative staff to adequately support post-award functions may have problems with grant-related compliance (e.g., late reporting)\n\n• Lack of communication between administrative offices and the HEI community may lead to researchers feeling unsupported and not knowing who to contact in HEIs about compliance issues.\n\n• HEIs need to recognise that most researchers and clinicians delivering funded research are not likely to fully understand the complex administrative and regulatory requirements of that research, and may therefore need expert assistance with compliance.\n\n• HEIs need to ensure they employ a program administrator or team who understand the issues around compliance and can ensure these are properly addressed for each research award.\n\n• There is a need for training of staff and students in grant-related administrative activity that is currently overlooked.\n\n\n\n• An internal ‘research administration’ website – such as the one developed and tested for usability at the University of Wisconsin-Stout Graduate School – could help the HEI community gain the necessary knowledge on compliance and federal/HEI grant regulations.\n\n• An easy-to-read and navigate website about a HEI's administrative services should include clear information on where to go and who to contact (e.g., for post-award queries).\n\n\n\n• Limited faculty services related to delivering and supporting grant management functions can lead to burden on central offices, researcher dissatisfaction and poor compliance.\n\n• Lack of faculty support with pre- and post-award requirements means researchers are having to spend more time than ever away from their research.\n\n\n\n• Holding workshops to assist faculty and researchers with grant requirements (e.g., budgeting) is a scalable approach to achieving a more shared faculty service for support with administrative activity, as demonstrated by the John Hopkins University’s Cornerstone Project\n\n• Effectiveness of faculty services and grant compliance activities can be evaluated using general service metrics (e.g., “percentage of accounts reviewed with a principal investigator in a given month”) and post-award performance indicators (e.g., “number of financial reports submitted past the sponsor due date”)\n\n\n\n• It has been shown that researchers are not always able to understand or comply with some of the funders' monitoring requirements ( such as related to finances and reporting).\n\n• Research management is highlighted as one of the most common issues in developing research sectors (such as in Africa), meaning researchers are either unaware of the HEI rules around research management, governance and ethical clearance, or have to do most of the work themselves.\n\n• As a result of receiving inadequate support in understanding funder requirements, researchers may agree to comply with contractual requirements that they may then find themselves unable to deliver.\n\n• Researchers find themselves unprepared for the time that is needed for certain compliance requirements, such as ethics approvals.\n\n• A lack of IT support in HEIs sometimes means that data security rules are inadequately followed, and this results in some grants being withdrawn.\n\n\n\n• Solutions to enhancing research management of externally funded research could involve better guidance for researchers (e.g., on appropriate terms in contracts, finances) and more support from senior investigators.\n\n• Better planning of the roles and responsibilities in post-award management (who will do what) can prevent delays to the research.\n\n• Where required, researchers should be helped with the recruitment of participants or volunteers (e.g., for community-based projects), particularly with issues such as compensations.\n\n\n\n• The time researchers spend managing their research can affect their career development, teaching duties and the HEI's performance (outputs and achievements).\n\n\n\n• HEI investment into professional development/upskilling of staff in research management, or hiring dedicated research managers, would remove significant workload from researchers and give them their time back.\n\nHEIs in different regions should share their best practices for managing research to achieve improvement at the local level where it is needed\n\n\n\n• There is inconsistency in how funders and countries approach research impact assessment (RIA).\n\n• Despite increased scrutiny into how publicly funded research impacts society, there is a lack of systematised knowledge or accepted standards as to how research impact should be assessed.\n\n• There is a need for more transparent measures of non-academic impact and more focus on public participation in research.\n\n\n\n• The Agency for Health Quality and Assessment (Catalonia) propose a ten-point guideline for effective RIA based on expert evidence and opinions at the International School of Research Impact (ISRI), which incorporates ten ‘core values’ of assessing impact: context, purpose, stakeholder needs, stakeholder engagement, conceptual frameworks, methods and data sources, indicators and metrics, ethics and conflicts of interest, communication, and community of practice.\n\n• ISRI and other funders who may adopt the guideline should ensure they address any gaps in geographical, disciplinary or stakeholder representation that may limit its effectiveness, and continue to evaluate and improve their RIA practices.\n\n• Funders should be explicit at the reporting stage about how they use the impact information provided by researchers for RIA, and notably whether it affects their future chances of funding success.\n\n• The UK’s national advisory group, INVOLVE, have addressed the need for more public engagement in research by requiring that all research reports include a plain English summary.\n\n\n\n• Local and regional knowledge gaps have been identified and need addressing in the evaluation of clinical and health services research.\n\n• There is a need for a more complete research evaluation cycle, where funders assess how the research they support impacts on the generation of knowledge, identification of research topics, priority setting, and decision-making.\n\n\n\n• According to a qualitative study by the Agency for Health Quality and Assessment (Catalonia), funders should evaluate the complete research cycle (from identification of knowledge needs to reporting the impacts of individual studies) and engage researchers in identifying opportunities where the whole process can be improved.\n\n• Funders should evaluate how the research they fund impacts on advancing knowledge and decision-making.\n\n• Funders should put more effort into research on research and knowledge transfer, using a variety of quantitative and qualitative methodologies and indicators to inform RIA.\n\n• Funders should harness local evaluation agencies to identify local or regional areas of need, assess the impact of current research on these areas, and refine their research agenda.\n\n• the Canadian Academy of Health Sciences Return of Investment (ROI) model suggests that funders assessing impact using quantitative indicators should factor in the interrelationship between research outputs and implementations of findings.\n\n\n\n• The enormous investments of UK’s research funders into tracked online platforms aim to enhance how we capture the impact of research but may be inadvertently impeding its productivity.\n\n• Duplication of effort in reporting research impact on different digital platforms costs researchers and HEIs significant time and effort that is taken away from progress and opportunities in science.\n\n• The mass of impact-related data stored across a range of platforms may create complexity for those who wish to measure it (i.e., external organisations, evaluators, and policymakers).\n\n\n\n• Organisations need to think about how to increase the actual impact of the research as well as how to improve how it is reported and assessed.\n\n• Organisations need to better recognise the value of sharing and re-using research data.\n\n• The research sector should promote connectivity and data sharing across the various reporting platforms (e.g., through ORCID) to reduce burden for researchers and increase efficiency for evaluations and impact assessments.\n\n• Funders and HEIs should promote learning through research on research.\n\n• HEIs and organisations should agree on common systems and taxonomies for describing and curating impact.\n\n• Open access mandates currently applied to publications represent a solution that should be applied to the output and impact data of individual research awards.\n\n\n\n• Increasing economic pressures and a changing research sector has led to more demand on funders to justify their public spending on research and demonstrate value for money.\n\n• Researchers face increasing administrative burden in having to report the same information to multiple organisations and stakeholders (including their funders), which obstructs them from pioneering lab work and disseminating their outputs to a wider audience.\n\n\n\n• There is opportunity for better cross-collaboration and data sharing between funding organisations and HEIs across the research ecosystem.\n\n• Advances in IT should be harnessed to replace systems that are no longer effective, potentially inhibit collaboration, or create unnecessary burden for users.\n\n• Systems should standardise use of virtual technology where possible, and work towards automatic information acquisition from published output and products.\n\n• Horizon 2020 exemplifies a collaborative research and innovation funding program within the EU that led to the creation of Researchfish – an online platform for tracking research outputs, assessing impacts, and connecting openly accessible research information and outputs with specific grants and researchers.\n\n• For policymakers, Researchfish data informs research strategy and policy planning; for researchers and administrators, the platform reduces the need for duplicative information requests.\n\n• Impact in Researchfish is tracked through imported citations (e.g., from Europe Pubmed Central) and relies on the information given by the researchers themselves.\n\n\n\n• Relying solely on web-based tools to track impact may create a rigid and inaccurate picture for funders and policymakers, in which important but informal examples of impact (e.g., conversations between colleagues, networking) are not captured in the absence of direct and regular communication with researchers.\n\n• Researchers report a lag between the end of a research study and the publication of findings, which may not coincide with the window for relevant policy discussions and assessments of impact.\n\n• Peer-reviewed publications require follow-up to track impact many years after a study has been completed, adding extra burden for research managers and evaluators.\n\n\n\n• Funders could stratify the impact-related information they collect from researchers to include different types (quantitative and qualitative) of self-corroborating information (e.g., asking researchers to report grant-related products and correlate these with visibility metrics)\n\n• Use of multiple web-based tools (e.g., Google News, media-monitoring software), to complement data captured from reporting platforms could enable funders to collect additional useful indicators of research impact (e.g., mentions in social media, citations in policy documents and alt-metrics)\n\n• Regularly contacting researchers for a narrative account on their dissemination, engagement and impact activities can give funders more accurate updates on impact than if they relied on annual submission of impact reports (e.g., to Researchfish) alone. Consideration is however needed for the time and effort this regular contact would cost to researchers and evaluators, and that the given information would need to be confirmed by ‘research users’ (i.e., policymakers and other end users)\n\n• The Metrics Menu Tool was developed and piloted by the AcademyHealth (USA) as a solution for tracking web-based quantitative and qualitative research impact data in real time. Grant holders were able to provide examples of impact as they occurred, and this led to collection of an enhanced set of detailed impact-related information (albeit requiring additional administrative resource from the funder)\n\n\n\n• There is a need to invest more effort into maximising the value of Researchfish impact data for the research community; in particular, developing data analysis and sharing, analytical capability and capacity, data integrity and connectivity with the research ecosystem\n\n• Unequal funder capacity and capability for analysing data from Researchfish represents a key challenge; smaller funders may not have the resources (staff and software) to develop in-house evaluation processes and systems for producing analytical reports (e.g., on impact data)\n\n• There is inconsistency in the completeness, quality and accuracy of data entered into Researchfish, which requires validation so as not to undermine the value of analyses (e.g., impact assessments)\n\n• There is room for improving the interoperability of Researchfish with other data systems to avoid the burden of double data entry. However, this cannot be achieved without agreement on data standards and appropriate data validation\n\n\n\n• A solution to funder capacity and capability for data analysis may be to provide training and administrators to those who need it, to use a third party, or set up a ‘consortium’ for analysing data across funders\n\n• The importance of entering outputs accurately into Researchfish needs to be communicated to researchers and can be helped by funders being more transparent about how the data they request is being used\n\n• Efforts to connect Researchfish with other information systems (e.g., ORCID) and facilitate the validation of data need to continue. Steps have already been made to share information with publication datasets, such as PubMed for instance.\n\n\n\n• In a research sector with a highly varied data management infrastructure, a lack of interoperability and standardisation between systems, HEIs and organisations can create burden for users.\n\n• There is growing demand on researchers and HEIs to report on the performance and compliance of grants, and multiple requests for the same information from different organisations means that researchers must manually re-enter it into different data systems.\n\n\n\n• Enabling system-to-system communication between platforms would increase the efficiency and accuracy of reporting, ensuring it is compliant with funder policies and provides HEIs and research managers with consistent impact metrics.\n\n• For HEIs, the increase in reporting requirements could be managed more easily by sharing information and promoting consistent use of universal key standards and unique identifiers when reporting outputs.\n\n• Specialised research information systems (e.g., Jisc) offer interoperable solutions to better information sharing that are tailored to the UK’s academic sector.\n\n• Jisc software enables transparent reporting, communication, and measurement of research data, and currently leads the sector in promoting standards, universal identifiers, and interoperability between data management systems.\n\n• Standards in HEI research administration and data management, including use of unique identifiers (e.g., ORCID, ISNI, DOIs), is promoted by the Consortia for Advancing Standards in Research Administration Information (CASRAI) through collaborative projects with universities.\n\n• Other systems promoted for HEI use include Current Research Information Systems (CRIS/IR), Je-S, Gateway to Research, open-source solutions for specialist/small HEIs, simple repositories, databases or spreadsheets, CASRAI templates, reusable pick-lists (CRediT, academic career levels) and glossaries for open access research data management.\n\n• Funders can also contribute to interoperability and re-use of research information in joint ventures with HEIs and initiatives, as exemplified by the collaboration of Research Councils UK (now UK Research and Innovation) and Jisc on the Overview of Systems Interoperability Project (OSIP)\n\n\n\n• Lack of communication and interoperability between HEI and funder systems (e.g., CRIS/IR and ResearchFish) can lead to errors in information flow and requires duplicative input of information from researchers.\n\n• Research information submitted to funders must comply with funder policies and cannot simply be imported from HEI systems (which may cause import errors).\n\n• Improvement is needed in the bi-directional flow of information between HEI and funder data management and reporting systems.\n\n\n\n• Automatic data importing would remove the burden of manually entering publication data from researchers.\n\n• HEIs should work with funders to transfer grants-linked publications data from internal information management systems to funder-supported platforms.\n\n• Automatic transfer of grants-linked publication records from CRIS/IR to Researchfish has been proven to be possible, where almost every record passed validity checks. In the six-institution collaborative pilot, automatic transfer of data prevented researchers from having to manually link around 2,500 publications to grant IDs (reportedly saving them time).\n\n\n\n• Universities collect and retain the research data they produce, but this data is often less well curated and can be very difficult to find externally, limiting its value and potential for reuse.\n\n• Many disciplines currently lack access to an appropriate subject-specific data centre and the funding support from research organisations to properly curate and encourage reuse of research information.\n\n\n\n• Data management plans and data curation centres can help HEIs better manage their data and researchers track their research outputs, as well as understand the ethical and legal requirements for dissemination and reuse.\n\n• The UK pilot research data registry and discovery service (RDRDS) is an example of an initiative that can help ensure that research data produced by HEIs can be found, understood, and effectively reused.\n\n• Funders should explore the value of data registries and discovery services, such as the RDRDS, for their own research data tracking, assessment and sharing needs (e.g., for reviewing the impact of funding and identifying trends and gaps).\n\n\n\n• A frequent problem in the management of sponsored research is the use of homegrown or proprietary information systems that are separate, non-integrated, or inadequate.\n\n• Duplication stems from issues with system interoperability that span the lifecycle of research awards and may represent a key source of burden for researchers.\n\n\n\n• As identified by a Delphi consultation, a critical factor for research management success is having a common ‘enterprise-level’ information system that can integrate and work across multiple existing HEI departments and systems (e.g., finance and Intellectual Property). However, achieving this would require additional funding and resource for system maintenance and regular software updates.\n\n\n\n• It is suggested that advances in IT are currently insufficiently harnessed to tackle administrative burden and inefficiency in research sectors, which leads to slow progress in improving HEI information repositories and grant management systems.\n\n• Absence of internal grant management software and reliance on manual input (e.g., in Excel) makes collating and process of data, as well as monitoring of grant status, complicated and time-consuming for HEIs.\n\n\n\n• Consulting researchers (as well as research coordinators, grant administrators and reviewers) on areas where managing grant information can be improved using software can help HEIs adopt new, or improve existing, systems.\n\n• What researchers, administrators and reviewers reportedly require from internal grants management systems is usability (e.g., easy registration of proposals, assessments or document and report checks) and an overall efficient flow of information throughout the grant cycle.\n\n\n\n• Funders often require grant holders to carry out and report on stakeholder engagement but may not always follow through with adequate support with encountered issues (e.g., political, administrative) when trying to engage with certain types of stakeholders.\n\n• Funders could easily learn where they need to better support their awardees by asking for feedback at the reporting stage.\n\n\n\n• The RHD Action Small Grants Programme learned of and was able to respond to grantees’ issues with engaging government stakeholders by requesting feedback on the funding programme and recommendations for improvement as part of the reporting process.\n\n\n\n• There is concern of inadequate researcher compliance with funder policies regarding transparency of reporting clinical research, and that some researchers may be selectively reporting positive findings.\n\n• Funders may need better ways of encouraging researchers to report trial findings transparently and reliably within a certain time window.\n\n• Having to collect and curate a reliable set of trial data from multiple sources (grant applications, grant management and reporting systems) poses a challenge for funders.\n\n• Funders have yet to universally adopt a trial registration policy to facilitate transparency of reporting and collection of trial data.\n\n\n\n• Trial registries are now supported by many funders and significantly reduce bias in outcome reporting and publication; as such, monitoring compliance with trial registration should be the focus of future funder policy initiatives.\n\n• More funders should encourage researchers to register their trials on public platforms (e.g., ISRCTN, EUCTR, ClinicalTrials.gov) and report trial registration numbers, along with updated details of outputs and protocols, to increase transparency of reporting.\n\n• Contacting researchers to remind them of the reporting window is shown to be effective in prompting them to report or publish findings.\n\n\n\n• Overreliance on technology in grant management can lead to duplication of effort for researchers when reporting research data.\n\n• Organisations are asking for more information and documentation to be reported, creating extra administrative costs, taking time away from program delivery and creating burden for researchers.\n\n• There is a perception that organisations could be clearer and more upfront with researchers about how the information they request at the reporting stage is used and who uses it.\n\n• Researchers report a lack of guidance and communication from funders regarding reporting requirements, and the timing of information requests is said to be problematic.\n\n• Effort in reporting is affected by factors such as the researcher’s workload and experience, the funder’s specific requirements, the administrative capacity in HEIs, and availability of staff training.\n\n\n\n• Based on the opinions of funding organisations and grantees, the level of administrative burden in compliance and reporting could be better monitored by funders as part of their evaluations by capturing ‘metrics’ such as “number of reporting requirements” and “length of time in providing requested information” along with the other information collected in reports.\n\n• Funders should streamline their grant management processes to reduce burden, ideally achieving a balance between ensuring accountability and considering researchers’ interests.\n\n• Funders should consider what information they require as minimum, and concentrate their monitoring activities on higher-risk grants\n\n• By adopting a ‘triage’ (i.e., risk-proportionate) approach to grant management, funders can free up capacity to provide extra support to those who need it most, such as new investigators.\n\n\n\n• Reporting and collecting research information can take hours or days and creates administrative burden for researchers and programme managers.\n\n• The time it takes to complete reports means stakeholders may not have access to the most current research information.\n\n\n\n• HEIs could reduce the time it takes to report to just minutes by using integrated software systems of data collection. This was exemplified by the Indiana Clinical Translational Science Institute’s implementation of the REDCap integrated grant management system.\n\n• Collection of progress reports in real time would allow programme managers to intervene quickly should issues arise.\n\n\n\n• Economic pressure on the health research system means that putting funding into research instead of directly into healthcare needs to be well-justified and demonstrate return in terms of performance.\n\n• Routine methods of managing and measuring performance (e.g., the use of standardised indicators) may not be the best way of monitoring relevant and valuable outcomes from research due to the difficulty of applying uniform indicators across the breadth of health areas and research activities.\n\n• Performance measurements tend to focus on measurable outputs (e.g., publications), and not outcomes that are more variable but indicative of improvements in health.\n\n• In measuring research outcomes, the time lag between the publication and impact of outcomes is not factored in and can be up to 20 years.\n\n\n\n• The UK Economic and social Research Council proposed a performance monitoring system (REGARD) for health-related research that is not based on uniform targets and indicators, but instead aims to meet five key criteria: that is relevant to funder objectives; it is decision-relevant; it encourages ‘truthful compliance’; it minimises unintended consequences; and it has acceptable net costs.\n\n• Utilising the above or a similar system would require the following methods of collecting research data: questionnaires to researchers and user surveys; harnessing bibliometric databases; analysing policy documents; expert review; case studies and economic evaluations.\n\n• As a caveat, some information can be collected regularly on all research funded activity, while some would only be collected on a sample of activities. Moreover, posing questions and making accurate assessments on certain activities (eg., policy and health impact) may be difficult but is feasible with the use of questionnaires, based on previous work.\n\n\n\n• Funders need to reduce burden and foster fairness, innovation, and creativity in their evaluation and grant management methods.\n\n• Current availability and accessibility of data that is used for evaluations is insufficient and should be improved.\n\n• Previous funder efforts to evaluate researcher burden, innovation and fairness in grant funding processes have been limited and focus on the pre-award phase.\n\n\n\n• Evaluation measures could better reflect the effort of researchers if they captured the relevant data. Metrics of administrative burden in grant management could include “time spent by researchers and HEIs preparing grantee variation applications, financial acquittals and end of grant reports” and “hours of internal administration time and total administrative costs”.\n\n• Funders should ask researchers about their experience with grant programs and where processes (e.g., usability of data systems) related to grant management can be improved.\n\n• RAND Australia have shown that metrics could be used to improve evaluation of grant programs at the National Health and Medical Research Council (NHMRC), and have led the design of a new framework to increase the efficiency and accessibility of grant management systems, support innovation and researchers, and allow more time for high-quality research.\n\n• The NHMRC has shown that changing grant management systems (in their case, from RGMS to Sapphire) can help improve usability and efficiency for users, saving valuable researcher time through easy features such as the ‘autosave’ function and live character counting. The next step for Sapphire is to connect its research data with external sources, collect more free-text responses from researchers, and provide more flexible online formats.\n\n\n\n• Community projects often rely on volunteers for delivery and lack the budgeting, staff, or experience for implementing formal monitoring and evaluation processes.\n\n• There is not enough awareness among community-focussed researchers of the importance of evaluation and measuring research performance and outcomes.\n\n\n\n• Commissioning and funding organisations should help the community project researchers they sponsor carry out evaluations.\n\n• Funders should clarify for those involved in community projects the reasons why they should be monitored and evaluated (e.g., to satisfy sponsors, inform future work), and outline the key components of a successful evaluation process (e.g., through a guide). Solutions should also be applied to any barriers or problems identified by the research groups.\n\n• Community groups should plan for monitoring and evaluation as soon as possible (e.g., deciding early if external evaluators are needed), and consider the different types of evaluations, what they should be evaluating (what outcomes or indicators), and when data should be collected.\n\n• The findings of monitoring and evaluation should be widely shared with other community groups and organisations, making use of online resources and social media.\n\n\n\n• Current evaluation systems (informed by reported research information) use criteria that can create bias and insufficiently reflect unforeseen circumstances (such as Covid-19) that may impede research progress and disproportionately disadvantage some groups (e.g., early-career researchers and female investigators).\n\n• Current funder evaluations may be capturing a limited set of performance metrics (e.g., focusing on journal output and research income) and should include other activities, such as mentorship, team building, and opportunities for underrepresented groups).\n\n\n\n• Funders must better recognise their responsibility for having effective research evaluation policies as a step to designing better systems of how research and researchers are valued, measured, and assessed.\n\n• Funders could learn from the impact of the Covid-19 pandemic on research performance to inform development of more equitable and balanced evaluation systems.\n\n\n\n• Long delays in post-award disbursements of funds can create burden for researchers and delay the research.\n\n• Delays to research are contributed to by internal bureaucracy and a duplicative HEI approvals process (e.g., including too many people in the approval queue).\n\n• Researchers also have to deal with late payments, long grant renewal periods, and an unpredictable grants process.\n\n\n\n• Solutions to ‘post-award lag’ and inefficiency that funders and HEIs could implement include switching to electronic grant tracking and electronic accounting systems, standardising forms and deadlines for funding calls, simplifying the approvals process, and employing more staff to deal with backlog.\n\n• Funders should shorten grant renewal periods and remove the requirement for researchers to submit new proposals if only a small portion of their funding requirements (e.g., up to 20%) have changed.\n\n• An example of previous reform to grants management processes to reduce post-award lag and administrative burden for grantees is the Space Science Programme at NASA. Programme leaders responded to the burdens identified by researchers by sending out letters, holding open meetings and assembling advisory groups with grant managers at other federal agencies.\n\n\n\n• There is a general perception across the UK's research sector that bureaucracy and burden have increased over time.\n\n• Complex and duplicative reporting requirements, slow internal approval processes and non-interoperable data systems have been identified as major issues.\n\n• Scrutiny of assurance processes has steadily increased, and new organisational requirements that have served their purpose are rarely removed.\n\n• The biggest contributors to administrative burden are HEI bureaucracy and internal delays (e.g., due to unnecessary hierarchy in operational/approval processes and lack of dedicated departments). Moreover, complex assurance and reporting processes perpetuate a culture of ‘risk aversion’ among organisations.\n\n• Particularly post-Covid, there is a need to reduce pressure on researchers and increase the efficiency of direct and indirect research activities.\n\n\n\n• Reform in the sector should focus on harmonisation (e.g., standardised data templates, interoperability of data and alternative CV’s), simplification, proportionality, flexibility (e.g., repurposing funding), transparency (e.g., clarifying the need for information requests), fairness (e.g., removing barriers to entry in funding), and sustainability.\n\n• Shorter applications, shorter review windows and funding decisions, and wider use of preprint platforms for quicker dissemination of outputs are recommended to improve efficiency.\n\n• HEIs and funders should both work to standardise some of the internal assurance, due diligence and reporting processes, and promote information sharing.\n\n• Periodic assessment of overall HEI research performance could replace project-level scrutiny and make assurance more efficient.\n\n• Funders should employ a principle of ‘ask once’ to reduce duplication in assurance and monitoring processes.\n\n• Funders should give HEIs and researchers more time post-award for project set-up (e.g., finances, recruitment) and respond quicker to project change requests and no-extensions.\n\n• Funders should explain the purpose of different information requests to researchers.\n\n• Funding councils and charities should coordinate their processes and support HEIs with award management and assurance. processes to improve efficiency and reduce burden (e.g., by exploring self-certification).\n\n• Funders such as NIHR, UKRI and Wellcome should consider replacing older digital platforms with a unified system that is simple to use and supports organisational diversity while keeping pace with the evolving sector.\n\n• HEIs should align their data management practices by transferring to the Jisc system.\n\n• Organisations and regulators should consult the research sector before implementing new requirements to agree on the best approaches.\n\nIn total, we identified 29 records (55% of the literature) which provided evidence of unnecessary effort or need for improvement in different areas of post-award management. All records also described solutions to the identified issues, most of which have been previously implemented and a few were recommendations from authors. Summaries of the findings for each record were categorised based on the component of post-award management the information related to and included: the publication reference and funding field, brief descriptions of the issues, and descriptions of solutions (Table 6). The six categories of post-award management where we captured this evidence were: Supporting researchers with tasks; Research impact assessment; Data management and accessibility; Reporting and digital tracking of outputs, outcomes, and impacts; Monitoring and evaluation strategies; and Award set up. The three most frequently cited areas of unnecessary effort and unmet need were: Supporting researchers with tasks (7 records), Research impact assessment (6 records), and Data management and accessibility (5 records). An additional general category, ‘Bureaucracy in research’ included two reports covering issues related to multiple areas of post-award management specific to the UK research sector.14\n\nConsulting the websites of funders (Table 2) revealed that all websites included information on post-award management processes, although to varying degrees of detail. Overall, we noted considerable variation in the funders’ approaches to monitoring and reporting: differences included the terminology used to describe post-award processes (e.g., ‘scientific reporting’, ‘project management’), specific reporting requirements (e.g., progress reports) and the frequency of reporting (e.g., annual, quarterly), the type of information requested (e.g, impacts) and where it must be reported (e.g., end-of-grant reports vs platforms), and the digital platforms used to support applications and award management. There were also differences in the level of detail relating to guidance and supporting information for researchers and HEIs (such as policies, justification for requirements and explanations of why information is asked for, how it is used, and who uses it). The main points of variation in practices are outlined in more detail below.\n\n\n\n- For most funders, specific reporting requirements and the frequency of reporting depend on the grant scheme or funding programme, meaning that the information asked of researchers can vary. Funders may also vary their requirements on a case-by-case basis or use a ‘risk-proportionate’ approach – for instance, as done by the National Institute for Health and Care Research.28 Some funders, however, may use the same approach to monitor all their awards and we found this is to be the case for the Canadian Institutes of Health Research, Alzheimer’s Research UK, the National Research Foundation, and the National Institutes of Health.\n\n- Most funders require submission of periodic progress reports as part of routine project monitoring. As an exception, the Canadian Institutes of Health Research require submission of a single electronic grant report at the end of a study, while the Medical Research Council generally asks that researchers submit study updates annually via Researchfish (although they may ask for updates on progress using other methods).\n\n- In addition to completing progress reports and publishing in journals, some National Institute for Health and Care Research (NIHR) funded researchers must also publish their full study outcomes and outputs on NIHR platforms, namely the NIHR Journals Library (NJL) or the NIHR Open Research platform (depending on programme). Recently, the NJL has transitioned from publishing full study reports to a flexible ‘threaded publication’ approach,20 where for some studies findings can be published as smaller reports and followed by a synopsis of all study outcomes after study completion. Notably, health and social care studies funded by NIHR must also report to the Health Research Authority, and this is in line with the ‘Make it Public’ transparency and openness strategy that the UK now applies to all publicly funded health research.\n\n- In addition to end-of-grant reports, the National Health and Medical Research Council in Australia requires that fellowship award recipients specifically also submit a single-page summary of the research, and all awardees are also required to annually update their electronic CVs to reflect latest grant outputs as part of routine ‘performance reporting’.\n\n- Most of the funders (7 out of 11) require funded clinical trials to be prospectively registered on at least one public trial registry platform (e.g., ISRCTN29) and for trial results to be transparently shared within a feasible time frame of study completion. For the National Institute for Health and Care Research, clinical trial investigators are also required to submit ‘performance reports’ to England’s Clinical Research Network, so that data such as recruitment can be reviewed against national benchmarks and used for publishing annual performance statistics. Trial and intervention study applicants to the Health Research Council New Zealand, on the other hand, are required to plan their own monitoring as part of application and in advance of funding decisions, as studies of this type must undergo periodic review of safety/efficacy and requests for appropriate panels must be made in advance of the project delivery phase.\n\n\n\n- Apart from the Canadian Institutes of Health Research and University Grants Committee Hong Kong, most funders use their own in-house digital systems to manage applications and funded awards, as well as for receiving and managing research reports.\n\n- Three funders – National Institute for Health and Care Research, the National Institutes of Health, and the European Research Council – each currently use more than one in-house system for managing studies; however, it must be noted that use of systems can be subject to change, for instance, as funders undergo restructuring or as part of funding programme improvement.\n\n- The National Institute for Health and Care Research and the Medical Research Council both require that researchers register their studies, and annually report their outputs, outcomes, and impacts, via the shared platform Researchfish. For both funders, this is a compulsory reporting requirement for all funded awards that is used for monitoring and research impact assessment in addition to other reports.\n\n- In Singapore, all publicly funded research is managed under a single digital system, the Integrated Grant Management System. This system is accessible to all funders, HEIs and researchers and is used for submission, management and tracking of all funding applications and research reports.\n\n\n\n- With the exception of one funder – the University Grants Committee Hong Kong (for whom this information was not found) – all the funders have dedicated web pages for monitoring and reporting requirements. These include guidance and relevant policies, and in some cases detail on what information is asked for (e.g., downloadable report templates). However, the level of detail and notably the focus of policies related to monitoring vary. For instance, the National Institutes of Health and the Canadian Institutes of Health Research both focus their monitoring policy on clinical trial registration and transparent reporting of outputs, whilst the policy of Alzheimer’s Research UK focuses on research impact assessment, and the National Health and Medical Research Council’s on evaluation strategies and ‘innovation’ of grant management practices. Most funders however make sure to update their monitoring policies regularly, although whether this is the case for the National Research Foundation and the European Research Council was unclear from their websites.\n\n- Most of the funders share downloadable report templates on websites, or provide a summary of the type of information they request from researchers. Alzheimer’s Research UK and Health Research Council New Zealand, on the other hand, do not seem to share their report contents on websites, which suggests they may send them directly to grantees (for instance, once the reporting window is open).\n\n\n\n- All funders give some indication on their websites as to who in HEIs may be best placed to fulfil certain compliance and monitoring activities (e.g., a project director).\n\n- All funders provide a list of relevant offices and research managers/administrators who researchers and HEIs can contact for information or assistance with managing their research awards.\n\n- Awardees with the National Institute for Health and Care Research receive monitoring support from dedicated research managers and teams, who are specifically assigned to monitor and risk-assess funded contracts and support their researchers with fulfilling reporting requirements. As an example, support is provided by sending researchers reminders of upcoming deadlines for progress and final reports.28\n\n- The Medical Research Council employ a Translational Research board and Research Funding Policy and Delivery team, both of whom help manage awards and respond to researchers’ enquiries or variation requests.\n\n- The National Institutes of Health provide their grant recipients with a ‘Welcome Wagon’ letter as part of early post-award communications, which includes helpful information and resources to help them set up their research and manage their research awards.\n\n- The National Research Foundation in Singapore have a web page with guidance and training videos on award management specifically for researchers.\n\n\nDiscussion\n\nPost-award management is an important condition of funding that serves many purposes but varies in the mechanisms and administrative effort involved. This section discusses the findings of the first scoping review on this topic, focussing on their implications in terms of effort in post-award management, the responsibilities involved, and the support that can be provided or remains needed. We also discuss the availability of evidence in this space, limitations, and future directions for research, and offer broad recommendations for both funders and HEIs.\n\nManaging funded research involves more than the signing of contracts and completion of progress reports. The landscape of post-award processes, tasks, and conditions for funding is complex and there is no clear relationship between organisation size, award type and the monitoring and reporting approach. Cataloguing and summarising the available evidence however allowed us to better understand processes and gauge where most of the effort may lie. We were also able to highlight areas where effort may be perceived as unnecessary and improvements are needed, focusing on solutions and recommendations that are relevant to funders, HEIs, and researchers.\n\nFor HEIs, significant effort is needed for compliance and the post-award set up of studies, which involves setting up the conditions for the award, obtaining necessary approvals and arranging timely funding disbursements,30 as well as ensuring that the correct infrastructure is in place for responsible and compliant management of finances and research data throughout the award. Notably, research sectors have become increasingly digitalised,31 not least because of Covid-19, and HEIs now store vast quantities of research data which they must ensure is accessible, discoverable to others externally and standardised32 for effective sharing and reuse by the research community. However, siloed approaches to managing data – where funders and HEIs all use their own systems – has led to an overwhelming presence of digital platforms, of which 36 were captured in this review alone and most of which lack interoperability, resulting in duplication of effort for users.33 Although numerous collaborative initiatives32,34,35 (such as Jisc and Current Research Information Systems-Institutional Repositories (CRIS-IR)) now provide HEIs with solutions for better system interoperability and data sharing with funders, they have yet to be standardised across the research sector14 and there is still room for reducing manual effort in and improving the transfer of grant-linked research data between systems. Moreover, while HEIs are encouraged to engage with specialised data services to improve the accessibility and reuse value of the data they hold, evidence that funders also engage with these services seems to be lacking34 and inconsistency in how funders themselves use technology for tracking research outputs, outcomes, and impacts may explain why research data is still not being efficiently shared across sectors,27 perpetuating unnecessary effort and research waste for users.\n\nImportantly, too many digital sources of data can also affect funders’ abilities to perform research impact assessments (RIA),36,37 which in today’s ‘accountability climate’, are crucial for demonstrating that research impact is ‘measurable’ (e.g., resulting in new policy or technology) and for the continued support of the funders’ research programmes.37–39 While the specific reporting requirements of funders may vary, we found they consistently request that researchers anticipate and report on the impacts of the research they fund. Moreover, the reported information must be relevant and updated after study completion, and as such tends to be collected frequently and using multiple methods, including progress reports, end-of-grant reports, impact statements, and online submissions to tracked impact platforms (such as Researchfish). However, research has shown that having a ‘plethora’ of data sources available to funders for RIA does not mean that assessments are always useful to funders, and there remains no consensus on RIA frameworks, or the meaning of ‘impact’.37,40–42 This brings into question the end value of impact reporting to stakeholders, and of adding more effort to this activity on both sides of the award.37 For instance, while there is evidence that new frameworks and tools for capturing broader impact data are being developed,8 the ‘value add’ of these versus the costs (in terms of money and effort) should be also considered to avoid placing unnecessary burden on routine funding operations or on the delivery of research activities.\n\nResearchers already report struggling with routine reporting requirements,43 as well as the multiple systems used to track research data and having to manually link study outputs with the identifiers of research awards.32 With respect to the accuracy of the data reported, some argue there is still room for improvement39 and for funders and HEIs this may mean training researchers in ‘impact literacy’ or explaining more clearly the type of impact information they should be reporting. The need for certain types of reporting, such as progress reports, and the need to include impact data in these reports is also up for debate, as it is suggested that funders mostly rely on end-of-grant reports or tracked platforms to collect data for retrospective analyses of the overall and long-term impacts of studies.37 Indeed, we found that not all funders require progress reports of researchers, and reducing effort in this area may therefore mean giving researchers more autonomy as to how they update funders on the progress of their awards – for instance, allowing them to report in real time or through more direct communication channels with funders.8\n\nA lot of the post-award effort discussed in this work is shared between researchers and many other staff within funders and HEIs, who help coordinate and deliver the complicated post-award management process.44,45 However, we found that specific responsibilities for requirements, and the level of support offered to researchers in HEIs, depends on availability of research management and administrative (RMA) infrastructure and other individual factors in institutional set up.6,7,46–50 As such, while certain award tasks, such as negotiation of contracts and hiring, are always delegated to relevant HEI departments (such as Human Resources and Finance) the level of support offered for other activities – such as review and approval of research operations, managing direct information requests and reporting – is not always clear due to differences in HEI facilities, resources, and internal funding. In addition, RMA appears to heavily vary by country,49,51,52 and even where it is readily available (such as in dedicated ‘grant offices’ or ‘post-award offices’3) a ‘systematic problem’ of administrative burden and issues with compliance is still being reported,53 with issues stemming from factors such as overburdened central offices,48 poor leadership,54 inadequate training,47,49 and ineffective relationships between researchers and administrators.46 The concern therefore is that not having the needed support for post-award tasks may affect the timely delivery of the research and reduce its impact, as well as return on the funders’ investments. As such, adoption or improvement of RMA and grant support functions in HEIs may be necessary, with the onus then on governments and funders to deliver the infrastructure and training required,55 investing in better research support to fund better quality research.56\n\nThere is evidence that strategies to improve funding systems now include efforts to optimise grant management processes15,16,17,57–59; however, as a research area, we believe that the post-award phase may still be in its formative stage. Evidence on post-award practice is limited in scale, robustness and focuses on interventions (e.g., training, alternative mechanisms) compared to topics like grantsmanship and peer review,11,60,61 and the literature aimed at researchers is mostly on improving the quality of grant applications, and not on what happens post-award or improving post-award skills (such as writing of progress reports62).\n\nMost literature in the post-award space also focuses on research impact assessment (RIA) and tends to be high-level, exploring RIA frameworks and strategies in isolation of the reporting that funders require (see Refs. 38, 63 for examples). We found only six publications8,39,41,42,64,65 that linked RIA back to the funders’ methods of information collection, and which considered the feasibility of funders being able to collect certain types of data (e.g., qualitative impact data) for the purpose of monitoring and RIA activities. These publications were useful as they showed how some solutions for funders (e.g., improving the accuracy of impact data) may affect individual reporting requirements (e.g., the need for telephone interviews with researchers) and the implications on effort for the evaluators and researchers directly involved in reporting.8 However, literature focusing just on how research is monitored by funders is sparser, and a large proportion of information had to be gathered either directly from funder websites or funding reports, or from publications and theses on award management systems. Much of the evidence on perceived unnecessary effort in post-award management was also gained from grey literature (e.g., opinion pieces64), with little observational data available, such as from faculty interviews and surveys with staff (as in Ref. 46).\n\nUltimately, we believe the reason for the lack of research in monitoring and reporting is simple: that feeding back to funders on research that has already been funded is generally seen as well-justified and less onerous than applying for funding or undergoing grant application review. For instance, we found that no record argued against funders needing to oversee their research investments in general, and the literature instead provided a catalogue of reasons why monitoring research is important to numerous stakeholders within and beyond academia. As such, despite how researchers may experience the effort that goes into managing research and complying with funders’ requirements, we and others believe they are still likely to see this effort as a ‘necessary burden’ in funding, which will seldom deter them from applying for funding or continuing working in research.3\n\nNevertheless, it is important to raise awareness of any unnecessary effort or issues with practices that have been accepted in the past but are now impacting on efficiency in funding processes or today’s research culture. To that end, the research sector will benefit from this review of previous work, and more exploratory research,54 independent reviews,14 needs assessments66 and systematic comparisons of practices. Notably for funders and HEIs, strategic changes should focus on ‘grant implementation’, ‘in-grant management’, and ‘digital platforms’,14 and the success of any future interventions (whether it is guidance and training or integration of new systems) should be prospectively evaluated (such as in Ref. 67) or followed up to determine the long-term effects as the research sector evolves and new burdens arise. Continuing to capture ‘effort’ and the experiences and perceptions of stakeholders is also crucial going forward, and in our opinion such assessments could complement the development of administrative ‘indicators’57 to appraise where effort in post-award management is concentrated, assess its end value to research, and identify areas for further improvement.\n\nWe have drawn on the evidence of common issues and potential solutions in post-award management (Table 6) to inform key recommendations for funders and HEIs. We believe these recommendations will be relevant to many funders internationally and could facilitate effective future changes to reduce unnecessary effort in research14 or identify where more research is needed to inform feasible opportunities for improvement in post-award management.\n\n\n\n- Funders should refine and, where possible, standardise their monitoring and evaluation processes and ensure they align with any future evidence on best practice. This should include large funders working with charities to better align processes.\n\n- Funders should evaluate and improve the frameworks they use for RIA but consider the effort involved for researchers and evaluators when changing monitoring and reporting requirements.\n\n- Funders should better engage HEIs, researchers, and other institutions and sponsors, in future decisions on monitoring approaches or when adding new reporting requirements.\n\n- Funders should make sure they clarify for researchers the purpose of post-award information requirements, what happens to the data and who uses it, as well what data (e.g., related to impact) is relevant to report.\n\n- Funders should ask researchers and HEIs for feedback on their programmes as part of routine reporting activity and include in this the time spent on administrative activities as a ‘metric’ of effort or burden.\n\n- Funders should streamline their compliance and assurance requirements to reduce duplication in HEI processes and delay to the start of research – for instance, by adopting a principle of ‘ask once’ when requesting information from HEIs.\n\n\n\n- HEIs should strengthen their grant management capacities, recognise the importance of non-research personnel in assisting with research operations, and particularly the role of research managers and administrators in enhancing the quality and success of research.\n\n- The HEI community should consider forming networks specifically for sharing information and practices relevant to the management of research awards, where possible standardising their processes such as through common digital systems or the use of standard contract agreements.\n\n- HEIs should provide regular feedback to funders to drive continuous improvement in post-award management.\n\n\n\n- Funders and HEIs should work with suppliers to further improve interoperability between digital systems to better share information and reduce duplication in data management and reporting.\n\n- Funders and HEIs should work with suppliers to facilitate the transfer of grants-linked output data from institutional systems to external data platforms and ensure universal standards are applied to validate the data submitted.\n\n- Funders and HEIs should both better support researchers through the post-award phase and with reporting activities, helping them build better working relationships, and secure future funding through the ultimate success of their research.\n\nThe broad nature of the topic and the breadth of terminology used to describe post-award management in the literature made screening for relevant papers more challenging than initially anticipated. Having to also manage a large number of citations and employ strict criteria for eligible literature, it is therefore possible that some relevant articles and resources will have been missed. Nevertheless, the literature sample we obtained contained more research data than anticipated and provides the key information to appraise the landscape of post-award management. We attempted to capture current funder practices as accurately as possible but acknowledge that the sample we have is small and that not every detail on practices will likely be published on websites. Moreover, the funding landscape is constantly changing and there is a limit to how much current information can be obtained without conducting consultations or case studies (such as in Ref. 68) with funders and HEIs. Finally, we acknowledge that the findings of the review and especially any assessments of ‘effort’ will not necessarily reflect all real-life experiences in research, and that researchers’ perspectives of funding and post-award management will vary, as we have recently found when interviewing researchers in the UK.43\n\n\nConclusions\n\nThe overall need to manage and report on research is clear and widely appreciated. However, the effort can be considerable and reports where it is perceived as unnecessary need the support of more rigorous evidence, and consultations between researchers, HEIs, funders and other relevant stakeholders, so that key administrative barriers to efficient research delivery can be identified and addressed more collaboratively in a connected, interoperable research environment. In the meantime, HEIs and researchers could benefit from more administrative support services, and researchers could particularly benefit from guidance on ‘impact’ and training in post-award management. Funders could also find ways of reducing duplication and research waste in reporting, with a goal to minimise the effort required to report whilst increasing its value and accountability to research end-users.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nAcknowledgements\n\nThe authors would like to thank the NIHR Coordinating Centre monitoring team based in Southampton, and Sheetal Bhurke, for permission to use an internal report comparing UK funder monitoring practices 28 in the review. We also thank all the NIHR staff who took the time to review the relevance of data and for contributing to the revision and editing of early versions of the manuscript.\n\n\nReferences\n\nLehman D, Ruzich C, Ghosh B, et al.: Journal of Information Systems Applied Research.\n\nHolbrook KA, Sanberg PR: Understanding the high cost of success in university research. Technology & Innovation. 2013; 15(3): 269–280. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHansen S, Moreland K: The Janus Face of Research Administration. 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}
|
[
{
"id": "188988",
"date": "28 Jul 2023",
"name": "Caitlin Brandenburg",
"expertise": [
"Reviewer Expertise Meta-research"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis scoping review on post-award reporting is interesting, robust, timely, and for the most part well-written. Methods were well-detailed and followed JBI scoping review standards. I have specific comments to strengthen the writing as outlined below.\nAbstract:\n“Inconsistent approaches to reporting and post-award management, and a growing demand for research information, can lead to perception of unnecessary administrative effort that impacts on decision-making and research activity”- meaning could be clearer, perhaps separate into 2 sentences?\n\nIntroduction:\n“involves reporting to funders on award-related activities,”- more specificity on who is reporting may help further define this process, for example “involves research grant recipients reporting…” or is the definition broader than that?\n\n“involves reporting to funders on award-related activities, and is how funders oversee the progress, outputs, outcomes, and impacts of the research they fund”- long sentence, would be best split into 2, with the second “This process is how funders oversee…”\n\n“The effort involved can be considerable..” as above could be more specific about who the effort is expended by - researchers?\n\n“feeling of ‘pressure’ among early career researchers”- why early career specifically? Is it that they are doing the bulk of this reporting work? Please elucidate.\n\n“An additional aim was to compare how funders currently approach post-award management, identify any unnecessary effort or need for improvement, and to use evidence of previous solutions to inform recommendations for both funders and HEIs.” Suggest use of semicolons here for consistency, as used in the list in the previous sentence.\n\nMethods:\n“the broad definition” - should be “a broad definition”\n\n“refers to any process – funder or HEI – “ - the meaning here is unclear, as the structure of the sentence implies that funder/HEI are examples of a process. Please restructure.\n\n“and duplicates removed” - how were duplicates identified and removed? E.g. manual deduplication, use of EndNote duplication feature?\n\nTable 6 is too lengthy to be useful- please provide a further summary of the main themes in the main text for the ease of the reader.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": [
{
"c_id": "10170",
"date": "29 Nov 2023",
"name": "Ksenia Crane",
"role": "Author Response",
"response": "We thank Caitlin Brandenburg for her review and have addressed all comments below: Comment 1. “Inconsistent approaches to reporting and post-award management, and a growing demand for research information, can lead to perception of unnecessary administrative effort that impacts on decision-making and research activity”- meaning could be clearer, perhaps separate into 2 sentences? Reply 1. We have reworded the Introduction part of the Abstract for better readability. Comment 2. “involves reporting to funders on award-related activities,”- more specificity on who is reporting may help further define this process, for example “involves research grant recipients reporting…” or is the definition broader than that? Reply 2. We have clarified that the definition is broad, referring to the stages after a decision to fund and involving awardees reporting to funders. Comment 3. “involves reporting to funders on award-related activities, and is how funders oversee the progress, outputs, outcomes, and impacts of the research they fund”- long sentence, would be best split into 2, with the second “This process is how funders oversee…” Reply 3. We have split the first sentence of the introduction into two sentences for readability. Comment 4. “The effort involved can be considerable..” as above could be more specific about who the effort is expended by - researchers? Reply 4. When talking about the effort involved, we deliberately avoided making it specific to researchers as many others (research managers, numerous HEI depts, funders, evaluators) are involved post-award management and reporting – and we show that others also experience unnecessary effort and burden in these processes. We refer to effort generally throughout to attempt to be as balanced as possible. We did add that this effort is particularly considerable for researchers (in brackets) to the Introduction. Comment 5. “feeling of ‘pressure’ among early career researchers”- why early career specifically? Is it that they are doing the bulk of this reporting work? Please elucidate. Reply 5. We clarified that the “feeling of pressure” among ECRs is actually pressure on research careers and the training environment that results from too much grant-related admin burden. Comment 6. “An additional aim was to compare how funders currently approach post-award management, identify any unnecessary effort or need for improvement, and to use evidence of previous solutions to inform recommendations for both funders and HEIs.” Suggest use of semicolons here for consistency, as used in the list in the previous sentence. Reply 6. We have added semicolons to the sentence indicated. Comment 7. “the broad definition” - should be “a broad definition” Reply 7. We have changed “the” to “a” in “the broad definition”. Comment 8. “refers to any process – funder or HEI – “ - the meaning here is unclear, as the structure of the sentence implies that funder/HEI are examples of a process. Please restructure. Reply 8. We have reworded the paragraph to clarify the meaning of post-award management and HEI and funder processes. Comment 9. “and duplicates removed” - how were duplicates identified and removed? E.g. manual deduplication, use of EndNote duplication feature? Reply 9. We have stated how many duplicates were removed in the results and have clarified that duplicates were removed using Endnote duplication function and manually Comment 10. Table 6 is too lengthy to be useful- please provide a further summary of the main themes in the main text for the ease of the reader. Reply 10. We agree that Table 6 required a summary in the main text and thank the reviewer for pointing this out. We have therefore revised and extended our Results section to include a summary for each theme in Table 6 (summarising both the issues and solutions)."
}
]
},
{
"id": "194311",
"date": "23 Aug 2023",
"name": "Simon Kerridge",
"expertise": [
"Reviewer Expertise Research Management and Administration"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall the article is thorough and very useful being an under-researched sub-area (post-award) in the under-researched area of research management and administration (RMA).\nHowever, there are a number of possible issues.\nOne overarching limitation is the skew/focus on RMA in the biomedical arena, which is not made sufficiently clear. Table 2 for example lists of the funder websites searched, and the databases used in the initial phase are predominantly biomedical. This is not specifically an issue, but should be highlighted in the limitations / scope. Given the UK base of the authors it would perhaps have been sensible to have looked at the ARMA Professional Development Framework, which would have supported their scoping of the duties in post-award RMA in Table 4.\nOne other issue was the inclusion of the Tickell report twice (the draft and the final), which may have skewed the data slightly.\nPlease note that while these issues mean that the paper is not perfect, it is still an excellent piece of work and contributes greatly to the field, giving much practical guidance on how post-award RMA can be improved from across the ecosystem.\nIn terms of the recommendations, the first for funders to harmonise might have mentioned some of the difficulties here - there have been many initiatives at RCUK (now UKRI) which have progressed... slowly.\nThe third funder bullet talks about engagement with \"HEIs, researchers, and other institutions and sponsors\", given the general tenet of the article I would have expected to see RMAs listed here too.\nThe second bullet for Recommendations for HEIs talks about forming networks for information sharing, it could be argued that ARMA fills this need, and has a post-award special interest group. On the same point \"standard contract agreement\" might have discussed the long standing Lambert agreement.\nRecommendations for both - the second point talks about standards, and might have brought in euroCRIS.\nFinally, it would have been great to have seen the underlying working data referenced to aid transparency.\nThere are a number of minor points:\nGiven the international nature of the review it is not clear why RA is not listed in the \"List of abbreviations\" [doing so might aid discoverability in North America]. And then perhaps as both RA and RMA are used, it might have been useful to relate them to each other.\n\nOne quote on p.23 is not in italics.\n\nOn p.28 the first bullet under Hunter et al. has \"( s\" which should probably be \"(s\"\n\nOn p.37 it was not clear to me why it was thought that there might be a \"clear relationship between organisation size\"...\n\nOn p.38 at the top, \"research sectors\" was not clear to me ... just \"research\" ?\n\nAlso on p.38 \"Impact literacy\" was introduced, but I was surprised not see a citation here - perhaps to Julie Bayley's work, e.g. https://books.emeraldinsight.com/book/detail/creating-meaningful-impact/?k=9781804551929\n\nHowever, as stated above, these are all fairly minor considerations and the overall content is rich and compelling and far outweighs these comments.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": [
{
"c_id": "10171",
"date": "29 Nov 2023",
"name": "Ksenia Crane",
"role": "Author Response",
"response": "We thank Simon Kerridge for his review and have addressed all comments below: Comment 1. One overarching limitation is the skew/focus on RMA in the biomedical arena, which is not made sufficiently clear. Table 2 for example lists of the funder websites searched, and the databases used in the initial phase are predominantly biomedical. This is not specifically an issue, but should be highlighted in the limitations / scope. Reply 1. We have added in the limitations that while we tried to capture a broad sample of organisational sizes and approaches to post-award management in our funder sample, it is predominantly in the health/biomedical space. Comment 2. Given the UK base of the authors it would perhaps have been sensible to have looked at the ARMA Professional Development Framework, which would have supported their scoping of the duties in post-award RMA in Table 4. Reply 2.Thank you for pointing us to the ARMA Professional Development Framework; we have included this as an additional post-review record. Please see sections characterising the literature (Table 3) and understanding the process (Table 4). We have also updated Figure 1 to include this record. Comment 3. One other issue was the inclusion of the Tickell report twice (the draft and the final), which may have skewed the data slightly. Reply 3. We agree with the reviewer on this point and have removed the interim report from our review; we are happy that we already included the most up-to-date information from the final report and that we reference to both reports on the UK government webpage. Comment 4. In terms of the recommendations, the first for funders to harmonise might have mentioned some of the difficulties here - there have been many initiatives at RCUK (now UKRI) which have progressed... slowly. Reply 4. We have reworded the recommendation to acknowledged that there are difficulties with harmonising processes (using the example of differences in funder priorities and requirements), and that these will have to be overcome collaboratively. Comment 5. The third funder bullet talks about engagement with \"HEIs, researchers, and other institutions and sponsors\", given the general tenet of the article I would have expected to see RMAs listed here too. Reply 5. We have added to the recommendation that funders should also include RMA experts in their decision-making. Comment 6. The second bullet for Recommendations for HEIs talks about forming networks for information sharing, it could be argued that ARMA fills this need, and has a post-award special interest group. On the same point \"standard contract agreement\" might have discussed the long standing Lambert agreement. Reply 6. We have reworded the recommendation and used ARMA as an example of an existing platform for HEI networking, which more HEIs should engage with to learn about effective award management and encourage harmonisation of HEI processes. Similar to Tickell’s recommendation, we have used the Lambert agreement for research contracts as an example of this. Comment 7. Recommendations for both - the second point talks about standards, and might have brought in euroCRIS. Reply 7. We have included euroCRIS as an example of an organisation that funders and HEIs should engage with to improve system-system transferability and validation of grant-linked data Comment 8. Finally, it would have been great to have seen the underlying working data referenced to aid transparency. Reply 8. We are happy that all our working data for this review is transparently reflected in the comprehensive information summary tables. We extracted only the most relevant information from publications and websites and made very little change (e.g., to wording) when summarising the data – thereby ensuring that we transparently report the available information on the subject as it exists in the public domain. As such, the raw data for this work is essentially the same data reported without the table formatting. There was also no thematic analysis applied; information was merely categorised (e.g., into areas of post-award management) and no assumptions or interpretations were made about reported authors’ findings or statements (e.g., about the purpose of post-award management). A large portion of the reviewed information was also extracted from the web pages of funders, which are subject to periodic updating. As such, it is possible that any raw data we uploaded at this point would not correspond to the information currently on these websites. Comment 9. Given the international nature of the review it is not clear why RA is not listed in the \"List of abbreviations\" [doing so might aid discoverability in North America]. And then perhaps as both RA and RMA are used, it might have been useful to relate them to each other. Reply 9. We have included RA in the list of abbreviations and have linked it to RMA. We have also made this link in the main text and mentioned in Table 6 (where applicable) that RAs are part of the institutional RMA structure seen in many HEIs in the US. Comment 10. One quote on p.23 is not in italics. Reply 10. We have italicised the quote. Comment 11. On p.28 the first bullet under Hunter et al. has \"( s\" which should probably be \"(s\" Reply 11. We have corrected the typo. Comment 12. On p.37 it was not clear to me why it was thought that there might be a \"clear relationship between organisation size\"... Reply 12. With the statement on p.37, we tried to convey an expectation that larger funders (e.g., the NIHR) and/or those operating through contracts rather than grants may have more complex requirements than grant-making charities for instance. However we have now toned down the statement. Comment 13. On p.38 at the top, \"research sectors\" was not clear to me ... just \"research\" ? Reply 13. We have changed “research sectors” to “research” on p.38 Comment 14. Also on p.38 \"Impact literacy\" was introduced, but I was surprised not see a citation here - perhaps to Julie Bayley's work, e.g. https://books.emeraldinsight.com/book/detail/creating-meaningful-impact/?k=9781804551929 Reply 14. We have added a citation to a publication of Bayley’s we have read as a reference “impact literacy” on p.38."
}
]
}
] | 1
|
https://f1000research.com/articles/12-863
|
https://f1000research.com/articles/12-1247/v1
|
28 Sep 23
|
{
"type": "Case Report",
"title": "Case Report: A successful treatment approach of rituximab and azathioprine for pemphigus vulgaris",
"authors": [
"Ashwini Potdukhe",
"Ranjana Sharma",
"Ruchira Ankar",
"Mayur Wanjari",
"Ranjana Sharma",
"Ruchira Ankar",
"Mayur Wanjari"
],
"abstract": "Pemphigus Vulgaris is an uncommon autoimmune skin disorder that is characterized by persistent and blistering lesions. In approximately 50% of patients, mucous membrane erosions are the initial symptom. The primary presenting symptom is often oral mucosal erosions. Affected individuals frequently experience flaccid blisters and erosions on healthy skin and mucous membranes, and other areas of the body may also be affected. This condition is the result of autoantibodies that target desmosomal antigens. We are presenting a case of a 28-year-old male who presented to the hospital with fluid-filled lesions on his forehead and in his oral cavity. A skin biopsy was performed, and he was diagnosed with pemphigus vulgaris. Initially, he was started on a combination of steroids and azathioprine, but he did not respond to this treatment regimen. However, he was successfully treated with injection rituximab. Rituximab has been found to be an effective treatment approach towards pemphigus vulgaris. It can help prevent further complications and reduce the severity of the disease. By targeting the autoantibodies that cause the disorder, rituximab can help control the patient's symptoms and improve their quality of life. It is important to note that early diagnosis and treatment can play a critical role in the management of pemphigus vulgaris.",
"keywords": [
"pemphigus Vulgaris",
"autoimmune",
"autoantibodies",
"lesions",
"steroids",
"case report."
],
"content": "Introduction\n\nPemphigus vulgaris (PV) is a grave autoimmune disorder characterised by blisters on the skin and mucous membranes. The root cause of this condition lies in the disruption of desmosomes, leading to a loss of adhesion among epidermal keratinocytes above the basal layer, resulting in flaccid blisters and erosions.1 Pemphigus is classified as an autoimmune disease owing to the production of autoantibodies and the development of IgG and IgA reservoirs against desmosome components.2 This condition typically affects individuals between the ages of 50 and 70, with children rarely affected by PV.3\n\nThe primary treatment options for PV include high-dose steroids and immunosuppressive medications, with rituximab being approved as an adjuvant medication.4 In India, the commonly used treatments are dexamethasone cyclophosphamide pulse therapy or oral corticosteroids with or without adjuvant immunosuppressants such as azathioprine, cyclophosphamide, mycophenolate mofetil, and cyclosporine. However, these medications can result in severe side effects, and many patients may succumb to treatment-related complications. Furthermore, some patients may not tolerate conventional treatments, which necessitates the use of alternative therapies.\n\nRituximab, a monoclonal antibody that targets the CD 20 antigen on the cell surface of B lymphocytes, is highly effective in treating pemphigus, particularly in cases of resistant disease or potentially fatal pemphigus.5 However, the high cost of this therapy compared to conventional options limits its use on a large scale in India.\n\n\nCase report\n\nA 28-year-old male presented to the outpatient department complaining of fluid-filled lesions on his forehead and oral cavity, accompanied by burning pain and itching. The patient reported bursting the lesions, resulting in a clear fluid discharge. Over one-month, new fluid-filled lesions developed all over his face, followed by his upper limbs, trunk, and lower limbs. These lesions were associated with mild itching and pain and showed little tendency to heal (Figures 1 and 2).\n\nThe patient reported no significant medical, family, psychosocial, or genetic history. He is a farmer by occupation. Initially, he developed lesions on his forehead that spread to his cheek and back. He sought treatment from a private hospital, where he was prescribed oral and topical medications. However, after following this regimen for 4–5 months, the patient reported incomplete resolution of his symptoms. He subsequently consulted another private practitioner due to worsening symptoms and the development of ulcers in his oral cavity, making it difficult for him to consume spicy foods.\n\nThe practitioner prescribed a course of oral antibiotic minocycline 100 mg twice daily and referred the patient to a tertiary care hospital for further treatment. The underlying cause of the patient’s symptoms must be identified and treated appropriately to prevent further complications.\n\nDuring his medical evaluation, he underwent a thorough cutaneous examination, which brought to light several hypopigmented patches and plaques with crusting and a few lesions on his trunk bilaterally, upper and lower extremities, scalp, and face. Additionally, upon examination of the buccal mucosa, mucus with a raw base was noted. All in all, it was determined that approximately 25% of his body surface area had been affected by these dermatological conditions.\n\nThe patient expressed dissatisfaction with the aggravation of his symptoms, which had persisted for one month. Specifically, he had developed fluid-filled lesions on both his forehead and within his oral cavity, which had caused him significant discomfort and concern.\n\nAdditionally, blood tests were conducted, revealing a white blood cell count of 10,300 cubic millimetres. Furthermore, a skin biopsy was taken from a filled lesion, and the outcome indicated rounded-up and separated keratinocytes.\n\nAll of the investigations that were conducted have confirmed the diagnosis of pemphigus vulgaris.\n\nThe patient began his treatment regimen with oral medication tablets, including Defcort 30 mg and 12 mg twice daily, alternating between doses. He was also prescribed Pantoprazole 40 mg once a day to be taken before meals and Cetirizine 10 mg once a day for allergy symptoms.\n\nIn addition to these oral medications, the patient received topical treatments for his body and face lesions. Specifically, he was instructed to apply Clop-G cream twice daily to his body lesions and Momate-F cream twice daily to his face. He also used Mucopain gel twice daily for 20 minutes before meals and Tessoral gel twice daily for 20 minutes after meals. Finally, the patient soaked in saline twice daily to address crusts on his skin.\n\nThe patient’s condition stabilised with symptomatic treatment, and a plan was made to administer injected rituximab. After obtaining the patient’s consent, rituximab was administered in 500 cc normal saline over six hours while the patient was observed on the fifth day of treatment. Following the completion of the injection, the patient began taking Azathioprine 50 mg tablets as a maintenance regimen for six weeks.\n\nOn the seventh day, the symptoms exhibited by the patient were significantly reduced, leading to a favourable prognosis. Consequently, the medical team overseeing the patient’s care deemed it appropriate to discharge them from the hospital. However, they were advised to schedule a follow-up appointment in two weeks to ensure the patient continues to recover properly and monitor their progress.\n\nThe patient’s written informed consent to publish their presenting case and clinical images has been successfully obtained.\n\n\nDiscussion\n\nPV is a severe and potentially life-threatening autoimmune disease. It can be fatal due to the loss of the epidermal barrier and body fluids, leading to subsequent infections. Therefore, PV must be diagnosed early and treated promptly to prevent fatal consequences. For a clinical diagnosis confirmation, histopathological analysis is required.6\n\nThe cornerstone of treatment for PV is systemic steroids, either with or without immunosuppression. However, some individuals may require higher doses of corticosteroids that can be unacceptable and difficult to manage. Unfortunately, we sometimes cannot reduce their high doses of drugs or provide treatment to those suffering from extreme cases.7\n\nThere are potential side effects linked with using rituximab. Seven patients had good drug tolerance and no adverse effects.5 Two individuals experienced angioedema, an acute side effect identified two hours after the infusion, and one patient required stopping of infusion. In contrast to earlier reports,5 the effects were seen during the second infusion. The second infusion was mainly uncomplicated, with the exception of one patient who experienced a slight infusion reaction during her initial infusion. Following rituximab infusion, sepsis occurred in two individuals (20%); they received the proper antibiotic treatment. Sepsis was experienced by patient number seven two weeks after beginning therapy. Acinetobacter was isolated from the blood on two separate occasions. Patient number eight developed sepsis after one week of initiating treatment, and the blood culture showed the growth of Staphylococcus aureus. The proper intravenous antibiotics were administered to both patients. Patient number seven made a full recovery. However, patient eight died because of sepsis. We recommended that rituximab be administered under close observation and in a setting with access to resuscitation equipment in case of infusion reactions. Sepsis is the most common side effect in patients with eroding skin, which serves as a portal of entry for organisms, including concurrent immunosuppressive medications. Sepsis is the most frequent cause of mortality in pemphigus.8 Strict clinical attention is necessary to identify sepsis early on, and efficient therapies are essential.9\n\nRituximab has a manageable adverse reaction, which includes infrequent infusion reactions and a low risk of infection—very few reports of severe adverse reactions to rituximab infusions.10 The injection rituximab received by our patient was well tolerated.11\n\nThe strength of this case report is that the therapeutic approach of rituximab is effective in PV, but continuous monitoring is required to minimise the side effects. Long-term follow-up data is required to draw a proper conclusion on this drug.\n\nFrom the patient’s perspective, the interventions provided were effective and led to a satisfactory outcome. During the follow-up, the patient reacted positively, indicating that the interventions had met his expectations and provided the desired results.\n\n\nConclusion\n\nPemphigus is a prevalent and potentially lethal organ-specific autoimmune disease arising from the production of autoantibodies targeting keratinocyte proteins. In cases where conventional immunosuppressive medications and corticosteroids fail or when significant adverse effects occur, rituximab may be an effective therapeutic regimen for pemphigus vulgaris (PV). Clinicians must remain cognizant that prolonged treatment with rituximab may result in positive outcomes. Furthermore, the response to rituximab treatment in pemphigus patients may be delayed. Nevertheless, clinicians should consider prolonged treatment with rituximab as it can yield favourable results in individuals suffering from pemphigus.\n\n\nAuthors contributions\n\nAll the authors have read and agreed to the final manuscript.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReferences\n\nAltman EM: Novel Therapies for Pemphigus Vulgaris. Am. J. Clin. Dermatol. 2020; 21: 765–782. Publisher Full Text\n\nCuevas-Gonzalez JC, Vega-Memíje ME, García-Vázquez FJ, et al.: Detection of apoptosis in pemphigus vulgaris by TUNEL technique. An. Bras. Dermatol. 2016; 91: 296–299. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKhaddour HH, Zaher D, Kassem T, et al.: Aggressive refractory pemphigus vulgaris that responded to plasmapheresis: a case report. J. Med. Case Rep. 2020; 14: 109. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLyakhovitsky A, Dascalu J, Drousiotis T, et al.: Hematological Inflammatory Markers in Patients with Pemphigus Vulgaris. Dermatology. 2021; 237: 912–920. PubMed Abstract | Publisher Full Text\n\nKanwar AJ, Tsuruta D, Vinay K, et al.: Efficacy and safety of rituximab treatment in Indian pemphigus patients: Rituximab in Indian pemphigus patients. J. Eur. Acad. Dermatol. Venereol. 2013; 27: e17–e23. PubMed Abstract | Publisher Full Text\n\nKhaddour HH, Zaher D, Kassem T, et al.: Aggressive refractory pemphigus vulgaris that responded to plasmapheresis: a case report. J. Med. Case Rep. 2020; 14: 109. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTurner MS, Sutton D, Sauder DN: The use of plasmapheresis and immunosuppression in treating pemphigus vulgaris. J. Am. Acad. Dermatol. 2000; 43: 1058–1064. Publisher Full Text\n\nKanwar AJ, Dhar S: Factors responsible for death in patients with pemphigus. J. Dermatol. 1994; 21: 655–659. PubMed Abstract | Publisher Full Text\n\nKanwar AJ, Tsuruta D, Vinay K, et al.: Efficacy and safety of rituximab treatment in Indian pemphigus patients: Rituximab in Indian pemphigus patients. J. Eur. Acad. Dermatol. Venereol. 2013; 27: e17–e23. PubMed Abstract | Publisher Full Text\n\nBarrera MV, Mendiola MV, Bosch RJ, et al.: Prolonged treatment with rituximab in patients with refractory pemphigus vulgaris. J. Dermatol. Treat. 2007; 18: 312–314. PubMed Abstract | Publisher Full Text\n\nBarrera MV, Mendiola MV, Bosch RJ, et al.: Prolonged treatment with rituximab in patients with refractory pemphigus vulgaris. J. Dermatol. Treat. 2007; 18: 312–314. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "221038",
"date": "16 Nov 2023",
"name": "Jun Yamagami",
"expertise": [
"Reviewer Expertise pemphigus"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nCase report by Potdukhe et al. presents a case of pemphigus vulgaris (PV) successfully treated with rituximab (RTX). Although this case is important to dermatologists, the authors need to describe the case in more detail.\nIn Diagnostic assessment, the authors need to show the pictures of histopathological findings (hematoxylin-eosin staining) and direct immunofluorescence (DIF). They should also show the results of anti-desmoglein antibody titers in the patient’s serum.\n\nBefore treatment, the authors should assess the severity of the patient’s clinical symptom using PDAI (pemphigus disease area index) or ABSIS (autoimmune bullous disorder intensity-score).\n\nIn Therapeutic intervention, the authors need to clearly indicate the protocol and dosage of RTX administration.\n\nIs the background of the case’s history and progression described in sufficient detail? No\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? No",
"responses": []
},
{
"id": "273726",
"date": "11 Jun 2024",
"name": "Stefania Barruscotti",
"expertise": [
"Reviewer Expertise Dermatology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear Editor,\nI am writing to provide my review and express my acceptance of the article titled \"Case Report: A successful treatment approach of rituximab and azathioprine for pemphigus vulgaris\".\nThe manuscript presents a case study that highlights the therapeutic potential of Rituximab in managing pemphigus vulgaris.\nThe authors have documented the clinical course of the patient diagnosed with pemphigus vulgaris, detailing the presentation, diagnosis, and treatment regimen. The use of Rituximab as a therapeutic approach is well-supported by a thorough review of relevant literature, and the case report effectively illustrates the drug's efficacy in this context.\nThe discussion on how Rituximab has improved the patient's quality of life adds a valuable dimension to the case report.\nIn conclusion, this case report is a contribution to the literature on pemphigus vulgaris and its treatment with Rituximab.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1247
|
https://f1000research.com/articles/12-1246/v1
|
28 Sep 23
|
{
"type": "Research Article",
"title": "Performance of the TIMI and GRACE scores in identifying the risk of death from acute coronary ischemic syndrome: a retrospective study in patients with chest pain at a Peruvian Hospital",
"authors": [
"Yessenia Herrera-Castillo",
"Jorge Inolopú",
"Guido Bendezu-Quispe",
"Jaime Rosales-Rimache",
"Yessenia Herrera-Castillo",
"Jorge Inolopú",
"Guido Bendezu-Quispe"
],
"abstract": "Background. Acute coronary syndrome (ACS) is one of the significant causes of death in the adult population globally, and mortality risk assessment is essential to improve prevention strategies. This study aimed to determine the performance of the TIMI and GRACE predictive models in identifying the risk of death from acute coronary syndrome (ACS) in patients with chest pain at a public hospital in Tumbes, Peru. Methods. We designed a retrospective cross-sectional study of medical records of patients with ACS treated at the José Alfredo Mendoza Olavarría Regional Hospital in Tumbes, Peru, from May to December 2022. The performance of the scores TIMI and GRACE for risk of death from ACS was evaluated using the receiver operating characteristic (ROC) curve analysis and calculating the area under the ROC curve (AUC) value with its 95% confidence interval. The AUC values of both scores were compared using Pearson's chi-square test. Results. Data from 106 patients were analyzed. The average age of the patients was 65 years (interquartile range [IQR]: 55-73), with 63.2% being male. The AUC values for the TIMI and GRACE scores were 95.1% (CI95: 90.9-99.2%) and 95.2% (85.7-100.0%), respectively, p=0.982. Conclusion. No difference was found in using the TIMI and GRACE scores to assess the risk of death in patients with ACS who attend a hospital for chest pain. Hence, either of the two scores would be helpful for the prognosis of death in patients with ACS.",
"keywords": [
"Cardiovascular Diseases",
"Acute Coronary Syndrome",
"GRACE",
"TIMI",
"Peru"
],
"content": "Introduction\n\nCardiovascular diseases (CVD) are a group of disorders that affect the heart and blood vessels, classified as coronary disease, heart failure, congenital heart disease, and cardiomyopathy.1 Approximately 17.9 million people died from CVD in 2019, representing 32% of deaths.2 The acute form of coronary disease is acute coronary syndrome (ACS), caused by decreased coronary artery perfusion due to stenosis, distal embolization, or occlusion of a coronary artery.3 The types of ACS include unstable angina, ST-elevation MI (STEMI), and Non-ST-Elevation MI (NSTEMI).4 The incidence of ACS in emergency rooms represents between 5 and 20% of chest pain, frequently present in patients older than 60 (ratio of men and women of 3:2).5 ACS mortality is between 10 and 80 deaths per 100,000 people yearly; global mortality is estimated to be 800,000 yearly.6\n\nPatients with ACS present angina pectoris that radiates to the left upper limb (arm) and jaw, dyspnea, diaphoresis, nausea, and vomiting. Due to the diversity of the symptoms presented by patients with ACS, it is necessary to carry out a detailed anamnesis and request additional tests, such as an electrocardiogram, biomarkers (serum troponin I and T), and chest X-Ray.7 Likewise, the initial assessment of the patient’s risk is essential. For this reason, different predictive models have been developed to assess the risk of ACS or associated events. Among the best-known models suggested in clinical practice guidelines are Thrombolysis in Myocardial Infarction (TIMI) and the Global Registry of Acute Coronary Events (GRACE), which are helpful in initial patient care.8 The TIMI risk score predicts mortality in 30 days and one year after an MI with ST-segment elevation; the AUC value is 0.7. A 7-point TIMI score should be considered a high risk of mortality during the patient’s hospitalization time after suffering a STEMI since it has greater sensitivity and specificity.9 The GRACE score provides good discrimination for death from type 1 myocardial infarction. The AUC incorporating death or future myocardial infarction for GRACE was 0.76 and 0.81, respectively. Likewise, for type 2 myocardial infarction, the GRACE score provided moderate discrimination in predicting death or future infarction, with an AUC of 0.70 and 0.72, respectively (p = 0.007 and p = 0.042 compared to type 1 myocardial infarction).2\n\nAccording to the Pan American Health Organization, in 2019, there were 2 million deaths due to cardiovascular diseases. The mortality rate varies between countries. For example, Haiti registered 428.7 deaths per 100,000 people, while Peru had 73.5 deaths per 100,000 inhabitants.10 The Ministry of Health of Peru reports that CVDs are the second-place cause of mortality between 2014 and 2016, representing 17.8%. Similarly, ischemic heart disease represents 6.2% of deaths.11 In the Tumbes Region, CVDs rank first, with 11.4% of all non-communicable diseases. Likewise, within the subcategories of non-communicable diseases, ischemic heart disease ranks fifth among this region’s top 10 causes of morbidity and mortality.12 According to what has been evidenced, the GRACE and TIMI predictive models are little used in clinical practice, and they are not considered part of epidemiological surveillance programs in populations at risk of cardiovascular diseases, mainly ACS. This situation generates a limitation in the response capacity for the timely approach of patients at risk of ACS, as well as shortcomings in strengthening strategies for primary prevention. This study aimed to determine the performance of the TIMI and GRACE predictive models in identifying the risk of death from ACS in patients with chest pain at a Hospital in Tumbes. We believe that identifying the risk of death is crucial in people at risk of CVD, and using the predictive model with the best performance would make it possible to strengthen prevention and therapeutic actions by the medical staff.\n\n\nMethods\n\nA retrospective cross-sectional study of medical records of patients with ACS treated at the José Alfredo Mendoza Olavarría Regional Hospital in Tumbes, Peru, was carried out from May to December 2022. This hospital is classified as a Level Health Establishment. II-2, and its annual care coverage in the cardiology service, is approximately 834 people. According to the information provided by the Statistics Office of the José Alfredo Mendoza Olavarría Regional Hospital, during the year 2021, 562 patients who reported chest pain were treated. Of these, 116 clinical histories were identified that were evaluated by electrocardiogram and had a cardiology report to identify ACS. This evaluation was performed within 10 minutes of clinical manifestations.13\n\nThe medical records of patients admitted to the internal medicine service by emergency, aged 45 or over, with a record of precordial pain in the last 48h, and with troponin measurement were included. We excluded incomplete medical records or those with insufficient data to estimate the risk using the TIMI and GRACE predictors. We also did not consider the medical records of patients with chest pain from causes other than cardiac.\n\nWith the information obtained, two predictive models (TIMI and GRACE) were used to assess the risk of death from ACS; and the mortality record was obtained as a standard of comparison. The TIMI and GRACE methods are validated instruments for IM whose sensitivity and specificity parameters are 0.786 and 0.539 for GRACE and 0.750 and 0.446 for TIMI, according to the findings presented by Santos M. et al.14\n\nFor GRACE, the score was obtained using the online application “GRACE ACS Risk and Mortality Calculator” (MD Aware, LLC, New York, United States; available at: www.mdcalc.com/calc/1099/grace-acs-risk-mortality-calculator#evidence), which allows the automatic calculation of the total score, as well as the identification of risk categories. This model measures eight variables15: age, heart rate, systolic blood pressure, blood creatinine, cardiac arrest on admission, ST segment deviation on the EKG, abnormal cardiac enzymes, and Killip classification based on Symptoms and signs. The maximum total score on the GRACE scale is 258. It allows classification into three categories16: low-risk group (≤108 for NSTEMI and ≤125 for STEMI), intermediate-risk group (109-140 for NSTEMI and 126-154 for STEMI), and high-risk group (≥141 for NSTEMI and ≥155 for STEMI).\n\nFor TIMI, the score was obtained using the online application “TIMI Risk Score for UA/NSTEMI” (MD Aware, LLC, New York, United States) (https://www.mdcalc.com/calc/111/timi-risk-score-ua-nstemi) that allows the automatic calculation of the total score, as well as the identification of risk categories. It consists of seven variables17: age ≥ 65 years, at least three cardiovascular risk factors (Hypertension, hypercholesterolemia, diabetes, family history of CAD, or current smoker), previous significant coronary stenosis greater than or equal to 50%, deviation of the ST segment, symptoms of severe angina ≥ 2 episodes in the last 24 hours, use of acetylsalicylic acid in the last seven days, and elevation of markers of myocardial injury. The death risk categories are the Low-Risk group (1–2 points), Intermediate Risk group (3–4 points), and High-Risk group: 5–7 points.\n\nThe descriptive characteristics of the study population were presented through absolute and relative frequencies for categorical variables, measures of central tendency and dispersion for the numeric ones, and according to the presence and absence of death due to ACS. TIMI and GRACE scores will be presented based on mean and standard deviation and their 95% confidence interval.\n\nWe evaluated the performance of the scores with the ROC curve analysis and calculation of the AUC value with its 95% confidence interval. The AUC values of the TIMI and GRACE scores were represented in ROC curve graphs, taking ACS mortality as a reference. On the other hand, comparing the AUC values of both scores was evaluated using Pearson’s chi-square test.\n\nData analysis was performed using the statistical program Stata version 17.0 (Stata Corp College Station, TX, USA).\n\nThis research was approved by the Ethics Committee of the José Alfredo Mendoza Olavarría de Tumbes Regional Hospital with Official Letter No. 064-2023/GOB.REG.TUMBES-DRST-HR-JAMO-II-2-T-DE, and the Ethical Review Committee from the César Vallejo University of the department of Trujillo in Peru, with the resolution RD N° 005-3-2022-UCV-VA-P23. We do not require obtaining informed consent since the research was retrospective. The information obtained from the review of medical records was handled exclusively by the principal investigator, guaranteeing the anonymity and coding of the records—the database was generated in an Excel spreadsheet encrypted with an exclusive access code for the principal investigator.\n\n\nResults\n\nA total of 116 medical records were found in the study period, of which four were excluded due to a lack of EKG reports and six without troponin results (Figure 1). Hence, 106 ACS cases were analyzed. The average age of the patients analyzed was 65 years (interquartile range [IQR]: 55-73), with 63.2% being male. The median hospitalization time since admission for emergencies was two days (IQR: 1-4). Table 1 shows that chest pain (97.2%), pain in the left arm (73.6%), and dyspnea (57.5%) were the three most frequent clinical manifestations among people with ACS. [se podría mencionar la incidencia de Muerte y las categorías de los scores de TIMI y GRACE.]\n\nTable 2 shows the frequencies of each predictor used in assessing the risk of death by the TIMI scale. The median and interquartile range scores were 2,1–4 with a range from 0 to 6. The most frequent predictor was having at least three cardiovascular risk factors (97.2%). Among these, we obtained frequencies for hypertension (56.5%), hypercholesterolemia (58.5%), DM2 (64.2%), family history of CAD (20.8%), and current smoking (22.6%). Troponin elevation (79.2%) was the second most frequent predictor. On the other hand, we found patients without the presence of any predictor (2.8%), as well as with one (19.8%), two (30.2%), three (46.2%), and four predictors (0.94%).\n\na Median and inter-quartile range.\n\nTable 3 shows the frequencies of each predictor used in assessing the risk of death by the GRACE scale. Unlike the TIMI scale, we observed median heart rate, systolic pressure, and blood creatinine of 97 bpm, 130 mmHg, and 1.2 mg/dL, respectively. Identifying rales at the base of the lung (13.2%) was the most frequent in the Killip categories.\n\na Median and inter-quartile range.\n\nThe medians for the TIMI and GRACE scores were 8% in both cases, but their IQQ was 5-20 and 2-14, respectively, these differences being significant (p=0.028, Wilcoxon non-parametric test). Figure 2 shows the AUC values for the TIMI and GRACE scores with 95.1% (CI95: 90.9-99.2%) and 95.2% (85.7-100.0%), respectively. We did not find significant differences (p=0.982, Pearson’s Chi-square) between both scores. On the other hand, the mortality rate due to ACS was 8.5% (CI95: 4.0-15.5%).\n\n\nDiscussion\n\nThis study aimed to evaluate the performance of the TIMI and GRACE scores in identifying the risk of death from acute coronary ischemic syndrome in patients with chest pain. No differences between AUC values were found concerning the risk of death in patients with ACS that arrives with chest pain at a public hospital in the north of Peru.\n\nPrevious studies in other contexts have compared the TIMI and GRACE scores as predictors of mortality in patients with NSTEMI. One study reported that the GRACE score had a better prediction than TIMI in patients with NSTEMI (GRACE AUC vs. TIMI AUC [hospital: 0.82 vs. 0.62; long-term mortality: 0.89 vs. 0.68; long-term cardiac mortality: 0.91 vs. 0.67], all with a p<0.05).18 Another study in China reported in-hospital mortality of 6.0% in patients with NSTEMI, and the GRACE AUC of 0.7930 (95% CI: 0.767-0.818) was better than the TIMI AUC (0.5588; 95% CI 0.532-0.586), p<0.001.19 These results are in line with a meta-analysis comparing different risk scores for ACS, showing that in validation studies, pooled c-statistics of 0.54 (95% CI=0.52-0.57) and 0.67 (95% CI=0.62-0.71) for short and long term were found for studies using TIMI score, while 0.83 (95% CI=0.79-9.87) and 0.80 (95% CI=0.74-0.89) were found for short and long term for studies using GRACE. Similar results were found for validation studies comparing TIMI and GRACE in STEMI patients.20 Regarding the GRACE score, it has been reported that it has a good predictive value for in-hospital death and death at six months in patients with NSTEMI. A previous study in 300 patients with NSTEMI with a six-month follow-up found that the high-risk category presented 10.5% of in-hospital deaths and 11.8% of deaths in the first six months (p=0.001 and p=0.013).21 The GRACE score, gender, diabetes mellitus, family history, and smoking were associated with hospital mortality. In contrast, the GRACE score, obesity, and lipid profile abnormalities were associated with death at six months.21 While the GRACE score is reported as a better risk predictor in ACS patients compared to TIMI, the results of this study do not find differences when using any of these scores. The non-identification of differences between these two scores in patients with ACS in the study population could be due to the small sample size, the fact that the patients come from a single health facility, and the possible inadequate recording of patient information in the medical record.\n\nThe literature also compares the GRACE, TIMI, and other scores for mortality in patients with ACS. For example, a study comparing the GRACE, TIMI, and RISK-PCI scores reported that the RISK-PCI score showed excellent potential for predicting 30-day mortality (AUC=0.96; 95%CI: 1.339-3.548), being non-inferior compared to the GRACE and TIMI scores.22 Another study, in patients with IMASTNE and diabetes, compared the Revised CADILLAC (Revised Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) score with the TIMI, GRACE, and PAMI (Primary Angioplasty in Myocardial Infarction) scores. In the long-term findings, only the CADILLAC score achieved acceptable discrimination of the prediction of death at six (0.7261), 12 (0.7319), and 24 (0.7256) months.23 Likewise, it has been reported that in patients with NSTEMI, the GRACE AUC was 0.81 versus 0.62 for the TIMI score, p<0.001, and the combination of TIMI and GRACE improved the predictive value of in-hospital events (AUC=0.71, 95% CI: 0.65-0.77), with a better PPV (37.1%) compared to that of the TIMI (33.3%) and GRACE (36.8%) scores independently.24 Another study indicates that a TIMI score >4 (OR=3.42; 95%CI: 1.35-8.66) and a GRACE score ≥150 (OR=8.43; 95%CI: 3.33-21.38) are independent predictors of mortality after six months of an episode of NSTEMI.25 What has been described indicates that the TIMI and GRACE scores are helpful for the prognosis of death in patients with ACS. However, other scores would be more useful in specific groups of patients, so future research could consider these scores and evaluate their usefulness and ease of use in the prognosis of death in patients with ACS.\n\nThe study’s limitations included the absence of variables (incorrectly localized pain, incorrectly filled out medical records, non-readable handwriting in medical records, misinterpretation of EKG) that could confuse the assessment of the risk of death from ACS. Likewise, some data used to calculate the scores obtained by both predictive models were obtained based on self-report rather than by measurement based on objective indicators. In Peru, a previous study of 234 cases of ACS found that the most significant proportion had a GRACE score with high risk (59% in ACS and 66% in IMA), with 9.4% of deaths. This study found an association between sex and the GRACE score with a high mortality risk.26 Another study, also in the Peruvian population, found that patients who presented a TIMI score (≥3) had a high risk of a combination of events (heart attack or angina) compared to those with a score ≤2 (RR= 4.56; 95%CI: 1.97-10.54).27 Given that the use of clinical scores depends on the health context in which they are used, we believe that the strength of this study is that it provides initial evidence regarding the comparability of these predictive scores for mortality in patients with ACS. This health problem leads the mortality in Peru.\n\n\nConclusions\n\nThere would be no difference in using the TIMI and GRACE scores to assess the risk of death in patients with ACS who attend a hospital for chest pain. Given that both scores are used in clinical settings and are easy to apply, using any of these as part of medical care in the Peruvian health system could help identify patients with a possibly worse prognosis. In the future, using larger sample sizes and a longer follow-up time will allow for more solid results regarding using these scores to assess the risk of death in patients with ACS.",
"appendix": "Data availability\n\nFigshare. data.csv DOI: 10.6084/m9.figshare.23897043.v1. 28\n\nThis project contains the following data:\n\n‐ The data contains information about 116 clinical histories were identified that were evaluated by electrocardiogram and had a cardiology report to identify ACS. The information is from a Peruvian Hospital\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC BY 4.0 Public domain dedication).\n\n\nAcknowledgments\n\nWe thank the Directorate of the Regional Hospital of Tumbes, who provided us with access to the information to carry out this investigation.\n\n\nReferences\n\nTiwari A, Chugh A, Sharma A: Ensemble framework for cardiovascular disease prediction. Comput. Biol. Med. 2022; 146: 105624. Publisher Full Text\n\nHung J, Roos A, Kadesjö E, et al.: Performance of the GRACE 2.0 score in patients with type 1 and type 2 myocardial infarction. Eur. Heart J. 2021; 42(26): 2552–2561. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang X-Y, Zhang F, Zhang C, et al.: The Biomarkers for Acute Myocardial Infarction and Heart Failure. Biomed. Res. Int. 2020; 2020: 2018035.\n\nBergmark BA, Mathenge N, Merlini PA, et al.: Acute coronary syndromes. Lancet. 2022; 399(10332): 1347–1358. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGach O, El HZ, Lancellotti P: Acute coronary syndrome. Rev. Med. Liege. 2018; 73(5-6): 243–250. PubMed Abstract\n\nRaul SQJ, Humberto MML, Fernanda GFM, et al.: Mortalidad del síndrome coronario agudo con elevación del Segmento ST mediante la escala de GRACE. Revista UNIANDES de Ciencias de la Salud. 2020; 3(2): 407–417.\n\nChang AM, Fischman DL, Hollander JE: Evaluation of Chest Pain and Acute Coronary Syndromes. Cardiol. Clin. 2018; 36(1): 1–12. PubMed Abstract | Publisher Full Text\n\nAnderson JL, Morrow DA: Acute Myocardial Infarction. N. Engl. J. Med. 2017; 376(21): 2053–2064. Publisher Full Text\n\nUgalde H, Yubini MC, Rozas S, et al.: Validación del puntaje de riesgo TIMI como predictor de mortalidad en pacientes chilenos con infarto agudo al miocardio con supradesnivel de ST. Rev. Med. Chil. 2017; 145: 572–578. PubMed Abstract | Publisher Full Text\n\nOPS: La carga de las enfermedades cardiovasculares en la Región de las Américas, 2000-2019. Portal de Datos de NMH. Organización Panamericana de la Salud; 2021.\n\nMinisterio de Salud: Análisis de Situación de Salud del Perú.2019. Reference Source\n\nMinisterio de Salud: Carga de enfermedad Región Ancash.2020. Reference Source\n\nBhatt DL, Lopes RD, Harrington RA: Diagnosis and Treatment of Acute Coronary Syndromes: A Review. JAMA. 2022; 327(7): 662–675. Publisher Full Text\n\nSantos Medina M, Gutiérrez Martínez ÁA, Obregón Santos ÁG, et al.: Estratificación de riesgo en pacientes con infarto agudo de miocardio mediante el uso de varias escalas. CorSalud. 2021; 13: 271–281.\n\nFox KA, Dabbous OH, Goldberg RJ, et al.: Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). BMJ (Clinical Research ed). 2006; 333(7578): 1091. PubMed Abstract | Publisher Full Text | Free Full Text\n\nElbarouni B, Goodman SG, Yan RT, et al.: Validation of the Global Registry of Acute Coronary Event (GRACE) risk score for in-hospital mortality in patients with acute coronary syndrome in Canada. Am. Heart J. 2009; 158(3): 392–399. PubMed Abstract | Publisher Full Text\n\nWiviott SD, Morrow DA, Frederick PD, et al.: Application of the Thrombolysis in Myocardial Infarction risk index in non-ST-segment elevation myocardial infarction: evaluation of patients in the National Registry of Myocardial Infarction. J. Am. Coll. Cardiol. 2006; 47(8): 1553–1558. PubMed Abstract | Publisher Full Text\n\nYanqiao L, Shen L, Yutong M, et al.: Comparison of GRACE and TIMI risk scores in the prediction of in-hospital and long-term outcomes among East Asian non-ST-elevation myocardial infarction patients. BMC Cardiovasc. Disord. 2022; 22(1): 4. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWu C, Gao XJ, Zhao YY, et al.: Prognostic value of TIMI and GRACE risk scores for in-hospital mortality in Chinese patients with non-ST-segment elevation myocardial infarction. Zhonghua Xin Xue Guan Bing Za Zhi. 2019; 47(4): 297–304. PubMed Abstract | Publisher Full Text\n\nD’Ascenzo F, Biondi-Zoccai G, Moretti C, et al.: TIMI, GRACE and alternative risk scores in Acute Coronary Syndromes: a meta-analysis of 40 derivation studies on 216,552 patients and of 42 validation studies on 31,625 patients. Contemp. Clin. Trials. 2012; 33(3): 507–514. PubMed Abstract | Publisher Full Text\n\nKumar D, Ashok A, Saghir T, et al.: Prognostic value of GRACE score for in-hospital and 6 months outcomes after non-ST elevation acute coronary syndrome. Egypt. Heart J. 2021; 73(1): 22. PubMed Abstract | Publisher Full Text\n\nJakimov T, Mrdović I, Filipović B, et al.: Comparison of RISK-PCI, GRACE, and TIMI risk scores for prediction of major adverse cardiac events in patients with acute coronary syndrome. Croat. Med. J. 2017; 58(6): 406–415. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen CW, Hsieh YC, Hsieh MH, et al.: Predictive Power of In-Hospital and Long-Term Mortality of the GRACE, TIMI, Revised CADILLAC and PAMI Score in NSTEMI Patients with Diabetes - Data from TSOC ACS-DM Registry. Acta Cardiol. Sin. 2020; 36(6): 595–602. PubMed Abstract | Publisher Full Text\n\nShen L, Lu YQ, Wang L, et al.: Value of TIMI and GRACE score systems in predicting in-hospital events in Chinese patients with non-STsegment elevation myocardial infarction. Acad. J. Second Mil. Univ. 2020; 41(9): 1005–1011.\n\nKumar D, Saghir T, Kumar R, et al.: Predictors of 6-month mortality in patients with non-st elevation acute coronary syndrome: A study in Pakistani population. J. Saudi Heart Assoc. 2021; 33(4): 286–292. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSimborth J: Determinación del riesgo de mortalidad utilizando el score GRACE en pacientes con síndrome coronario agudo, Arequipa.2021.\n\nZevallos J: Aplicación del “Timi risk score”, en pacientes con sospecha de angina, que acuden por dolor torácico al servicio de emergencia del Hospital Nacional Daniel Alcides Carrión del Callao durante el periodo enero 2010-diciembre 2010. Lima: Universidad Nacional Mayor de San Marcos; 2014.\n\nRosales-Rimache J: data.csv. figshare. Dataset. 2023. Publisher Full Text"
}
|
[
{
"id": "229722",
"date": "23 Dec 2023",
"name": "Akash Batta",
"expertise": [
"Reviewer Expertise Atrial fibrillation",
"coronary artery disease",
"heart failure",
"TAVR"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors of the index study have retrospectively analysed their ACS population and compared the performance of the 2 most commonly used prediction models: TIMI and GRACE scores. While there are certain merits of the study, there are major flaws which limit the clinical value of this paper. Most importantly, the retrospective nature and the very small number of patients limits its generalisability. The follow up duration is not clear. The authors should elaborate upon the mortality rate of ACS worldwide and in their country and stratify according to the clinical profile. The introduction largely comprises of redundant information and should be focused on your research instead. In light of newer biomarkers which are widely available, the risk scores have been significantly improved e.g. NLR, FAR etc. which are cost effective and readily available. This should also be discussed and the value of the scores then revisited. In summary, the report seems inadequate and of little clinical value in its current status.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
},
{
"id": "225077",
"date": "23 Dec 2023",
"name": "Jawad Basit",
"expertise": [
"Reviewer Expertise preventive cardiology",
"risk stratification in cardiology",
"risk prediction models in ACS",
"interventional cardiology",
"PCI",
"TAVR and mitral valve repairs",
"CAD and heart failure."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbstract: The wording can be improved. Lines like, '' We designed a retrospective cross-sectional study of medical records of patients with ACS treated at the José Alfredo Mendoza Olavarría Regional Hospital in Tumbes, Peru, from May to December 2022'' should be better presented. One never designs a retrospective study. It is always conducted; should be rephrased. ''The words such as death should be replaced with all cause mortality etc which are more appropriate for scientific literature. ata from 106 patients were analyzed. The average age of the patients was 65 years (interquartile range [IQR]: 55-73), with 63.2% being male. The AUC values for the TIMI and GRACE scores were 95.1% (CI95: 90.9-99.2%) and 95.2% (85.7-100.0%), respectively, p=0.982'' The results should be expanded. Sensitivities, cut offs, specificities etc should be reported. C statistic should be reported as a fraction of 1 i.e 0.95 instead of 95.1% as AUC/c statistic is never a percentage. Lines like no difference was found.... should be replaced with the excellent prediction accuracy of TIMI and GRACE score to for prediction of mortality in patients presenting with ACS. An additional line can however be added to compare the two risk assessment models.\n\nNot sure how can Peru be a scientific keyword, Should be avoided.\n\nIn short, abstract needs major changes.\nINTRODUCTION: It should be contracted. Instead of focusing on irrelevant details of ACS, focus mainly on the risk stratification of TIMI and GRACE and their clinical utility. The introduction serves to establish the rationale of the study; unnecessary stuff should be avoided.\n\nMETHODS: Level Health Establishment. II-2, ; Not able to decipher if there is grammatical mistake. ''The TIMI and GRACE methods are validated instruments for IM whose sensitivity and specificity parameters are 0.786 and 0.539 for GRACE and 0.750 and 0.446 for TIMI, according to the findings presented by Santos M. et al.1'' The sensitivities and specificities should be presented as percentages not as fractions. ''On the other hand, comparing the AUC values of both scores was evaluated using Pearson’s chi-square test'' should be rephrased and explained more to improve clarity.\nRESULTS: The baseline table 1: Instead of writing percentages of Yes, No; mention only the percentage of patients that depicted a specific baseline characteristic. The results are too short for a full length paper. Mortality rates should be discussed. Sensitivities, specificities, cut offs, negative and positives predictive values should be reported. Follow ups should be given importance and reported. The lack of any comment on follow-up of patients and whether this is for in-hospitals or long term mortality would hinder this data to be pooled in a meta-analysis. Instead of writing CI 95, write 95% CI.\nDon't report AUC as percentages. It is against the convention. Report both values and its CI as fraction. All c- statistics should be reported with 95% CI as well as p-values.\nMoreover, the authors should consider adding calibration data in the results. It would not only help the meta-analysts but also provide a deeper insight of clinical relevance.\n\nDISCUSSION: The discussion has not cited and discussed a very very relevant meta-analysis on the topic. It should be cited and difference in results should be explained well. some pathophysiology/etiology should be discussed on how these scores are able to predict so well. Why only these scores were used as prediction tools? there are lots of other scores, why were they not used. This all should be discussed in relevant sections of discussion How the GRACE score is performing better than reported by the meta-analysis by J. basit et al., this discrepancy should be discussed.\nCONCLUSIONS: should be rephrased. It should begin with something like. TIMI and GRACE scores are excellent predictors of mortality in ....... This should be followed by their comparison however a clinical caution should be recommended due to a very small sample size. Need of large prospective studies should be highlighted.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1246
|
https://f1000research.com/articles/12-167/v1
|
13 Feb 23
|
{
"type": "Research Article",
"title": "Reconstructing financial analysis courses in higher vocational education in China: a factor analysis approach",
"authors": [
"Weiwei Yan",
"Pengge Sun",
"Pengge Sun"
],
"abstract": "Background: The development of information technology has had a significant impact on traditional financial analysis. For large amounts of data and complex business environments, financial analysts are required to use technical analysis tools to process mass data and deeply integrate financial analysis and enterprise value to enhance the competitiveness of enterprises. This requires the reconstruction of the financial analysis courses in higher vocational education in China. This manuscript studies the problems existing in traditional financial analysis courses and reconstructs these. Methods: A factor analysis approach is adopted to reconstruct the financial analysis courses. We study these courses from three perspectives — coursebooks, teachers, and teaching methods. We collected the data of relevant courses from online platforms in China and used content analysis to find the problems existing in the three areas. Results: The authors found that the content of the coursebooks were incomplete and outdated, the teachers lacked practical ability and were unaware of data analysis tools. Furthermore, their teaching methods were inefficient. Conclusions: The study reconstructs the financial analysis courses based on three aspects. First, the contents are supplemented with enterprise strategy, macro-environment analysis, industry analysis, business analysis, and the application of data analysis tools. Second, the teachers can work in the company to develop their vocational skills, and participate in training programs to learn data analysis tools. Third, the teaching methods can be dynamic and dual-purpose by cooperating with enterprises to enrich practical teaching. Furthermore, colleges and enterprises can make enterprise work a teaching task, develop simulation training platforms, and provide vocational skill grade certificates.",
"keywords": [
"financial analysis course",
"Course construction",
"factor analysis approach"
],
"content": "1. Introduction\n\n“Vocational education means education provided in order to train high-quality technical and skilled talents and equip educates with the professional ethics, scientific, cultural and professional knowledge, technical skills and other comprehensive professional qualities and ability to act required for practicing a certain profession or achieving career development” [1]. This clear definition of vocational education points out the direction of vocational education personnel training, the goal of talent training in higher vocational education emphasizes developing the practical abilities and technical skills needed for the job, which results in reforming and innovating the practice-oriented curriculum.1 The integration of industry and education can improve students’ technical skills and practical abilities.2 Additionally, colleges and enterprises can cooperate in various ways, such as the Teaching Factory,3 Vocational skill grade certificate,4 and skills competition project.5 Therefore, financial analysis courses in vocational education also pay attention to the deep connection between enterprises and practice. The development of information technology and the change of the learning scene has produced blended teaching [2].6 The coronavirus disease (COVID-19) pandemic has further accelerated the integration of information technology and education, such that online teaching has gradually become an integral part of normal teaching activities.7 The construction of high-quality blended teaching and online courses require an overall adjustment of the course content, course group structure, and teaching and learning methods.8 Therefore, three aspects of financial analysis courses in vocational education should be reformed: coursebooks, teachers, and teaching methods. Analyzing financial statements has become one of the core professional skills expected of business students.9 However, the traditional financial statement analysis framework, which is centered on four abilities-solvency, profitability, operating ability and growth ability, cannot meet the current enterprise requirements.10 The Harvard Analysis framework, including strategic, accounting, financial, and prospect analyses, has been increasingly applied to analyzing specific enterprises; strategic analysis is the starting point and the most important content.11 At any rate, financial analysis cannot be limited to the interpretation of financial data, but should be used as a starting point to analyze business behavior.12\n\nBased on updates to the financial analysis framework and new directions in curriculum development, we try to reconstruct the financial analysis course. We expect this study to provide a reference not only for teaching reforms in the financial analysis courses at higher vocational colleges, but also for further research on financial analysis courses.\n\n\n2. Methods\n\nGenerally, teachers, coursebooks and teaching methods are the basic elements of teaching construction. Now, to train high-quality workers and skilled personnel with knowledge, skills and virtues, a threefold teaching [3] reform is proposed in the Implementation Plan of National Vocational Education Reform. We adopt a factor analysis approach to study the existing problems with traditional financial analysis courses and reconstruct them from three perspectives — coursebooks, teachers, and teaching methods.\n\nAn integrated financial statement analysis project requires the quantitative analysis of a real company’s financial statements and preparing a written research report. The project includes supporting activities, such as in-class instruction on financial ratios, a computer lab session on Excel, draft papers, peer reviews of writing, and paper revisions.13 The content of the coursebooks should, therefore, keep up with the developments and changes in the industry.14 Technology and data analysis skills are also suggested to be integrated into the curriculum to meet the data-driven needs of the accounting profession.15\n\nTeachers can work in enterprises and participate in the identification of the corresponding skill levels required to reconstruct their personal knowledge structure and improve their practical skills.16 To meet the demands of online teaching, teachers also need to develop fluency in digital literacy.7 Thus, senior technical and skilled personnel from industry enterprises can be introduced as part-time teachers to enrich and improve the existing teachers’ team.17\n\nWe can thus, build a student-centered teaching system, increase the proportion of practical teaching in the system, and adopt a project-based teaching method.18 Other teaching methods, such as heuristics, inquiry, discussion, and participation can be used to strengthen teaching interactions and improve students’ independent learning ability.19\n\nTo clarify the current situation of coursebooks, teachers, and teaching methods in financial analysis courses, we adopted a content analysis-based approach. The Ministry of Education of the People’s Republic of China organized 22 open online course platforms to offer online programs. We collected and analyzed the course contents that included financial analysis.\n\n\n3. Results\n\nWe found 78 courses that included financial analysis, of which 33 were for vocational college students and 45 were for undergraduate students, the data are shown in Table 1.\n\nWe analyzed whether the courses included the following contents, and the data are shown in Table 2.\n\n1 Others include Excel and introduction to data analysis technology.\n\n2 Proportion equals the total number of courses (78) divided by the number of courses that contain the content.\n\n3.2.1 The contents in the coursebooks are incomplete and out of date\n\nThe current financial analysis framework based on the four abilities in coursebooks is ineffective. It over-emphasizes the indexes and ignores the relationships between financial data and enterprise business; the analysis of operating efficiency remains superficial making it difficult to create value.\n\nInformation technology has changed the way enterprises operate and their accounting processes. First, information systems can automatically generate accounting records and statements, which result in great changes to the work done by accounting personnel; as a result, accountants may need to be transformed into analysts. Second, company employees can upload almost all business data online once the business occurs using various information processing systems, such as ERP, CRM and SCM [4]. Thus, the timeliness of accounting has improved drastically, so that the traditional post-analysis of finance can be upgraded to a real-time analysis, which may further improve the quality of the financial analysis. Third, to better analyze business operations through financial data, the analyst needs to understand the company’s strategy and business, as well as the macro environment and industry. Hence, we surmise that the current contents in the coursebooks are incomplete as the following topics can also be included: enterprise strategy, macro-environment analysis, industry analysis, and business analysis.\n\nData has gradually penetrated into all walks of life leading to the continuous creation of massive data. Data mining, and the application and analysis of data-based decision-making have become the focus of research in various fields, further highlighting the importance of data as a factor of production. The traditional financial analysis framework based on limited information and reliant on human manual analysis can be transformed into a framework based on massive data and information technology. Moreover, generating, recording, and storing massive data lays a foundation for the subsequent in-depth analysis of different needs; the ability to acquire and process data has correspondingly become a critical ability in financial analysis. Thus, we think data analysis technology should become an essential component of the financial analysis course, thus demonstrating that the current content of the coursebooks is out of date.\n\n3.2.2 Teachers lack practical ability and are unaware of data analysis tools\n\nThe traditional financial analysis course is taught by teachers with professional foundations in either accounting, financial management, or auditing. Most teachers lack practical abilities as they have not received professional training on financial analysis in universities or enterprises. Also, the lack of enterprise strategy, macro-environment analysis, industry analysis, and business analysis in the coursebooks further reduces the motivation of teachers to improve their practical ability. This disconnection between teachers and practical ability may change financial analysis courses into interpretation and calculation of several indicators; as a result, students may not be able to solve practical problems after taking the course.\n\nThe teachers are also unaware of data analysis tools because of their professional background. The era of big data is characterized by large quantities and multiple types of data, high timeliness but low value density; data mining and analysis technologies are, thus needed to improve the value of data. Meanwhile, the topics of enterprise strategy, macro-environment analysis, industry analysis, and business analysis in the coursebooks involve a large amount of external and internal data. Therefore, data analysis capability is an important requirement for a financial analyst.\n\n3.2.3 Teaching methods are inefficient\n\nIn traditional financial analysis courses, teachers mainly adopt lecture and case based teaching methods; they often choose several listed companies, explain representative indicators of various abilities and calculation methods, analyze the trend of the enterprise’s financial situation and the change of the indicators combined with comparing them with the indicators of the industry. They finally, briefly describe business changes as reflected by the index changes. The purpose of teaching focuses on the comprehensiveness of analysis and the accuracy of index calculation. Obviously, the current teaching methods are not integrated with practice; thus, a more systematic approach of teaching is required.\n\n\n4. Discussion\n\nWe reconstruct the financial analysis course from three perspectives.\n\nWe propose that the contents in coursebooks can be supplemented with topics related to enterprise strategy, macro-environment analysis, industry analysis, business analysis, and the application of digital technology tools. Meanwhile, the judgment and reconstruction of enterprise value are the purposes of financial analysis, while analyzing the business from financial data and excavating the core competitiveness of the enterprise are its key contents.\n\nTechnical analysis tools can be used to extract and process the relevant data. Since Python is one of the most popular programming languages and is open source, we choose it as the tool for technical analysis; the framework diagram is shown in Figure 1.\n\nSpecifically, we think coursebooks can contain the following contents, as shown in Table 3.\n\nThe current status of accounting professional teachers, who lack work experience and abilities related to the application of technology, can be changed in three ways. First, teachers can participate in training programs, including robotic process automation financial robots, Python design and development, and commercial business intelligence, along with those on company strategy, enterprise management, and other latest business management topics. Second, teachers are required to work in specific companies as a financial analyst. The college is therefore responsible for balancing work and teaching to guarantee teachers’ work time in these financial analysis positions; the teachers can then accumulate practical experience and improve their ability to solve practical problems. Moreover, in the face of the status that industry development is ahead of education, teachers going to enterprises can come into contact with and learn about more advanced technologies, systems, and management modes allowing them to update the knowledge they need to meet the needs of leading industries. Third, the college can improve the team structure and overall quality by employing senior financial analysts as part-time teachers; financial analysis experts with rich practical experience can not only combine teaching and application, but can also help other teachers in the team improve their teaching level, thus increasing the teachers’ practical ability.\n\nEffective teaching in higher vocational education requires the combination of theoretical and practical learning. We think colleges and enterprises can cooperate here to improve students’ professional competitiveness. First, taking the work content as a teaching task allows them to establish a dynamic curriculum of the dual subject. In this manner, students are guided to conduct an in-depth analysis of the business activities based on continuous operation data. The students can then use technology-based analysis tools to extract and process data, such as macro data and the data of other companies in the industry, as a basis for analyzing the specific operational situation reflected in the company’s financial data. Thus, they can evaluate the competitiveness, risk areas, and value of the enterprises from the perspective of internal management. They can then make recommendations for business improvement and submit them to the enterprise in the form of a comprehensive financial analysis report, which in turn can help enterprises better manage risks and make operational decisions. Apart from this, teachers will receive the job satisfaction of service enterprises as an important part of students’ performance to improve the rationality of teaching evaluation. Meanwhile, the communication between teachers and enterprises can help continuously optimize the teaching content; the framework for this is shown in Figure 2. Second, colleges and enterprises can co-construct a simulation platform based on the information of listed companies to allow students to exercise and cultivate their analytical abilities from the perspective of external investment analysis. Third, colleges and enterprises can also jointly develop vocational skill grade certificates to not only train students’ vocational ability, but also help set standards in the field of financial analysis.\n\n\n5. Conclusion\n\nIn the era of the digital economy, the ability to carry out a financial analysis ability is increasingly valuable and the curriculum plays an important role in such talent training. We think its content can be supplemented with enterprise strategy, macro-environment analysis, industry analysis, business analysis, and the application of digital technology tools. The teachers can work in companies to develop these vocational skills and participate in training programs to learn data analysis tools. The teaching methods can be dynamic and dual natured by cooperating with enterprises to enrich practical teaching; colleges and enterprises can make enterprise work a teaching task, develop simulation training platforms, and provide vocational skill grade certificates. We expect this study to provide a reference not only for the teaching reform of financial analysis courses in higher vocational colleges, but also for further research on such courses.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReferences\n\nDing J: Reformation and Innovation of Practice-oriented Curriculum in Vocational Education. Research in Higher Education of Engineering. 2015; 01: 119–124.\n\nChen Z: Connotation, Essence and Practice Paths of Production-education integration in Vocational Education. Education and Vocation. 2018; 05: 35–41.\n\nChen LIANG: Reflections on the Dual Educational Path of Vocational Colleges and Enterprises from the Perspective of Singapore’s “Teaching Factory”. Journal of Jincheng Institute of Technology. 2020; 13(01): 28–31.\n\nNan XG, Zhang P: Construction of vocational education curriculum system based on 1+X certificates system: problems, logic and approach. Chinese Vocational and Technical Education. 2020; (32): 5–10\n\nChen Z, Li S: Innovation of Collaborative Education System in Higher Vocational Colleges. Research in Higher Education of Engineering. 2020; 03: 138–142.\n\nHan Y: The new development about teaching and learning of internet+. China University Teaching. 2019; 12: 209–207. Publisher Full Text\n\nDaguang W, Li W: Stage Characteristics of Large-Scale Online Teaching in Chinese Universities:Empirical Research Based on Group Investigation of Students, Faculty and Academic Staff. Journal of East China Normal University (Educational Sciences). 2020: 38(07): 1–30\n\nJi H, Wang J, Zhang G: Theoretical logic and Path Selection of Industry Curriculum. Research in Higher Education of Engineering. 2019; 04: 188–193.\n\nZhang X, Su L: Analysis of financial statements: theoretical connotation and subject orientation. Finance Research. 2015; 01: 25–33.\n\nLi X, Cai L: Corporate Finance Analysis: Framework and Beyond. Research on Financial and Economic Issues. 2006; 10: 67–73.\n\nShi D, Wang B: The Global Harvard Analytical Framework: Literature review and research prospects. Finance and Accounting Monthly. 2019: (11): 53–60\n\nWei W, Tang D: Research on the effectiveness and Improvement of Financial Analysis Method- Based on the perspective of scientific method. Finance and Accounting Monthly. 2021; 23: 36–40.\n\nGrimm SD, Blazovich JL: Developing student competencies: An integrated approach to a financial statement analysis project. Journal of Accounting Education. 2016; 35: 69–101. Publisher Full Text\n\nCao P, Zhang P, Pan H, et al.: A new approach to dual system of development of coursebooks. Journal of Shijiazhuang University of Applied Technology. 2021; 33(03): 28–32.\n\nAndiola LM, Masters E, Norman C: Integrating technology and data analytic skills into the accounting curriculum: Accounting department leaders’ experiences and insights. Journal of Accounting Education. 2020; 50: 100655–100618. Publisher Full Text\n\nZhang W, Zhang F, Lingli L: Research on the Professional Development Approach of Teachers in Vocational Colleges under the “1+X” Certificate system. Journal of Vocational Education. 2020; (01): 94–97.\n\nZhixiang G: Thinking on the “Double-qualified” Teachers Team Building in the Background of Production teaching Integration in Vocational Colleges. Journal of Vocational Education. 2019; 02: 99–102.\n\nXiujie W, Zhang Y: Values, Problems and Paths of “Three Teaching” Reform in Higher Vocational Education Under the Background of “Double High Plan”. Education and Vocation. 2021; 09: 11–18.\n\nZeng F: Deepening the reform of “Threefold Education” in higher vocational colleges. Education and Vocation. 2020; 24: 62–65.\n\n\nFootnotes\n\n1 Vocational Education Law of the People’s Republic of China (2022 Revision).\n\n2 Combination of online and offline teaching.\n\n3 Threefold teaching means teachers, coursebooks and teaching methods.\n\n4 ERP refers to enterprise resource planning, CRM refers to customer relationship management and SCM refers to supply chain management."
}
|
[
{
"id": "163219",
"date": "28 Feb 2023",
"name": "Konstantinos (Kostas) G. Arvanitis",
"expertise": [
"Reviewer Expertise Agriculture 4.0",
"Automation",
"Internet of Things",
"Engineering Education",
"Agricultural Education and Extension."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript entitled “Reconstructing financial analysis courses in higher vocational education in China: a factor analysis approach”, although it is utterly interesting however, it seems to be rather concise. It reads more as a brief report rather than a research article, according to the standards and guidelines of the F1000Research.\nIf the authors wish to proceed with this work as research article, the following comments and suggestion should be taken into consideration:\nIn order to substantiate the scientific contribution, the article's introduction should be reworked. Additional justifications about the current state of research and the requirements and special limitations, as well as the research purpose, of this work are required. For this purpose, the authors should include significantly more references of the current literature in order to elaborate on the state of the art on the subject of study (the number of 19 references is quite low for a research article).\n\nThe methodology followed in this work is briefly defined. Further analysis of the methods that were implemented is strongly suggested in order to contribute to scientific knowledge. The same comment and suggestion applies to the presentation and assessment of the results, as well. Including some charts which depict the results is also advised for the benefit of the readers.\n\nThe conclusions of the research and their association with the results need to be further defined. The results must be thoroughly interpreted in perspective of the working hypotheses and the findings of the research, as well as to their implications in the broadest context possible. Moreover, some details about future directions should be pointed point out.\n\nFinally, the paper is written in appropriate English language, however some minor proofreading and spell-checking is suggested.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "10291",
"date": "06 Oct 2023",
"name": "Weiwei Yan",
"role": "Author Response",
"response": "Thank you very much for your review！ I have added more references of the current literature in order to elaborate on the state of the art on the subject of study, as well as the content of data analysis. I have modified the content of the conclusion to be interpreted in perspective of the working hypotheses and the findings of the research, and future directions have been pointed out. Finally, I have done proofreading and spell-checking to make sure language is appropriate. Thank you again for your careful review"
}
]
}
] | 1
|
https://f1000research.com/articles/12-167
|
https://f1000research.com/articles/12-49/v1
|
12 Jan 23
|
{
"type": "Research Article",
"title": "Circadian disruption does not alter tumorigenesis in a mouse model of lymphoma",
"authors": [
"Rebecca M Mello",
"Marie Pariollaud",
"Katja A Lamia",
"Rebecca M Mello",
"Marie Pariollaud"
],
"abstract": "Background: Disruption of natural diurnal light cycles, such as that experienced by shift workers, is linked to enhanced cancer incidence. Several mouse models of cancer have been shown to develop more severe disease when exposed to irregular light/dark cycles, further supporting the connection between circadian disruption and increased cancer risk. Cryptochrome 2 (CRY2), a repressive component of the molecular circadian clock, facilitates the turnover of the oncoprotein c-MYC, one mechanism that may link the molecular clock to tumorigenesis. In Eμ-MYC mice, which express transgenic c-MYC in B cells and develop aggressive lymphomas and leukemia, global Cry2 deletion reduces overall survival and enhances tumor formation. Moreover, lighting conditions that mimic the disruption experienced by shift workers dampens Cry2 transcripts in peripheral tissues of C57BL/6J mice. Thus, we hypothesized that exposure to disruptive lighting conditions would enhance tumor burden in Eμ-MYC mice. Methods: We housed Eμ-MYC mice in light-tight boxes set to either the control (continuous cycles of 12-hours of the light followed by 12-hours of dark, LD12:12) or chronic jetlag (eight-hour light phase advances every two to three days, CJL) lighting conditions and assessed the impact of disrupted light cycles on overall survival and tumor formation in Eμ-MYC mice. Results: Environmental disruption of circadian rhythms did not alter tumor location, tumor growth, or overall survival in female or male Eμ-MYC mice. Conclusions: Our findings support emerging evidence that suggests the impact of circadian disruption on tumorigenesis is dependent on the origin of malignancies.",
"keywords": [
"c-MYC",
"circadian rhythm",
"lymphoma",
"circadian disruption",
"chronic jetlag",
"CRY2"
],
"content": "Introduction\n\nCircadian rhythms describe the diurnal oscillation of behavior and physiology in anticipation of environmental fluctuations. In mammals, lighting cues are transmitted from the retina, via the retinohypothalamic tract, to the central clock located in the suprachiasmatic nuclei (SCN) in the anterior hypothalamus. These light-driven signals reset the timing or “phase” of the SCN circadian clocks, which determine the timing of activity and sleep-wake patterns.1 The SCN indirectly synchronizes clocks in peripheral tissues through a combination of neuronal, behavioral, and hormonal cues that are incompletely defined. Disruption of the circadian network due to environmental disturbances, such as that experienced by night shift workers, increases the risk of disease, including malignancy.2 Epidemiological studies observed increased risk of non-Hodgkin’s lymphoma in night shift workers.3 However, rates of B cell and other subtypes of lymphoma were indistinguishable between shift workers and the general population.4 Chronic jetlag (CJL) lighting protocols that mimic the divergent environmental lighting schedule experienced by shift workers have been shown to increase the formation and progression of cancers such as osteosarcoma, hepatocellular carcinomas, breast cancer, and lung adenocarcinoma in mice,5–11 suggesting that the impact of circadian disruption on tumorigenesis is not constrained by the cell type of origin and independent of oncogenic drivers. Additionally, multiple studies show that people who live further west within a time zone have an increased risk of developing several types of malignancies, including leukemias and lymphomas.12,13 Nevertheless, the connection between circadian disruption and tumorigenesis remains poorly understood.14\n\nIn mammals, the transcription factors brain and muscle ARNT-like protein 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) form a heterodimer that activates transcription of genes driven by E-box elements (collectively known as clock-controlled genes, CCGs). CCGs include those that encode periods (PER1-3) and cryptochromes (CRY1-2), which repress BMAL1-CLOCK transactivation activity, resulting in a transcription-translation feedback loop (TTFL) that underpins daily oscillations.15 A secondary TTFL includes nuclear receptor subfamily 1 group D members 1 (NR1D1, a.k.a. REVERBα) and 2 (NR1D2, a.k.a. REVERBβ). BMAL1/CLOCK transactivates Nr1d1 and Nr1d2 mRNA expression, and NR1D1 and NR1D2 in turn repress Bmal1 transcription.15 CCGs comprise thousands of genes, including many involved in proliferation, DNA damage response and repair, and autophagy, which likely contribute to linking dysregulation of the circadian clock to tumorigenesis.\n\nGenetically engineered mouse models (GEMMs) of cancer are valuable research tools utilized to characterize oncogenic or tumor suppressive genes in combination with environmental stressors or novel therapeutic approaches.16 Eμ-MYC mice express human c-MYC under the control of the immunoglobulin heavy chain (IgH) enhancer resulting in constitutive activation of c-MYC in the B cell lineage.17 Eμ-MYC mice develop spontaneous lymphoma and leukemia in pre-B cells and rapidly succumb to disease.18 Cry2 deficient Eμ-MYC mice develop an increased number of tumors in the lymph nodes and experience reduced overall survival compared to wildtype littermates.19 This phenomenon is largely attributed to CRY2 post-translational regulation of c-MYC. CRY2, in complex with the SKP-CULLIN-F-box (SCF) E3 ubiquitin ligase containing FBXL3, SCFFBXL3, can bind phosphorylated c-MYC resulting in the polyubiquitination of c-MYC and subsequent proteasomal degradation.19 Here we investigate whether environmental circadian disruption, by means of altered light exposures, influences tumorigenesis in Eμ-MYC mice. We use a disruptive lighting schedule, chronic jetlag (CJL), that we previously demonstrated disrupts rhythmic expression of Cry2 mRNA in peripheral tissues of C57BL/6J mice.11 Thus, we expected that CJL would enhance tumor development and decrease overall survival in Eμ-MYC mice via loss of CRY2-dependent modulation of c-MYC. To our surprise, and in contrast to all other mouse models of cancer studied to date, CJL impacted neither tumor burden nor survival in Eμ-MYC mice.\n\n\nMethods\n\nMale Eμ-MYC+/- mice on a C57BL/6 background were purchased from The Jackson Laboratory at eight weeks of age. Eμ-MYC mice express human c-MYC under the control of the immunoglobulin heavy chain (IgH) enhancer resulting in constitutive activation of c-MYC in the B cell lineage.17 The Eμ-MYC+/- mice were housed in the Dorris Neuroscience Center vivarium at Scripps Research and bred with the laboratory colony of C57BL/6 females originally purchased from the Scripps Research breeding colony. All mice used in the research described here were heterozygous for the Eμ-MYC transgene (Eμ-MYC+/-). During breeding for experiments, all mice were included in the study (i.e., no excluded animals). Food and water were provided ad libitum. All efforts were made to ameliorate any suffering of the animals involved in this study: mice showing any signs of advanced disease such as grossly visible tumors, rapid breathing, weight loss, etc., were euthanized by CO2 inhalation. All animal care and treatments were in accordance with The Scripps Research Institute guidelines for the care and use of animals and were approved by the Institutional Animal Care and Use Committee (IACUC) under protocol number 10-0019.\n\nAt four weeks of age, mouse littermates were separated and randomly assigned to light-tight boxes set to either the control (continuous cycles of 12 hours of the light followed by 12 hours of dark, LD12:12) or chronic jetlag (eight-hour light phase advances every two to three days, CJL,5,6,9–11) lighting conditions (Figure 1A). For the 12-week tumor burden endpoint study, male and female mice were housed in LD12:12 (n=19) or CJL (n=20) for eight weeks before euthanasia at zeitgeber time (ZT, hours after lights on) ZT9 on the day following the first synchronized 24-hour period (i.e., day two of week nine). To minimize potential confounders, dissections of the LD12:12 and CJL were alternated. For the survival study, male and female Eμ-MYC littermates were housed in LD12:12 (n=23) or CJL (n=23) and monitored weekly for signs of advanced disease. For all analyses, the experimental unit is a single animal. Animals found deceased were not assessed for total tumor weight. Sample size was determined by power analysis guided by the expected variability in outcomes using data from Ref. 19. Experimenters were aware of group allocation.\n\n(A) Schematic depicting the experimental lighting conditions of the Eμ-MYC mice. The white areas represent periods of lights on, and the black areas represent periods of lights off. Control lighting consists of a rotating 12-hour light phase and 12-hour dark phase (LD12:12) and the chronic jetlag lighting includes an eight-hour phase advance every two to three days (CJL). (B) Fraction of mice with tumors observed at the indicated lymph node (LN) in Eμ-MYC females (left, n=21) and males (right, n=18) housed LD12:12 or CJL lighting conditions for eight weeks. (C) Scatter plot with mean of total tumor weight in female and male Eμ-MYC mice after eight weeks in LD12:12 (black) or CJL (red) lighting conditions. There were no significant (ns, p>0.05) differences between groups by two-way ANOVA.\n\nRNA was extracted from liver and spleen tissue that was flash frozen in liquid nitrogen at the time of sacrifice. One mL of Qiazol reagent (Qiagen cat # 799306) was used to isolate RNA from 50 mg of tissue. Tissue homogenization was achieved by bullet blender tissue homogenizer. 200 μl of chloroform was added to homogenized lysates which were transferred into a phase lock tube (VWR cat # 10847-802). Samples were centrifuged for 15 minutes at 13,000 rmp/4 °C. The aqueous phase was transferred to a new tube and 500 μl of isopropanol was used to precipitate RNA. Samples were centrifuged for 15 minutes at 13,000 rpm/4 °C to pellet RNA. Pellet was washed with 1 mL of 75% ethanol, dried, and diluted in 50 μl nuclease free water. Each sample yielded 2–5 μg/μl of RNA quantified by NanoDrop 2000 spectrophotometer (Thermo scientific cat # ND2000). cDNA was prepared using 1 μg of RNA and 4 μl of QScript cDNA Supermix (VWR cat # 101414-106). Thermocyling conditions were 25 °C for 5 minutes, 42 °C for 30 minutes, and 85 °C for 5 minutes and executed using C1000 Touch Thermal Cycler (Bio-Rad cat # 1851148). cDNA was diluted 1:40 with nuclease free water and 4 μl of diluted cDNA, 5 μl of with iQ SYBR Green Supermix (Bio-Rad cat # 1708885), and 0.5 μl of each forward and reverse primers (10 μM) was used per qPCR reaction. cDNA levels were measured by CFX96 Touch Real Time PCR Detection system (Bio-Rad cat # 1845096). Cycling conditions were, step 1: 95 °C for 3 minutes, step 2: 95 °C for 10 seconds, step 3: 55 °C for 10 seconds, step 4: 72 °C for 30 seconds, step 5: go to step 2 39x, step 6: 95°C for 10 seconds, step 7: melt curve 65–95 °C, increments 0.5 °C for 5 seconds + plate read. Amplification was measured and analyzed by Bio-Rad CFX Manager 3.1. Starting quantity (SQ) as determined by the software was used for statistical analysis. Raw data available.20 The following primers were used to detect U36b4 (Forward: AGATGCAGCAGATCCGCA, Reverse: GTTCTTGCCCATCAGCACC), Bmal1 (Forward: TCAAGACGACATAGGACACCT, Reverse: GGACATTGGCTAAAACAACAGTG), P21 (Forward: CCAGGCCAAGATGGTGTCTT, Reverse: TGAGAAAGGATCAGCCAT TGC), E2f1 (Forward: AGGGAAAGGTGTGAAATCTCC, Reverse: TTGGTGATGACATAGATGCGC).\n\nCrushed liver and spleen tissues were lysed using RIPA buffer supplemented with protease (Thermo Scientific cat # A32953) and phosphatase (Sigma cat # P5266 and cat # P0044) inhibitors. Protein levels were normalized using the Pierce BCA Protein Assay Kit (Thermofisher cat # PI23225). Lysates were separated in an 8% agarose gel by electrophoresis (Bio-Rad cat # 1658001) and transferred using the Trans-blot Turbo transfer system (Bio-Rad cat # 17001915). Membranes were blocked in 5% milk in Tris-buffered saline supplemented with 1% Tween-20 (TBST) for one hour and washed 3X in TBST for 5 minutes before being placed in primary antibodies overnight at 4 °C. Antibodies were diluted 1:1000 for polyclonal antibody raised in rabbit against BMAL1 (Abcam cat # ab93806), polyclonal antibodies raised in guinea pigs against the C-termini of CRY1 (amino acids 583–606) or CRY2 (amino acids 563–592),21 monoclonal antibody raised in rabbit against c-MYC (Abcam cat # ab32072); 1:2,000 for monoclonal antibody raised in mouse against REV-ERBα22; 1:50,000 for monoclonal antibody raised in mouse against β-ACTIN (Sigma cat # A1978) in TBST supplemented with 3% bovine serum albumin (BSA). Membranes were washed 3X in TBST for 5 minutes before incubation in secondary antibody (Goat Anti-Mouse IgG (H + L)-HRP Conjugate (Bio-Rad cat # 1706516), Goat Anti-Rabbit IgG (H + L)-HRP Conjugate (Bio-Rad cat # 1706515), Goat Anti-Guinea Pig IgG-HRP Conjugate (Sigma cat # A7289)) diluted 1:5000 in TBST supplemented with 3% BSA for 1 hour at room temperature. Membranes were washed 3X in TBST for 5 minutes before imaging using SuperSignal West Pico PLUS Chemiluminescent Substrate (Fisher scientific cat # PI34095). Imaging and quantification were performed using the ChemiDoc XRS+ System (Bio-Rad cat # 1708265) and Image Lab software version 6.1.0 build 7. Proteins detected by immunoblotting were normalized to the housekeeping protein β-ACTIN. Brightness and contrast of blots were adjusted using PowerPoint version 2022. Any and all adjustments that were made were applied to the entire image. Raw data are available.20\n\nStatistical analyses were performed using GraphPad Prism 8 software. The statistics for this research could be reproduced using open-source graphical program for statistical analysis JASP. Significance for total tumor weight from the tumor burden and survival cohorts were determined by two-way ANOVA; qPCR and Western blots were determined by t-test; Kaplan-meier survival curves were determined by Log-rank (Mantel-Cox) test. Significance threshold was set at 0.05 acceptable false positive (p<0.05).\n\n\nResults\n\nExposure to circadian disruption through altered lighting enhances tumor growth and reduces overall survival in c57BL6/J wildtype mice (due to increased spontaneous development of hepatocellular carcinoma) and in genetically engineered mouse models (GEMMs) of cancer.5–7,9–11,23 We chose to use a chronic jetlag (CJL) protocol that has been used in several of these studies.5,6,9–11 Throughout this study, CJL denotes a lighting schedule in which the lights are turned on eight hours earlier (i.e., the light phase is advanced by eight hours) every two to three days (Figure 1A) to mimic circadian disruption experienced by rotating shift workers.\n\nEμ-MYC mice were housed in either CJL or control (12 hours of light followed by 12 hours of dark, indefinitely; LD12:12) lighting conditions at four weeks of age (Figure 1A). Mice were maintained in CJL or LD12:12 lighting conditions for eight weeks before euthanasia at zeitgeber time (ZT, hours after lights on) ZT9 on the day following the first synchronized 24-hour period (i.e., day 2 of week 9). Four mice were excluded from the study because they died before the designated endpoint. CJL affected neither the tumor spectrum (Figure 1B) nor overall tumor burden as revealed by the combined weight of all tumors dissected from each animal (Figure 1C) in male or female Eμ-MYC mice.\n\nAt four weeks of age, female and male Eμ-MYC mice were placed in either LD12:12 or CJL lighting conditions. Mice were housed in these conditions until they exhibited signs of advanced disease (e.g., grossly visible tumors, rapid breathing), at which point mice were euthanized and total tumor weight was recorded. There was no significant difference in the overall survival (Figure 2A) or the terminal tumor weight (Figure 2B) of male or female Eμ-MYC mice exposed to CJL compared to those housed in control lighting conditions.\n\n(A) Kaplan-Meier survival curves for female Eμ-MYC mice housed in LD12:12 (solid black, n=11) or in CJL (solid red, n=12) and male Eμ-MYC mice housed in LD12:12 (dashed black, n=12) or in CJL (dashed red, n=11). (B) Scatter plot with mean of total tumor weight at the time of euthanasia of female Eμ-MYC mice housed in LD12:12 (black, n=4) or in CJL (red, n=5) and male Eμ-MYC mice housed in LD12:12 (black, n=5) or in CJL (red, n=8). There were no significant (ns, p>0.05) differences between groups by logrank test (A) or by two-way ANOVA (B).\n\nWe previously demonstrated that CJL disrupts locomotor activity rhythms in c57BL/6J mice and alters rhythmic gene expression patterns in peripheral tissues of both healthy and tumor-bearing mice.11 To examine the impact of CJL on gene expression in the context of MYC-driven lymphoma, we euthanized Eμ-MYC mice at ZT9, when Bmal1 mRNA is typically low and REV-ERBα protein is typically high in peripheral organs. Livers and spleens were flash frozen at the time of dissection to evaluate molecular circadian rhythms. Consistent with findings in healthy mice,11 Bmal1 mRNA was significantly increased at ZT9 in samples prepared from livers of male and female Eμ-MYC mice that had been exposed to CJL compared to littermates housed in control LD12:12 lighting conditions (Figure 3A). Conversely, NR1D1 protein tended to be lower in liver tissue collected at ZT9 from mice housed in CJL compared to the control group (Figure 3B,C).\n\n(A–F) Detection of the indicated transcripts by qPCR (A,D) and proteins by immunoblotting (B,C,E,F) in liver (A–C) or spleen (D–F) tissues collected at ZT9 from Eμ-MYC mice housed in LD12:12 or CJL lighting conditions for eight weeks. Error bars indicate standard deviation. *p<0.05, **p<0.01, ***p<0.001, or not significant (ns, p>0.05) by t-test.\n\nIn Eμ-MYC mice, human c-MYC is expressed at a high level in B cells via transgenic expression under the control of the IgH enhancer resulting in generation of MYC-driven lymphomas.17 The spleen is the site of B cell maturation and we have previously shown that deletion of the clock component Cry2 leads to enhanced expression of MYC in the spleen of Eμ-MYC mice.19 Thus, we assessed the impact of circadian disruption in the spleen tissues of the Eμ-MYC mice. There was no significant difference in Bmal1 transcript levels in the spleen tissue from mice exposed to CJL compared to those housed in control lighting conditions (Figure 3D), in contrast to the significant elevation in liver of the same animals (Figure 3A). NR1D1 protein was significantly lower in spleens collected from mice that had been exposed to CJL, regardless of sex (Figure 3E,F).\n\nWe assessed the impact of CJL on c-MYC protein levels and expression of c-MYC transcriptional targets, P21 and E2f1, in the peripheral tissues of Eμ-MYC mice. c-MYC protein levels were highly variable and were not significantly different in liver tissues of mice housed in CJL compared to those housed in LD12:12 (Figure 4A). There was a significant increase in expression of P21 in liver tissue from mice housed in CJL relative to those housed in LD12:12 (Figure 4B). This is consistent with previous reports of circadian regulation of P21 in murine hepatocytes.24 There was no difference in E2f1 expression in livers collected from mice housed in control or CJL conditions (Figure 4C). Similarly, neither c-MYC protein (Figure 4D) nor expression of the MYC target genes P21 (Figure 4E) and E2f1 (Figure 4F) was affected by CJL in the spleen tissue of male Eμ-MYC mice. Taken together, these findings show that CJL disrupts molecular circadian rhythms in liver and spleen tissues of Eμ-MYC mice.\n\n(A–F) Detection of the indicated proteins by immunoblotting (A, D) and transcripts by qPCR (B,C,E,F) in liver (A–C) or spleen (D–F) tissues collected at ZT9 from male Eμ-MYC mice housed in LD12:12 or CJL lighting conditions for eight weeks. Error bars indicate standard deviation. *p<0.05 or not significant (ns, p>0.05) by t-test.\n\n\nDiscussion\n\nEpidemiological research supports the idea that disruption of circadian rhythms, such as that experienced by shift workers, increases the incidence of several types of cancer.5–10 The evidence for such a connection is strongest for breast cancer, due at least in part to the volume of research performed in that area. A recent study found that the incidence of chronic lymphocytic leukemia is increased among those who have ever done night shift work, but rates of B cell lymphoma and other subtypes of lymphoma were indistinguishable between shift workers and the general population.4 An earlier study reported increased risk of non-Hodgkin’s lymphoma in shift workers.3 One limitation of epidemiological studies is the large variability in human lifestyles and genetics; thus, mouse models of cancer provide an alternative approach with reduced heterogeneity. Almost 20 years ago, human tumor xenografts were found to grow faster when transplanted into mice in which the suprachiasmatic nuclei were destroyed.25 To better mimic chronic disruption of a functional circadian timing system experienced by shift workers, circadian biologists have widely adopted the use of altered lighting schedules, broadly referred to as chronic jetlag (CJL).5,7,8,10,11,26–30 Several studies have demonstrated that various types of CJL increase the tumor burden in mouse models of cancer.7,8,10,11,26,27\n\nFurther supporting the notion that circadian disruption broadly enhances tumorigenesis, genetic disruption of various circadian clock components enhances tumor burden in mouse models of cancer.7,9,23,31–36 However, a few contrary examples in which inactivation of Bmal1 or of both Cry1 and Cry2 reduced tumor formation35,37 illustrate the error in considering either circadian disruption or cancer as monolith.38\n\nTo understand the impact of environmental circadian disruption on tumorigenesis, it is essential to recognize how disruption of regular light exposures impacts malignancy in a variety of contexts. This study specifically assessed the impact of CJL on the Eμ-MYC mouse model of lymphoma, based on previous reports demonstrating that CRY2 facilitates the turnover of c-MYC and that genetic depletion of Cry2 in Eμ-MYC mice enhances tumorigenesis.19 Here, we explored the possibility that environmental circadian disruption would likewise enhance c-MYC accumulation and tumor burden in Eμ-MYC mice.\n\nOur established protocol of CJL disrupts circadian expression of Cry2 mRNA in peripheral tissues of wildtype C57BL/6J mice.11 Therefore, we anticipated that CJL would influence c-MYC in Eμ-MYC mice by disrupting CRY2-mediated turnover of c-MYC and would thus alter the progression of MYC-driven lymphoma. Unexpectedly, we measured no difference in the number of lymph node tumors or overall survival of Eμ-MYC mice housed in CJL conditions compared to their littermates maintained in standard LD12:12 light-dark cycles.\n\nWhile we measured disruption of molecular circadian rhythms in liver and spleen tissue collected from Eμ-MYC mice that were housed in CJL, the impact of CJL seems to be less severe in spleens. Interestingly, we also observed a less severe impact of CJL on circadian gene expression in spleens of healthy mice than in their livers.11 The influence of circadian disruption in spleens of Eμ-MYC mice may be further subdued by the aggressiveness18 or the intrinsic heterogeneity39,40 of Eμ-MYC lymphoma. Eμ-MYC mice can develop tumors with biological similarities to Burkitt lymphoma or diffuse large B cell lymphoma that exhibit divergent activation of c-MYC.40 This is consistent with our observations of variable levels of c-MYC protein in the liver (Figure 4A) and spleen (Figure 4D) of the Eμ-MYC mice independent of lighting condition. The heterogeneity in c-MYC levels was an unexpected confounding factor in this study. Nevertheless, given that spleen is the site for B cell maturation, the apparently lower sensitivity of spleen to circadian disruption caused by CJL may contribute to the lack of impact on B cell lymphoma observed in this study.\n\n\nConclusions\n\nOur findings suggest that environmental circadian disruption similar to that experienced by shift workers does not influence MYC-driven lymphomagenesis in a c57BL/6J mouse model. Given the strong evidence that altered light exposures can impact lymphoid cancers in people, additional investigation is needed to identify the mechanistic underpinning for this phenomenon that is not present in the mouse model studied here.",
"appendix": "Data availability\n\nFigshare: Underlying data for ‘Circadian disruption does not alter tumorigenesis in a mouse model of lymphoma’, https://doi.org/10.6084/m9.figshare.20492892.v3. 20\n\nThis project contains the following underlying data:\n\n• Data file 1: EuMYC_F_TumorBurden_BMAL1_Liver.xlsx\n\n• Data file 2: EuMYC_F_TumorBurden_Bmal1_Spleen.xlsx\n\n• Data file 3: EuMYC_F_TumorBurden_U36b4_Liver.xlsx\n\n• Data file 4: EuMYC_F_TumorBurden_U36b4_Spleen.xlsx\n\n• Data file 5: EuMYC_M_Tumorbuden_Liver_Bmal1.xlsx\n\n• Data file 6: EuMYC_M_Tumorbuden_Liver_E2f1.xlsx\n\n• Data file 7: EuMYC_M_Tumorbuden_Liver_P21.xlsx\n\n• Data file 8: EuMYC_M_Tumorbuden_Liver_U36b4.xlsx\n\n• Data file 9: EuMYC_M_Tumorbuden_Spleen_Bmal1.xlsx\n\n• Data file 10: EuMYC_M_Tumorbuden_Spleen_E2F1.xlsx\n\n• Data file 11: EuMYC_M_Tumorbuden_Spleen_p21.xlsx\n\n• Data file 12: EuMYC_M_Tumorbuden_Spleen_U36b4.xlsx\n\n• Data file 13: Mouse_Information.xlsx\n\n• Supplementary file 1: Eu-MYC_F_TB_Liver_Actin_1_merge.tif\n\n• Supplementary file 2: Eu-MYC_F_TB_Liver_Actin_2_merge.tif\n\n• Supplementary file 3: Eu-MYC_F_TB_Liver_NR1D1_1_merge.tif\n\n• Supplementary file 4: Eu-MYC_F_TB_Liver_NR1D1_merge.tif\n\n• Supplementary file 5: Eu-MYC_M_TB_Liver_Actin_1_merge.tif\n\n• Supplementary file 6: Eu-MYC_M_TB_Liver_Actin_2_merge.tif\n\n• Supplementary file 7: Eu-MYC_M_TB_Liver_c-MYC_1_merge.tif\n\n• Supplementary file 8: Eu-MYC_M_TB_Liver_c-MYC_2_merge.tif\n\n• Supplementary file 9: Eu-MYC_M_TB_Liver_NR1D1_1_merge.tif\n\n• Supplementary file 10: Eu-MYC_M_TB_Liver_NR1D1_2_merge.tif\n\n• Supplementary file 11: EuMYC_M_TB_Spleen_gel1_ACTIN_merge.tif\n\n• Supplementary file 12: EuMYC_M_TB_Spleen_gel1_MYC_2_merge.tif\n\n• Supplementary file 13: EuMYC_M_TB_Spleen_gel1_NR1D1_merge.tif\n\n• Supplementary file 14: EuMYC_M_TB_Spleen_gel2_ACTIN_merge.tif\n\n• Supplementary file 15: EuMYC_M_TB_Spleen_gel2_MYC_2_merge.tif\n\n• Supplementary file 16: EuMYC_M_TB_Spleen_gel2_NR1D1_merge.tif\n\n• Supplementary file 17: EuMYC_TB_Spleen_F_ACTIN_gel6_merge[32504].tif\n\n• Supplementary file 18: EuMYC_TB_Spleen_F_NR1D1_gel6_merge[32506].tif\n\n• Supplementary file 19: TumorBurden_F_gel4_actin_merge[32512].tif\n\nRepository: ARRIVE checklist for ‘Circadian disruption does not alter tumorigenesis in a mouse model of lymphoma’, https://doi.org/10.6084/m9.figshare.20492892.v3. 20\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgements\n\nWe thank Anne-Laure Huber and Alanna Chan for helpful discussions based on their prior research that formed the basis for this project, Nuria Casanova Vallve for aiding in murine dissections, and Judy Valecko for administrative assistance.\n\n\nReferences\n\nReppert SM, Weaver DR: Coordination of circadian timing in mammals. Nature. 2002; 418: 935–941. Publisher Full Text\n\nBass J, Lazar MA: Circadian time signatures of fitness and disease. Science (New York, N.Y.). 2016; 354: 994–999. PubMed Abstract | Publisher Full Text\n\nLahti TA, Partonen T, Kyyrönen P, et al.: Night-time work predisposes to non-Hodgkin lymphoma. Int. J. Cancer. 2008; 123: 2148–2151. PubMed Abstract | Publisher Full Text\n\nCocco P, et al.: Night shift work and lymphoma: results from an Italian multicentre case–control study. Occup. Environ. Med. 2022; 79: 452–459. PubMed Abstract | Publisher Full Text\n\nFilipski E, et al.: Effects of chronic jet lag on tumor progression in mice. Cancer Res. 2004; 64: 7879–7885. PubMed Abstract | Publisher Full Text\n\nFilipski E, et al.: Circadian disruption accelerates liver carcinogenesis in mice. Mutat. Res. 2009; 680: 95–105. PubMed Abstract | Publisher Full Text\n\nKettner NM, et al.: Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis. Cancer Cell. 2016; 30: 909–924. 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PubMed Abstract | Publisher Full Text\n\nGu F, et al.: Longitude Position in a Time Zone and Cancer Risk in the United States. Cancer Epidemiol. Biomarkers Prev. 2017; 26: 1306–1311. PubMed Abstract | Publisher Full Text\n\nPariollaud M, Lamia KA: Cancer in the Fourth Dimension: What Is the Impact of Circadian Disruption? Cancer Discov. 2020; 10: 1455–1464. PubMed Abstract | Publisher Full Text\n\nPartch CL, Green CB, Takahashi JS: Molecular architecture of the mammalian circadian clock. Trends Cell Biol. 2014; 24: 90–99. PubMed Abstract | Publisher Full Text\n\nFrese KK, Tuveson DA: Maximizing mouse cancer models. Nat. Rev. Cancer. 2007; 7: 654–658. Publisher Full Text\n\nAdams JM, et al.: The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature. 1985; 318: 533–538. PubMed Abstract | Publisher Full Text\n\nHarris AW, et al.: The E mu-myc transgenic mouse. A model for high-incidence spontaneous lymphoma and leukemia of early B cells. J. Exp. Med. 1988; 167: 353–371. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHuber AL, et al.: CRY2 and FBXL3 Cooperatively Degrade c-MYC. Mol. Cell. 2016; 64: 774–789. PubMed Abstract | Publisher Full Text\n\nMello R, Lamia K, Pariollaud M:Circadian disruption does not alter tumorigenesis in a mouse model of lymphoma. figshare. [Dataset].2022. Publisher Full Text\n\nLamia KA, et al.: Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature. 2011; 480: 552–556. PubMed Abstract | Publisher Full Text\n\nPariollaud M, et al.: Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation. J. Clin. Invest. 2018; 128: 2281–2296. PubMed Abstract | Publisher Full Text\n\nLee S, Donehower LA, Herron AJ, et al.: Disrupting circadian homeostasis of sympathetic signaling promotes tumor development in mice. PLoS One. 2010; 5: e10995–e10995. PubMed Abstract | Publisher Full Text\n\nGréchez-Cassiau A, Rayet B, Guillaumond F, et al.: The Circadian Clock Component BMAL1 Is a Critical Regulator of p21WAF1/CIP1 Expression and Hepatocyte Proliferation. J. Biol. Chem. 2008; 283: 4535–4542. PubMed Abstract | Publisher Full Text\n\nFilipski E, et al.: Host circadian clock as a control point in tumor progression. J. Natl. Cancer Inst. 2002; 94: 690–697. PubMed Abstract | Publisher Full Text\n\nHadadi E, et al.: Chronic circadian disruption modulates breast cancer stemness and immune microenvironment to drive metastasis in mice. Nat. Commun. 2020; 11: 3193. PubMed Abstract | Publisher Full Text\n\nPapagiannakopoulos T, et al.: Circadian Rhythm Disruption Promotes Lung Tumorigenesis. Cell Metab. 2016; 24: 324–331. PubMed Abstract | Publisher Full Text\n\nLi Q, et al.: Circadian rhythm disruption in a mouse model of Rett syndrome circadian disruption in RTT. Neurobiol. Dis. 2015; 77: 155–164. PubMed Abstract | Publisher Full Text\n\nCasiraghi LP, Alzamendi A, Giovambattista A, et al.: Effects of chronic forced circadian desynchronization on body weight and metabolism in male mice. Physiol. Rep. 2016; 4: e12743. PubMed Abstract | Publisher Full Text\n\nKettner NM, et al.: Circadian Dysfunction Induces Leptin Resistance in Mice. Cell Metab. 2015; 22: 448–459. PubMed Abstract | Publisher Full Text\n\nFu L, Pelicano H, Liu J, et al.: The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell. 2002; 111: 41–50. PubMed Abstract | Publisher Full Text\n\nJanich P, et al.: The circadian molecular clock creates epidermal stem cell heterogeneity. Nature. 2011; 480: 209–214. PubMed Abstract | Publisher Full Text\n\nMteyrek A, et al.: Critical cholangiocarcinogenesis control by cryptochrome clock genes. Int. J. Cancer. 2017; 140: 2473–2483. PubMed Abstract | Publisher Full Text\n\nMteyrek A, Filipski E, Guettier C, et al.: Clock gene Per2 as a controller of liver carcinogenesis. Oncotarget. 2016; 7: 85832–85847. PubMed Abstract | Publisher Full Text\n\nOzturk N, Lee JH, Gaddameedhi S, et al.: Loss of cryptochrome reduces cancer risk in p53 mutant mice. Proc. Natl. Acad. Sci. U. S. A. 2009; 106: 2841–2846. PubMed Abstract | Publisher Full Text\n\nPuram RV, et al.: Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML. Cell. 2016; 165: 303–316. PubMed Abstract | Publisher Full Text\n\nWang J, et al.: Circadian protein BMAL1 promotes breast cancer cell invasion and metastasis by up-regulating matrix metalloproteinase9 expression. Cancer Cell Int. 2019; 19: 182. PubMed Abstract | Publisher Full Text\n\nSancar A, Gelder RNV: Clocks, cancer, and chronochemotherapy. Science (New York, N.Y.). 2021; 371: eabb0738. PubMed Abstract | Publisher Full Text\n\nMori S, et al.: Utilization of pathway signatures to reveal distinct types of B lymphoma in the Emicro-myc model and human diffuse large B-cell lymphoma. Cancer Res. 2008; 68: 8525–8534. PubMed Abstract | Publisher Full Text\n\nRempel RE, et al.: Utilization of the Eμ-Myc mouse to model heterogeneity of therapeutic response. Mol. Cancer Ther. 2014; 13: 3219–3229. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "160077",
"date": "25 Jan 2023",
"name": "Chi Van Dang",
"expertise": [
"Reviewer Expertise molecular and cell biology of cancer"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript by Mello et al. reports experiments that document the lack of an effect of circadian disruption by chronic jet-lag lighting protocol (CJL) on the development and progression of lymphoma in the Eu-Myc transgenic model. The authors previously reported that homozygous loss of Cry2, which mediates Myc protein degradation, increased Eu-Myc tumorigenesis with shorten survival. Hence, with CJL, which decreases the expression of Cry2, they surmised that CJL would enhance tumorigenesis and phenocopy genetic homozygous loss of Cry2. The intention of the study is laudable, however, the assumption that hypomorphic Cry2 (ie, via CJL) would mimic Cry2 null state seems non-compelling. Specifically, in the authors’ 2016 Molecular Cell paper, crossings were performed of EuMyc+/-;Cry2+/- males to Cry2+/- females to generate EuMyc+/-;Cry2+/+ and EuMyc+/-;Cry2-/- mice for analysis. The authors did not report the fate of the EuMyc+/-;Cry2+/- hemizygous Cry2 males compared to EuMyc+/-;Cry2-/- homozygous Cry2 loss males. It would be instructive, if the authors have the old data to report the survival of the Cry+/- hemizygous Cry2 EuMyc mice. This is particularly important, because the dosage effect of Cry2 could be the major driver of the EuMyc model unrelated to circadian disruption (eg. CJL) per se.\nAlthough the findings of the manuscript by Mello et al. are negative, they are important to document in the literature. However, the distinction between hemizygous and homozygous loss of Cry2 should be explicitly stated so that the study is more instructive for readers.\nMinor:\nFigure 2. Please comment on whether there are any survival differences between female CJL and female 12:12 L:D mice if the experiment was terminated at 200 days.\n\nFigures 3 and 4. Please define the immunoblot lanes; presumably these represent individual animals. If so, please add to the figure legend. The authors may want to comment on the variability of Myc levels in the individual spleens, which should have lymphoma, and whether the extent of variability may mask any potential effect of CJL. For the associated bar graphs, please indicate the sample size.\n\nReferences 9 and 27 are duplicates.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "10248",
"date": "29 Nov 2023",
"name": "Katja Lamia",
"role": "Author Response",
"response": "Thank you for recognizing that it is important to report these unexpected negative findings. We agree that genetic deletion of Cry2 is very different from hypomorphic or temporally altered expression of Cry2 caused by CJL and have clarified this in the revised text for this manuscript (see Abstract – Background, last four lines; Abstract – Conclusions, first five lines; third paragraph of Introduction; second and fourth paragraphs of Discussion). We further expanded the discussion on this point to more broadly address the pervasive expectation that enhanced tumorigenesis caused by chronic circadian disruption will be related to mechanisms discovered through genetic deletion of various clock components (e.g. Bmal1, Cry1, Cry2, Per1, Per2, etc) (see second paragraph of Discussion). Unfortunately, we did not collect data on tumorigenesis in Cry2+/- heterozygous Eμ-MYC mice in our previous study. We re-analyzed the survival data shown in Figure 2 by excluding all data collected after 200 days and found that there is no significant difference (p=0.27 by Mantel-Cox test; p=0.39 by Gehan-Beslow-Wilcoxon test). Thank you for your careful reading of the manuscript so we can improve the labeling of figures and remove duplicated references. We added more details to the legend for Figures 3 and 4 to explain that each lane represents an individual animal. We replaced the bar graphs with graphs that show each data point, which makes the number of samples in each group clear. We agree that the variability of MYC levels could make it difficult to detect a difference caused by CJL and have expanded discussion on this point (section “CJL does not alter c-MYC in liver or spleen and fifth paragraph of Discussion). We removed two duplicated references. We made every effort to include all necessary details to allow replication by others and to make all source data underlying the results available to ensure reproducibility by including them as supplementary data files and/or uploading them to figshare as detailed in the section “Data availability”. If specific methodological details or underlying data are missing, please provide more information so that we can correct the omissions."
}
]
},
{
"id": "160078",
"date": "30 Jan 2023",
"name": "Eric Zhang",
"expertise": [
"Reviewer Expertise circadian rhythms",
"physiology",
"neuroscience"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nGeneral comments This study described a phenomenon that 8-week chronic jet lag, which was reported to disrupt circadian rhythm in C57BL/6J mice, did not exacerbate lymphomas in Eμ-MYC mice. The results and conclusions are striking, for it is widely accepted that disruption of circadian rhythm could promote the progression of cancers, and such influences have been confirmed in animal models and number of clinical studies. As the authors indicated in the Conclusions part, it would be important and interesting if the mechanism under this phenomenon is investigated. As for the current version, more experimental data is needed to strengthen each part of the conclusions.\nMajor points: 1. Survival curve and total tumor weight are the only two indicators to support that long-term CJL does not impact the progress of lymphomas in Eμ-MYC mice. To address tumor burden, it will be better to have photos of tumor samples in addition to the statistical data. And other pathological analysis of lymphoma and the overall health of mice are needed to give a more detailed description on the cancer progression.\n2. Although there are evidences that such chronic jet lag protocol could disrupt the rhythm of C57BL/6J mice, how it works on Eμ-MYC mice still needs to be addressed in this paper, and it is also necessary to show the original rhythmicity of Eμ-MYC mice under LD/DD condition. Although the authors explained why they sampled at ZT9, a time course sampling (or at least anti-phase sampling) could better describe the influence of CJL on the peripheral tissues in Eμ-MYC mice.\n3. At first, based on the phenotypes in Cry2 KO mice, the authors hypothesized that CJL may also promote the progression of cancer in Eμ-MYC mice due to the disruption of circadian clock, but surprisingly found the opposite results. However, the disruption of circadian clock induced by CJL is different from Cry2 KO. For in the reference 11, the core clock genes such as Bmal1, Cry1, Cry2, and Per2, showed a different phase after CJL with remained, though dampened rhythmicity, while it is not like that in Cry2 KO mice. It is likely that the altered c-MYC is downstream of decreased CRY2 in Cry2 KO mice, and in Eμ-MYC mice, the expression level of c-MYC itself is variable, so Cry2 may not play a role in the case of Eμ-MYC mice.\nTherefore, this reviewer suggests the authors to make some rearrangement on this article, especially the Background and Discussion parts, in order to focus on the phenomenon of this article.\nMinor points: 1. Fig.1C and Fig.2B described the same factor, so it will be better to use the same range of y axis.\n2. The data quality of Fig.3E could be improved, for Actin is not consistent now.\n3. It will be better for the authors to make some preliminary hypothesis of the mechanism according to previous and the current studies in the Discussion part.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "10249",
"date": "29 Nov 2023",
"name": "Katja Lamia",
"role": "Author Response",
"response": "Thank you for recognizing the importance of these surprising findings and for your suggestions that have helped us to improve this manuscript. Please see below for description of how we have addressed your concerns: 1. We now include photos of representative tumors in Supplementary Figure S1. We cannot exclude the possibility that a more detailed analysis of the lymphoma phenotype might reveal a subtle effect of CJL on cancer progression but this is beyond the scope of this study. We clarified this in the revised text (see second paragraph of Results). 2. We agree that a time course would be preferable but this would require a large number of animals and is beyond the scope of this study. Based on further communication with the reviewer, we sequenced RNA collected from the livers of Eμ-MYC mice that we collected at ZT9 to get a more complete picture of the impact of CJL on circadian clock progression. We now include excerpts from these data in new figure 3D and provide accession number GSE242159 to make these new data available. These data are in good agreement with those that we have published previously from samples collected from c57BL6/J mice at the same circadian phase, suggesting that the impact of CJL on peripheral clocks is similar in Eμ-MYC mice. We also directly state the limitation that we did not measure gene expression at multiple phases of the circadian cycle (see fifth paragraph of Discussion). 3. We agree with the reviewer that the impact of CJL on circadian rhythms is very different from that caused by deletion of Cry2 and that the highly variable expression of c-MYC in Eμ-MYC mice could make it difficult to detect a subtle difference in c-MYC stability. We have rearranged the article and expanded the Background and Discussion to clarify these points (see Abstract – Background, last four lines; Abstract – Conclusions, first five lines; third paragraph of Introduction; second and fourth paragraphs of Discussion). Thank you for your careful reading of this manuscript and for your helpful suggestions under \"minor points\". We updated Figures 1C and 2B to use the same y axis. We replaced Figure 3E with new Western blots and quantitation (now in panel 3F). We agree with your suggestion to include some preliminary hypotheses regarding mechanism and have expanded the Discussion as suggested (see new sixth and final paragraph of Discussion)."
}
]
}
] | 1
|
https://f1000research.com/articles/12-49
|
https://f1000research.com/articles/12-1244/v1
|
28 Sep 23
|
{
"type": "Case Study",
"title": "Violence in the Education: The Post-Revolutionary Situation in Hungary (1956-1957)",
"authors": [
"Lajos Somogyvári"
],
"abstract": "Background: The author attempts to introduce an unusual approach towards schools, universities, and dormitories, including their users (professors, teachers, parents, and students): How can the educational issues be seen through the lenses of special police forces in a specific historical moment? After the 1956 Hungarian revolution, a brutal pacification process took place all over the country, supported by the Soviet troops and special armed forces, police battalions of the restarting communist power.\n\nMethods: In this historical study, I used mainly military archive documents to show the perspective of the communist restauration and confront their viewpoints with party reports and some oral histories by eyewitnesses, who suffered several injuries during the repression. The paper is based on narrative analysis, as the official explanation presented various stories to justify their actions, while the reality in the background might be very different from this. Results: Between November 1956 and May 1957, these soldiers or officers became a familiar image in educational institutions. They blamed teachers and professors for misleading their students and thus creating a narrative of the counter-revolution of October 1956, while they identified themselves as parents or teachers (instead of the real ones, who lost their rights to do this, due to the participation in the revolution). Conversely, physical and verbal aggression was a widespread routine of the army officers. Conclusions: In extraordinary situations, during historical crises violence became suddenly real, allowed, and/or supported by many political actors to achieve their goals. After the consolidation of power, these special army and police forces were released and their activities were stopped by the authorities of the Ministry of National Defence because their presence was realized as an uncomfortable situation for the politicians. Such studies may give lessons us to learn, about how these scenes escalate into a point of no return.",
"keywords": [
"Hungary",
"history of violence",
"history of education",
"1956 Revolution",
"armed forces",
"narrative analysis"
],
"content": "Introduction\n\nMy research questions concentrate on the everyday life experiences of the post-revolutionary situation, interpretations, self-images, and justifications of different affairs in education; the basic corpus will be provided by the narratives of the armed forces (karhatalom, karhatalmisták in Hungarian), supplemented and confronted oral histories of eyewitnesses, and minutes of party meetings from distinct levels. The following tabooed and traumatized stories have been hidden and latent since then; verbal and physical violence, aggression, and various forms of intervention have a multifaceted nature, showing the whole spectrum of student/teacher reactions from resistance to collaboration.\n\nThis topic is very sensitive and suppressed; it is hard to speak about it even now. There are some other written testimonies, but most of the sources came from the contemporary authentic party and military documents, which may have influenced scholars and theories by their particular language. The communist utopia started with the establishment of an ideological worldview, which transformed the categories and perception of social reality by altering the meaning of everyday words (we will see how the revolutionary days turned into a counter-revolutionary concept within just a few weeks and determined the interpretation of what happened in October-November 1956 for decades).1\n\nEven in the 2010s and 2020s, this language, when explaining the communist period, using their key ideas, without reflection, affected Hungarian historiography: it is a very good example of how the last stage of socialization has been depicted in agriculture. Many historians accept the developed discourses of the late 1950s and early 1960s (their fundamental sources), defining this radical change as a cooperative movement, meanwhile, other academics operate with the term collectivization: the former covers the intrinsic pressure and suggests a voluntary-like process, while the latter one underlines and reflects the original Stalinist initiative.2 This short detour just wants to shed more light on the language of communism and its usage, which is crucial in my interpretation.\n\nThe characteristics of the records (and archives) from the 1950s and’60s demonstrate another important aspect when seeing the limitations of the usual ‘archive-based research’ in the history of education: silences and scattered references influence and form our historical reality, with the need to offer a reasonable explanation for the past.3 The narratives made by the military forces and party representatives conceal some elements and emphasize others: in this case, the research was more like a puzzle solving from dispersed hints and vanished cues, because my main sources tried to erase what really happened in Hungarian education in these months, condemned forgetting the shocking details. After the end of socialism, 1956 became a central point of Hungarian self-identity and one the most important parts of our 20th-century history. Today, literature on the revolutionary events and the consequences is available in English as well: most of them introduce the geopolitical situation of the Cold War, displaying Hungary as a puffer zone between the two world orders.4 Beside the politically focused works, there have been some studies closer to my approach; oral stories from the children of the executed or imprisoned victims of the retaliation,5 or the voices of refugee students in a Reception Centre.6 If we additionally consider Hungarian historiography, the appearance of military forces and their roles in the 1956 Hungarian education is a remarkably absent topic. There has been only one exception, which has drawn my attention to the special armed troops visiting schools armed groups and their activities.7 This paper, which started with a lost and found dossier by me in the National Archive in 2016, meets my research interests.\n\n\nMethods\n\nIn this case, we face a sensitive and complex socio-historical issue – by describing it, I followed two main principles. First, it is crucial to commemorate these tabooed events and prevent to forget them. On the other hand, I do not featured concrete names in the analysis (except of the widely known politicians, as Kádár) to give respect for the people who were affected and follow the actual Hungarian legislation on the right to informational self-determination and on the freedom of information (Act CXII of 2011, see: https://net.jogtar.hu/jogszabaly?docid=a1100112.tv). This study received ethical approval from the Ethics Committee of the University of Pannonia, Hungary. I do not utilize personal stories or interviews – that is why I focused only on the archives and the published oral histories, ad perpetuam rei memoriam.\n\nUnforeseen documents popped up when I made investigations about denominational instructions in the academic year of 1956-1957: a file, entitled K. A. (likely the capital letters of the then head of Educational Ministry, Albert Kónya), which contained records about teacher beatings, rude interrogations, and threatening incidents.8 This was a lucky coincidence, as this folder has been totally unknown in the Hungarian historiography, which I found accidentally in fragmentary documentation – many files were destroyed during and after the 1956 revolution. In the next step, I gathered the official Party archives on a national level, searching traces of violence in schools after October 1956: more and more details emerged, related to the activities of special armed forces, included in my first paper on the subject.9 Following this logic, I analyzed the historical logs of these regiments and battalions in the Hungarian Military Archive,10 and contrasted the official discourses with two retrospective personal testimonies from public oral histories.11 There are two main, complete corpora as the basis of my study, the first one is the paper collection of Albert Kónya, who was a deputy minister and provisional head of the Educational Ministry at that time. His documents are stored in the Hungarian National Archive, Section of Culture, Educational Ministry (MNL OL XIX-I-2-j), from our point of view the fourth box (4. d.) is the most important. To start research here, you have to apply, signing for your purpose (private or scientific), topic, and time period. It is open and free for every Hungarian and non-Hungarian citizen, the application form and all possible regulations and restrictions are readable here: https://mnl.gov.hu/uj_kutatoknak.12 Accessing to the second type of sources, a similar process needed (application, including purpose, topic and time) at the Military Archive (https://militaria.hu/adatb/leveltariuj/). There is a thematical compilation here, called the Hungarian People’s Army Special Collection (MN KGy, Magyar Néphadsereg Különgyűjteménye), including papers about the 1956 revolution and restoration of the communist power afterward (F. 1956-os gyűjtemény, 1956 collection).13 All other materials used in the paper do not constitute a group like the previous ones, they are separate documents, scattered references, that add official and non-official interpretations of the verbal and physical aggression between 1956 Autumn and the Spring of 1957: meeting of the Hungarian Socialist Workers’ Party (HSWP) and personal memories about the events.\n\nThe co-occurrence of the actors (armed forces and people who were involved in the education) and their activities with a certain degree of aggression and reaction (violence, resistance, collaboration, etc.) are the key features of my paper, which provided the sources to scrutinize my topic. Following the three-step research (see Figure 1), I will answer the following research questions by using this collection of data:\n\n(1) How can the connections between armed forces and educational actors (teachers, principals, lecturers, students and parents) be characterized?\n\n(2) What kind of police and special force interventions took place in the educational institutions?\n\n(3) What image of educators, educational roles and the responsibility of the youngsters and adults do the declarative narratives of the power depict?\n\n(4) What face of the enemy emerged from the sources?\n\nAll of these aspects are inseparably intertwined in the search of guiltiness for the heart-breaking and shameful events in October (a euphemistic definition of the 1956 first revolution, then counter-revolution) and finding accountable persons to judge over.14 My analysis is based on the military archives, offering a special point of view, adding other perspectives and alternatives to consider as well (to provide balance).\n\nFrom sources to methodology\n\nThe files of the deputy minister, Military Archives, and the Party meetings show us the basics of the official understanding of the extreme clashes in education. They had different accents and intentions during these months: the bodies of the state party tried to take pacification under control (more or less successfully) on every level, while the special forces often crossed the legal borders as emissaries of people’s power, agents of real communism. The different goals caused friction and conflicts between party secretariats, police captains, and Soviet and Hungarian colonels; the relevant actors during the stabilization period. Committees of the Hungarian Socialist Workers’ Party (HSWP) had to fight on two parallel fronts, namely, against the extreme, radical leftists, who wanted to get revenge for the revolution (from their point of view counter-revolution), on the other hand, against reformer communists and remaining followers of the failed revolt from the right side of the political palette. The armed/police forces were close to the former side, released by the power in a purposely uncontrolled situation to force discipline and order on society.\n\nThe oppressed and occupied country did not have a voice to express their opinion and feelings, which casts a long shadow on the everyday Hungarian perception and remembrance of 1956 and 1957. Invisible violence15 was a substantial element of the existing socialism: experience of suppression and atmosphere of real hard-core communism inherited from generation to generation. In the long years after 1956, the legitimation of the new Kádár-regime was based on a historical compromise:16 The ruling power wanted every citizen to forget what had happened, and in exchange, it offered a limited opportunity for material prosperity. The only official requisition was remaining as apolitical and neutral as possible, avoiding the dogmas and taboos of the political power, like the unquestionable statement about counter-revolution, and neglecting any other meaning of that October. If you have a discussion with an elderly person from your audience after a conference speech, and he or she shares his or her own memories about going to school in Hungary in late 1956 and early 1957, this was to be shared with you only, privately and nothing else. This can be a long-term consequence either of this previous cultural tradition or of frustrating and hurting emotions from those months. The partly hidden and latent nature of past events and the psychological distress connoted with them made oral histories very difficult, so in my research, I am only adding two testimonies from public collections of eyewitness accounts: Oral History Archive for teachers, and memories from a well-known journalist’s webpage, both published on the internet, accessible for everyone.17 These descriptions tell the commonly known events of the revolution and vengeance from a specific perspective: history from below.18\n\nMilitary archives covering every territory, give a complete overview of the whole country because when the special forces were withdrawn, their commandants had to outline the activities related to law enforcement in the form of historical logs. All of these logs remained and microfilmed,19 which is a very good starting point to the analysis, while other sources (party documents, meetings, reports, interviews, etc.) are very fragmented and concerned with particular issues. However, the latter data also underpins the whole picture. To set the framework of this undiscovered historical field, using the theoretical background of emotions and violence in history can be fruitful here,20 in order to present meanings and contexts of abusing power. Every element of this investigation is unique: the chosen topic, the archives, and the nature of the sources, which all pose challenges in the methodology. I focused on the textual appearances of schooling, students, and teachers, including their relations with the armed forces. By doing so, the main topics of these archives could easily be detected, these are the following: interpretation of the revolution and resistance, activities to restore communist power and legitimizing the actions and brutalities during the retaliation. Reconstructing the official argumentations and stories was the last step in the research.\n\nThe study is based on narrative analysis, because one obvious characteristic of the examined army logs is narrativity: they told us stories with traditional elements, like conflict, heroes and enemies, problem-solving, happy end, and so on. The writers (military leaders) wrapped up the pacification process as a success, their ‘emplotment’ produced familiar literary genres, with enough ‘explanatory power’21 to give plausible explanations for the resistance in society – both they and their political supervisors needed this. Revolution meant collapse and chaos, a time of uncertainty to the Party apparatchiks and loyal soldiers, a kind of tragedy, followed by the triumph of the good (a romance), the victory as a restoration of the communist power.\n\nAccording to Eileen H. Tamura,22 to understand historical reality and the human agency within, it is essential to consider individual events, which is logical in an idiographic discipline. The narratives provided by the heads of special armed/police forces contain two main organizing principles:\n\n(1) scapegoat-theories,\n\n(2) and the takeover of educational roles from teachers and professors.\n\nFrom their point of view, it was a rational and logical decision: many educators were involved in (counter-) revolutionary activities; they became responsible for every later opposition, and thus, lost their rights to instruct the younger generations. The battalion commanders, lieutenant colonels, and officers started acting as quasi-educators in three dimensions, laid down and transmitted in the reports to the superior bodies of the HSWP. They:\n\n(1) are the ones to guide misled students, instead of original teachers,\n\n(2) regulate principles, leaders and faculty staff,\n\n(3) threaten parents to hold down their children.\n\nThere might have been many psychological factors in the background of verbal and physical aggression (individual motives, fear and hate, the feasibility of a new rebel, group pressure, anti-intellectualism, etc.), but I will not examine these, as they are not my focus, and they can be found in the sources. The next chapters will detail the developing relationships between armed forces and educational actors through diverse interventions in the everyday life of schooling.\n\n\nResults\n\nOn 12 December 1956, at 4 a.m., a secondary high school teacher was arrested in Eger, a small Hungarian city, in his home.23 There were two soldiers, one detective, one driver, and an authority-appointed witness; the scene must have been very similar to how Solzhenitsyn illustrated a typical arrest during Stalinism; “The sharp night-time ring or the rude knock at the door. The insolent entrance of the unwiped jackboots of the unsleeping State Security operatives. The frightened and cowed civilian witness at their backs.”24 The teacher was accused of hiding weapons by an anonymous denunciation. The armed forces unit did not find anything, yet the arrest and imprisonment of the teacher was inevitable. Weeks later, his wife still had no answers because of the demand for ‘military dictatorship’ no information was distributed; but according to the appendix of the document,25 he was released in early 1957. The whole faculty staff stood up for him; they wrote a letter of solidarity, stating his innocence – all of them signed the statement, which testified to extraordinary courage at that time.\n\nSometimes teachers were called to the municipality during worktime, as in an elementary teacher’s case, in a village near the Romanian border in February 1957.26 When he entered the official room, his ID card was expropriated, then (without any question) the police officers began to beat him; he got slapped, and his hands and other body parts punched with a stick. It was accompanied by hateful comments (verbal and physical aggression usually went hand in hand): “Did you want to demolish the power of people? We will give you power! (…) So far, there has been no dictatorship, now there will be the dictatorship of the proletariat!”27 After some hours standing in a dark cell, he was let go, but banned from every school in Hungary, because “a counter-revolutionary teacher doesn’t have the right to teach”.28 His only crime was finalizing the minutes of the local revolutionary committee in October 1956. There are several other documents proving the ubiquity of such incidents: teachers feared removal, arrest, and beating;29 the Party apparatchiks and workers condemned them as a whole.30 Furthermore, principals were frequently subjected to extreme physical abuse, without any hearing.31\n\nIf there was a hearing, it often had a very intimidating atmosphere. For example, the police captain in Szeged said the following sentences to university students after they had been taken into custody: “The university buildings will be shot up, from the basement to attic! (…) All professors are fascists; they only joined the Party to hide their medals as former members of the Order of Vitéz”.32 A universal topos appeared here: teachers and lecturers are the successors of the Horthy era (this Order was a creation of that regime), an emblematic period of fascism before 1945, which was a misleading simplification of communism. Other officers defined the “bloody” professors as “pimps”, the armed forces would “take care of them” – these expressions were deeply emotional, and full of negative attitudes.33\n\nHouse searches, framed as inspections, meant another important interventional form of the special forces as a following symptom of arrest, or as independent activities. The most well-detailed incident happened at Miskolc University on 20 February 1957: we have four sources that day, from different perspectives,34 which gives us an exceptional opportunity to dig deeper. In the report of the notorious ‘Tizeshonvéd’ zászlóalj (Battalion no. 10.)35 self-justification, legitimacy of action, and euphemism amalgamated: 300 officers were involved in the attack, which was caused by a scandal. According to the rapporteur, the students humiliated the flag of the international working class by hanging out red rags, and women’s underwear on it from the windows of their hostel, answering the official flag of the main building. The armed forces made a blockade around the student hostel, and started the search: they found guns, leaflets, and confidential papers of the State Security (ÁVH); while the youngsters mocked the officials (“bloody Kádár-soldiers”, whistled the Soviet hymn ironically), and behaved so “arrogantly and shamelessly”, that they were scolded like misbehaving children.36 There is no explanation as to what is meant by the last comment.\n\nThe rector’s memorandum provides more information: 60 students and 10 lecturers were arrested; many were beaten during the search, including the vice-rector, a dean, and some students “were very sick”37 because of the thrashing. The leader criticized both the provocation by the students (the red rags) and the violation of law by the armed forces.38 The scandal reached the highest levels of the party bodies. In a meeting of the HSWP Organisational Committee, the party secretary of Borsod briefly recapped the events: the soldiers tried “to correct the thinking [of students] with some slaps (…) Professors are offended because they were beaten too …”.39 An oral narration from a former student remembered this way:\n\n“… we had to stand by the wall, with our hands behind us. And from then on, they started beating and beating us. (…) they took the nightsticks and banged. Then other officers came, asked our names and occupations of our fathers, and depending on the answer, they began to hit again. Most of us were from the working class in Miskolc (…) which aroused wild rage in the soldiers because they could have been the same (…) laborers; when they heard “engine fitter”, they said “You m … f … er”, and began to beat.”40\n\nThe quotation reflects to a very important factor of the communist systems: the determining class,41 the social background that determines everything from schooling to employment; and the whole identity of a citizen in Hungary. From the official point of view, every (counter-) revolutionary person had a bourgeois, aristocratic, and fascist heritage, which connects the rebels with the previous Horthy Period (1920-1944), but reality always refuted this preconception, because the majority of the freedom fighters were from the working class. This schizophrenic situation (insisting on the ideology, as opposed to people’s own experiences and made-up interpretations) caused a lot of stress and frustration among the loyal members of the new power and resulted in a spiral of violent acts.\n\nA slogan was spreading very fast in early 1957: ‘We will start again in March’ (in Hungarian: Márciusban Újra Kezdjük, in short: M.Ú.K.). It referred to the national commemoration of the 1848 Revolution (March 15) with the oppressed revolt and suggested a new uprising. More and more affairs refer to the probability of such an event, but we do not know much about the real background of such a movement (there are studies that stated that issuing this idea was the initiative of the power, in order to strengthen its position).42 For instance, in Kecskemét downtown, shop windows were inundated with handmade leaflets and posters before 15th March, with the mysterious signatures KEFI and TBSz. The secret police made a covert action to unveil delinquents, and a fewdays later, they uncovered a ‘conspiracy’ at the Piarista Gimnázium (Piarist Secondary School), a denominational institution, which was a lucky coincidence for the authorities, as a good illustration of the entwined clerical-fascist assault against people’s democracy.43 The fliers and placards were produced by 11 students. The detectives diagnosed that only one of them was of laborer origin, the others were sons of lawyers and previously leading functionaries, which confirmed the bourgeois character of their propaganda activities. They constituted the Revolutionary Youngsters of Kecskemét (Kecskeméti Forradalmi Ifjúság, KEFI), also known as Turul Brotherhood (Turul Bajtársi Szövetség, TBSz)44 – the latter one invoked a radical interwar right-wing organization, but we do not have more information as to whether a real continuity existed between them.\n\nThere was a symbolic fight in these months about ruling the streets and public opinion: these propaganda messages occupied the public sphere, which originally fell within the scope of the party and its ideology after 1945, and operated in short impressive slogans.45 The longstanding social resistance borrowed this instrument from communists in order to score the victory over them (at least) symbolically when the making and distribution of posters and leaflets remained the last battlefield. Teacher trainees majoring in art created posters in Szeged, but they were caught in the act while gluing; after that, 30 police officers in civil clothes, the armed forces, and the Party Committee made joint raids on Fridays and Saturdays for three weeks.46 In Borsod County, anti-Soviet poems and handbills spread in all schools: “We do not learn for Kádár”, “Russians go away”, “We will not learn the Russian language”, and “Our leader is Mindszenty”.47\n\nThe title includes two key phrases from the vocabulary of armed forces: administrative actions meant removals from schools, under the term ‘information work’ including political debates, meetings, and briefings arranged to give parents, students, teachers, and principals a kind of ideological indoctrination. Schools were evaluated as centers of the counter-revolution in the papers of the 1st Regiment of Revolutionary Armed Forces,48 and they set the goal to purify the institutions of the negative spirit: for example, a girls’ schoolteacher was arrested, because she had educated children in an anti-democratic spirit.49 A compelling dichotomy50 defined the school perception of army/police officers: some teachers and students personified the face of the enemy as agitators of the counter-revolution, warmongers who risked peace. On the other hand, there were loyal socialist citizens, supporters of the workers’ state, and many hesitating people. There was no mercy on the first group; meanwhile the latter ones had to be strengthened further: thus school-visiting groups were formed, who involved parents and teachers with communist confidence, principals, and school departments in the work.\n\nThese groups used intimidation and persuasion as their tools: teaching staff was made responsible for every conflict in schools; so out of fear or conviction, they reported everything to the battalions. The armed forces participated in the discussions between form teachers and students, as in parent-teacher association (PTA) meetings, they warned parents to protect their children from the risks of counter-revolutionary activities (according to the accounts,51 they did so in an objective, rational manner, which is doubtful). Principals did not allow these gunmen to work in every school (a clear sign of a living struggle), as the troop leader of the 7th platoon faced this issue and answered in agreement with the Party: “We have to get into the schools and classrooms”.52 The units made lesson plans to analyze topics with children, with titles like “What is the meaning of Kossuth-crest?” [an old traditional Hungarian symbol and a chosen crest of the 1956 Revolution], “The significance of the red flag and red star”, and “What are the pieces of evidence that happenings in October were counter-revolutionary?”. Soldiers and police officers taking the role of teachers by giving lectures and instructions declared that every educator is obliged to act adopting the official standpoint of the government, “even if they had political concerns”.53\n\nHelping to build pioneer patrols, establishing Communist Youth League (Kommunista Ifjúsági Szövetség, KISZ) and Youth Guard (Ifjú Gárda), restarting Party in teaching staffs, planning trips, and leading cultural centers – these are just some activities associated with the armed forces. The operative, secret police work was more hidden, the only certain point is that every battalion had to assign liaison officers to do this in Budapest (no information outside the capital city). The sources mentioned such activities two times:\n\n“The use of children of communist parents in exploring counter-revolutionary elements proved to be a very good method. These children told us what some teachers had incited them to do, which classmates had boasted that they or their parents possessed guns illegally.”54\n\n“A young, 17-year-old boy offered us to help catch a person who was actively engaged [in the events of October], and advertised to others that he was working for the secret police …”55\n\nThe functioning system followed the ancient political phrase of ‘Divide et impera’ (divide and rule): thus they separated different groups and confronted them with each other; the pure form of educational micropolitics56 intertwined every situation and context. Another 17-year-old student was arrested in Veszprém on 29 April 1957, with the charge of conspiracy against the people’s democracy. The beatings lasted for days; his eardrum broke in, and the interrogators wanted him to speak about the ‘Young Hungarian Alliance’, a naïve local teenager movement, which was planned to start again in March (not successfully) and distribute leaflets. He refused to make a confession. Six days later, they let him go, but one week later, arrested him again.57 The forms of punishment applied were diverse: slaps, beaten by a baton, and gymnastics (squats and pushups) repeatedly on a circular basis, and they also threatened him by being banned from every secondary school in Hungary (that was a real punishment at the time). The only way out was if he signed a statement about future cooperation with the police. After two days of punishment, he signed the paper, admitted the counter-revolutionary propaganda, and offered his services to state security to avoid punishment. After his release, he never went to the meetings with officers, and the connection was disrupted when he moved to Budapest.58\n\nA very different narrative speaks about officials and students’ relationship in the case of the university dormitory in Buda, District I.59 The historical log of the 3rd Regiment provides a whole story, with a plot of how misled students got directed in the right direction by the officers. The start is a confusing period when the resistance was alive in January 1957. The site was the Buda Castle District, where several underground basements provided ways to hide and store illegal materials, and to transport them from one place to another. The armed forces raided there many times, putting students under pressure by threatening them with issuing a shooting order, without relevant results, so new methods were necessary. The 1st Battalion arranged a dance event for the university students, under strict control: another typical educational activity turned into a bizarre scene, where gunmen surrounded the dancing pairs.\n\nOn 23 February 1957, at midnight, a meeting was being held between a lieutenant colonel, a first sergeant, a first lieutenant, and the community of the dormitory. The situation described looked like a parents-children discussion, full of protection and intimacy literally in the form of a dialogue:\n\n“Student: ‘Comrade Lieutenant Colonel! We asked you to forget the past! (…)\n\nLieutenant Colonel: ‘We are angry with you, like good fathers (…) Do you take any steps to get closer to us?\n\nStudent: ‘Please, trust us in the future!\n\nLieutenant Colonel: ‘You have to deserve it first.’”60\n\nThe following topics shaped the political debate from 7 p.m. to 2 a.m.: the Miskolc University scandal, the role of the armed forces, the events in October as a revolution, the political roles of the university students, etc. The youngsters were very critical and well–informed; they had not acquired the concept of counter-revolution, but the end of the story is a happy ending from the viewpoint of the armed forces. Some university students were convinced at the meeting, and they later visited secondary high schools with the officers to convey the message: “Our friends, fellow students – we were deceived!” [by the counter-revolutionists, the enemies of the communist system, and the people’s state].61 From the viewpoint of the armed forces, after March, their victory was fulfilled – from the opposition to achieving the common goals; it was a long development history.\n\n\nConclusions\n\nThe 6th Battalion of the 2nd Regiment summarized the significance of these activities: “The enemy attacked through schools”,62 from the viewpoint of the churches and the counter-revolution, therefore a definite change toward the true way of building socialism was brought about. In previous years, some teachers educated children improperly, so “we had to take the issues of youngsters in our hands”.63 From a retrospective point of view (June 1957), it was a triumph, but without the help of communist officers and loyal teachers, this progress could not have been imaginable. A chaotic period emerged from the sources, a whole spectrum of possible practices, and contexts changed over time, meanwhile the official discourses tried to suggest a planned evolution and a coherent argument about the reasons of the (counter-) revolution. The armed forces existed only for a limited time of the communist takeover between November 1956 and June 1957: first, the politicians needed this power. After the stabilization, they became an unnecessary ballast that had to be terminated. In the light of recent developments (e. g. Russian aggression against Ukraine, children faced acts of war, violent environments of schooling) the topic of my study is very relevant. Perhaps learning from the past, and reading how these situations developed is a big benefit of such analyses.",
"appendix": "Data availability\n\nThe underlying data for this study is under restriction by the Archival resources of the Hungarian National Archive (MNL, Magyar Nemzeti Levéltár, https://mnl.gov.hu/) and the Military Archives (HL, Hadtörténelmi Levéltár, https://militaria.hu/adatb/leveltariuj/). To request access to the same data used in this study, researchers should contact to these institutions, the e-mail addresses are the following: info@mnl.gov.hu (Hungarian National Archive), and kutato@mail.militaria.hu (Military Archives). In the case of the Hungarian National Archive, a pre-registration is required with a full name and e-mail address (https://www.eleveltar.hu/auth#step=1), after a successful registration one can submit a request in the electronic database (https://www.eleveltar.hu/) with the precise number of the document (like XIX-I-2-j. 4. d. in this paper). Filling a Supporting Statement and a Visitor Ticket (Támogatói nyilatkozat, Látogató jegy, here: https://m.militaria.hu/adatb/leveltariuj/content/letoltheto_urlapok_kutatoszolgalathoz_es_kozhivatali_tevekenyseghez ) is needed to access to the files in the Military Archives. The Supporting Statement has to be signed and stamped by a scientific institution, indicating the subject and timeframe; the Visitor Ticket included your personal data (name, date and place of birth, mother’s name, address), and the purpose of the research (private or scientific). All of these forms are in Hungarian, but you can ask for help by writing an e-mail to the Research Office (kutato@mail.militaria.hu).\n\n\nAcknowledgments\n\nThe author is deeply grateful for those, who share their memories about that period – this paper is a way to thank to all of them.\n\n\nFootnotes\n\n1 S. Kotkin, Magnetic Mountain: Stalinism as a Civilisation (Berkeley: University of California, 1995); J. Hellbeck, Revolution on My Mind: Writing a Diary Under Stalin (Cambridge–London: Harvard University Press, 2006); and I. Paperno, Stories of the Soviet Experience: Memoirs, Diaries, Dreams (Ithaca–London: Cornell University Press, 2009). These compelling works illustrate the perception of the communist world, the discrepancy between official and private languages and different identity-making mechanisms in many ways.\n\n2 S. Horváth and J. Ö. Kovács, ed., Állami erőszak és kollektivizálás a kommunista diktatúrában [State Violence and Collectivisation in the Communist Dictatorship] (Budapest: MTA BTK, 2015).\n\n3 G. McCulloch, Documentary Research: In Education, History and the Social Sciences (London-New York: Routledge, 2004), 44-45. McCulloch cited here Carolyn Steedman’s lines about archives and their emotional, physical effects on historians; here, one goal seems to be ubiquitous: to give justice to the voiceless and forgotten people who were oppressed in 1956 and 1957 in Hungary.\n\n4 Cs. Békés, M. Byrne and J. M. Rainer, ed., The 1956 Hungarian Revolution: A History in Documents (Budapest-New York: Central European University Press, 2002); J. Granville, The First Domino: International decision making during the Hungarian Crisis of 1956 (College Station: Texas A&M University Press, 2004); C. Gati, Failed Illusions: Moscow, Washington, Budapest, and the 1956 Hungarian Revolt (Washington-Stanford: Woodrow Wilson Center Press and Stanford University Press, 2006); J. M. Rainer and K. Somlai, ed., The 1956 Hungarian Revolution and the Soviet Bloc Countries: Reactions and Repercussions (Budapest: The Institute for the History of 1956 Hungarian Revolution and Historical Archives of the Hungarian State Security, 2007).\n\n5 Zs. Kőrösi and A. Molnár, ed., Carrying a secret in my heart … Children of the Victims of the Reprisal after the Hungarian Revolution in 1956. An oral history (Budapest-New York: Central European University Press, 2003).\n\n6 V. Sheridan, ʻSupport and surveillance: 1956 Hungarian refugee students in transit to the Joyce Kilmer Reception Centre and to higher education scholarships in the USA’, History of Education 45, no. 6 (2016): 775–793.\n\n7 R. Maruzs, ʻKülönleges feladatok a karhatalomban [Special roles in the armed forces]’ in A dolgozó népet szolgálták? Fegyveres testületek és pártirányításuk a szocializmusban [Did they serve the working people? Armed forces and their control by the political party in state socialism]. Eds. I. Ötvös and P. Triber (Budapest: NEB, 2018), 67–82.\n\n8 Magyar Nemzeti Levéltár Országos Levéltár (MNL OL) [Hungarian National Archive] XIX-I-2-j. 4. d.\n\n9 L. Somogyvári,’”Eddig nem volt diktatúra, most lesz proletárdiktatúra!” Rendteremtés a pedagógus-társadalomban 1956 után [”So far, there has been no dictatorship, now there will be the dictatorship of proletariat!” Pacification of teachers after 1956]’ in A tanulás új útjai [New ways of learning]. Ed. J. Mrázik (Budapest: HERA, 2017), 620–633.\n\n10 L. Somogyvári, ‘A karhatalom vidéken: iskolák, egyetemek és diákszállók az 1956–1957-es tanévben [Armed forces in the countryside: schools, universities and dormitories in the 1956–1957 semester]’ in Jövőformáló human tudományok [Humanities in the service of the future]. Ed. J. Tóth (Budapest, Akadémiai Kiadó, 2022), 114–121.\n\n11 Tanári kézikönyv az 1956-os forradalom történetét feldolgozó SULINET digitalis órához [Teachers’ handbook to the digital SULINET lesson about the 1956 revolution]. Retrieved from: https://mek.oszk.hu/01900/01937/html/szerviz/. Borenich Péter honlapja [Webpage of Péter Borenich]. Retrieved from: https://borenichpeter.hu/\n\n12 The text is in Hungarian, but the Information Office at the Archive can help everyone to fill the form.\n\n13 To find these sources, there is a guidance here: https://militaria.hu/adatb/leveltariuj/f/08_viii_xiii_fondfocsoport_magyar_ nephadsereg_iratainak_segedletei\n\n14 Az MSZMP Ideiglenes Központi Bizottságának határozata, 1956. december 5. [Decree of the HSWP Provisional Executive Committee on 5 December 1956] in A Magyar Szocialista Munkáspárt határozatai és dokumentumai, 1956-1962 [Documents and Resolutions of Hungarian Socialist Workers’ Party, 1956-1962]. Eds. Á. Ságvári and H. Vass (Budapest: Kossuth, 1964), 13–17. This document defined the evaluation of the 1956 revolution as a counter-revolution until 1989: counter-revolution had to understand as an essential attack against the workers’-farmers’ state (the real revolutionary organisation) after December 1956. In short, the main reasons of the rebellion are: two opposite poles of the Party (the dogmatic, sectarian, Stalinist clique, and the revisionist, right-wing group of Imre Nagy), the Horthy-fascism, and of course, the international imperialism.\n\n15 J. Baberowski, Räume der Gewalt (Frankfurt am Main: Fischer Verlag Gmbh, 2015), 110–132.\n\n16 B. Kovrig, ʻHungary in the era of the Kádár compromise’, International Journal 33, no. 6 (1978): 720–739.\n\n17 Tanári kézikönyv az 1956-os forradalom történetét feldolgozó SULINET digitalis órához [Teachers’ handbook to the digital SULINET lesson about the 1956 revolution]. Retrieved from: https://mek.oszk.hu/01900/01937/html/szerviz/. Borenich Péter honlapja [Webpage of Péter Borenich]. Retrieved from: https://borenichpeter.hu/\n\n18 K. Myers and I. Grosvenor, Collaborative Research: History from Below (Bristol: University of Bristol/AHRC Connected Communities Programme, 2018). This fascinating book underscores the role of communities and the importance of participation in such researches: the everyday perception of communism very much differs from what we have known from the usual sources. For example, one of my projects aims to reveal the schooling experience of the so-called ʻclass-alienate’ children, who were not allowed to enter secondary and higher education in the 1950s because of their social class (former aristocrats, sons and daughters of the members of gendarmerie, etc.), to shed a light on the situation. We are not able to find these stories in the archives, only in oral sources.\n\n19 Hadtörténelmi Levéltár (HL) [Military Archives] MN KGY, F. 10. d., 11. d. There is a selection called: Magyar Néphadsereg Különgyűjtemény (MN KGY), F. 1956-os gyűjtemény [Hungarian People’s Army Special Collection, 1956 collection]. 10. doboz (Budapest), 11. doboz (vidék) [Box 10. Budapest, Box 11. Countryside].\n\n20 B. H. Rosenwein (2002). Worrying about Emotions in History. American Historical Review 107, no. 3 (2002): 821–845.; N. W. Sobe, ‘Researching emotion and affect in the history of education’ History of Education 41, no. 5 (2012): 689–695.; C. Tilly, The Politics of Collective Violence (Cambridge: Cambridge University Press, 2003); C. Veiga,’The body’s civilisation/decivilisation: emotional, social, and historical tensions’ Paedagogica Historica 54 no. 1–2 (2018): 20–31.\n\n21 H. White, Metahistory: The Historical Imagination in Nineteenth-century Europe (Baltimore-London: The Johns Hopkins University Press, 1973). The categories (like tragedy, romance, modes of arguments) of this influential work fit very well in my sources, which may be an evidence of the literary abilities of the colonels.\n\n22 E. H. Tamura, ʻNarrative History and Theory’, History of Education Quarterly 51, no. 2 (2011): 150–157.\n\n23 ʻKónya Albert felterjesztése’ [Memorandum of Albert Kónya] XIX-I-2-n. 8. d. 123/1957, 14 February 1957, MNL OL.\n\n24 A. I. Solzehnitsyn, The Gulag Archipelago, 1918-1956. An Experiment in Literary Investigation (New York: Harper-Perennial Classics, 2002), 4.\n\n25 ‘A tanári kar nyilatkozata’ [Statement of the teaching staff], In ʻKónya Albert felterjesztése’ [Memorandum of Albert Kónya] XIX-I-2-n. 8. d. 123/1957, 14 February 1957, MNL OL.\n\n26 ʻJelentés az 1957. évi február 20-i Békés megyei kiszállásról’ [Report on a trip in Békés county on 20 February 1957] XIX-I-2-j. 4. d. 21 February 1957, MNL OL.\n\n27 Ibid.\n\n28 Ibid.\n\n29 ʻJelentés a pedagógusok közt végzett politikai és szakszervezeti munkáról’ [Report on political and trade-union work amongst teachers] MSZMP KB APO [Department of Agitation and Propaganda at the Central Committee of HSWP], M-KS 288-22, 21 March 1957, MNL OL.\n\n30 ʻTájékoztató a KB Agit. Prop. Osztályon tartott értekezletről’ [Information about the Session at the Central Committee Agitation and Propaganda Department] MSZMP KB APO, M-KS 288-22, 12 June 1957, MNL OL.\n\n31 ʻFeljegyzés Kónya Albert művelődésügyi kormánybiztos elvtárs részére’ [Notes to Comrade Albert Kónya, commissioner for education] XIX-I-2-j. 4. d. 25 February 1957, MNL OL.\n\n32 ʻMelléklet – Jegyzőkönyv Nagy Imre orvostanhallgató bejelentéséről’ [Appendix – Minutes of the notification of Imre Nagy medical student] XIX-I-2-j. 4. d. 3571/1956, MNL OL.\n\n33 Ibid.\n\n34 A miskolci „Tizes honvéd” karhatalmi zászlóalj története [The history of Miskolc Battalion no. 10] HL MN KGY F. 1956, 11. d. 21. ő. e.; ʻFeljegyzés Kállai elvtárs részére’ [Notes to Comrade Kállai] XIX-I-2-j. 4. d. 26 February 1957, MNL OL; MSZMP Szervező Bizottság ülése [Meeting of the HSWP Organizational Committee] KS-288-6. 30 December 1956, MNL OL; R. Ungváry, ʻA megtorlás Miskolcon’ [Retiliation in Miskolc] Oral History Archive, Interview no. 120., made in 1987-1988. Retrieved from: http://mek.oszk.hu/01900/01937/html/szerviz/oha/ungmeg.htm\n\n35 A miskolci „Tizes honvéd” karhatalmi zászlóalj története [The history of Miskolc Battalion no. 10] HL MN KGY F. 1956, 11. d. 21. ő. e.\n\n36 Ibid.\n\n37 ʻFeljegyzés Kállai elvtárs részére’ [Notes to Comrade Kállai] XIX-I-2-j. 4. d. 26 February 1957, MNL OL.\n\n38 Ibid.\n\n39 MSZMP Szervező Bizottság ülése [Meeting of the HSWP Organizational Committee] KS-288-6. 30 December 1956, MNL OL. The original location is not here (see the date), this document was lost, intentionally or accidentally – every level of archival collections is incomplete in the year of 1956 and 1957 in Hungary.\n\n40 R. Ungváry, ʻA megtorlás Miskolcon’ [Retiliation in Miskolc] Oral History Archive, Interview no. 120., made in 1987-1988. Retrieved from: http://mek.oszk.hu/01900/01937/html/szerviz/oha/ungmeg.htm\n\n41 S. Fitzpatrick, ʻAscribing Class: The Construction of Social Identity in Soviet Russia’ The Journal of Modern History 65, no. 4 (1993): 745-770.\n\n42 Zs. Krahulcsán,’MUK és HUKUK. A politikai rendőrség és az 1957. tavaszi „provokációk”’ [We will start again in March and if you start again, you will get again. The secret police and „provocations” in 1957 Spring] Betekintő 1, no. 2 (2007). Retrieved from: http://www.betekinto.hu/sites/default/files/betekinto-szamok/2007_2_krahulcsan.pdf 28 April 2021.\n\n43 Only 8 secondary grammar schools remained in the maintenance of the Roman Catholic Church after the nationalisation, one in Kecskemét. R. Braham, Education in the Hungarian People’s Republic (Washington: US Government Printing Office, 1970), p. 77. Retrieved from: https://files.eric.ed.gov/fulltext/ED039635.pdf 28 April 2021.\n\n44 A kecskeméti honvéd tiszti karhatalom története [The history of Kecskemét armed forces] HL MN KGY F. 1956, 11. d. 3. ő. e.; R. Kerepeszki, ʻ”Az egyetem nem a tudomány, hanem a reakció és a jobboldali gondolat fellegvára”. Jobboldalinak minősített egyetemi szervezkedések 1945–1956 között’ [„University is not the citadel of sciences, but reaction and right wing ideology”. Uiversity organizations, qualified as right wing orientated between 1945 and 1956] in Búvópatakok. A jobboldal és az állambiztonság 1945–1989 [Underground streams: The right wing ad secret police, 1945-1989]. ed. K. Ungváry (Budapest: 1956-os Intézet-Jaffa, 2013), 293-319. There was a university based underground group in Szeged that time, called Turul Guard (Turul Gárda – turul bird was a symbol of the ancient Hungarians and the national identity), further investigations needed to see suspected connections between Szeged and Kecskemét.\n\n45 P. Kenez, The birth of the propaganda state. Soviet methods of mass mobilization, 1917–1929 (Cambridge: Cambridge University Press, 1985); M. Rolf, Soviet Mass Festivals, 1917–1991 (Pittsburgh: University of Pittsburgh Press, 2013). The Hungarian communist practice of mobilizing and manipulating masses followed the Soviet role model, methods and tools are very similar in the hands of Party members or revolutionists.\n\n46 A Szegedi Honvéd tiszti karhatalom története [The history of armed forces in Szeged] HL MN KGY F. 1956, 11. d. 10. ő. e.\n\n47 A miskolci „Tizes honvéd” … Language instructions and religious education were the two main battlefields in schools, Mindszenty, the head of Catholic Church was an emblematic person of anti-communism.\n\n48 I. Honvéd Forradalmi Ezred Parancsnokság története [The history of the Commandant of the 1st Revolutionary Regiment] HL MN KGY F. 1956, 10. d. 1. ő. e. Through the Regiment’s naming, the new power tried to sequester and confiscate the meaning and connotations of revolution from the real rebels – the battle continued on a verbal level.\n\n49 Ibid.\n\n50 J. Kornai, ʻ1956 in Hungary: as I saw it then and as I see it now’ Public Choice 187, no 1-2 (2020): 15-26. In his essay, the famous Hungarian economist tried to exceed the traditional dichotomy of revolution vs. counter-revolution, including the ideas and bias related to it.\n\n51 I. Honvéd Forradalmi Ezred Parancsnokság története [The history of the Commandant of the 1st Revolutionary Regiment] HL MN KGY F. 1956, 10. d. 1. ő. e.; 2. Forradalmi Ezred története [The history of 2nd Revolutionary Regiment] HL MN KGY F. 1956, 10. d. 2. ő.e.; Budai III. Forradalmi Karhatalmi ezred I. ker. századának története [The History of the Company in 1st District, Buda, 3rd Regiment] HL MN KGY F. 1956, 10. d. 5. ő. e.\n\n52 2. Forradalmi Ezred története [The history of 2nd Revolutionary Regiment] HL MN KGY F. 1956, 10. d. 2. ő.e.\n\n53 Ibid.\n\n54 I. Honvéd Forradalmi Ezred … 65. [1st Hungarian Revolutionary Regiment]\n\n55 Budai III. Forradalmi Karhatalmi ezred I. ker. századának története [The History of the Company in 1st District, Buda, 3rd Regiment] HL MN KGY F. 1956, 10. d. 5. ő. e.\n\n56 P. T. Webb, ʻRe-mapping power in educational micropolitics’ Critical Studies in Education 49, no. 2 (2008): 127-142.\n\n57 P. Borenich, ʻTörténetem … a Veszprém Megyei Rendőr-főkapitányság Politikai Nyomozó Osztályával (1957) [My story … With the Department of the Secret Police at the Veszprém County Police Headquarters (1957)]. Manuscript. Retrieved from: https://borenichpeter.hu/dokumentum-osszeallitasok-tenyfeltaro-riportok/83-tortenetem-a-veszprem-megyei-rendor-fokapitanysag-politikai-nyomozo-osztalyaval 28 April 2021. Security police, armed forces, police forces or state security have been mixing concepts in the discourses since then, because of overlapping functions and structures, especially in the years of 1956 and 1957.\n\n58 Ibid.\n\n59 Budai III. Forradalmi Karhatalmi ezred … I. Vida ed., Diák- és ifjúsági mozgalmak, 1956–1958 [Students Movements, 1956–1958] (Budapest: Gondolat, 2007), 35., 78-79. The location is maybe the Central Dormitory of the BME on the András Hess square, an iconic location related to the student movement.\n\n60 Budai III. Forradalmi Karhatalmi ezred …\n\n61 Ibid.\n\n62 2. Forradalmi Ezred századainak története [The history of Battalions of the 2nd Revolutionary Regiment] HL MN KGY F. 1956, 10. d. 3. ő. e.\n\n63 Ibid."
}
|
[
{
"id": "211274",
"date": "17 Nov 2023",
"name": "Antonio Francisco Canales Serrano",
"expertise": [
"Reviewer Expertise History of Education"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article deals with a very interesting topic and makes a relevant contribution to the field of study of the history of education and especially to the history of education under dictatorships. The use of previously unexplored sources, as well as their variety, is remarkable. I would like to make a single suggestion to the author. Is \"violence\" really the best term for the title? Wouldn't \"repression and control\" be preferable? Violence refers primarily to the use of physical force and this is not strictly the case here.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes\n\nIs the case presented with sufficient detail to be useful for teaching or other practitioners? Yes",
"responses": [
{
"c_id": "10591",
"date": "29 Nov 2023",
"name": "Lajos Somogyvari",
"role": "Author Response",
"response": "Yes, this is a good point: violence is a too narrow term in this sense, so I will change the title to: Repression and Control in the Education..., Just wait for the next reviews and collect their suggestions. Thanks! Lajos"
}
]
},
{
"id": "211272",
"date": "13 Dec 2023",
"name": "Michal Šimáně",
"expertise": [
"Reviewer Expertise History of Education",
"Pedagogy",
"History of Everyday Life"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe author's text reveals little or completely unknown facts from a critical period of contemporary Hungarian history. Through the historiographical approach of the history of everyday life, he provides some insights into the shape of education not only in the short period of the Hungarian Revolution, but especially in the period that followed the suppression of this revolution. Specifically, it traces the approximate period from the autumn of 1956 to the spring and summer of 1957. The topic may seem marginal from this point of view, but from the point of view of Hungarian history of education, it is one of the neuralgic points and therefore represents a very specific and significant topic. This is evidenced by the words of the author, who states in his text that even after more than half of a century since the events described, it is still a very sensitive issue for many (and not only for the witnesses of these events). Until now, it has essentially been a kind of a taboo. For this reason, I see the publication of the results of research on this topic as very beneficial. On the basis of the information presented in the text, I even believe that the study may contribute to a certain correction of the view of the issue that has been presented so far in Hungarian history of education. For this reason, the contribution of the text can be seen as very crucial as well. The paper is also valuable with regard to the sources and methodology used. In fact, the author works with sources that he discovered by chance and about which nothing has been known before. After all, without this \"luck\" this study could not have been produced.\nI also appreciate the fact that the author's methodological description is very extensive. This gives the reader a detailed insight into the methodological \"kitchen\" of the author and at the same time they can follow step by step how the author worked with different types of sources and how the whole text was created. The very detailed methodological description may have been deliberate, because it also allows an implicit understanding of certain limitations found in the study; for example, a certain \"fragmentation\" of the themes that construct the main part of the text. The author does not, as the reader might expect, focus on one area of education (e.g. primary education) and deal with it in depth, but, given the currently available sources (of which, I assume, there were only a limited number), he gives an insight into the different levels of education and rather \"shows\" the different approaches and procedures the repressive regime of the time used for its purposes. This also causes a certain \"episodicity\" of some of the stories described, or it may constantly raise new questions for the reader, which the text, even considering the availability of sources, cannot answer. Therefore, the study can also be considered a first step towards further in-depth research on the topic. The question is whether it will be possible to find new sources or living witnesses who would be willing to share with us more about the topic. This fact, among other things, raises another question. Namely, whether the author tried to find such witnesses himself and if so, how successful he was in this matter. From the text, unless I have missed something, this is not entirely clear.\nThe research results themselves are presented in the text in a very appropriate way. They are very suggestive and give the reader a very accurate picture of the everyday reality of the education sector in the period under review and the approaches and procedures that the repressive authorities chose to deal with the situations that arose. In this context, it is a bit of a pity that the author does not also attempt a more general view and summary in the conclusion. In fact, the results presented in the text not only illustrate the situation prevailing in the education system in Hungary at the turn of 1956 and 1957, but de facto show the elements typical of the functioning of totalitarian regimes. In other words, in this light, the text also extends beyond the borders of Hungary, thus undoubtedly acquiring an international dimension in addition to a regional one.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes\n\nIs the case presented with sufficient detail to be useful for teaching or other practitioners? Yes",
"responses": []
},
{
"id": "211271",
"date": "13 Dec 2023",
"name": "Iveta Kestere",
"expertise": [
"Reviewer Expertise History of education",
"particularly",
"history of education in the Soviet Union",
"education of New Soviet Man",
"visual propaganda in education",
"as well as childhood representations within museums."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article ‘Violence in the Education: The Post-Revolutionary Situation in Hungary (1956-1957)’ analyses an under-researched topic, namely the repressions in the field of education after the failure of the Hungarian anti-Soviet revolution of 1956. Lajos Somogyvári's source material is professionally retrieved, it is unique, it reveals to the reader the mechanism of how the totalitarian power dealt with its opponents by humiliating and physically influencing them. This study is another important contribution to the history of 20th century’s totalitarianisms. The focus of the study is revealed by the four research questions, the methodology and the sources used are clearly presented. The author's ethical position, with respect for the actors of recent history, is to be commended. I have just some suggestions to make the text better understandable for an international audience. First and foremost, I would recommend that the author prefaces the article with more background information on the events in Hungary in 1956-57, such as how Hungary came to the Soviet sphere of influence, why the revolution or uprising of 1956 against the existing government started, what forces initiated and led the uprising, what the rebels wanted, and how the uprising was put down. Secondly, I suggest to consider some concepts that the reader may not be familiar with: for example, “After the end of socialism” (p.3) Here I suggest using a more familiar term, such as the collapse of the Soviet Union or the collapse of the Socialist Blok. “Reformer communists” (p.5), “Party apparatchiks” (p.6) and “pioneer patrols” (p.10): the text should explain what they were. “…the loyal members of the new power” (p.8) What is meant by \"the new power\" here? Third, I think that the rich material gives rise to broader conclusions that should be more clearly linked to the research questions on page 4. The valuable thoughts expressed in the conclusion section of the summary may also be useful. Admittedly, the meaning of some expressions in the text is not very clear: “came from the contemporary authentic party and military documents” (p.3), “the last stage of socialization has been depicted in agriculture” (p.3), “the special armed troops visiting schools armed groups”(p.3.), “agents of real communism” (p.5), “real hard-core communism” (p.5), “between form teachers and students” (p.9). As there are some other parts of the text that are difficult to read or can be misunderstood, perhaps the services of a proofreading could be helpful here. Some technical notes. I recommend that links to archive material should not be included in the text, but only in footnotes. Is Figure 1 (p.5) necessary? The research process is well described in the text and does not appear to be so complex as to need a scheme. With a few shortcomings addressed, the article by Lajos Somogyvári will certainly be a valuable asset for the international audience of researchers in recent history and totalitarianism, as well as historians of education.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly\n\nIs the case presented with sufficient detail to be useful for teaching or other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1244
|
https://f1000research.com/articles/12-1239/v1
|
28 Sep 23
|
{
"type": "Research Article",
"title": "A bibliometric analysis of publication output in selected South American countries",
"authors": [
"Aparna Narayan",
"Bharti Chogtu",
"Manthan Janodia",
"Raghu Radhakrishnan",
"Santhosh K. Venkata",
"Aparna Narayan",
"Bharti Chogtu",
"Manthan Janodia",
"Raghu Radhakrishnan"
],
"abstract": "Research output provides an insight into the development of the scientific capability of a country. Budget allocation for research and development (R&D) is directly proportional to the research output of a country. Bibliometric analysis of South American countries has not been done in many studies. The purpose of this paper was to analyse research outputs from South American countries on various metrics. An analysis was done for a period of 11 years from 2010 to 2020. The analysis revealed that Brazil with highest percentage of research spend has lowest Field Weighted Citation Impact (FWCI). This contrasts with Uruguay, whose FWCI is high despite comparatively lower spend on R&D and lower publication output. Although Argentina has the highest percentage of researchers per million population (1202), it has the least papers per researchers (0.3 per year) among the countries studied. A huge disparity in terms of percentage of research spent, research output, papers per researcher, and output with national and international co-authorship was observed.",
"keywords": [
"South America",
"Publications",
"Citation",
"Research",
"GDP",
"FWCI"
],
"content": "Introduction\n\nThe research output of any country is an important indicator of its progress and knowledge development. It is imperative to assess the priority given to improving the R&D culture among the scientific community. Scientists in most countries receive varying proportions of funds from numerous sources and funding agencies mandate that the outcomes of the research is shared globally and has a societal impact. Dissemination of research transpires through publication in scientific journals which have high impact among the scientific community. Research through collaborations – institutional, national, and international – lead to cross pollination of ideas and magnifies research visibility. The USA is traditionally considered to be a hotspot of academic research. Mervis (2017) has reported that since 2012, the share of basic research funding in USA has decreased whereas corporate funding has significantly increased.\n\nAccording to World Bank data, research expenditure as a percentage of Gross Domestic Product (GDP) has increased from 0.57 in 2000 to 0.80 in 2015 in Latin America and the Caribbean. In the study by Zacca et al., 2014 have reported that the bibliometric analysis of South America’s scientific output in the field of public health is less than half the global average in terms of number of publication and citations, low visibility and fewer collaborations are cited as the reasons of the same. Ciocca & Delgado (2017) have discussed the limitations that research faces in South American countries including an insufficient budget, poor infrastructure, the high cost of scientific material, and other uncertainty among scientists. In a recent study presented by (Estenssoro et al., 2016) Brazil proposed strategies to freeze of their research budget up to 42% of the total budget in 2019. A study by Angelo (2019) reported that international collaboration is prudent in all sectors of production, including scientific output, and plays an important role in magnifying research visibility. Brazil, Mexico, Chile, and Argentina are the main countries in South America with high research outputs. One of the challenges faced by researchers is their lack of fluency in the English language, which makes it difficult for them to collaborate with researchers in the USA and Europe (Coronel et al., 2011). Notwithstanding these shortcomings, a study by Packer and Meneghini (2006) for Latin American and Caribbean Centre on Health Sciences Information (BIREME)/Pan American Health Organization (PAH O)/World Health Organisation observed that articles published by authors from Brazilian institutions with more than 100 citations, received more citations for papers published with international collaborations (84.3%) than Brazilian institutions alone (15.7%). Glänzel et al., (2006) and Koljatic & Silva (2001) have provided scientific output from Brazil and South American countries in the fields of economics and business administration. Hermes-Lima et al., (2007) noted that South America’s research publications increased from 1.8% in 1991-1995 to 3.4% during 1999-2003.\n\nScientific and technological policies in Argentina have aimed to create knowledge to solve local issues such as social, productive, and environmental problems. A study by Miguel et al., 2015 found that more than 25% of research output in Argentina addressed local topics of interest, including social sciences, economy, management, agricultural and biological sciences, earth and planetary and environmental sciences, published mostly in foreign journals. In recent years, owing to geopolitical instability, research in Argentina has suffered due to financial austerity by the government which led to a reduction in science funding by 40% between 2015 and 2018 (Catanzaro, 2018). In the study by Cross et al., 2017 have reported that globally, Brazil ranked thirteenth in terms of research publications produced between 2011 and 2016 and is the only South American country to feature among the top 20 countries publishing most research papers worldwide, spending approximately USD 20 billion (79.2 billion reais) on research in 2016 (Faleiros, 2018). Chile has seen growing anger among its scientific community due to the lack of government funding (Bajak, 2017). Colombia, on the other hand, proposed the creation of a Ministry of Science, Technology, and Innovation in 2018 to address concerns about research funding (Bajak, 2018), which was voted for by the country’s senate. This move is expected to improve scientific priorities in the country (Wight, 2019). Study by Jose and Michael, 2018 have reported that Ecuador’s government has implemented policies to boost scientific productivity in recent years, with the country’s research productivity improving 5.16 times more between 2006 – 2015.\n\nBibliometric analysis of publication outcomes of authors from Latin America publishing during the period 1989 to 2018, in topics related to epilepsy, is reported by Morán-Mariños et al., 2020, the published paper describes the scholarly output and citations outcomes of those publications during the period 1989 to 2018. A study by Alarcon-Ruiz et al. in 2019 reported that publication outcomes of Latin American countries in the form of scholarly outcomes, citations, collaborations, etc., are presented for the period 2003 to 2017 in stokes topic, it was seen from the published data that the publication number and collaboration has been increasing and citation numbers are following the increment with the lower rate. A detailed presentation of publication data related to the subject area of Energy for the Latin American region is reported by Araújo and Costa, 2016. This work presented the details related to publication outcome from Latin American countries in the subject area of Energy. Bibliometric analysis in terms of number of publications, citation in the subject area of health reforms (Macías-Chapula, 2002) and Economics (Bonilla et al., 2015) is discussed in detail. Analysis of scientific research in the subject of physics at the institutional level of Latin America is reported by Luna-Morales et al., 2022), the study showed that over the years the publication outcomes in terms of numbers and citations are constantly increasing. Bibliometric and scientometric analysis of scholarly publication in the subject area of Science and Technology in Latin America is reported by Gonzalez-Brambila (2021) study involves understanding the publications number, citations and institutional breakup.\n\nA detailed study of LATAM publications in the areas of innovation in business, management, and accounting for the period 1983 to 2018 (Cortés-Sánchez, 2019) showed that Brazil and Colombia had more cited work compared to other countries in the region. Furthermore, it was seen that those publications co-authored with non-LATAM authors had the highest impact in terms of citations and h-index. A bibliometric study by Bonilla et al. (2015) on the quantitative output of publications in the field of economics from Latin American countries using the Web of Science database for the period 1994 to 2013 showed that Brazil, Mexico, Chile, Argentina and Columbia have significant numbers of publications in the area of economics. It was also seen that publication numbers have been increasing significantly over the last five years. Bibliometric analysis of research on health inequalities was carried out in Latin American and Caribbean countries (Almeida-Filho et al., 2003) using the indexed publication published between 1971 and 2000. The results reported publication growth in countries like Brazil, Chile, and Mexico. Analysis of publications indexed in the Scopus and Web of Science databases between 1987 to 2016 (Tello Gamarra et al., 2018) showed that growth in publications over this period in Latin America was not significant, relative to other parts of the world.\n\nRecently, there have been many collaborative studies with countries like the United States, Spain, and the United Kingdom. Analysis of the Scopus database under the category “Public Health, Environmental and Occupational Health” for the period 1996-2011 in the region of Latin America (Zacca-González et al., 2014) presented this in terms of citation, publication numbers, co-authors, and collaborations. A study reported by Teixeira, 2014 provided descriptions of the evolution, function, and influence of the National Systems of Innovations in these Latin countries and analyzed the literature published during the period 2006-2010. Analysis of publications from 2000-2017 in Social Science Citation indexed journals on the theme of corporate social responsibility in Latin America was presented by Jaén et al., 2018 and helped in identifying several key areas of industrial concentration in the Latin American region. A bibliometric study of scientific journals to understand the influence of internationalization in science by (Zitt & Bassecoulard, 2004). Capobianco et al., 2019 reported the use of Scopus indexed publications from the period 1983-2017 for the analysis, to show the effect on publication quality and other metrics in the context of national and international competitiveness. Another analysis of publication impact on documents published during the period of 2002 to 2016 in Web of Science indexed journals was presented by Ahmad et al., 2018. This presented a detailed discussion of citation analysis, the profiles of journals, the countries contributing, the type of documents published and subject in which the journal is publication. Though material sciences are a growing research field in Uruguay, they are still underrepresented as compared to global average (Aguiar et al., 2018). Given its share of the world population and GDP, publications from South America are still fewer than what might be expected (Van Noorden, 2014). Elango et al., 2021 report analyses the publication outcome in terms of scholarly output and citations from India and South Korea. Islam and Roy, 2021, presented the improved research productivity in terms of publication numbers from Bangladesh during the period 1971-2020.\n\nDespite the challenges, South American countries have witnessed an economic growth in the last two decades leading to enhanced investments in R&D, eventually translating into increased publications from research, few studies have attempted to understand the scientific publication landscape of South America in recent years as certain changes have occurred. There is a need to understand the change in the research metrics with changes happening at the global level. The research analysis of Latin American countries will give us an insight into the publications, citations, FWCI, research spent and international collaborations. From the background study reported by different researchers it is clear that the bibliometric study is important to understand the publication phenomena across the country, this data can be further used for strategizing or policy formation at the country level.\n\nWith this background, this paper aimed at analyzing the research output of South American countries and correlating the percentage of research spend to research output and to research output per million population, Field Weighted Citation Impact (FWCI), papers per researcher, and research output within different subject categories. The study aims at comparing these metrics between the countries in this region. The correlation between R&D spent and research outcomes have been analyzed and how these numbers are changing over the years. Also this article focuses on how the different countries in this region work in different research areas and the impact of internationalization on research quality. Overall, this study aims to summarize the research contributions of seven major South American countries based on their overall research contribution.\n\n\nMethods\n\nData were extracted from one of the largest abstract and citation databases of peer-reviewed literature; Scopus and its affiliate SciVal. The ranking agencies, Quacquarelli Symonds (QS) and Times Higher Education (THE) provide global and regional ranking of universities based on scientific output in these citation databases. Furthermore, Scopus and SciVal provide options to retrieve various scientific parameters through certain permutations and combinations for each country as well as for the region. All types of articles, such as journal papers, conference proceedings, and book chapters were considered for analysis rather than concentrating solely on journal papers. Since book chapters and conference proceedings can also be cited, these article categories were retained for analysis. Publication analysis was carried out in terms of trends in publication, citation, relation between publication outcomes across LATAM countries, subject wise trend analysis of publication for a period of eleven years from 2010 through 2020.\n\nThe search string with regard to publication during the period 2010 to 2020 is used to understand the publication trends, citation trends, collaboration trends, quality publications trends across various subject areas like Arts & Humanities, Engineering & Technology, Life Sciences & Medicine, Natural Sciences and Social Sciences.\n\nWorld Bank Indicators for identifying research expenditure as a percentage of GDP, researchers per million population, and total scientific output were used. The latest data related to research expenditure by the countries, population data, researcher population data are extracted from the available world Bank indicators were captured for the analysis.\n\nSelection of countries for analysis\n\nSeven countries were selected for analysis based on certain parameters, such as total population, research output in a given year, research expenditure as a percentage of GDP spent by the countries, and publications with national and international collaborations. Based on predefined criteria, Argentina, Brazil, Chile, Colombia, Ecuador, Mexico, and Uruguay were selected. Venezuela and Cuba were excluded due to the current political situations in those countries. The remaining South American countries were excluded as they did not meet the predefined criteria above.\n\nResearch spend versus research output\n\nThe analysis of scientific disciplines was based on subject categories. Publications are divided into different subject categories in Scopus. Around 300 subject categories are used within the five major subject areas namely Art and Humanities, Engineering and Technology, Life Science and Medicine, Physical Science and Social Science and Management. The subject categories were classified based on the QS and THE, however, several similar categories (with name variations) were combined for ease of analysis. QS provides five subject categories, while THE provides for eleven subjects. The five major subject areas referred to above were used for carrying out analysis of publication of in terms of number of publication, citation received during the period of study, international collaboration publications and its output, publications in the top quartile journals.\n\nSelection of countries for analysis\n\nIt could be deduced from this analysis that Brazil has the highest percentage of research spend and the lowest Field Weighted Citation Impact (FWCI) among the South American countries studied. Contrary to that, Uruguay has a lower percentage of research spend than all other countries, except Colombia, but it exhibited the highest FWCI. Uruguay has around 645 researchers per million population according to World Bank data compared to 900 researchers per million population for Brazil.\n\nThis shows that despite fewer researchers per million population, the FWCI of Uruguay is significantly better. From the Figure 1, Figure 2 and Figure 3, it is clear that the difference in the total number of scientific articles published from Brazil and Uruguay is great. In 2014, Brazil collectively published 53,606 articles compared to a total of 809 articles published by Uruguay. R&D expenditure as a percentage of GDP for Brazil in 2015 was 1.27%, compared to 0.36% for Uruguay. Chile spent 0.36% (2016), Colombia 0.27% (2016), and Ecuador 0.44% (2014) of their GDP on R&D. The percentages of GDP spent on R&D by Argentina and Mexico were 0.63% (2015) and 0.50% (2016) respectively, as shown in Figure 1, which were higher than many other Latin American countries, aside from Brazil. The amount spent on research by Brazil is quantitatively proportional to output in terms of the total number of research publications, but it is inversely proportional to FWCI. This contrasts with Uruguay, whose FWCI is high despite comparatively lower spend on R&D and lower publication output. The research outputs of Argentina and Mexico are proportional to the percentage of research spend as shown in Figure 2. Chile has 502 researchers per million population, Colombia has 131, Uruguay 645, and Mexico 245.\n\nNumber of researchers versus quality of publications\n\nAs seen in Figure 3, among the countries studied, despite having the highest number of researchers per million population (1202), Argentina has the least papers per researcher (0.3 per year). Although R&D spend by Colombia is lower and there are less researchers per million population, the figures for papers per researcher is 2.9 per year, which is the highest of all the countries studied. This is followed by Chile (1.7 per year) even though it has the lowest percentage of GDP spent on research. Brazil has the highest percentage of research spend and 0.5 papers per researcher per year. Uruguay and Mexico have 0.7 and 0.6 papers per researcher per year, respectively. Research output is not proportional to the percentage of GDP spent on research as represented in Figure 4. From the data projected in Figure 4 expenditure on research is not directly propositional to the output of research by the country. Research spending should be combined with strategies to help increase output per researcher by other means such as collaborations that emphasize publishing in high quality journals.\n\nNational collaborations have accounted for an improved FWCI for Uruguay whereas it has not led to improved FWCI for Brazil. Uruguay, with 650 researchers per million population, and a 0.44% GDP spend on R&D, achieved a higher FWCI than Colombia, Chile, Mexico, and Argentina. Carefully crafted national collaborations are an important parameter for improved research output as well as research visibility. Uruguay, Ecuador, and Chile have better FWCI with international collaborations. Uruguay has a better FWCI than Ecuador, which has a smaller percentage of international collaboration although this is greater than that of Chile. Notably, Brazil has the least international collaboration leading to the worst FWCI of the countries. The data show a direct correlation between international collaboration and FWCI.\n\nImpact of collaborations on research output\n\nIn this study, the analysis aims to understand the impact of collaboration as a signifier of research outreach. It has been observed that Brazil has the highest quantum of publications with national collaborations (36.3%), followed by Argentina (31.8%), Mexico (28.2%), Colombia (19.2%), Chile (16.3%), Ecuador (10.3%) and finally Uruguay (7.9%), having the least number of national collaborations is shown in Figure 5a.\n\nInternational collaboration refers to publications with at least one author having an affiliation outside the home country. The impact of this collaboration is analyzed and represented in Figure 5b. It is apparent that during 2010-20, Ecuador produced the largest percentage of publications with international co-authorship (65.7%), followed by Uruguay (64.4%), Chile (57.1%), Colombia (46.2%), Argentina (42.8%) and Mexico (40%). Brazil (29.5%) had the least number of international co-authored publications.\n\nTo understand the impact of these publications, the FWCI was compared with the collaboration. Although Brazil has the highest percentage of national collaborations, it has the least international collaborations and the lowest FWCI (0.76) in comparison to all other countries. Ecuador has the highest FWCI (1.71) with greater international collaboration at around 65.7%. Uruguay with international collaborative work of 64.4% and an FWCI around 1.66. It was also noted that the countries with higher international collaboration have higher citation impact.\n\nCitation impact of South American research output\n\nCitation impact of the South American countries is analyzed in Figure 6(a) and Figure 6(b). Figure 6(a) compares publication output in the top 10% of journals versus citations per paper, which reflects the quality of publication. Publication from Uruguay has the highest citations per paper of 17.9, while citation per paper for Ecuador has lowest c/p at 11.1; publication from Argentina has citations per paper of 15. Publication from Chile has 15.9 citations per paper compared to 12.4 for Mexico. Figure 6(b) represents citations per paper with FWCI for each country. Uruguay has the highest citations per paper (17.9) with the highest FWCI of 1.34; Ecuador with the least citations per paper 11.1 has FWCI of 1.1. Countries like Mexico, Argentina, and Chile follow a similar trend – Mexico with 12.4 citations per paper has 0.92 FWCI, Argentina has 15 citations per paper with 1.05 FWCI, and Chile has 15.9 citations per paper with 1.19 FWCI. Colombia and Mexico show a different trend; Colombia has 11.8 citations per paper and a FWCI of 0.98 and Ecuador has 12.4 citations per paper with a FWCI of 1.1. These details clearly establish the direct correlation between FWCI and citations per paper, i.e., the higher the citation per paper, the greater the FWCI.\n\nSubject area analysis\n\nTable 1 shows the outcomes of countries in the subject areas for the period 2010-20. The majority of the publications (35-50%) are in the subject areas of Life Sciences and Medicine, with a similar trend seen for all countries studied. The least number of publications is in the Arts and Humanities, which is around 1% to 5% across the LATAM countries. Ecuador and Colombia produce more papers in Engineering and Technology whereas Argentina, Chile, Mexico, and Uruguay produce more publications in Physical Sciences. Brazil’s outcome is almost similar in both these subject areas. Social Science and Management publications are the fourth largest among all countries, with a similar share of publications (around 10-12%). Chile produces a large percentage of Arts and Humanities publications while Brazil produces the least. Similarly, Uruguay produces a large percentage of Life Sciences and Medicine publications, and Chile has the least. It is of note that South America has about 45% of publications in the subject category Life Science and Medicine against a global trend of 35% whereas the total publication output in the subject category Engineering and Technology is less in South America (20%) compared to global figures (28%).\n\nFigure 7 to Figure 11 depict the percentage of international collaboration by the size of the bubble (i.e., the larger the bubble, the more international collaboration). The countries subjected to analysis show a better FWCI in the subject areas of Life Sciences and Medicine as compared to Arts and Humanities which has the lowest FWCI.\n\nAmong the subject categories, Ecuador’s FWCI is highest in Arts, despite lower scholarly output. A plausible explanation is that this is due to the high number of publications through international collaboration. Brazil has the least FWCI in the subject category of Arts, which is lower than the average across Latin America. Uruguay’s FWCI is less than Chile, Colombia, Mexico, and Argentina. However, the FWCI of these four countries in the subject category Arts is better than the average for the region. Similarly, for the subject category Engineering and Technology, Ecuador and Chile have higher FWCI despite lower scholarly output compared to Brazil, Mexico, Columbia, and Argentina. Uruguay’s performance is better in the subject category Life Science and Medicine, and is followed by Ecuador, Chile, Argentina, Colombia, and Mexico. Brazil appears last in the list. Ecuador, Chile, Colombia, and Argentina perform better than Brazil, Uruguay, and Mexico in the subject category Physical Sciences. In Social Science, Chile has the highest FWCI compared to Ecuador, Uruguay, Mexico, Argentina, and Brazil. Notable performance for Ecuador, Uruguay and Chile could be attributed to their improved international collaborations compared to their counterparts.\n\n\nConclusion\n\nThe research outcomes of a region provide an insight into the focus on knowledge building and working towards societal challenges. These metrics provide information about the quality of higher education and the amount of research spent which further gives an idea about the commitment of government towards progression of science and development. Bibliometrics is one of the ways in which research outcomes can be quantified. Bibliometric data includes information related to number of publications, quality of publication, which is a direct indicator for the research spent, human resource available, government policies on research and development. One of the metrics explored in this analysis is collaborative publication which is an indicator of how the authors and researchers are open to collaborate with different countries and target global challenges in addition to their local and national challenges.\n\nIn the work presented a detailed bibliometric study of south American countries (LATAM countries) namely Argentina, Brazil, Chile, Colombia, Ecuador, Mexico and Uruguay has been done. A detailed analysis was presented about the publication outcome of all the above countries during the period 2010 to 2020 in Scopus indexed journals. The study also presented a detailed analysis of the research outcome in terms of scholarly output, citations per publication, Field Weighted Citation Impact, Citation count. An analysis about the collaboration of researchers across the globe is presented with reference to collaborative publications. The publication outcomes were also analyzed based on the journal subject area which gives us an understanding of the research focus areas in this region. A huge disparity in terms of percentage of research spend, research output, papers per researcher, and output with national and international authors has been found. Higher research spent can improve the quality of publications and thereby citations but paradoxically a positive correlation has not been observed between research spent and increased FWCI. Brazil, with higher research spend, has lower research productivity while Chile, with lower spend on research has the highest figures for papers per researcher. Ecuador has the highest percentage of publications with international co-authorship while Uruguay has the highest FWCI and higher international collaborations. Chile produces a large percentage of Arts and Humanities publications whilst Uruguay produces a large percentage in Life Sciences and Medicine. FWCI of Ecuador is highest in Arts despite low scholarly output. As a global trend in this region also international collaborations have led to an increase in FWCI and greater research impact.\n\nThe countries need to focus on prominent areas of research and collaborate with other countries to increase the visibility of research. Individual nations should recognize their research expertise and work with researchers across the globe which applies more to small countries with low economies where the research spent is low.",
"appendix": "Data availability\n\nOpen Science Framework: LATAM\n\nhttps://doi.org/10.17605/OSF.IO/FU3QC (Santhosh et al., 2023)\n\nThis project contains the following underlying data:\n\n• Citation_top10.xlsx (description of file)\n\n• FWCI_Citation_National.xlsx: Citation data of all the LATAM countries\n\n• FWCI_publicationoutput.xlsx: FWCI data compared with publication of LATAM countries\n\n• FWCI_citation_Scholary.xlsx: FWCI data compared with publication and citation of LATAM countries\n\n• FWCI_Publicationoutcome_Arts.xlsx: FWCI data compared with publication and citation of LATAM countries in arts & Humanities subject area\n\n• FWCI_publicationoutcome_Eng.xlsx: FWCI data compared with publication and citation of LATAM countries in Engineering & Technology subject area\n\n• FWCI_publicationoutcome_life.xlsx: FWCI data compared with publication and citation of LATAM countries in Life Science & Medicine subject area\n\n• FWCI_Publicationoutcome_Natural.xlsx: FWCI data compared with publication and citation of LATAM countries in Natural Science subject area\n\n• FWCI_publicationoutcome_Social.xlsx: FWCI data compared with publication and citation of LATAM countries in Social Science subject area\n\n• NationalCollaboration_FWCI.xlsx: FWCI data compared with National collaboration of LATAM countries.\n\n• Internationalcollaboration_FWCI.xlsx: FWCI data compared with international collaboration of LATAM countries\n\n• working.xlsx: LATAM bibliometric data\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Universal).\n\n\nReferences\n\nAhmad K, Ming ZJ, Rafi M: Assessing the digital library research output: bibliometric analysis from 2002 to 2016. 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Science. 2017; 10. Publisher Full Text\n\nMiguel S, Gonzalez C, Chinchilla-Rodriguez Z: Local and global issues in the Argentinian scientific production in Scopus, 2008-2012. National and international dimensions of the research/Lo local y lo global en la producción científica argentina con visibilidad en Scopus, 2008-2012. Dimensiones nacionales e internacionales de la investigación. Información, Cultura y Sociedad. 2015; (32): 59–79. Publisher Full Text\n\nMorán-Mariños C, Pacheco-Mendoza J, Metcalf T, et al.: Collaborative scientific production of epilepsy in Latin America from 1989 to 2018: A bibliometric analysis. Heliyon. 2020; 6(11): e05493. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPacker AL, Meneghini R: Articles with authors affiliated to Brazilian institutions published from 1994 to 2003 with 100 or more citations: I-the weight of international collaboration and the role of the networks. An. Acad. Bras. Cienc. 2006; 78: 841–853. PubMed Abstract | Publisher Full Text\n\nTello Gamarra J, Machado Leo R, Silva Avila AM, et al.: Innovation studies in Latin America: a bibliometric analysis. J. Technol. Manag. Innov. 2018; 13(4): 24–36. Publisher Full Text\n\nTeixeira AA: Evolution, roots and influence of the literature on National Systems of Innovation: a bibliometric account. Camb. J. Econ. 2014; 38(1): 181–214. Publisher Full Text Reference Source\n\nVan Noorden R: South America: by the numbers. Nature. 2014; 510(7504): 202–203. Publisher Full Text\n\nWight AJ: Colombia creates its first science ministry. Nature. 2019; 565(7737): 273–274. PubMed Abstract | Publisher Full Text\n\nZacca-González G, Chinchilla-Rodríguez Z, Vargas-Quesada B, et al.: Bibliometric analysis of regional Latin America's scientific output in public health through SCImago journal & country rank. BMC Public Health. 2014; 14(1): 1–11. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZitt M, Bassecoulard E: Internationalisation in science in the prism of bibliometric indicators. Handbook of quantitative science and technology research. Dordrecht: Springer; 2004; (pp. 407–436). Publisher Full Text"
}
|
[
{
"id": "221512",
"date": "22 Nov 2023",
"name": "Muhammad Imran",
"expertise": [
"Reviewer Expertise Surgery",
"general surgery",
"surgical oncology",
"breast",
"thyroid",
"trauma",
"colorectal",
"medical education",
"curriculum",
"assessment"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbstract: The abstract discusses the correlation between research output and the scientific capability of a country, emphasizing the direct proportionality between budget allocation for research and development (R&D) and a country's research output. Notably, the study fills a gap by conducting a bibliometric analysis specifically focused on South American countries, a region less explored in previous research. The abstract hints at a significant disparity in various research metrics, including research spending, output, papers per researcher, and collaborative efforts, both nationally and internationally.\nIntroduction: The introduction provides a comprehensive overview of the significance of research output as an indicator of a country's progress and knowledge development. It effectively highlights the global importance of R&D culture, funding sources, and the dissemination of research through publications. The inclusion of key statistics, such as the World Bank data on research expenditure in Latin America and the Caribbean, adds credibility and context to the study. The reference to specific studies addressing the challenges faced by South American countries in research, funding, and international collaboration establishes a strong foundation for the subsequent analysis. The article's rationale effectively establishes the importance of understanding the scientific capability of countries through research output. The assertion that budget allocation for R&D is directly proportional to research output provides a clear justification for the study. The decision to focus on South American countries adds novelty, addressing a gap in existing literature where bibliometric analysis in this region has been limited. The research question is well-defined and aligns with the stated purpose of the paper.\n\nMethods: The methods section is clear and detailed, outlining the data sources, selection criteria for countries, and search strategies. The decision to include various types of articles, such as journal papers, conference proceedings, and book chapters, enhances the inclusivity of the analysis. The study's focus on trends in publication, citation, and collaboration across different subject areas for an 11-year period ensures a thorough and comprehensive analysis. Figures and tables are appropriate and reflect the findings in an elaborative way.\n\nThe findings section provides a detailed and insightful analysis of the research output and collaboration patterns of the selected South American countries. The use of visual representations, such as figures and tables, enhances the clarity of the presentation. The examination of research spend versus output, the impact of collaborations on research quality, and the citation impact of South American research output adds depth to the study. The identification of disparities between research spend and output, as well as the correlation between international collaboration and research impact, offers valuable insights.\nConclusion: The conclusion succinctly summarizes the key findings and emphasizes the importance of bibliometric analysis in understanding the research landscape of South American countries. The acknowledgement of disparities and the recommendation for countries to recognize their research expertise and collaborate globally provide a thoughtful conclusion. The section effectively ties back to the initial rationale, reinforcing the significance of the study in informing strategic decisions and policies at the country level.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "212601",
"date": "04 Dec 2023",
"name": "Kishor Chandra Satpathy",
"expertise": [
"Reviewer Expertise Library Management",
"Digital Library",
"IR",
"Innovative Library Space",
"Bibliometric Studies",
"Archival Studies",
"and Library Outreach Activities"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbstract: The study provides a concise bibliometric overview of the research output and scientific temper of the seven major South American countries (LATAM) based on various metric indicators during 2010–2020. The data shows notable differences between these nations on a number of indicators. In doing so, the study aims to close the knowledge gap in the less-explored areas, which may be useful for allocating resources and making numerous other policy decisions pertaining to the Latin American region.\nIntroduction: The study offers background data and a global scenario of research output measures, which serve as the main catalysts for national R&D cultures. It contains a fair overview of the relevant literature, with an emphasis on the relationship between South American countries' research output and their R&D spending. It is noteworthy that during the past 20 years, there has been economic expansion, which has raised R&D expenditures and, in turn, raised research output. As a result, the study emphasized how internationalisation affects both the volume and caliber of research conducted in this field. Though research output has increased, the analysis shows a dearth of publications that highlight the South American countries' research landscape, which justifies the rationale and scope of the study. The study also focuses on how the countries perform in various research arenas and the impact of internalization of research quality and quantity thereof. The research query is well-defined, provides insight into the publications, citations, FWCI, research expenditures, and collaboration scenarios of Latin American countries, and clearly aligns with the scope and objectives of the study.\nMethods: This section addresses topics such as a broad summary of the data sources, search techniques, and criteria for selecting nations within the parameters of the study's aims and scope. The decision to include journal articles, conference proceedings, book chapters, and other types of documents from a variety of subject areas during the designated time period is also incorporated. The relevant figures and tables provide an elaborative representation of the findings. A thorough and perceptive study of the research output and partnership patterns of the chosen South American countries is given in the findings section.\nThe use of visual representations, such as figures and tables, enhances the clarity of the presentation. The examination of research expenses versus output, the impact of collaborations on research quality, and the citation impact of South American research output add depth to the study. The identification of disparities between research spending and output, as well as the correlation between international collaboration and research impact, adds valuable insights.\nConclusion: It summarizes the major findings with respect to the stated research queries of the study in the context of the research landscape of the LATAM countries based on the Scopus output, and it will contribute to the existing literature.\nComments: Title: Expressive Abstract: Precisely presented Language/Presentation: Excellent Objectives of the Study: Specifically mentioned. Literature Review: Included in the introduction section References: Rightly appended.\nOverall remarks: In general, the paper is well-written to highlight the less explored areas of LATAM countries. The findings might be used for strategizing policy formation at the country level. Overall, I see the potential for this study to contribute to the existing literature. The topic and the discussions are interesting.\nMay be considered for indexing.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "212600",
"date": "12 Apr 2024",
"name": "Manu T R",
"expertise": [
"Reviewer Expertise Research Data Management",
"Scholarly Communication",
"Open Access",
"Open Science",
"Consortia Access Management",
"E-Resources Management",
"Science Communication",
"Science Mapping",
"Marketing of Library Resources Services and Products"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary of the article The researchers have undertaken a study of bibliometric analysis of publications of selected LATAM countries to identify their research growth and analyzed with their research funding/spent, population growth/ researcher population of selected countries. The researchers identified the subject-wise trend analysis of publication for eleven years from 2010 through 2020. The SciVal, a Scopus sources were used to retrieve the required data for this study. In findings, researchers shown percentage research spent vs field weighted citation impact (FWCI), percentage research spent vs scholarly output, scholarly output per researcher, international collaboration, collaboration vs. weighted citation impact, citation impact of South American research output, subject area analysis, etc. to fulfill the mentioned objectives. It will benefit researchers, policymakers, and funders to analyze ROI in scholarly research output of these countries and focus on the less-funded research areas. In this manuscript, the researchers may consider addressing the following to make it more significant: Abstract\nData sources for support data can be specified in the abstract to make it clear and comprehensive from the beginning.\n\nIntroduction\n\nAdding the highlights on current expenditure on R&D and of the selected countries’ would add more value to this article. Growth of expenditure on R&D over a period from 2010 to 2020\nMethodology\nA clear definition of Field Weighted Citation Impact (FWCI) and weightage of different disciplines may be required in the methodology. It states that the latest data related to research expenditure by the countries, population data, and researcher population data are extracted, but the researchers have analyzed publications from 2010 to 2020. Not recent publications have been considered. Would it be correct to consider comparing the research expenditure or GDP of a particular year and the publication of the same year because research expenditure or GDP is also increased over the period? The same case can be applicable to compare the researcher population.\n\nCited References\nMost cited references are from prior to 2020. Only a few recently published citations are referred to. More recently published citations are required.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1239
|
https://f1000research.com/articles/12-554/v1
|
26 May 23
|
{
"type": "Research Article",
"title": "Suspension of zinc oxide nanoparticles (ZnO-NP) as an intraoperative wound irrigation to prevent infection after fracture fixation",
"authors": [
"Krisna Yuarno Phatama",
"Respati S. Dradjat",
"Edi Mustamsir",
"Dwi Yuni Nurhidayati",
"Dewi Santosaningsih",
"Dwikora Novembri Utomo",
"Mohamad Hidayat",
"Respati S. Dradjat",
"Edi Mustamsir",
"Dwi Yuni Nurhidayati",
"Dewi Santosaningsih",
"Dwikora Novembri Utomo",
"Mohamad Hidayat"
],
"abstract": "Background: Infection after fracture fixation (IAFF) associated with an implant in orthopaedic surgery is a feared complication, leading to non-union, loss of function, amputation, and even mortality and morbidity to the patient. A biofilm formation on the implant surface increases the difficulty of treatment. Therefore, surgical infection prevention with an effective antiseptic solution is required. This study aims to reveal more about the antibacterial effect of ZnO-NP suspension, particularly Staphylococcus aureus and its biofilm, in preventing surgical infection. Method: An in vitro experimental study with a posttest-only control group design was used to see the antimicrobial activity and inhibitory effect of Staphylococcus aureus biofilm formation between a 20% zinc oxide nanoparticle (ZnO-NP) suspension (20 mg/mL) compared to 0.3% povidone-iodine solution. The statistical result was tested using an independent t-test antibacterial activity. Meanwhile biofilm identification was evaluated using Mann-Whitney & Kruskal Wallis test for each group. Result: 20% ZnO-NP suspension has a minimum inhibitory concentration at 4 g/mL and a minimum bactericidal concentration at 16 g/mL, same as 0.3% povidone-iodine administration and its statistically significant (p-value 0.001). Minimum biofilm inhibitory concentration was seen at a concentration of 20% ZnO-NP suspension of 2 μg, while at higher doses, it showed lysis of bacterial cells. Conclusion: 20% ZnO-NP suspension is a promising solution for preventing surgical infection due to its antibacterial and antibiofilm effects.",
"keywords": [
"ZnO-NP suspension",
"Wound Irrigation",
"Staphylococcus aureus",
"Biofilm",
"Infection After Fracture Fixation"
],
"content": "Introduction\n\nInfection after fracture fixation (IAFF) related to an implant in orthopaedic surgery is a commonly feared complication, resulting in non-union, poor functional outcome until loss of function, amputation, and even mortality and morbidity to the patient.1,2 This complication also carries a meaningful socioeconomic burden because treatment takes a long time and has high cost.3 Staphylococcus aureus is the most common cause of surgical site infection.4 Surgical site infection occurs because the microorganisms and dead tissue debris attached to the wound surface form biofilms. The formation of biofilm and the resistance of the microorganisms that form it to antimicrobials cause this process to continue into IAFF. Furthermore, the biofilm formation on the implant surface increases the difficulty of treatment.5 Therefore, the prevention of surgical infection becomes essential.\n\nIntraoperative wound irrigation is one of the most important procedures for infection prevention. Normal saline is the most popular option because it is safe and acts as a diluent agent. However, normal saline does not have an antiseptic effect, so it cannot eradicate bacteria.6–8 Another option is povidone-iodine as an effective antiseptic. Unfortunately, an in vitro study showed that povidone-iodine could be toxic even at small concentrations and exposure duration of 1 minute.9 Because of the importance of intraoperative wound irrigation for infection prevention, a safe (non-toxic) and effective antiseptic solution is required.\n\nZinc oxide, especially in the form of a nanoparticle (ZnO-NP) suspension, appears to be very promising as a choice of intraoperative wound irrigation compared to non-antiseptic normal saline and toxic povidone-iodine.10 ZnO-NP is an effective antimicrobial material that damages the cell membrane of bacteria. Conversely, ZnO-NP is categorized as a safe substance to consume by the American Food and Drug Administration (FDA).11 This study aims to reveal more about the antibacterial effect of ZnO-NP suspension, particularly Staphylococcus aureus and its biofilm, in preventing surgical infection.\n\n\nMethods\n\nThis research was conducted between June and December 2022 at the Laboratory of Clinical Microbiology, Faculty of Medicine, Universitas Brawijaya – Clinical Microbiology Installation of Dr. Saiful Anwar General Hospital.\n\nAn in vitro experimental study with a posttest-only control group design was used to see the antimicrobial activity and inhibitory effect of Staphylococcus aureus biofilm formation between a 20% ZnO-NP suspension (20 mg/mL) and compared to 0.3% povidone-iodine solution as the positive control.\n\nThe sample of this study is an isolate of Staphylococcus aureus bacteria obtained from the clinical isolate in the Clinical Microbiology Laboratory, Faculty of Medicine, Universitas Brawijaya. The isolate was stored in temperature -20°C in Tryptic Soy Broth media (TSB – Merck 105459).\n\nIdentification of Staphylococcus aureus bacteria\n\nThe procedure used for the identification of Staphylococcus aureus was Gram staining. In this study, the isolate used was Staphylococcus aureus. Furthermore, the identification and test of antimicrobial sensitivity with the Vitek® 2 system method were carried out. The procedure used for gram staining is listed below:\n\n1. Glass objects (GEA 7105) were cleaned with cotton swab (Onemed size S) and passed over fire to remove fat or other substances, then left to cool for a while.\n\n2. The bacterial preparation was made on a glass object with one inoculation, allowed to dry in air, then fixed on a Bunsen lamp.\n\n3. The preparation was poured with crystal violet solution (Sigma-aldrich V5265), after one minute, the preparation was rinsed with water.\n\n4. A Lugol solution (MERCK 1.09261.1000) was poured into the preparation, after one minute, the preparation was rinsed with water.\n\n5. A 90% alcohol was poured into the preparation and rinsed with water after 5-10 seconds.\n\n6. After that, a safranin (Sigma-aldrich 94635) was poured into the preparation, after 30 seconds, rinsed with water.\n\n7. The preparation was dried with blotting paper (Ahlstrom-Munksjö Grade 240), then viewed under a light microscope (Olympus CX-21, USA) with 1000× magnification. It shows round purple and clustered bacteria identified as gram-positive cocci.\n\nAfter gram staining, the preparation was identified as gram-positive cocci, an antimicrobial sensitivity was performed using the Vitek® 2 system (Biomérieux, USA). It was a system to identify bacteria isolates using GP ID cards with faster and accurate bacterial identification.\n\nBacterial inoculation in nutrient agar plate (NAP)\n\nStaphylococcus aureus bacterial suspension was inoculated and placed in an incubator (Digisystem DSI-500D) that has been set for 24 hours at 37°C on Mueller-Hinton agar media (Sigma-aldrich 70191) to obtain separate colonies with four suspensions. The targeted bacterial concentration was 5 × 105 colony forming unit per millilitre (CFU/mL).\n\nAntimicrobial susceptibility test of ZnO-NP suspension and 0.3% povidone-iodine solution using broth dilution method\n\nThe broth dilution method was used to assess the antibacterial activity, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), of various antiseptic solutions. The principle of the broth dilution method is to expose the bacteria to be tested with a certain substance (in this study, an antiseptic solution). In general, the concentration of the solution used is a serial dilution multiple of two (2, 4, 6, 8, 10, 12, 14, 16 (μg/mL)). The first MIC value is the lowest ZnO-NP concentration, indicating a clear suspension. All 32 samples bacterial suspensions of various concentrations (2, 4, 6, 8, 10, 12, 14, 16 (μg/mL)) of ZnO-NP with four replication of each, were inoculated on Mueller Hinton agar and incubated at 37°C for 24 hours in an incubator that has been set (Digisystem DSI-500D) to determine the MBC value of ZnO-NP against Staphylococcus aureus. The MBC value is obtained when all bacteria are killed.\n\nBiofilm identification\n\nBiofilm formation was evaluated by inoculating Staphylococcus aureus bacteria cultured overnight plus tryptic soy broth (TSB – Merck 105459) into microwell in congo red agar plate. The congo red agar was made by infusing the congo red dye into mannitol salt agar (oxoid). After incubating for 24 hours at 37°C, the medium was rinsed twice using phosphate-buffered saline (PBS – Sigma-aldrich P4474) and then dried. The formation of biofilms is considered positive when a layer of violet crystalline colour appears on the walls and base of the tube, and the observation can be done by naked eye. The formation of rings at the level of the surface of a liquid is not considered meaningful in the formation of biofilms. MBIC from ZnO-NP suspension was assessed by evaluating biofilms formed on the surface of the microwell wall. Using the same method as the method for assessing the formation of biofilms, before incubation, a certain concentration of ZnO-NP suspension is added (1, 2, 3 μg/mL). Each concentration represents the intervention groups, rather than positive and negative control. A 1 μg/mL concentration of ZnO-NP suspension for group micro 1, 2 μg/mL concentration of ZnO-NP suspension for group micro 2 and 3 μg/mL concentration of ZnO-NP suspension for group micro 3. The ZnO-NP concentration is distinguished for the categorization of intervention groups. Then after the incubation is completed, staining is carried out, and the formed biofilm is evaluated using a scanning electron microscope (SEM - SU8600 Hitachi Europe) and based on optical density (OD) determined by an ELISA reader (Accuris Smartreader 96-T) with a wavelength of 630 nm (OD 630 nm). The lowest concentration that causes inhibition of biofilms on the surface of the microwell wall is considered to be MBIC. Meanwhile, concentrations without biofilm growth are considered minimum biofilm eradication concentration (MBEC) values.\n\nBiofilm assay\n\nIsolates from the microbiology lab, with a glucose TSB of 1% (Merck 105459). 200 μl or 0.2 ml of diluted suspension was added to 96 sterile microtiter wells. A total 20 wells were filled, 4 to each group negative control (A1-A4), positive control (A5-A8), micro 1 (A9-A12), micro 2 (B1-B4) and micro 3 (B5-8). After that, a suspension of ZnO-NP is added: 1 μg/mL to group micro 1, 2 μg/mL to group micro 2, and 3 μg/mL to group micro 3. Then incubated for 24 hours at a temperature of 37°C; after incubation, the suspension was removed, and the microtiter well was washed 3× with 0.2 ml sterile PBS pH 7.2 to remove planktonic cells (freeform). The biofilm formed at the wall or bottom of the well is stained with 1% violet crystals and left for 20 minutes. After that, 1 molar 200 μg hydrochloric acid (HCl) in concentrated isopropanol was added. The excess violet crystals are washed with water, the microtiter wells are then dried in an inverted position. Biofilm formation was assessed based on OD determined by an ELISA reader with a wavelength of 630 nm (OD 630 nm).\n\nTo evaluate the effect of various ZnO-NP suspension concentrations on the growth of colonies of Staphylococcus aureus bacteria, SPSS 25 (IBM Corp. 2017) (RRID:SCR_002865) for Windows statistical test program was used. Data distribution was tested for normality using the Shapiro-Wilk test, while homogeneity was tested using the Levene test. A comparison of the average number of colonies between 0.3% povidone-iodine and 20% ZnO-NP suspension has been done using an independent t-test.\n\nThe biofilm identification and assay result shows that data was not normally distributed and heterogenous; therefore, a Mann-Whitney test was used to determine the correlation between variables. The results of comparisons between groups were carried out with the Mann-Whitney test. It is statistically significance if the p-value < 0.05. All the statistical result from normality and homogeneity test to statistical data will be included in the underlying data.25\n\nAll protocols were approved by the Health Research Ethics Commission of General Hospital Dr. Saiful Anwar Malang with ethical approval number 400/104/K.3/302/2022.\n\n\nResults\n\nThe experiment’s broth dilution method results showed that the MIC was at a concentration of 4 g/mL, where the black line began to appear and became clear in the test tube for ZnO-NP suspension. While the results of the colony forming unit (CFU) calculation and linear regression from serially increasing the dose of ZnO-NP at a concentration of 4 g/mL are shown in Table 1, and calculation results of methicillin-resistant Staphylococcus aureus (MRSA) colonies on Mueller–Hinton media with exposure to ZnO-NP suspension compared with 0.3% povidone-iodine are shown in Table 2.\n\nThe results of bacterial inoculation on Mueller–Hinton above show that the larger the dose, will decrease the number of bacteria (CFU). The dosage of MIC (4 g/mL) showed a decrease in CFU of as much as 99.3%, and a dose of 16 g/mL could eradicate all bacteria. In addition, the dose of 16 g/mL is the MBC. After all those procedures, the average number of colonies was compared. The independent t-test showed a significant difference between the number of colonies formed on the ZnO-NP 4 g/mL administration and 0.3% povidone-iodine (p-value = 0.001). Using 0.3% povidone-iodine causes bacteria not to grow at all. Similarly, administering ZnO-NP solution with a 16 g/mL concentration also caused no bacterial growth. Thus, the MBC concentration of ZnO-NP suspension had the same effect as 0.3% povidone-iodine administration. Biofilm identification was carried out in Congo Red agar to obtain a biofilm image with a picture of a black colony.\n\nAnalysis of the effect of ZnO-NP suspension in inhibiting the growth of biofilm-producing Staphylococcus aureus by SEM examination. SEM examination was carried out to qualitatively determine biofilms’ formation in Staphylococcus aureus bacteria. The formation of biofilms can be seen from the matrix extracellular of the biofilms formed and seen in SEM. SEM examinations were performed on negative, positive, and treatment groups (Figures 1 and 2).\n\nThis study found that the picture of biofilm formation in the treatment group was less compared to the control group (+). Coupled with the increased dose of ZnO-NP application to colonies of Staphylococcus aureus bacteria, there is less and less biofilm formation. MBIC was seen at a concentration of ZnO-NP suspension of 2 μg, while at higher doses, it showed lysis of bacterial cells.\n\nDescriptive analysis is used to find out an overview of the purchasing variables. This descriptive analysis is expected to provide an overview of the state of patient data. To find out the description for each variable can be seen in Table 3.\n\nThe Mann-Whitney test was used to determine significant differences between the treatments with ordinal data scales or data that do not meet the assumptions of normality and homogeneity. Further analysis was carried out using Kruskal Wallis to test whether significant differences exist between one treatment group and another.\n\nBased on the results of the Mann Whitney’s analysis in Table 4, it was found that the p-value for OD was 0.003, the result of the p-value < 0.05 for the OD parameter, which means that there is a significant difference between the treatments at an error rate of 5%. Testing to determine the differences between each group used the Kruskal-Wallis test. The results of the comparison between each group were carried out in Table 5, showing a significant difference in the average group if the p-value < 0.05.\n\n\nDiscussion\n\nStaphylococcus aureus is a gram-positive bacteria that can cause various diseases. Infection by this pathogen is common both in the community and in hospitals. Staphylococcus aureus is also a bacterium that often causes infections in bones and joints.12 Zinc oxide nanoparticle (ZnO-NP) is a white to yellowish-white crystalline powder which are soluble in water. The most common crystal structures are wurtzite (hexagonal) and zinc alloys. The physico-chemical properties of ZnO-NP contribute to its antibacterial activity.13\n\nThis study proves that ZnO-NP suspension has antibacterial activity with MIC at 4 g/mL, effectively killing 99.3% of bacteria. In a maximal dose of 16 g/mL, ZnONP suspension killed 100% bacteria. Based on Table 2 above, in 2 g/mL, CFU count 1.9 × 108; in 4 g/mL, the CFU decreases to 2.5 × 105. For dose 16 g/mL, the CFU is 0, the same as 0.3% povidone-iodine. This study’s MBC had a killing power equivalent to that of diluted 0.3% povidone-iodine. A diluted povidone-iodine solution has been recommended for wound irrigation.14 This study shows that ZnO-NP is a potential antiseptic agent and can provide an effect equivalent to other recommended antiseptic solutions.15 On the other hand, there are significant differences in MBC values from those found in this study compared to previous studies. In this study, the MBC value obtained from the experiment was 16 g/mL, this was 7.81 g/mL in previous studies, reaching 50% of this study.16 In contrast, the studies above on poultry feedstuffs showed MBC as high as 100 g/mL. This difference could be caused by differences in the isolates used.\n\nThere are several antibacterial mechanism of ZnO-NP: (1) the release of ROS reactive oxygen species (ROS) generated on the surface of nanomaterials can attack the bacterial cell wall, and the antibacterial activity is further enhanced by increasing the surface area17; (2) another possible mechanism for the antibacterial activity of ZnO is the release of Zn2+ ions which can damage cell membranes and penetrate intracellular contents17; (3) Contact between bacterial cells and particles causes changes in the microenvironment within the contact area of organisms and particles. Brayner et al. also showed that the bacterial cell wall was damaged and disorganized after contact with ZnO-NP nanoparticles. The abrasive ZnO-NP causes an increase in membrane permeability leading to the subsequent cellular internalization of the nanoparticles18 and; (4) other mechanisms. It is also believed that the antimicrobial activity of ZnO may be related to its photocatalytic activity. By absorbing UV light which activates its interaction with bacteria, suspension of ZnO nanoparticles can produce ROS such as H2O2, which has a phototoxic effect on bacteria.19\n\nZnO-NP has been developed for research purposes and health-related applications. Not only does it have antibacterial activity, but ZnO-NP inhibits biofilm formation.19 Based on SEM and OD in this study, MBIC is at a dose of 2 μg/mL and is statistically significant. While bacteriolysis effectively started at a dose of 3 μg/mL. Research conducted by Abdelraheem also found the same thing. ZnO-NP was found to suppress the expression of the ica A, ica D, and fnb A genes, the main genes forming biofilms in Staphylococcus aureus.19 Based on the study’s results, it was used as a background to assess the ability of ZnO-NP to inhibit the formation of biofilms against Staphylococcus aureus bacteria. In research by Jasim and Abdelraheem, it was also explained that ZnO-NP is effective in inhibiting the formation of biofilms in Vancomycin and Linezolid-resistant Staphylococcus aureus so that it can also be used on multi-resistant Staphylococcus aureus against antibiotics.19,20 In another study by Abdulkareem, ZnO-NP was also used in dental implants and had benefits in antimicrobials and inhibition of biofilm formation.21\n\nZnO-NP has several mechanisms that inhibit biofilm formation: (1) inhibiting the adhesion and proliferation stages; (2) changing the formation of amyloid fibrils; and (3) inhibiting the Quorum sensing mechanism, which is not yet known in detail. The workings of ZnO-NP suspension are thought to have started by degrading biofilms with an effective dose of 2 μg/mL, and then after the biofilm is destroyed, the bacterial cells die with a higher dose. Without biofilms, bacteria become more susceptible to antibacterials agents.22–24\n\n\nConclusions\n\n20% ZnO-NP suspension is a promising solution for preventing surgical infection due to its antibacterial and antibiofilm effects. It has a minimum inhibitory concentration (MIC) for Staphylococcus aureus at 4 g/mL and a minimum bactericidal concentration (MBC) at 16 g/mL. A higher suspension dose effectively eradicates Staphylococcus aureus bacteria and its biofilm, which has minimal biofilm inhibitory concentration (MBIC) at a dose of 2 μg/mL. This study has limitations because it does not evaluate the expression of genes that form Staphylococcus aureus biofilm formation; therefore, further research is needed.\n\n\nAuthor contribution\n\nKrisna Yuarno Phatama: Conceptualization, Writing – Original Draft Preparation, Validation, Project Administration, Methodology\n\nRespati S. Dradjat: Conceptualization, Writing – Original Draft Preparation, Supervision\n\nEdi Mustamsir: Conceptualization, Writing – Original Draft Preparation, Supervision\n\nDwi Yuni Nurhidayati: Supervision, Validation, Data Curation, Resources\n\nDewi Santosaningsih: Supervision, Validation, Data Curation, Resources\n\nDwikora Novembri Utomo: Writing – Review & Editing, Supervision, Validation\n\nMohamad Hidayat: Writing – Review & Editing, Supervision, Validation",
"appendix": "Data availability\n\nSome data underlying the results are available as part of the article, and the others are available on the list of additional resources below.\n\nZenodo: Suspension of Zinc Oxide Nanoparticles (ZnO-NP) as an Intraoperative Wound Irrigation to Prevent Infection After Fracture Fixation, https://doi.org/10.5281/zenodo.7765281. 25\n\nThis project contains the following underlying data:\n\n- Raw Data Fixed.xlsx\n\n- Descriptive ZnO-NP & PI CFU.xlsx (Descriptive comparative CFU between ZnO-NP and PI)\n\n- Descriptive OD.xlsx (Descriptive Optical Density of Biofilm)\n\n- Normality & Homogeneity Test.xlsx\n\n- Statistical Test.xlsx (Mann-whitney & Kruskal-wallis test)\n\n- Control Negative - UMM4247(x18k).jpg (SEM)\n\n- Control Negative - UMM4247(x18k).txt (SEM)\n\n- Control Negative - UMM4248(x18k).jpg (SEM)\n\n- Control Negative - UMM4248(x18k).txt (SEM)\n\n- Control Positive - UMM4249(x18k).jpg (SEM)\n\n- Control Positive - UMM4249(x18k).txt (SEM)\n\n- Control Positive - UMM4250(x18k).jpg (SEM)\n\n- Control Positive - UMM4250(x18k).txt (SEM)\n\n- Micro 1 - UMM4251(x18k).jpg (SEM)\n\n- Micro 1 - UMM4251(x18k).txt (SEM)\n\n- Micro 1 - UMM4252(x18k).jpg (SEM)\n\n- Micro 1 - UMM4252(x18k).txt (SEM)\n\n- Micro 1 - UMM4253(x18k).jpg (SEM)\n\n- Micro 1 - UMM4253(x18k).txt (SEM)\n\n- Micro 1 - UMM4254(x18k).jpg (SEM)\n\n- Micro 1 - UMM4254(x18k).txt (SEM)\n\n- Micro 2 - UMM4255(x18k).jpg (SEM)\n\n- Micro 2 - UMM4255(x18k).txt (SEM)\n\n- Micro 2 - UMM4256(x18k).jpg (SEM)\n\n- Micro 2 - UMM4256(x18k).txt (SEM)\n\n- Micro 2 - UMM4257(x18k).jpg (SEM)\n\n- Micro 2 - UMM4257(x18k).txt (SEM)\n\n- Micro 2 - UMM4258(x18k).jpg (SEM)\n\n- Micro 2 - UMM4258(x18k).txt (SEM)\n\n- Micro 3 - UMM4263(x18k).jpg (SEM)\n\n- Micro 3 - UMM4263(x18k).txt (SEM)\n\n- Micro 3 - UMM4265(x18k).jpg (SEM)\n\n- Micro 3 - UMM4265(x18k).txt (SEM)\n\n- Micro 3 - UMM4266(x18k).jpg (SEM)\n\n- Micro 3 - UMM4266(x18k).txt (SEM)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nZenodo: Suspension of Zinc Oxide Nanoparticles (ZnO-NP) as an Intraoperative Wound Irrigation to Prevent Infection After Fracture Fixation, https://doi.org/10.5281/zenodo.7765281. 25\n\nThis project contains the following reporting guidelines:\n\n- Author Checklist.pdf (ARRIVE checklist)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nSteinmetz S, Wernly D, Moerenhout K, et al.: Infection after fracture fixation. EFORT Open Rev. 2019; 4: 468–475. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHak DJ, Fitzpatrick D, Bishop JA, et al.: Delayed union and nonunions: epidemiology, clinical issues, and financial aspects. Injury. 2014; 45: S3–S7. Publisher Full Text\n\nThakore R v, Greenberg SE, Shi H, et al.: Surgical site infection in orthopedic trauma: A case-control study evaluating risk factors and cost. J. Clin. Orthop. Trauma. 2015; 6: 220–226. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTong SYC, Davis JS, Eichenberger E, et al.: Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin. Microbiol. Rev. 2015; 28: 603–661. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlmoudi MM, Hussein AS, Abu Hassan MI, et al.: A systematic review on antibacterial activity of zinc against Streptococcus mutans. Saudi Dent. J. 2018; 30: 283–291. Publisher Full Text\n\nTande AJ, Patel R: Prosthetic joint infection. Clin. Microbiol. Rev. 2014; 27: 302–345. Publisher Full Text\n\nSuleiman LI, Mesko DR, Nam D: Intraoperative Considerations for Treatment/Prevention of Prosthetic Joint Infection. Curr. Rev. Musculoskelet. Med. 2018; 11: 401–408. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBruins MJ, Juffer P, Wolfhagen MJHM, et al.: Salt Tolerance of Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus. J. Clin. Microbiol. 2007; 45: 682–683. Publisher Full Text\n\nvon Keudell A , Canseco JA, Gomoll AH: Deleterious Effects of Diluted Povidone–Iodine on Articular Cartilage. J. Arthroplast. 2013; 28: 918–921. Publisher Full Text\n\nXie Y, He Y, Irwin PL, et al.: Antibacterial activity and mechanism of action of zinc oxide nanoparticles against Campylobacter jejuni. Appl. Environ. Microbiol. 2011; 77: 2325–2331. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAslam Z, Roome T, Razzak A, et al.: Investigation of wound healing potential of photo-active curcumin-ZnO-nanoconjugates in excisional wound model. Photodiagn. Photodyn. Ther. 2022; 39: 102956. PubMed Abstract | Publisher Full Text\n\nUematsu H, Yamashita K, Kunisawa S, et al.: Estimating the disease burden of methicillin-resistant Staphylococcus aureus in Japan: Retrospective database study of Japanese hospitals. PLoS One. 2017; 12: e0179767. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMahamuni-Badiger PP, Patil PM, Badiger M v, et al.: Biofilm formation to inhibition: Role of zinc oxide-based nanoparticles. Mater. Sci. Eng. C Mater. Biol. Appl. 2020; 108: 110319. PubMed Abstract | Publisher Full Text\n\nGoswami K, Austin MS: Intraoperative povidone-iodine irrigation for infection prevention. Arthroplast. Today. 2019; 5: 306–308. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRuder JA, Springer BD: Treatment of Periprosthetic Joint Infection Using Antimicrobials: Dilute Povidone-Iodine Lavage. J. Bone. Jt. Infect. 2017; 2: 10–14. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlekish M, Ismail ZB, Albiss B, et al.: In vitro antibacterial effects of zinc oxide nanoparticles on multiple drug-resistant strains of Staphylococcus aureus and Escherichia coli: An alternative approach for antibacterial therapy of mastitis in sheep. Vet. World. 2018; 11: 1428–1432. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDimapilis EAS, Hsu CS, Mendoza RMO, et al.: Zinc oxide nanoparticles for water disinfection. Sustain. Environ. Res. 2018; 28: 47–56. Publisher Full Text\n\nHeinlaan M, Ivask A, Blinova I, et al.: Toxicity of nanosized and bulk ZnO, CuO and TiO2 to bacteria Vibrio fischeri and crustaceans Daphnia magna and Thamnocephalus platyurus. Chemosphere. 2008; 71: 1308–1316. PubMed Abstract | Publisher Full Text\n\nJones N, Ray B, Ranjit KT, et al.: Antibacterial activity of ZnO nanoparticle suspensions on a broad spectrum of microorganisms. FEMS Microbiol. Lett. 2008; 279: 71–76. PubMed Abstract | Publisher Full Text\n\nAbdelraheem WM, Khairy RMM, Zaki AI, et al.: Effect of ZnO nanoparticles on methicillin, vancomycin, linezolid resistance and biofilm formation in Staphylococcus aureus isolates. Ann. Clin. Microbiol. Antimicrob. 2021; 20: 54. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAdams LK, Lyon DY, Alvarez PJJ: Comparative eco-toxicity of nanoscale TiO2, SiO2, and ZnO water suspensions. Water Res. 2006; 40: 3527–3532. Publisher Full Text\n\nMcGuffie MJ, Hong J, Bahng JH, et al.: Zinc oxide nanoparticle suspensions and layer-by-layer coatings inhibit staphylococcal growth. Nanomedicine. 2016; 12: 33–42. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBhattacharyya P, Agarwal B, Goswami M, et al.: Zinc oxide nanoparticle inhibits the biofilm formation of Streptococcus pneumoniae. Antonie Van Leeuwenhoek. 2018; 111: 89–99. PubMed Abstract | Publisher Full Text\n\nShkodenko L, Kassirov I, Koshel E: Metal Oxide Nanoparticles Against Bacterial Biofilms: Perspectives and Limitations. Microorganisms. 2020; 8: 1–21. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPhatama KY, Dradjat RS, Mustamsir E, et al.: Suspension of Zinc Oxide Nanoparticles (ZnO-NP) as an Intraoperative Wound Irrigation to Prevent Infection After Fracture Fixation. [Data]. Zenodo. 2023. Publisher Full Text"
}
|
[
{
"id": "175827",
"date": "20 Jul 2023",
"name": "Ismail Hadisoebroto Dilogo",
"expertise": [
"Reviewer Expertise As a fellow orthopedic surgeon",
"this study helps provide an additional choice of antiseptic fluids to be used in cases of fractures that require fixation."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nGeneral Comments\nThank you for your submission to the F1000Research\n\nOverall, this manuscript is already well-written and shows its purposes thoroughly.\nAbstract\nSince this study was finding out the MIC and MBC for ZnO-NP suspensions, please also mention these particular findings in the abstract section.\nIntroduction\nThe introduction section has been showing the magnitude and importance of this study concisely.\n\nPlease briefly state what measurement that will be showing the antibacterial effect of ZnO-NP suspension for the biofilm of S. aureus in the aim of this study.\nMaterial and method\nThe method section has been written thoroughly so that the study procedures can be well understood.\nResult\nIf available, could the author include several documentations of agar that show the bacterial colonies in each agar that were using the concentration of ZnO-NP?\n\nDiscussion\nPlease also add a discussion mention the brief comparison of Zno-NP with other substances, such as povidone-iodine properties, as infection prevention agents.\nConclusions\nThe conclusions have been written concisely while showing a summary of the results of this study that has been discussed thoroughly.\nFigures and Tables\nIn Tables 1 and 2 please add a description of the dosage unit that was used.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10279",
"date": "29 Nov 2023",
"name": "Krisna Yuarno Phatama",
"role": "Author Response",
"response": "Dear Reviewer, Greetings Thank you for all the appreciation you have given to our manuscript. We would be glad if our research could be useful and can be followed by other researchers. We have tried to follow and improve some of your suggestions, but there are several points that have actually been included in our manuscript. Once again, thanks for the suggestion. Regards, All authors"
}
]
},
{
"id": "175829",
"date": "19 Apr 2024",
"name": "Nicolaas C. Budhiparama",
"expertise": [
"Reviewer Expertise Orthopaedics and Traumatology",
"and Genetic"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nGeneral remarks Well-written paper with good methods and discussion allowing future replication of the research. There are several recently published papers (systematic review and RCTs) on a similar topic (antibacterial use of zinc oxide); therefore, the author can provide a more thorough argument on the clinical importance of the study. There are many studies regarding the antibacterial effect of zinc oxide nanoparticles. What is the novelty of your study? Also, please check the English language.\nAbstract: Define the complete form of abbreviations at their first mention in the title, abstract, text, figures, and tables. Hence, the complete form of ZnO-NP in the abstract section should be mentioned in the background (i.e., first mention), not in the method.\nIntroduction:\nIAFF is not an official terminology. Please use the official or generally used terminology. Please re-arrange the aim of the study. It should be clearly mentioned, not only “to reveal more about the antibacterial effect”. The hypothesis can be provided in the intro paragraph.\nMethods:\nThe methods are unclear. Please keep your tenses constant in the methodology section. Since it is a report of procedures that were performed in the past, the past tense should be used constantly throughout the section. There is a mix of past & present tenses in this section, which is inappropriate. Research design: How did the authors determine the concentration of Zn-NP and povidone-iodine used? Was it from previous experiments/reports? If so, please provide citations for this. The introduction justified the reasons for using Zn-NP and povidone-iodine, but the justification for such concentration (20% and 0.3%, respectively) was not elaborated anywhere.\n\nWhy does this study use 20% suspension instead of a higher/ lower percentage?\n\nIdentification of S. aureus bacteria, gram staining Step 5: Do you mean isopropyl alcohol? Identification of S. aureus bacteria: How accurate is the Vitek® 2 system (Biomérieux, USA) in bacteria identification (especially gram-positive cocci)? Please give the accuracy rate (%) and a citation. Please provide a citation for the broth dilution method. It might be better if the authors provide a schematic diagram for the experiment methods & workflow. It is to increase the readability and ensure the reproducibility of your work. The full form of MBIC and its definition should be first mentioned in this section. Biofilm identification: “The formation of biofilms is considered positive when a layer of violet crystalline colour appears on the walls and base of the tube, and the observation can be done by naked eye”. It will be easier to understand the process if the authors provide some photographs of the biofilm identification process. Please explain how you measure the biofilm. Did you measure the width of the biofilm? Because suddenly, you have the mean and SD of biofilm, which unclear what’s the meaning of the mean and SD. Is it the wide area, the depth, or any measurement? And how you measure it. It is also unclear how you decide on the MBC and MIC. What is the minimum amount or percentage? Please recheck your statistic. It said that you use Mann-Whitney in biofilms, while you have groups of biofilms. Surely cannot use Mann-Whitney for more than 2 groups. Also, Mann-Whitney is for comparison, not correlation, as you said in “data analysis” section. Again, please rewrite or recheck the statistic you use.\nResults:\n“The experiment’s broth dilution method results showed that the MIC was at a concentration of 4 g/mL, where the black line began to appear and became clear in the test tube for ZnO-NP suspension.” Again, there is no proof of this. Please provide some photographs of these so that non-expert readers can understand your work easily. Your data presentation could be improved by using graphs rather than tables. It is difficult to understand your data in its present forms. For group replication, it is sufficient to provide the mean/SD of the group in the graphs (not the individual data). Tables 1-5 are better replaced by graphs. The tables may go into the supplementary files.\n\n“This study found that the picture of biofilm formation in the treatment group was less compared to the control group (+). Coupled with the increased dose of ZnO-NP application to colonies of Staphylococcus aureus bacteria, there is less and less biofilm formation. MBIC was seen at a concentration of ZnO-NP suspension of 2 μg, while at higher doses, it showed lysis of bacterial cells.”\n\nHow did the authors come to this conclusion? Which part of the results section shows this data? The methodology of this assay was also poorly structured, so it’s hard to understand. As I suggested in the Method section, a scheme comprising your experiment workflow may increase your readability. “… bacteria, there is less and less biofilm formation.” Does it mean the formation of biofilm cannot be fully prevented by this ZnO-NP solution? Does this mean that we directly need to use bactericidal doses to effectively prevent IAFF?\n\nYou don’t have to mention why you use Mann-Whitney or any statistic steps in the results section. Last paragraph: The text in this section should mention data interpretation and their implication, not only mentioning statistical significance. What is the meaning of Table 4? What did you compare? Between which group?\nDiscussion:\n\nThe first paragraph of the discussion should be “What did you find in your study”, not the theory or literature. What about the effect of ZnO coatings on metal implants? Does it also aid the prevention of infection after fracture fixation? The explanation of ZnO-NP antimicrobial and inhibition of biofilm mechanisms should be more deeply elaborated. Please add your study limitations and suggestion for future research. Similar former researches can be provided to show any conflicting or supporting results (previous research on zinc oxide use cited in the intro was not related to medical use of ZnO-NP) Why the author chose zinc oxide compared to other substances (the author only compared to povidone-iodine) has not been explained in the intro as well (other than its safe to consume) Clinical reasoning on the use of zinc oxide can be compared with recently published papers and has been further explained in the discussion paragraph.\n\nConclusion:\n\nAlthough the conclusions were correct, they only partially answered the main topic of this study, which was to reveal the efficacy of ZnO-NP suspension as intraoperative wound irrigation to prevent infection after fracture fixation. In vivo studies were needed to fully answer this purpose.\nPlease move your study limitation and suggestion to the last paragraph of the discussion. It is unclear how the authors concluded that the MBIC to prevent biofilm formation was 2 μg/ml.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-554
|
https://f1000research.com/articles/12-153/v1
|
10 Feb 23
|
{
"type": "Research Article",
"title": "Oncofertility awareness among primary care physicians in India",
"authors": [
"Prathima Tholeti",
"Shubhashree Uppangala",
"Rajesh Kumar Jayaram",
"Karthik S Udupa",
"Guruprasad Kalthur",
"Norah Spears",
"Teresa Woodruff",
"Satish K Adiga",
"Prathima Tholeti",
"Shubhashree Uppangala",
"Rajesh Kumar Jayaram",
"Karthik S Udupa",
"Guruprasad Kalthur",
"Norah Spears",
"Teresa Woodruff"
],
"abstract": "Background: Primary care physicians not only coordinate referrals to oncology services but can play a crucial role in successful fertility preservation referrals in cancer-diagnosed patients. Hence, it is important to assess their knowledge and attitudes towards fertility preservation. Methods: An eighteen-item oncofertility survey was administered to primary care physicians between May 2019 to September 2020. Results: A total of forty-six responses were received and analysed. About 60% of primary care physicians did not have adequate knowledge about available fertility preservation options and only 26-32% were aware of international guidelines recommending fertility preservation in cancer patients. Conclusions: Imparting awareness and knowledge of fertility preservation and its options to primary care physicians could enable an integrated cancer care model while also facilitating successful oncofertility referrals in countries like India.",
"keywords": [
"Fertility preservation",
"oncofertility",
"primary care physicians",
"general physicians",
"paediatricians"
],
"content": "Introduction\n\nOncofertility – integrating cancer care with fertility preservation (FP) – is expected to be an essential part of the standard care for patients,1 with international guidelines recommending fertility preservation counselling as routine for reproductive-age cancer patients and for prepubertal children undergoing gonadotoxic therapies.2 However, successful implementation of oncofertility care requires a coordinated referral system among healthcare providers.3 While it is established that the role of oncologists and reproductive specialists is key for successful oncofertility,3,4 it is also believed that primary care physicians (PCPs) can play an important role in ensuring successful fertility preservation referrals.5\n\nPCPs inclusive of general physicians (GPs) and paediatricians (PEDs), are considered as gatekeepers of the healthcare system who provide comprehensive, individual-centric and coordinated continuous care.6 It has been reported that about two thirds of patients with long-term or complex health issues prefer interpersonal continuity with a PCP whom they know, trust and who also knows their medical history.7,8 PCPs not only coordinate referrals to oncology or other specialty services, but are also involved in providing general medical care, emotional support and overall decision making for the patient during cancer care.9 Post-treatment physical and psychosocial surveillance by primary care clinicians is recommended by the American Society of Clinical Oncology breast cancer survivorship guidelines, which also recommend that PCPs expedite referrals to reproductive endocrinologists in survivors experiencing infertility.10\n\nIt is therefore important for PCPs dealing with cancer patients or patients with non-malignant conditions requiring gonadotoxic therapies, to be adequately knowledgeable both of the adverse gonadotoxic effects of chemo- and radiotherapy as well as the options available to mitigate them. The awareness of PCPs of international fertility preservation guidelines and on the available fertility preservation options are expected to strengthen the likelihood of fertility preservation referrals.11 Therefore, this study was aimed to assess the awareness, knowledge and perceptions of PCPs towards fertility preservation, along with exploring the existing barriers to oncofertility establishment in India.\n\n\nMethods\n\nThe study was approved by the Institutional Ethics Committee, Kasturba Medical College & Kasturba Hospital, Manipal, India (IEC No: 880/2017), and is in continuation of a previously published study.4 The earlier work included the use of an eighteen-item survey, which was given to oncologists and gynaecologists to explore their attitudes towards fertility preservation. The survey was designed in collaboration with the Oncofertility Consortium, USA. Content validation for the survey was done by experts in the field12 and a pilot study was conducted on a small group of healthcare providers to validate the comprehensibility of the survey questions (unpublished). In our new study, the survey was administered randomly to GPs and PEDs of the country at various national conferences and virtual platforms from May 2019 to September 2020. Written informed consent was taken from all the subjects participating in the survey.\n\nIn brief, the survey contained a total of eighteen questions, of which ten were aimed at understanding the participants’ knowledge, attitudes, and practice trends in oncofertility, including their familiarity with existing oncofertility barriers in India, and sought the respondent’s suggestions, if any, for effective use of fertility preservation. The remaining eight questions covered the demographics of the survey respondents and contextual details such as the number of new cancer patients treated in a month and the patient age groups. The questions were of different complexities, including those of a dichotomous nature, assessment tools with grading scales, multiple choice items where only one response could be selected, multiple response items where more than one answer could be selected, and even open-ended questions. During the analysis, the survey responses were assigned numerical values (Yes=1, No=0), and the data was analysed using descriptive statistics calculated with Microsoft Excel. In questions containing grading scales or multiple choice, options such as ‘not aware’, ‘aware but inadequate knowledge’, ‘knowledgeable’, ‘very knowledgeable’, were clubbed as two categories – ‘inadequate knowledge’ and ‘knowledgeable’. For open-ended questions such as suggestions for oncofertility practice, all the responses were considered and grouped based on similarity of the suggestions made. Questions that showed a high variation in responses, such as more than half of the participants not answering, were not included in the analysis.\n\n\nResults\n\nOut of 105 survey forms distributed, 23 responses each from general physicians (GPs) and pediatricians (PEDs) were received, with an average response rate of 43.8%. The demographics of the PCPs are shown in Table 1.\n\nAbout 32% of GPs (7 of 22) and 26% of PEDs (6 of 23) were aware of the American Society for Clinical Oncology (ASCO) guidelines on fertility preservation (Figure 1A). When assessing the knowledge of different fertility preservation options available for both prepubertal and adult cancer patients, about 60% of the PCPs did not have an adequate knowledge on established fertility preservation (FP) options (Figure 1B). However, PEDs had a slightly higher level of knowledge of some of the FP options such as sperm banking (35%; 8 of 23), immature testicular tissue freezing (30%; 7 of 23), ovarian tissue freezing (35%; 8 of 23) and oocyte freezing (39%; 9 of 23), and were more knowledgeable of the time needed to undertake each of the options compared to GPs.\n\n(A) Awareness of ASCO fertility preservation guidelines among PCPs. (B) PCPs’ knowledge of various fertility preservation options. The various options on the X axis are: Sperm freezing (SF), Testicular tissue cryopreservation (TTC), Oocyte banking (OB), Ovarian tissue cryopreservation (OTC), IVF followed by embryo freezing (IVF) and GnRHa pre-treatment (GnRHa). (C) Opinion on whether fertility preservation compromises cancer treatment. (D) Frequency of initiating fertility preservation discussions with cancer patients (teal bar: general physicians; black bar: pediatricians).\n\nWhen asked their opinion on the statement, “offering fertility preservation compromises cancer treatment”, 56% of GPs (13 of 23) and 52% of PEDs (12 of 23) disagreed with the statement, indicating a positive attitude towards oncofertility (Figure 1C). Further, the frequency of fertility preservation counselling or referrals showed that 78% of GPs (18 of 23) and 65% of PEDs (15 of 23) initiated FP discussions with the cancer-diagnosed patients only occasionally or when asked; only 21-35% of them reported routine discussions (Figure 1D).\n\nThe majority of PCPs (>60%) in both groups were comfortable discussing most of the available FP options. However, when it came to female fertility preservation options, a minority of GPs were not comfortable discussing oocyte freezing (37%; 7 of 19), ovarian tissue freezing (35%; 7 of 17) or IVF (33%; 6 of 18) options, which could be reflective of inadequate knowledge in this area.\n\nParticipants were asked to select the most appropriate of the listed barriers for effective oncofertility implementation in India. PCPs from both groups felt ‘financial burden’ (76% of GPs, 74% of PEDs), ‘lack of patient awareness’ (62% of GPs, 78% of PEDs) and ‘lack of physician awareness’ (57% of GPs, 74% of PEDs) to be the biggest barriers to FP. PCPs felt that ‘lack of FP facilities’ (43% of GPs, 65% of PEDs) and ‘emotional status of patient’ (43% of GPs, 48% of PEDs) were other important barriers (Figure 2).\n\n(Teal bar: general physicians; black bar: pediatricians.)\n\nOne of the major suggestions given, in the open-ended questions, was to create ‘awareness among primary healthcare providers in fertility preservation’ (36% of GPs, 67% of PEDs). More than 40% of GPs and PEDs felt there was a need for bringing about social awareness among the general public about oncofertility programs and educating the patient and their family. Other suggestions included, ‘routine medical education’, and ‘affordable costs’, which would help bring about effective implementation of oncofertility programs.\n\n\nDiscussion\n\nThis study showed, for the first time, the perceptions and attitudes towards oncofertility among PCPs in India. Lack of knowledge about the current international FP guidelines and of the available FP options were key observations made in this survey.\n\nIn India, the established fertility preservation options include sperm, oocyte and embryo banking for post-pubertal and adult cancer patients while prepubertal options that are available include ovarian or immature testicular tissue cryopreservation, which are still considered experimental. Other options such as gonadal shielding, GnRH analogs are also offered to cancer-diagnosed patients.13 However, the majority of PCPs participating in our study reported inadequate knowledge of even the established fertility preservation options along with a reduced awareness of the American Society of Clinical Oncology Fertility Preservation (ASCO-FP) guidelines. This is in line with a cross-sectional study in India on female cancer patients of reproductive age revealing that 68% reported a lack of information received from primary physicians about fertility risks and FP options.14 There could be several contributing factors to the above finding in our study, one of which could be the lack of knowledge about FP in India, since more than 90% of healthcare workers in other parts of the country reported the need for continued medical education programs or seminars in oncofertility.15 Secondly, the ASCO-FP guidelines are mainly targeted to oncologists and other cancer-care providers,2 and not to primary care physicians, though organizations such as the American Academy of Pediatrics have recommended fertility preservation counselling for pediatric and adolescent patients.11 While ASCO has released primary care focused cancer survivorship guidelines for a few cancers,10,16 there is a need for fertility preservation guidelines before the onset of cancer treatment in pediatric and reproductive-age patients, that can be applicable to primary care settings. Also, PCPs’ depth of knowledge pertaining to long-term effects of cancer treatment could be limited due to their lack of exposure to relevant literature pertaining to the field,17 therefore, conducting educational programs for PCPs to increase awareness and knowledge of the various fertility preservation options could aid PCPs in their discussions with patients. In an online survey conducted by Nahata et al., it was seen that the majority of pediatricians felt inadequately trained in fertility risks and sexual function, which was reflective in their comfort level when discussing such issues.18 Though our study reported a higher comfort level among PEDs in discussing most FP options, a majority of them have suggested the need for fertility preservation awareness programs.\n\nIn India, the burden of cancer is steadily increasing, with the Globocan project predicting 1.7 million new cases by 2035.19 However, the ratio of new cancer cases per clinical oncologist is 677:1 and it has been reported that medical oncologists from low- and middle-income countries such as India have a substantial workload compared to high-income countries.20–22 While the onus of FP counselling is placed on oncologists and gynecologists,2 in the given situation, an integrated care model would be more appropriate. As PCPs have a continual relationship with the patients and are more familiar with their wishes, PCPs can be a part of the FP referrals or discussions, to enable patients to think through their decisions, rather than these discussions taking place only with the oncologists or surgeons.23–25 For this to succeed however, knowledge dissemination and awareness building of fertility preservation among PCPs in developing countries like India is essential, as emphasized by the findings of the present study. Our earlier study specifically looked at oncologists and gynaecologists’ attitude towards fertility preservation, who also emphasized the need for oncofertility awareness.4 A shared care model will not only promote oncofertility referrals but will also enable patients to take informed decisions towards preserving their fertility.\n\nThe scope of oncofertility has started to include fertility preservation in patients with non-oncological conditions who are at high risk of infertility due to gonadotoxic treatments, or individuals with sexual development or auto-immune disorders, and also, in the gender-diverse population.26 The successful establishment of fertility preservation in (non)-oncological conditions therefore requires physicians, both primary care and specialists, to have adequate knowledge of fertility preservation and its related guidelines.\n\n\nConclusions\n\nOur pilot study highlights the dearth of oncofertility awareness among PCPs. With more information, this group could play a crucial role in patient decision-making, thereby helping in the successful establishment of oncofertility as part of standard cancer care. The involvement of PCPs whom the patients know and trust and who are also familiar with the patient’s wishes or life goals, in fertility preservation discussions could prove beneficial to the cancer-diagnosed patients and subsequently improve their quality-of-life post cancer care. This study should contribute to what is currently only limited literature in this area. Limitations of this study include a small sample size and selection bias due to random recruitment of survey participants at conferences.\n\n\nAuthor contributions\n\nPT: Collected and analyzed the data, wrote paper; SU, RKJ, KSU, GK, NS, TKW: Revised the manuscript critically for important intellectual content; SKA: Conceived and designed the study, wrote paper. PT is the guarantor of this work and as such, had full access to all the data and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors have given final approval for publication.",
"appendix": "Data availability\n\nOpen Science Framework: ‘Oncofertility awareness among primary care physicians in India.’ https://doi.org/10.17605/OSF.IO/N7GVKh. 12\n\nThis project contains the following underlying data:\n\n- Oncofertility survey, data description sheet and content validity analysis (zip file)\n\n- Survey responses (raw data) (zip file)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgements\n\nThe authors thank all the general physicians and pediatricians who participated in the survey.\n\n\nReferences\n\nAnazodo A, Laws P, Logan S, et al.: How can we improve oncofertility care for patients? A systematic scoping review of current international practice and models of care. Hum. Reprod. Update. 2019; 25(2): 159–179. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOktay K, Harvey BE, Partridge AH, et al.: Fertility preservation in patients with cancer: ASCO clinical practice guideline update. J. Clin. Oncol. 2018; 36(19): 1994–2001. PubMed Abstract | Publisher Full Text\n\nWoodruff TK: Oncofertility: A grand collaboration between reproductive medicine and oncology. Reproduction. 2015; 150(3): S1–S10. Publisher Full Text\n\nTholeti P, Uppangala S, Bhat V, et al.: Oncofertility: Knowledge, attitudes, and barriers among Indian oncologists and gynecologists. J. Adolesc. Young Adult Oncol. 2021 Feb; 10(1): 71–77. PubMed Abstract | Publisher Full Text\n\nSaraf AJ, Nahata L: Fertility counselling and preservation: Considerations for the pediatric endocrinologist. Transl Pediatr. 2017; 6(4): 313–322. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFaizi N, Khalique N, Ahmad A, et al.: The dire need for primary care specialization in India: Concerns and challenges. J. Family Med. Prim. Care. 2016; 5(2): 228–233. PubMed Abstract | Publisher Full Text | Free Full Text\n\nContinuity and coordination of care: A practice brief to support implementation of the WHO Framework on integrated people-centred health services. Geneva:World Health Organization;Accessed November 7, 2018.Reference Source\n\nBaker R, Boulton M, Windridge K, et al.: Interpersonal continuity of care: A cross-sectional survey of primary care patients’ preferences and their experiences. Br. J. Gen. Pract. 2007; 57(537): 283–289. PubMed Abstract\n\nHickner J, Kent S, Naragon P, et al.: Physicians' and patients' views of cancer care by family physicians: A report from the American Academy of Family Physicians National Research Network. Fam. Med. 2007 Feb; 39(2): 126–131. PubMed Abstract\n\nRunowicz CD, Leach CR, Henry NL, et al.: American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. CA Cancer J. Clin. 2016 Jan-Feb; 66(1): 43–73. PubMed Abstract | Publisher Full Text\n\nKlipstein S, Fallat ME, Savelli S, et al.: Fertility preservation for pediatric and adolescent patients with cancer: Medical and ethical considerations. Pediatrics. 2020 Mar; 145(3): e20193994. PubMed Abstract | Publisher Full Text\n\nTholeti P, Uppangala S, Jayaram RK, et al.: Underlying data for ‘Oncofertility awareness among primary care physicians in India’, at Open Science Framework.Publisher Full Text\n\nSalama M, Ataman-Millhouse L, Braham M, et al.: Installing oncofertility programs for common cancers in limited resource settings (Repro-Can-OPEN Study): An extrapolation during the global crisis of the Coronavirus (COVID-19) pandemic. J. Assist. Reprod. Genet. 2020 Jul; 37(7): 1567–1577. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMahey R, Kandpal S, Gupta M, et al.: Knowledge and awareness about fertility preservation among female patients with cancer: A cross-sectional study. Obstet. Gynecol. Sci. 2020 Jul; 63(4): 480–489. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMalhotra N, Gupta M, Yadav A, et al.: Knowledge, attitude, and intentions towards fertility preservation in cancer patients among healthcare workers in Northern India. JBRA Assist. Reprod. 2022 Apr 17; 26(2): 305–309. PubMed Abstract | Publisher Full Text\n\nResnick MJ, Lacchetti C, Penson DF: American Society of Clinical Oncology. Prostate Cancer Survivorship Care Guidelines: American Society of Clinical Oncology Practice Guideline Endorsement. J. Oncol. Pract. 2015; 11(3): e445–e449. PubMed Abstract | Publisher Full Text\n\nNekhylyoduv L, Aziz NM, Lerro C, et al.: Oncologists' and primary care physicians' awareness of late and long-term effects of chemotherapy: Implications for care of the growing population of survivors. J. Oncol. Pract. 2014; 10(2): e29–e36. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNahata L, Ziniel SI, Garvey KC, et al.: Fertility and sexual function: A gap in training in pediatric endocrinology. J. Pediatr. Endocrinol. Metab. 2017 Jan 1; 30(1): 3–10. PubMed Abstract | Publisher Full Text\n\nMallath MK, Taylor DG, Badwe RA, et al.: The growing burden of cancer in India: epidemiology and social context. Lancet Oncol. 2014 May; 15(6): e205–e212. PubMed Abstract | Publisher Full Text\n\nMathew A: Global survey of clinical oncology workforce. J. Glob. Oncol. 2018 Sep; 4: 1–12. PubMed Abstract | Publisher Full Text\n\nGyawali B, Jalink M, Effing SMA, et al.: Oncology training programmes for general practitioners: A scoping review. ecancermedicalscience. 2021; 15: 1241. Publisher Full Text\n\nSengar M, Fundytus A, Hopman WM, et al.: Medical oncology in India: Workload, infrastructure, and delivery of care. Indian J. Med. Paediatr. Oncol. 2019; 40: 121–127. Publisher Full Text\n\nSada YH, Street RL Jr, Singh H, et al.: Primary care and communication in shared cancer care: A qualitative study. Am. J. Manag. Care. 2011; 17(4): 259–265. PubMed Abstract\n\nBanks I, Weller D, Ungan M, et al.: ECCO essential requirements for quality cancer care: Primary care. Crit. Rev. Oncol. Hematol. 2019 Oct; 142: 187–199. PubMed Abstract | Publisher Full Text\n\nMathur A, Orellana RE, Frohnmayer A, et al.: Patients’ perception of patient–provider communication in fertility preservation decision making among young women with cancer: A qualitative study. SAGE Open. 2013; 3: 215824401350529–215824401350510. Publisher Full Text\n\nWoodruff TK, Ataman-Millhouse L, Acharya KS, et al.: A View from the past into our collective future: The oncofertility consortium vision statement. J. Assist. Reprod. Genet. 2021 Jan; 38(1): 3–15. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "178270",
"date": "17 Jul 2023",
"name": "Padma Rekha Jirge",
"expertise": [
"Reviewer Expertise Ovarian reserve"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIt is a well conducted and well written manuscript. It addresses a relevant issue. It is interesting that the authors have gone beyond the specialist and interviewed primary care physicians. It is an important step towards improving awareness about oncofertility. The limitations of the study are the small numbers included.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10244",
"date": "06 Oct 2023",
"name": "Satish Adiga",
"role": "Author Response",
"response": "We thank the reviewer for the constructive comments."
}
]
},
{
"id": "190272",
"date": "25 Aug 2023",
"name": "Regina Barragan-Carrillo",
"expertise": [
"Reviewer Expertise Urologic oncology",
"disparities in cancer care"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI reviewed thoughtfully the manuscript Oncofertility awareness among primary care physicians in India. In this the authors present an exploration of the current knowledge and barriers to fertility preservation in India among PCPs. I congratulate the authors for addressing a topic needing assessment in LMICs.\nMy main concerns are regarding the paper's impact in the current knowledge, as usually young patients diagnosed with a malignancy are under the care of a specialized team (pediatric oncologist/hematologist), and I do not fully understand if the lack of knowledge of PCP in such a specialized topic is something of importance in their care-continuum. I think if the authors could really justify the importance of understanding the knowledge of PCP in their paper, it could strengthen it.\nOverall, I found the paper well-written and understandable.\nThe data presented was only a description of the obtained answers, were there any correlations made to understand? For example, what are the characteristics of the physicians with the highest knowledge of oncofertility?\nDuring the discussion, there have been other publications in LMICs for example, in Mexico, also in other parts of the world outside the US like Italy. I recommend making a more exhaustive review of the currently published literature to correlate your results with the currently available literature.\nDuring the discussion I would also recommend a deeper exploration of the reported barriers, are these similar to their context? Or as these unique in the Indian population?\nIn the conclusion, once again I would clearly state why you consider that this is relevant information for the reader.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "10243",
"date": "06 Oct 2023",
"name": "Satish Adiga",
"role": "Author Response",
"response": "We thank the reviewer for the constructive comments. The manuscript has been revised accordingly. Hereby addressing the reviewer’s comments: 1. My main concerns are regarding the paper's impact in the current knowledge, as usually young patients diagnosed with a malignancy are under the care of a specialized team (pediatric oncologist/hematologist), and I do not fully understand if the lack of knowledge of PCP in such a specialized topic is something of importance in their care-continuum. I think if the authors could really justify the importance of understanding the knowledge of PCP in their paper, it could strengthen it. Ans: We agree with the reviewer’s concern. The cancer patients are usually referred to specialized team, but literature as well as discussions with PCPs during the survey distribution have shown that these patients interact with their PCPs during the course of cancer treatment and wish to have their PCPs involved. The introduction section has been revised to emphasize further the role of PCPs in the cancer care continuum. 2. The data presented was only a description of the obtained answers, were there any correlations made to understand? For example, what are the characteristics of the physicians with the highest knowledge of oncofertility? Ans: Due to the small sample size in each group conclusions could not be drawn regarding the characteristics of the PCPs with higher oncofertility knowledge. This has now been mentioned as a limitation of the study. 3. During the discussion, there have been other publications in LMICs for example, in Mexico, also in other parts of the world outside the US like Italy. I recommend making a more exhaustive review of the currently published literature to correlate your results with the currently available literature. During the discussion I would also recommend a deeper exploration of the reported barriers, are these similar to their context? Or as these unique in the Indian population? Ans: Thank you for the suggestion. We agree, there have been other publications about oncofertility trends among oncologists or gynaecologists. However, among PCPs there is very limited literature, and this manuscript is the first of its kind, especially in India. Oncofertility awareness among PCPs is an area with great potential to leverage the role of PCPs in successful oncofertility referrals. Hence, the limited review based on existing literature in this area. However, as per the reviewer’s suggestions, the barriers have been compared with other developing countries and revised accordingly. 4. In the conclusion, once again I would clearly state why you consider that this is relevant information for the reader. Ans: Thank you for the suggestion. It has now been addressed and revised accordingly."
}
]
},
{
"id": "178269",
"date": "14 Sep 2023",
"name": "Alex C. Varghese",
"expertise": [
"Reviewer Expertise Assisted Reproductive Technologies"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript entitled \"Oncofertility awareness among primary care physicians in India\" provides a preliminary survey based analysis highlighting the dearth of oncofertility awareness among PCPs. Specific comments are:\n1) The discussion section can have the following additional details:\n\nAny published estimates of reproductive cancers/prepubertal cancers in India per population/incidences.\n\nA paragraph on the current status of fertility preservation in IVF units across the country and gaps in services. Anazodo et al. (20191) described a model to increase the oncofertility implementation - worth mentioning in the current manuscript.\n\nThe authors have mentioned about the need for the shared care model for oncofertility referrals. Please explain how this could be achieved in an Indian context tailored to the identified determinants and how the improvement strategies for the guideline-specific barriers should be developed.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10245",
"date": "06 Oct 2023",
"name": "Satish Adiga",
"role": "Author Response",
"response": "We thank the reviewer for the constructive comments. The manuscript has been revised accordingly. Hereby addressing the reviewer’s comments: 1) The discussion section can have the following additional details: Any published estimates of reproductive cancers/prepubertal cancers in India per population/incidences. Ans: Thank you for the suggestion, it has now been added accordingly. 2. A paragraph on the current status of fertility preservation in IVF units across the country and gaps in services. Anazodo et al. (20191) described a model to increase the oncofertility implementation - worth mentioning in the current manuscript. Ans: Thank you for the suggestion. There is however, currently no data reporting the fertility preservation referral rates in India, but there are a few studies reporting the frequency of counselling for infertility-risk, which has now been added. The models of care mentioned in the recommended publication have now been added in the discussion section. 3. The authors have mentioned about the need for the shared care model for oncofertility referrals. Please explain how this could be achieved in an Indian context tailored to the identified determinants and how the improvement strategies for the guideline-specific barriers should be developed. Ans: Thank you for the suggestion. It has been addressed to the best of the author’s knowledge and available literature which is limited."
}
]
}
] | 1
|
https://f1000research.com/articles/12-153
|
https://f1000research.com/articles/12-1236/v1
|
27 Sep 23
|
{
"type": "Case Report",
"title": "Case Report: A successful surgical approach towards rare congenital left diaphragmatic hernia associated with respiratory distress syndrome",
"authors": [
"Ashwini Potdukhe",
"Mayur Wanjari",
"Ranjana Sharma",
"Ruchira Ankar",
"Arati Raut",
"Anjali Alone",
"Mayur Wanjari",
"Ranjana Sharma",
"Ruchira Ankar",
"Arati Raut",
"Anjali Alone"
],
"abstract": "Background: Congenital diaphragmatic hernia (CDH) is a life-threatening condition. It happens when the fetal diaphragm does not develop normally during pregnancy. In CDH, the diaphragm breach permits abdominal contents to leak into the thoracic cavity. Pulmonary hypoplasia and pulmonary vascular disease are present in varying degrees of CHD syndrome. Typically leads to pulmonary hypertension, due to anatomical and functional pulmonary vascular abnormalities. Case presentation: Here we report a case of a 5-day-old male neonate born with respiratory distress. After undergoing radiological examination patient was diagnosed with CDH. Transabdominal surgical management was given. The prognosis was good. Conclusion: Transabdominal surgical approach was effective in the case of CDH management.",
"keywords": [
"respiratory distress",
"pulmonary hypoplasia",
"pulmonary vascular disease",
"prenatal period",
"congenital diaphragmatic hernia."
],
"content": "Introduction\n\nCongenital diaphragmatic hernia (CDH) is a condition in which partial or total agenesis of the diaphragm occurs, resulting in the thoracic and abdominal cavities becoming connected. Nearly five people are affected among every 10000 live births. It is more prevalent in males and with multiple pregnancies.1 The primary pathology behind this disease is the impaired development or defective fusion of the pleuroperitoneal membrane.2 Worldwide, survival rates increased to 50 % due to medical and surgical care advancements and enhanced diagnostic methods. It mostly depends on primary pulmonary hypoplasia, hypertension, and heart failure.3 The time of surgical repair also affects later morbidities. Also, initial stabilisation at birth, early diagnosis, and surgical intervention give positive outcomes.4\n\n\nPatient and observation\n\nHere we presented a case of a 5-day-old male neonate who came to the emergency department complaining of respiratory distress at birth. He was born to a primigravida mother at 39 gestational weeks with a 3.1 kg weight through normal vaginal delivery at the regional government hospital. He had severe respiratory distress, cyanosis, tachypnoea, bradycardia and hypoxic condition on admission. They had no family history of conditions like blood pressure, thyroid disorder, or diabetes.\n\nClinical finding\n\nOn vital sign monitoring, vitals were respiratory rate 88, heart rate 146 bpm, saturation 58%. On auscultation of the lungs, less air entry into the left lung was noted.\n\nIn laboratory investigations, patient values were described in Table 1.\n\nOn radiological examination, the thorax left hemithorax showed multiple gaseous distended bowel loops within, with preserved peristaltic movement. Also, 4×2 cm defects were identified, which shows a left diaphragmatic hernia (Figure 1).\n\nTherapeutic intervention\n\nThe newborn infant experienced difficulty in maintaining proper oxygen levels, leading the physician to initiate ventilator support. Following appropriate medical intervention, the infant’s condition became stable, prompting the physician to plan a surgical procedure for repairing a diaphragmatic hernia. The surgery occurred on the second day after the infant’s condition had stabilized. The surgical closure of the 4×2 cm defect was conducted on the left diaphragm using intermittent sutures. However, post-surgery, the abdominal contents unexpectedly breached into the thoracic cavity, necessitating the rescheduling of a second surgical procedure. After an interval of eight days, the second surgery was carried out, during which a compound flap was introduced into the abdomen. This step was completed smoothly, indicating an uneventful surgical procedure and a favourable prognosis.\n\nAfter the surgery patient’s condition was stable, the patient’s asymptomatic vitals were stable, and the patient was discharged after one and half months with a favourable outcome.\n\n\nDiscussion\n\nThe most common type of CDH is the left-sided posterolateral defect, and it is reported in 85% of cases, while only 12% are represented on the right side. Anterior defects through the foramen Morgagni are less commonly reported in only 1-5% of patients with CDH. These defects contribute to the right sides.5\n\nAdvancement in fatal ultrasonography means 60% of CDH cases are diagnosed before the foetus’s birth.6 After birth, the child’s diagnosis is confirmed with the clinical and radiological examinations and symptoms that appear after a few hours of the birth. 5-25% of CDH cases present late, usually diagnosed during routine check-ups, after injury, or as complications such as necrosis, perforations, intestinal blockage, peritonitis, or respiratory or digestive discomfort.7\n\nSymptoms include abdominal or chest pain, wheezing, dyspnoea, cough, apnoea, nausea, and vomiting.8 Respiratory symptoms most commonly occur in younger patients and are more frequent in right-sided CDH. At the same time, gastrointestinal symptoms are found in older patients and associated with left sides CDH cases.9\n\nPatients diagnosed with CDH must be transferred to the surgical unit for further management and to avoid subsequent consequences. Treatment of patients in delayed presenting cases requires the stable condition of the baby and prompt surgical interventions.10 Open surgery is most commonly preferred, even though there is evidence of some reported cases managed through the laparoscopic approach. Delayed presented cases have a better outcome than those diagnosed antenatally or just after birth. Management of both cases varies. The survival rate is approximately 97-100% compared to neonatal CDH, with patients having a good recovery rate and fewer complications after surgery.11\n\nThe mortality rate attributed to Congenital Diaphragmatic Hernia (CDH) varies significantly among different medical centres and remains notably elevated, despite the widespread adoption of innovative therapeutic approaches. The ECMO report indicates that specialised referral centres with considerable expertise have demonstrated the potential to save many infants. The survival rate for newborns delivered alive ranges approximately from 60% to 80%.12 Various novel therapeutic strategies have been introduced for infants facing this condition, albeit without adequately controlled research to validate their effectiveness.\n\nThere is currently no substantiated evidence supporting the notion of “maturing” the fetal lung. Administering prenatal corticosteroids after the 34th week of pregnancy might be deemed necessary in cases of CDH-related pregnancies. However, this approach is not currently recommended. Simultaneously, there might be advantages to scheduling the delivery of a fetus with CDH. Nevertheless, there is a lack of controlled studies endorsing the timing of such deliveries on an elective basis or favouring a cesarean section over a vaginal delivery.13\n\n\nConclusion\n\nCongenital Diaphragmatic Hernia usually occurs in neonates, but some cases can be diagnosed in older children. CDH is a therapeutic challenge. Although CDH can be diagnosed antenatally by ultrasonography and surgical repair is being done in many centres, the morbidity and mortality are still high because many aspects of the disease are still unknown, so more research and clinical studies need to be done for a better understanding of disease and adequate management.\n\n\nConsent\n\nWritten informed consent for publication of their clinical details and clinical images was obtained from the patient’s guardian.",
"appendix": "References\n\nKovler ML, Jelin EB: Fetal intervention for congenital diaphragmatic hernia. Semin. Pediatr. Surg. 2019; 28: 150818. Publisher Full Text\n\nAnekar AA, Nanjundachar S, Desai D, et al.: Case Report: Late-Presenting Congenital Diaphragmatic Hernia With Tension Gastrothorax. Front. Pediatr. 2021; 9: 618596. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCannata G, Caporilli C, Grassi F: Management of Congenital Diaphragmatic Hernia (CDH): Role of Molecular Genetics. Int. J. Mol. Sci. 2021; 22: 6353. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDuan M, James TELH, Chandran S: Right-sided congenital diaphragmatic hernia masqueraded as right lobar pneumonia in a term newborn infant. BMJ Case Rep. CP. 2021; 14: e244975. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKim JM, Couluris M, Schnapf BM: Late-Presenting Left-Sided Morgagni Congenital Diaphragmatic Hernia in a 9-Year-Old Male. ISRN Pulmonology. 2011; 2011: 1–4. Publisher Full Text\n\nvan den Hout L , Sluiter I, Gischler S, et al.: Can we improve outcome of congenital diaphragmatic hernia? Pediatr. Surg. Int. 2009; 25: 733–743. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHosgor M, Karaca I, Karkiner A, et al.: Associated malformations in delayed presentation of congenital diaphragmatic hernia. J. Pediatr. Surg. 2004; 39: 1073–1076. Publisher Full Text\n\nBălănescu R, Ulici A, Mălureanu D, et al.: Morgagni Diaphragmatic Hernia In A 7-Months-Old Boy. A Case Report. Jurnalul de Chirurgie (Iaşi). 2022; 8: 291–295.\n\nKitano Y, Lally KP, Lally PA: Congenital Diaphragmatic Hernia Study Group. Late-presenting congenital diaphragmatic hernia. J. Pediatr. Surg. 2005; 40: 1839–1843. PubMed Abstract | Publisher Full Text\n\nAngrisani L, Lorenzo M, Santoro T, et al.: Hernia of foramen of Morgagni in adult: case report of laparoscopic repair. JSLS. 2000; 4: 177–181. PubMed Abstract\n\nMontedonico S, Nakazawa N, Puri P: Congenital diaphragmatic hernia and retinoids: searching for an etiology. Pediatr. Surg. Int. 2008; 24: 755–761. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDelaney CA, Rozance PJ, Sandoval JA, et al.: Late onset diaphragmatic hernia complicated by intestinal strangulation. Curr. Opin. Pediatr. 2012; 24: 274–276. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTopor L, Pătrăncuş T, Caragaţa R, et al.: Left congenital diaphragmatic hernia -- case report. Chir. Buchar. Rom. 2015; 110: 84–87."
}
|
[
{
"id": "234515",
"date": "09 Jan 2024",
"name": "Faisal Ahmed",
"expertise": [
"Reviewer Expertise CDH is not rare in neonates but the authors may focus on the causes of surgical failure."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nGeneral:\nCongenital diaphragmatic hernia (CDH) has an incidence of 1:3000–1:5000 per live births and is not rare in the neonatal period. What is the rarity in your case?\nTitle:\nWhat is the rarity in your case?; it should be mentioned.\nAbstract: Background:\nIt is not usual to use a \"leak\" for this condition. Please use another word to describe CDH.\nCase presentation:\nPlease mention CDH location (left or right), patient follow-up, and outcome.\nConclusion:\nThe conclusion section needs a revision. You cannot conclude this issue based on one case. Please reduce your tone.\nKeywords:\nAdd a \"case report\" in your Keywords.\nIntroduction:\nPlease mention the rarity in your case in this section. The last sentence in this section should end with a sentence summarizing the case and serving as a transition to the next section, such as\" \"We report a case of...\"\nCase presentation:\nPlease mention the initial assessment findings in your case and prenatal recommendations. The laboratory data in Table One may be reduced if did not mention any pathologic findings. Please mention the details of the first surgical procedure. What are the causes of postoperative complications, how investigated, and what are the second surgical procedure findings? You should mention how you flow the patient.\nDiscussion:\nFor individual cases, it is advisable to describe how the case is rare/unusual and the educational/scientific merit of its publication, followed by an overview of the topic and a comparison of your case with similar cases described in the literature. Paragraph 4, please define delayed presenting. Do you mean the presentation after 5 days is delayed presentation? \"The survival rate is approximately 97-100% compared to neonatal CDH\"; your case already is a neonate. Please recheck and revise this section. Discuss the main cause of surgical failure and recommendation; as your case had a failure in the first surgery. Please discuss factor by factor with scientific adequate explanations.\nConclusion:\nIt should be in ONE paragraph It should provide a one-sentence summary of your case It should provide a take-home message. What can we learn from this case? It should not contain very general statements that are not strictly related to your case.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": []
},
{
"id": "234589",
"date": "20 Mar 2024",
"name": "Ferdinando Antonio Gulino",
"expertise": [
"Reviewer Expertise Obstetrics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript \"Case Report: A successful surgical approach towards rare congenital left diaphragmatic hernia associated with respiratory distress syndrome\" is an interesting Case Report on the management of congenital left diaphragmatic hernia in a 5-days newborn.\nThe abstract is too concise, it needs to be expanded. The article looks not original, the authors describe a routine procedure for this type of pathology: what does it add to scientific literature, Which is the aim of the study? it is better to specify it in the introduction. A figure of the surgical findings of the hernia could be useful for the readers. The authors have to increase the data about the patient, also regarding the prenatal management: why this condition was not diagnosed previously? In this way, they could consider previous literature data on prenatal ultrasonographic diagnosis. The authors have not adequately highlighted the strengths and limitations of their study. I suggest better specifying these points in the discussion and the conclusion of this work. The description of the case report was not performed following the CARE criteria (https://www.care-statement.org/checklist); considering that it is a case report I suggest following this checklist. The reference list is too short, the authors could consider some recent works about the management of this condition. What are the actual clinical implications of this study? it is important to report the results obtained by the authors in the context of clinical practice and to adequately highlight what contribution this study adds to the literature already existing on the topic and to future study perspectives.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": []
},
{
"id": "234529",
"date": "13 Sep 2024",
"name": "Felix Dittgen",
"expertise": [
"Reviewer Expertise Neonatology CDH ECMO"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nLate presenting CDH is a well-known problem and often described in literature. Of course, it is great that it was possible to save the life of the newborn in India, but one statement is totally wrong: It is very difficult to measure the defect size by ultrasound and the picture, which was presented does not show the defect, but the stomach ore a dilated part of the herniated intestine. Laboratory values do not have any impact one therapy and prognosis of CDH despite you may find signs for a severe sepsis.\n\nIs the background of the case’s history and progression described in sufficient detail? No\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1236
|
https://f1000research.com/articles/12-1235/v1
|
27 Sep 23
|
{
"type": "Review",
"title": "Clinical neuropsychological characteristics of bipolar disorder, with a focus on cognitive and linguistic pattern: a conceptual analysis",
"authors": [
"Evgenia Gkintoni"
],
"abstract": "Neuropsychology is an academic discipline that investigates the intricate interplay between the brain, mind, and behavior. It accomplishes this by examining the underlying structure and activities of the brain, with a particular focus on psychological phenomena such as language, motivation, memory, attention, thinking, consciousness, learning, and efficacy. The assessment of neuropsychological changes in individuals diagnosed with bipolar disorder has received limited attention in comparison to other psychiatric conditions, such as schizophrenia, for instance. Nevertheless, there has been a growing interest in the etiological implications, therapies, preventions, and prognostic factors related to social competence and the quality of life of patients. The objective of this review is to compile and analyze the existing research conducted thus far on the association between cognitive abnormalities and bipolar disorder. This study has examined research conducted across many stages of the condition, including depression and mania. Additionally, it has explored comparative studies involving people with schizophrenia, as well as the potential impact of psychopharmaceutical interventions.",
"keywords": [
"Neuropsychology",
"Bipolar Disorder",
"Mania",
"Depression"
],
"content": "Introduction\n\nNeuropsychology is the field of study that investigates the intricate link between the brain, mind, and behavior. This inquiry examines the anatomical composition and cognitive mechanisms that serve as the foundation for complex mental activities, including but not limited to consciousness, attention, learning, memory, reasoning, language, motivation, and affectivity (García & García 2006). The clinical domain of neuropsychology is widely acknowledged as a fundamental field seamlessly incorporated into the flourishing realm of neuroscience and the broader cognitive sciences (Gkintoni & Dimakos, 2022). Recent models in the field of clinical neuropsychology aim to elucidate cognitive impairments through connectionist theories. These hypotheses propose a novel conceptual framework for understanding brain processes and cognitive functions, drawing upon brain maps of information processing. According to Beaumont et al. (1996), this paradigm posits that examining brain processing may elucidate psychiatric problems.\n\nIn bipolar disorder, several writers have investigated cognitive impairments across different disorder phases using several clinical instruments, neuropsychological assessments, and neuroimaging modalities for visualizing brain activity (Sackeim et al., 1983). Nevertheless, it is worth noting that the field of research on this subject has not garnered substantial attention, nor has it been well assessed compared to other mental conditions, such as schizophrenia (Martínez-Aran et al., 1999a; Miklowitz, 1992).\n\nIn a concise historical analysis, it is worth mentioning that early neuropsychological investigations on bipolar disorder indicated the presence of distinct right hemisphere dysfunction. This conclusion was drawn from observations of impaired visuospatial abilities in individuals with bipolar disorder and findings that their intelligence quotient (IQ) scores were comparatively lower on the manipulative scale than on the verbal scale (Dalby and Williams, 1986). The hypothesis, proposed initially by Flor-Henry and Yeudal in the late 1970s, has undergone various revisions. For instance, Kluger and Goldberg conducted a meta-analysis in 1990, revealing that affective patients' characteristics were more similar to those with diffuse bilateral brain injury rather than individuals with lesions in the right hemisphere (Kluger and Goldberg, 1990). Furthermore, the previous study conducted by Bearden et al. (2001) highlights that individuals with bipolar disorder typically do not exhibit visuospatial impairments in straightforward tasks during affective episodes. However, these deficits arise during more intricate tasks involving memory, nonverbal conceptualization, and abstract reasoning abilities. As a result of this observation, they contend that the cognitive profile does not align with localized impairment alone in the right hemisphere but rather with the interplay of multiple integrated neuroanatomical systems, encompassing frontal-executive processes, attention, and memory (Gkintoni et al., 2022a).\n\nConversely, there has been a growing interest in examining cognitive impairments in individuals with bipolar disorder in recent years (Martinez-Aran et al., 2005). This interest has been fueled, at least partly, by studies aiming to identify potential similarities or differences in the neurocognitive functioning of patients with bipolar disorder compared to those with schizophrenia, often used as comparison groups in research studies (Gkintoni et al., 2017). Despite conflicting findings and a lack of consistency in the samples utilized, these comparative studies have generated hypotheses regarding the shared and distinct neuropsychological and neurobiological foundations of both disorders. Additionally, they have contributed to the development of conceptual and methodological frameworks within various domains of neuropsychiatry.\n\nThe earliest comparative investigations have generated a growing interest in the involvement of cognitive functions in bipolar disorder regarding its etiological implications and potential treatments for patients. Notably, impairments in neurocognitive functioning can be highly significant in their ability to serve as markers of functional prognosis (Antonopoulou et al., 2021,2022). They can predict various outcomes, such as adjustment, social competence, and quality of life in individuals affected by these deficits (Austin et al., 2001).\n\nHence, there is a recognized need to conduct further research to define the neuropsychological profiles of individuals in both the acute and clinical remission stages of bipolar illness. This will enable the formulation of epistemic and intervention theories. Research conducted on individuals with bipolar disorder during non-asymptomatic phases offers the potential to uncover cognitive characteristics.\n\nBipolar disorder is a psychiatric disorder distinguished by alternating episodes of mania and depression. The clinical manifestations of bipolar disorder are widely recognized, but there is an increasing scholarly focus on comprehending the cognitive aspects of this condition. Neuropsychological functioning pertains to the cognitive capacities and mechanisms linked to the brain's functioning (Gkintoni et al., 2023). Numerous research has been conducted to examine the neuropsychological functioning of individuals diagnosed with bipolar disorder, focusing on their cognitive abilities during periods of euthymia (i.e., stable mood states). Torres et al. (2007) conducted a meta-analysis to investigate the neuropsychological performance of persons diagnosed with euthymic bipolar illness compared to a control group of healthy individuals. The research revealed notable disparities of medium-to-large effect sizes in attention/processing speed, episodic memory, and executive functioning between the sick and control groups. The results of this study indicate that patients diagnosed with bipolar disorder may exhibit cognitive impairments in these categories. Martínez-Arán et al. (2005) conducted an independent study to examine and compare the cognitive abilities of patients with bipolar exhibiting high-functioning and low-functioning characteristics concerning a control group of individuals without bipolar disorder. The study found that patients with bipolar illness have worse cognitive function than non-patients. Verbal memory and executive functioning were impaired in cognitively impaired people.\n\nBora et al. (2009) did a meta-analysis to examine cognitive deficits in affective psychoses such as bipolar illness and major depressive disorder. The study found that patients with bipolar disorder had similar attentional processing, learning, and memory impairments to patients with euthymic bipolar disorder. Cognitive impairments may be widespread in emotional psychoses, according to this study. Additionally, several researchers have examined specific cognitive domains in patients with bipolar disorder. Clark et al. (2002) found attention abnormalities in patients with bipolar disorder. This suggests that these inadequacies may indicate disorder vulnerability. Reinke et al. (2013) examined language-processing brain areas and verbal memory in patients with euthymic bipolar illness. The study found changes in intrinsic functional connectivity across brain regions connected to language, suggesting a relationship between language deficiencies and verbal memory delays in bipolar disorder. It is essential to understand that bipolar disorder might cause cognitive impairments after euthymia. Cognitive impairments may occur during manic and depressive periods, according to research. In depressive episodes, patients with bipolar disorder have abnormalities in reward processing, short-term spatial memory recall, and sensitivity to negative feedback, according to Roiser et al. (2009). This study suggests that the impairments are caused by the disease rather than mood-stabilizing medicines. Data suggests that bipolar disorder may impair attention, processing speed, memory, executive functioning, sustained attention, and language. The illness's euthymic and symptomatic phases may reveal these shortcomings. Further research is needed to understand the genesis and therapeutic implications of bipolar disorder's cognitive features.\n\n\nNeurobiological pattern in bipolar disorder\n\nBipolar disorder is a complex mental illness that causes mania and sadness. The neurobiology of bipolar disorder has been studied extensively to determine its processes and biomarkers. The neurological correlates of bipolar disorder have been shown via neuroimaging. Strakowski et al. (2012) and (2004) found anomalies in brain areas and networks involved in emotional regulation, cognitive processing, and reward systems. The pathophysiology of bipolar disorder has been linked to alterations in multiple brain regions, such as the prefrontal cortex, amygdala, striatum, thalamus, and limbic circuits (Strakowski et al., 2012; Strakowski et al., 2004; DelBello et al., 2004). The investigation of bipolar disorder has explicitly focused on the prefrontal cortex, particularly the ventromedial prefrontal cortex (vmPFC). The presence of dysfunction within the vmPFC and its interconnections with other cerebral regions, including the amygdala and striatum, has been linked to the occurrence of emotional dysregulation and mood instability (Strakowski et al., 2012; Abé et al., 2021).\n\nDisturbances may influence the occurrence and advancement of bipolar disorder in the connection and regulation of the aforementioned brain regions (Strakowski et al., 2012; DelBello et al., 2004). The neurobiological characteristics of bipolar disorder are also influenced to a great extent by genetic factors. Previous research has successfully discovered genetic risk factors linked to changes in the brain's structural and functional aspects, specifically in the vmPFC (Abé et al., 2021). The neurological mechanisms underlying bipolar illness are further influenced by the interaction between hereditary predisposition and environmental circumstances (Abé et al., 2021). Cognitive deficiencies are frequently found in patients diagnosed with bipolar disorder, and research in neurobiology has yielded valuable insights into the brain underpinnings of these impairments. Cognitive dysfunction in bipolar disorder has been linked to abnormalities in brain regions implicated in cognitive functions, including the prefrontal cortex, temporal lobe, and cerebellum (Strakowski et al., 2004; Simonsen et al., 2008). The comprehension of the neurobiological underpinnings of cognitive deficits might provide valuable insights for designing and implementing specific therapies to enhance cognitive performance in individuals diagnosed with bipolar illness.\n\nIn summary, findings from neurobiological investigations on bipolar disease have shown deviations in brain morphology, connectivity, and activity, specifically within areas implicated in emotional regulation, cognitive functioning, and reward mechanisms (Gkintoni et al., 2021). The involvement of the prefrontal cortex, limbic circuits, and their interplay has been identified as playing a role in the pathophysiology of bipolar disorder (Coffman et al., 1990). The neurobiological patterns found in this illness are additionally influenced by genetic variables and their interplay with environmental influences. Ongoing investigation in this domain is necessary to enhance our comprehension of the fundamental mechanisms further and facilitate the development of more efficacious interventions for persons diagnosed with bipolar illness.\n\n\nNeuropsychological findings during affective episodes\n\nTypically, within the context of therapeutic practice, it is commonly noted that these patients present with cognitive challenges. Furthermore, many of these individuals have exhibited cognitive decline and deterioration throughout the acute stages (Sweeney et al., 2000). According to Martínez-Aran et al. (2007), there have been observed variations in the fluency of thought and speech, impairments in learning and memory, and modifications in associative patterns and attentional processes during both depressed and manic episodes. Challenges have also been noted in activities that necessitate sequential processing and evaluate cognitive abilities at a higher level, such as abstraction and adaptability (Bearden et al., 2001).\n\nCertain researchers have observed comparable impairments in both types of affective episodes (Bulbena and Berrios, 1993) and suggest the presence of a widespread cognitive dysfunction that may be linked to a shared pathophysiological mechanism involving multiple neuronal regions, including the dorsolateral prefrontal cortex. This brain region maintains numerous connections with cortical systems involved in information processing. However, alternative research suggests that individuals with bipolar I disorder exhibit distinct cognitive profiles during episodes of mania and depression (Sweeney et al., 2000). These differences are primarily observed in tasks that require the emotional processing of stimuli. Murphy et al. (1999) suggest that the observed cognitive variations could be associated with divergent activation patterns within the subgenual area of the corpus callosum. Drevets et al. (1997) found that this brain area is overactive during manic episodes and underactive during depressive periods. Thus, the ventromedial prefrontal cortex, which is highly connected to the limbic system, may be involved in these cognitive processes. Research shows that individuals experiencing a manic episode often have trouble focusing. This deficiency is connected to diminished prefrontal and hippocampal cortical volume, according to Sax et al. in 1999. The deficit seen in mania is often attributed to attention impairment (Clark et al., 2001). Distraction in healthcare situations is also important. Subsequent investigations have revealed a significant decline in executive functioning, as evidenced by deficiencies in cognitive tasks such as the Tower of London (Sweeney et al., 2000) and the Stroop Color-Word Stroop test (Golden et al., 2002; McGrath et al., 1997). In addition, researchers have also noted impairments in spatial working memory (Sweeney et al., 2000). Several studies have examined the cognitive deficits associated with manic episodes. For instance, Sweeney et al. (2000) found impairments in various aspects of memory, while Clark et al. (2001) identified deficits specifically in verbal learning. McGrath (2001) posit that some scholars have proposed a potential link between the observed memory impairments during this phase of the disorder and altered patterns of verbal association (Fleck et al., 2003).\n\nIn the realm of language, particularly concerning verbal fluency, while certain studies have failed to identify impairments during manic episodes (Calev et al., 1989), a recent investigation (Lebowitz et al., 2001) has demonstrated that individuals with a more remarkable history of manic episodes exhibit a substantial number of errors in both phonological and semantic fluency tasks.\n\nIn a study conducted by Bearden et al. (2001), a limited number of patients with bipolar disorder were examined across various phases of the disorder. The findings revealed that individuals with bipolar disorder exhibited a deficit in verbal learning ability while in a manic state compared to their performance during the remission phase. However, no significant differences were observed in short-term free recall ability across different mood states. These results led the authors to propose that the experience of mania may specifically impact complex processing or memory functions while leaving more straightforward cognitive tasks unaffected.\n\nIn the context of examining symptomatic episodes of schizophrenia and mania, certain researchers (Morice, 1990) have observed that there are no discernible distinctions in the neurocognitive impairment profiles of patients with schizophrenia and bipolar disorder. This observation is particularly evident in tasks that evaluate executive function, such as the Wisconsin Card Sorting Test. Consequently, it can be inferred that some of the deficits identified in these patients are not exclusive to either diagnostic category. However, according to Goldberg et al. (1993), there is evidence of more pronounced dysfunction in the frontal region among individuals diagnosed with schizophrenia. Additionally, Raust et al. (2014) propose the possibility of temporary global brain dysfunction in individuals experiencing mania and a more enduring prefrontal dysfunction in those with schizophrenia.\n\nDuring episodes of depression, individuals diagnosed with bipolar disorder have impairments in memory, particularly in the episodic aspect. This observation, as reported by Sweeney et al. (2000), indicates a resemblance between patients with bipolar and patients with unipolar depression, implying the presence of temporal lobe dysfunction in both cohorts. Nevertheless, Borkowska and Rybakowski (2001) conducted a study that revealed distinct cognitive profiles between individuals with bipolar and unipolar depression. Specifically, individuals with bipolar depression had poorer performance on tasks assessing some components of frontal lobe functions. The heightened cognitive impairment observed in individuals with bipolar depression and its correlation with frontal brain activity may indicate potential variations in the underlying causes compared to unipolar affective illness.\n\nBy contrast, a subsequent investigation conducted by Donnelly, Murphy, Goodwin, and Waldman (1982) revealed that the patients mentioned above exhibited diminished cognitive abilities, as indicated by lower IQ scores, during periods of depression compared to their euthymic phase. This decline in IQ scores persisted even when accounting for practice effects, as the reduction was observed again during subsequent depressive episodes.\n\nOne of the explanations proposed regarding the cognitive impairments observed in bipolar disorder during acute phases is presented by Albus et al. (1996). They argue that these deficits result from the presence of psychotic symptoms and their impact on neuropsychological functioning rather than being solely attributed to the clinical diagnosis of bipolar disorder. However, it is worth noting that subsequent research, as indicated by Mojtabai et al. (2000), has not confirmed this assertion. Furthermore, Micklowitz et al. (1992) conducted additional research that indicates individuals diagnosed with bipolar disorder who exhibit symptoms of psychosis are prone to have a more severe and persistent illness trajectory. This finding suggests that these patients may therefore encounter more pronounced cognitive decline as time progresses. Nevertheless, there remains a dearth of comprehensive research investigating the precise impact of psychotic symptoms on cognitive functioning within bipolar disorder.\n\n\nNeuropsychological findings in euthymia\n\nIn recent years, there has been an accumulation of empirical data indicating the presence of cognitive impairments in many individuals diagnosed with bipolar disorder during periods of remission or euthymic states (Taylor & Vaidya, 2005). The results of this study indicate that specific cognitive impairments are not limited to affective episodes or dependent on the individual's current condition but persist even after the resolution of such events. This suggests that individuals with bipolar disorder do not fully recover between episodes. This statement contradicts Kraepelin's original proposition on manic-depressive psychosis, as he posited that it does not exhibit a decline in functioning following the acute phase, in contrast to schizophrenia (Ferrier and Thompson, 2002). The classical understanding of bipolar disorder was primarily embraced within psychiatry, even without comprehensive empirical investigations, and has persisted throughout the years.\n\nHowever, there is an ongoing debate in neuropsychology regarding the cognitive impairments present during the acute phases of a condition and if these impairments continue in a state of clinical remission (McGrath 2001). One could posit that most of these deficits resolve during periods of euthymia, with only a subset appearing to endure (Altshuler, 1993). It is not commonly observed that there is a pervasive intellectual deficit, but rather indications of constraints in certain cognitive functions or information processing strategies (Bearden et al., 2001).\n\nNevertheless, there is a lack of clarity in the medical literature regarding whether the deficits observed can be attributed to a decline in cognitive function that occurs as the disorder progresses or if they are pre-existing in individuals before the onset of clinical episodes of bipolar disorder. This ambiguity suggests the potential presence of trait markers rather than cognitive dysfunctions dependent on the clinical state. The literature contains several research (Sigurdsson et al., 1999) that examine the correlation between bipolar disorder and a history of delayed motor, social, and language development in individuals. Nevertheless, the limited body of research on this matter hinders the ability to ascertain whether cognitive dysfunction indicates susceptibility to bipolar disorder.\n\nComparative investigations conducted on individuals in the asymptomatic phase of bipolar illness and schizophrenia have failed to yield definitive findings about the cognitive profiles exhibited by individuals with both disorders during periods of remission. Morice (1990) reported no statistically significant distinctions in neurocognitive impairment profiles. However, subsequent research conducted by Hawkins et al. (1997) revealed that patients with euthymic bipolar exhibited poorer performance in attentional tests assessing visuomotor speed (specifically, Digit-Symbol and Trail Making Test) compared to stabilized individuals with schizophrenia. Nevertheless, the prevailing evidence consistently indicates the presence of notable cognitive impairment in individuals diagnosed with schizophrenia across a range of cognitive domains. Specifically, studies have revealed deficits in psychomotor speed, attention, and working memory (Elvevag and Goldberg, 2000), executive functions (Krabbendam et al., 2000), and verbal function (Gruzelier et al., 1988). Notably, these cognitive deficits are more pronounced in patients with schizophrenia than in individuals with bipolar and unipolar affective disorders. The results mentioned above align with traditional nosological concepts, which posited that bipolar disorder, in contrast to schizophrenia, does not exhibit a pervasive cognitive deficit or impairment that is unrelated to illness episodes or the premorbid state (Miller, 1975). However, it is worth noting that this perspective has been subject to reevaluation in recent times.\n\nThe abovementioned questions about stability and the selectivity and specificity of cognitive deficits in bipolar disorder continue to lack clarity. The current situation can be attributed, at least in part, to the limited amount of scientific research conducted on neuropsychological assessment in euthymic individuals with bipolar disorder (Miller, 1975). Furthermore, the existing body of literature generally lacks definitive findings regarding cognitive impairments in patients with bipolar I disorder during the euthymic phase (Hawkins et al., 1997).\n\nThe observed variations in the outcomes are attributed to the presence of errors or methodological inconsistencies across most studies. These errors include the utilization of diverse and occasionally ambiguous remission criteria, diagnostic heterogeneity, limited sample sizes, inadequate control over the impact of pharmacological treatment and subclinical symptoms, and the influence of practice (Martínez-Aran et al., 1999b). It is essential to highlight the significant lack of longitudinal studies incorporating cognitive assessments before and after the onset of the disorder, as well as during periods of illness and clinical remission. These studies would provide valuable insights into whether alterations in intellectual function are attributable to clinical status, genetic predisposition, or treatment conditions (Stoll et al., 1996).\n\nThe final variable under consideration, medicine, holds significance due to its impact on psychological functions, as evidenced by studies on the administration of psychopharmacological therapies such as lithium (Ananth et al., 1987). These medications have been found to induce memory impairments and psychomotor deceleration potentially. Nevertheless, it is frequently seen that patients do not exhibit these deficiencies (Honig et al., 1999). A study conducted by Kessing (1998) revealed a significant correlation between the frequency of episodes and lithium medication and two of the five assessments of overall cognitive performance. In a study conducted by Lund et al. (Bearden et al., 2001), it was discovered that individuals with bipolar disorder who received long-term treatment with lithium exhibited average performance levels on attention and memory tasks compared to the general population (Shaw et al., 1987). Similarly, Engelsmann, Katz, Ghadirian, and Schachter (Engelsmann et al., 1988) observed that the memory scores of patients with bipolar treated with lithium, both in the short and long term, remained consistently stable over six years.\n\nAccording to Bearden et al. (2001), concentration difficulties may arise due to using alternative mood stabilizers, such as carbamazepine or valproate. Nevertheless, Thompson et al. (2006) have presented research suggesting that individuals with epilepsy may improve their attention span when undergoing carbamazepine treatment compared to alternative anticonvulsant medications.\n\nAccording to Martinez-Aran et al. (2002), tricyclic antidepressants have been found to enhance cognitive function, but they may have a negative impact on memory. Similarly, long-term antipsychotic medication has been associated with improved overall performance. Nevertheless, when administered in high quantities, it has been found to potentially result in decreased performance on verbal memory or attention assessments (Cassens et al., 1990). Regarding this matter, most of the research undertaken on antipsychotics, explicitly focusing on individuals diagnosed with schizophrenia, has reached the consensus that the cognitive impairments identified in these patients are primarily attributable to the disorder itself rather than the treatment with antipsychotic medication.\n\nThe collective results indicate that although medication may result in a certain level of cognitive deceleration, the neuropsychological impairments observed in individuals with bipolar disorder do not seem to be a consequence of pharmaceutical intervention (Bearden et al., 2001). Nevertheless, it is imperative to acknowledge that there remains a dearth of knowledge regarding the impact of medication on cognitive abilities in individuals with bipolar disorder, given the limited number of studies conducted within this specific population. Furthermore, it is imperative to consider the challenges that arise when evaluating the impact of psychotropic drugs on patients who are frequently prescribed many medications and may even get varying dosages over a period.\n\nFurthermore, additional findings derived from some research studies suggest that the observed effect is more likely attributable to the progression and development of the condition rather than the existence of endophenotypes or markers on a neuropsychological level. Therefore, previous research has proposed that individuals with recurrent or severe mood disorders may experience deficits in neuropsychological functioning during the euthymic phase (Zarate et al., 2000; McKay et al., 1995). Additionally, the number of episodes, particularly those characterized by depression, may impact these impairments, as indicated by Kessing et al.'s study (1998). The study by Tham et al. (1997) revealed a notable correlation between decreased cognitive functioning and increased occurrences of relapses or episodes of mania or depression, as well as a greater frequency of hospitalizations compared to individuals with normal cognitive functioning. Denicoff et al. (1999) observed that individuals with a more severe course of illness, characterized by a higher number of episodes and hospitalizations and a longer duration of sickness, exhibited poorer performance in memory, attention, and abstraction tasks. Similarly, previous researchers (Cavanagh et al., 2002) have likewise documented a potential collective adverse impact on the verbal learning and memory systems, as well as the frontal or executive system, concerning the length of the disorder and occurrences of manic and depressive episodes.\n\nHence, there has been a proposition suggesting that affective episodes could potentially result in brain tissue damage or lesions, referred to as a psychic imprint or scar. This proposition implies that the persistent cognitive deficits observed during the euthymic phase may serve as a functional manifestation of such damage, particularly concerning learning and memory functions (Altshuler, 1993). Nevertheless, the idea suggesting a gradual deterioration in cognitive functioning from the premorbid state concerning the trajectory of bipolar disorder lacks empirical validity, as indicated by long-term follow-up studies (Dhingra and Rabins, 1991). The extent to which the deficiencies reported in previous investigations (Savard et al., 1980) can be attributed to the senior age of the participants tested rather than the chronicity or severity of the disorder remains uncertain. Moreover, it is conceivable that the existence of chronicity and cognitive impairment could indicate the disorder's severity. Patients with bipolar illness with reduced cognitive ability may have more episodes. Thus, chronicity may signal cognitive deficits and the condition rather than causing cognitive decline (Tohen et al., 1990; Tohen, 2000). However, more research is needed to prove this concept.\n\nThe sustained cognitive deficiencies experienced by patients with bipolar illness during the euthymic phase have caused much debate. Recent research has focused on cognitive functions, particularly memory and executive function. Due to their frequent association with maladaptive tendencies, these domains have drawn examination. Ferrier and Thompson (2002) found lasting memory and executive function deficits alone or in combination.\n\n\nLearning and memory\n\nMultiple studies have provided evidence of a decrease in cognitive abilities, specifically in the domains of learning and memory. Specifically, the impairment has been observed in verbal or explicit declarative memory, as assessed by the California Verbal Learning Test (CVLT) (Cavanagh et al., 2002; Delis et al., 1987). Hence, a decrease in learning and memory of words was reported in euthymic individuals with bipolar disorder compared to control subjects, specifically regarding accessible and directed recall (Atre-Vaidya & Hussain, 1999; van Gorp et al., 1999).\n\nThe findings presented in this study have been independently verified by other researchers (Ferrier et al., 1999), who propose that specific memory impairments continue to exist even during remission in individuals with bipolar disorder (Thompson et al., 2001; Thompson, 2007). Nevertheless, there remains uncertainty regarding the potential impact of subclinical depressive-type symptomatology on this dysfunction, which could be observed in individuals with euthymic bipolar disorder (Ferrier et al., 1999). Additionally, it is unclear whether various factors associated with the progression of the disorder, such as the frequency of depressive episodes, the duration of bipolar disorder (Van Gorp et al., 1998), or the number of manic episodes (Cavanagh et al., 2002), may also contribute to this dysfunction.\n\nTherefore, the current findings do not provide sufficient evidence to determine whether the observed learning and verbal memory impairments mentioned earlier can be considered as inherent cognitive traits of these patients, as indicated by Gourovitch et al. (1999) in their investigation of monozygotic twins who differ in their bipolar disorder status. This study compared twins who were affected, unaffected, and those without the disorder. The results of this study suggest that genetic factors associated with the disorder may contribute to subtle alterations in overall memory or retrieval function rather than being directly implicated in its initiation and advancement.\n\n\nExecutive function\n\nThe cognitive domain, referred to as executive function, holds significance due to its inclusion of a range of advanced cognitive processes, including but not limited to planning, decision-making, problem-solving, cognitive flexibility, and inhibitory control (Gkintoni et al., 2022b; Halkiopoulos et al., 2022). Extensive research has been conducted on the clinical neuropsychological characteristics of bipolar disorder, with a particular focus on examining executive function. In their study, Bora and Pantelis (2015) undertook a meta-analysis intending to examine and contrast the cognitive impairment observed in individuals who have undergone their initial episode of bipolar disorder (FEBP), the inaugural episode of schizophrenia (FES), and a control group comprising individuals without any psychiatric disorders. The study found that patients with Frontal Epilepsy-Related Brain Pathology (FEBP) had severe cognitive deficits, notably in executive tasks. In numerous cognitive domains, including executive skills, functional electrical stimulation (FES) was inferior to functional electrical brain stimulation (FEBP). This study suggests that patients with bipolar disorder and schizophrenia have executive function issues. Bora and Pantelis (2015) found that patients with bipolar disorder experiencing their first episode have impairment levels between schizophrenia and those without psychiatric disorders.\n\nIn addition to meta-analyses, Sparding et al. (2021) did a longitudinal investigation of the cognitive functioning of patients with bipolar illness. The study found a substantial difference in executive functioning speed and accuracy between patients with bipolar I and II. The findings of Sparding et al. (2021) indicate the potential existence of variations in executive function between individuals diagnosed with bipolar I disorder and those diagnosed with bipolar II disorder. The examination of the relationship between executive function and everyday functioning in individuals with bipolar disorder has also been conducted. The study conducted by Depp et al. (2012) employed a meta-analytic approach to investigate the association between cognitive abilities and everyday functioning in individuals diagnosed with bipolar disorder. The research revealed that individuals diagnosed with bipolar disorder frequently experience neurocognitive impairments, particularly in executive function, significantly impacting their ability to function effectively. The level of correlation between cognitive ability, specifically executive function, and everyday functioning was found to be comparable to the correlation observed in individuals with schizophrenia (Depp et al., 2012).\n\nWhile it is frequently observed that patients with bipolar in a euthymic state exhibit abnormalities in executive function, significant disagreement exists regarding the precise degree to which impaired executive functioning is specifically linked to bipolar disorder (Rubinsztein et al., 2000).\n\nAccording to a study conducted by Ferrier and Thompson (2002), it has been noted that individuals with bipolar disorder who are in a euthymic state demonstrate inferior performance on tasks related to executive function, notably the Wisconsin Card Sorting Test (Graham Beaumont, 1981; Heaton, 1981). This phenomenon is notably apparent when examining the number of accomplished categories and perseverative errors in individuals diagnosed with bipolar disorder compared to a control group of individuals without the disorder who are in good health.\n\nHowever, several studies have been unable to detect any deficiencies in different tests assessing frontal function, such as the Trail Making Test (TMT) and the FAS, as documented by Van Gorp et al. (1998) and other scholars (Bauwens et al., 1991; Cavanagh et al. 2002). Nevertheless, it is imperative to acknowledge that instances that deviate from this prevailing pattern exist. An example of a study conducted by Ferrier et al. (1999) involved observing changes in the TMT, FAS, and Tower of London tests among patients in remission. The abovementioned modifications became apparent solely after accounting for age, premorbid IQ, and subclinical depressive symptoms.\n\nHowever, certain studies have proposed that executive deficits may not manifest initially at the onset of the disorder but rather emerge and progress throughout the illness. The chronic nature of the disorder can potentially impact these deficits, resulting in confusion and challenges in differentiating between executive deficits and the duration of the disorder (Martinez-Aran et al., 2002). This observation suggests that the maintenance of clinical remission and the prevention of relapse may function to hinder further decline and potentially promote progress.\n\nIn general, the existing body of literature consistently suggests that individuals diagnosed with bipolar disorder may exhibit impairments in executive function. The deficits mentioned above are evident during both the symptomatic and euthymic phases of the disorder, and they play a role in causing functional impairment. Nevertheless, it is imperative to acknowledge that the presence of executive function impairments in individuals with bipolar disorder is not consistently observed across all studies. Therefore, additional research is warranted to understand better the underlying mechanisms and potential therapeutic implications associated with these neuropsychological traits.\n\n\nAttention\n\nAttention is a core cognitive function that plays a fundamental role in many higher-order cognitive processes, from memory to executive functions. Attentional deficits in bipolar disorder (BD) can substantially impact various aspects of daily functioning, the trajectory of the illness, and its overall prognosis. An in-depth examination of attention as a prominent factor in the clinical neuropsychological manifestations of bipolar disorder pertains to deficits in attention observed throughout various phases (Wilder-Willis et al., 2001).\n\nPrior studies have demonstrated that many individuals diagnosed with bipolar disorder exhibit deficits in their attentional system during acute episodes. The manifestation of this dysfunction is notably apparent in assessments of selective attention, such as the Stroop Color-Word test, as well as sustained attention, exemplified by the continuous performance test. Nevertheless, it seems that these attentional deficits are less prevalent among individuals diagnosed with bipolar disorder who are experiencing a euthymic state. The discovery was reported by Quraishi and Frangou in 2002. Many feel that selective attentional deficiencies rely on a person's state. Van Gorp et al. (1998) found that selective attention is unaffected by euthymia.\n\nHowever, research has shown that patients with bipolar illness may have chronic concentration issues (Clark et al., 2002). This is particularly true for people with subjective cognitive difficulties (Martinez-Aran et al., 2002). These issues may be more likely in people with more recurrent depression or longer-term bipolar disorder (Clark et al., 2002).\n\nIn some circumstances, early attentional mechanisms may impede psychomotor slowing. Cognitive impairment can be reversed, especially after depressive episodes end. This illness can also cause depression-like symptoms including intrusive rumination or mania-like symptoms such as focus issues. Psychomotor slowing is linked to motivation and pharmacological therapies like lithium or antipsychotics (Martinez-Aran et al., 2002; Shaw et al., 1987). This implies that the manifestation of psychomotor slowing is contingent upon the individual's current state (Paradiso et al., 1997). However, it is worth noting that specific authors have observed a consistent impairment in psychomotor speed among patients with bipolar, even during periods of euthymia (Hawkins et al., 1997).\n\nIn summary, examining attention is a pivotal factor in comprehending the neuropsychological terrain associated with bipolar disorder. The improvement of attentional deficits through addressing and rehabilitating them has been shown to substantially impact the overall quality of life and functional outcomes of individuals diagnosed with BD.\n\n\nLanguage\n\nComprehending the neuropsychological and language characteristics of bipolar disorder can be advantageous in the clinical context for diagnosis and intervention. Linguistic patterns provide a concrete and observable collection of actions that assist physicians in assessing an individual's position within their mood cycle and the intensity of their symptoms at that time. Integrating this approach with a comprehensive neuropsychological evaluation yields an extensive comprehension of the individual's condition (Graham Beaumont, 1981). During episodes of mania, individuals may display symptoms of pressurized speech characterized by quick, excessive, and urgent talking patterns. Individuals with this communication style may exhibit challenges in being interrupted and may demonstrate a tendency to transition rapidly between different subjects. Individuals diagnosed with bipolar disorder, particularly during episodes of mania, may display tangential speech, characterized by a tendency to deviate from the central topic without returning to it, or circumstantial speech, which includes extraneous details and a prolonged approach to conveying the main message. Specific individuals diagnosed with bipolar disorder (BD) have reported experiencing heightened levels of verbal creativity, whether in hypomania or mania. The individuals in question may opt to employ a more intricate lexicon, establish distinctive language associations, or use poetic or metaphorical discourse. During the depression, individuals may experience a decrease in the frequency of their speech and an increase in its monotony. The individual may exhibit diminished verbal expression and employ a restricted lexicon, indicative of their depressive state. During episodes of intense mania or depression, individuals may experience challenges in comprehending a person's words due to the disorganization of their ideas. This may be incoherent or characterized by \"word salad\" speech patterns.\n\nRegarding language, disruptions in communication among patients with bipolar who are generally stable appear to be associated with worse performance in tasks that require concept formulation and verbal fluency. On the other hand, in patients with schizophrenia, these disruptions are more likely to be connected to attention and working memory processes. Nevertheless, there exist disparities in the findings of the studies mentioned above. Van Gorp et al. (1998) reported insignificant disparities in verbal fluency between individuals diagnosed with bipolar disorder and those without the condition. Conversely, Ferrier et al. (1999) observed substandard performance in fluency tasks among individuals with bipolar disorder who were in a euthymic state. Moreover, it has been postulated that these disparities may be associated with depressed subsyndromal symptomatology (Martínez-Aran et al., 1999a).\n\nConcerning this matter, it is worth noting that while patients are commonly characterized as asymptomatic or euthymic in research studies, many exhibit subsyndromal fluctuations that impact their overall functioning. These fluctuations appear to be associated with cognitive dysfunctions, as discussed in the literature (Ferrier and Thompson, 2002), and with suboptimal psychosocial adjustment (Bauwens et al., 1991). Hence, there is a significant scholarly interest in investigating the occurrence and characteristics of subclinical symptoms in individuals with euthymic bipolar disorder and quantifying them through clinical symptom assessment scales (specifically for depression and mania). This research aims to explore the impact of these symptoms on patients' cognitive abilities, as assessed using neuropsychological testing. In conclusion, the results of the studies suggest lasting cognitive deficits in a specific group of individuals with bipolar disorder during periods of mood stability. These impairments are most observed in the domains of memory and executive function, which may suggest the presence of inherent characteristics rather than temporary alterations. However, these findings sometimes appear primarily linked to clinical and pharmacological factors. Hence, their research entails examining and regulating several factors that could impact the occurrence of these impairments, including subclinical or subsyndromal symptomatology, pharmaceutical intervention, and the trajectory and progression of the condition.\n\n\nDiscussion and conclusions\n\nBipolar disorder is distinguished by alternating episodes of mania and depression. The clinical manifestations of bipolar disorder have been extensively examined, prompting a surge of scholarly attention towards comprehending the neuropsychological aspects of this condition. Neuropsychological functioning pertains to the cognitive capacities and mechanisms that underpin behavior and mental processes. Numerous studies have been conducted to examine the neuropsychological functioning of individuals diagnosed with bipolar disorder. Torres et al. (2007) conducted a meta-analysis to investigate the neuropsychological performance of individuals diagnosed with bipolar disorder who were in a euthymic state characterized by the absence of symptoms. The above research revealed that individuals diagnosed with bipolar disorder exhibited impairments in attention and processing speed, episodic memory, and executive functioning compared to those without the disorder.\n\nThe neuropsychological impairments observed in individuals with bipolar disorder have been subject to comparison with those observed in individuals with schizophrenia. The study conducted by Hill et al. (2013) investigated the neuropsychological impairments observed in individuals diagnosed with schizophrenia and psychotic bipolar disorder. The research revealed that individuals with bipolar disorder, similar to those with schizophrenia, exhibited persistent cognitive deficits characteristic of enduring traits. Nevertheless, a greater degree of cognitive impairments was consistently observed in individuals diagnosed with bipolar disorder who also experienced psychosis compared to those with bipolar disorder who did not exhibit psychotic symptoms. The present findings indicate that there may exist resemblances in the neuropsychological deficits observed in individuals with bipolar disorder and schizophrenia while also highlighting particular distinctions associated with psychosis. Researchers have also examined the correlation between cognitive impairments and daily functioning in individuals diagnosed with bipolar disorder. Depp et al. (2012) conducted a meta-analysis to investigate the correlation between cognitive abilities and everyday functioning in individuals diagnosed with bipolar disorder. The research revealed a significant correlation between cognitive impairments and functional disability in individuals diagnosed with bipolar disorder. The extent to which cognitive impairment affects functioning varies across distinct cognitive domains and functional indicators. The findings mentioned above indicate that cognitive deficits associated with bipolar disorder can substantially impact individuals' day-to-day functioning.\n\nTo summarize, investigations into the neuropsychological aspects of bipolar disorder have yielded findings supporting cognitive deficits in attention and processing speed, memory, and executive functioning. These impairments have the potential to manifest in individuals with both euthymic and symptomatic bipolar disorder and can have adverse effects on their psychosocial and daily functioning. The cognitive impairments observed in individuals with bipolar disorder exhibit similarities to those observed in individuals with schizophrenia, although distinctions may exist associated with psychosis. The existing comprehension regarding the stability, selectivity, and specificity of cognitive impairments in individuals with bipolar disorder is constrained due to several methodological inconsistencies. The observed disparities encompass variations in the criteria used to determine remission, diverse diagnostic profiles, limited sample sizes, and insufficient control over the influence of pharmacological treatment, subclinical symptoms, and practice effects.\n\nAdditional investigation is required to understand better the fundamental mechanisms and potential factors that may moderate neuropsychological impairments in individuals with bipolar disorder. Further research is necessary to ascertain the neuropsychological characteristics of individuals during the acute and clinical remission phases of bipolar disorder. This will facilitate the formulation of epistemological perspectives and hypotheses for intervention.\n\nThis study highlights the notable association between cognitive impairment and bipolar disorder. Despite the extensive corpus of evidence suggesting cognitive impairments in individuals diagnosed with bipolar disorder, a dearth of comprehensive comprehension of the neuropsychological profiles these patients display persists. Acquiring such knowledge is essential to effectively evaluate the intensity of symptoms, assess the effectiveness of treatment, and make predictions about functional outcomes. The impairments, as mentioned above, encompass disturbances in memory, attention, executive functioning, and language, are not limited to affective episodes but endure consistently even during periods of stable mood, suggesting a possible enduring nature to these deficits. However, there remains a dearth of clarity on whether these cognitive impairments indicate bipolar disorder or if they predate the onset of the disorder. Clarifying this matter is of utmost importance to improve diagnostic accuracy and develop more efficacious treatment approaches.",
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Portico. Publisher Full Text\n\nMartínez-Arán A, Vieta E, Colom F, et al.: Do Cognitive Complaints in Euthymic Bipolar Patients Reflect Objective Cognitive Impairment?Psychotherapy and Psychosomatics.2005; 74(5): 295–302. Portico. Publisher Full Text\n\nMartínez-Arán A, Vieta E, Torrent C, et al.: Functional outcome in bipolar disorder: the role of clinical and cognitive factors.Bipolar Disorders.2007; 9(1-2): 103–113. Publisher Full Text\n\nMcGrath J, Chapple B, Wright M: Working memory in schizophrenia and mania: correlation with symptoms during the acute and subacute phases.Acta Psychiatrica Scandinavica.2001; 103(3): 181–188. Portico. Publisher Full Text PubMed Abstract |\n\nMcGrath RG: EXPLORATORY LEARNING, INNOVATIVE CAPACITY, AND MANAGERIAL OVERSIGHT.Academy of Management Journal.2001; 44(1), 118–131. Publisher Full Text\n\nMcGrath J, Scheldt S, Welham J, et al.: Performance on tests sensitive to impaired executive ability in schizophrenia, mania and well controls: acute and subacute phases. Schizophr. Res. 1997; 26(2–3): 127–137. Publisher Full Text\n\nMcKay AP, Tarbuck AF, Shapleske J, et al.: Neuropsychological Function in Manic-Depressive Psychosis Evidence for Persistent Deficits in Patients with Chronic, Severe Illness. Br. J. Psychiatry. 1995; 167(1): 51–57. PubMed Abstract | Publisher Full Text\n\nMiklowitz DJ: Longitudinal Outcome and Medication Noncompliance among Manic Patients with and without Mood-Incongruent Psychotic Features. J. Nerv. Ment. Dis. 1992; 180(11): 703–711. PubMed Abstract | Publisher Full Text\n\nMiller WR: Psychological deficit in depression. Psychol. Bull. 1975; 82(2): 238–260. Publisher Full Text\n\nMojtabai R, Bromet EJ, Harvey PD, et al.: Neuropsychological Differences Between First-Admission Schizophrenia and Psychotic Affective Disorders. Am. J. Psychiatr. 2000; 157(9): 1453–1460. PubMed Abstract | Publisher Full Text\n\nMorice R: Cognitive Inflexibility and Pre-frontal Dysfunction in Schizophrenia and Mania. Br. J. Psychiatry. 1990; 157(1): 50–54. PubMed Abstract | Publisher Full Text\n\nMurphy FC, Sahakian BJ, Rubinsztein JS, et al.: Emotional bias and inhibitory control processes in mania and depression. Psychol. Med. 1999; 29(6): 1307–1321. PubMed Abstract | Publisher Full Text\n\nParadiso S, Lamberty GJ, Garvey MJ, et al.: Cognitive Impairment in the Euthymic Phase of Chronic Unipolar Depression. The Journal of Nervous &Amp Mental Disease. 1997; 185(12): 748–754. Publisher Full Text\n\nQuraishi S, Frangou S: Neuropsychology of bipolar disorder: a review. J. Affect. Disord. 2002; 72(3): 209–226. Publisher Full Text\n\nReinke B, Ven V, Matura S, et al.: Altered Intrinsic Functional Connectivity in Language-Related Brain Regions in Association with Verbal Memory Performance in Euthymic Bipolar Patients.Brain Sciences. 2013; 3(4): 1357–1373. Publisher Full Text\n\nRoiser JP, Cannon DM, Gandhi SK, et al.: Hot and cold cognition in unmedicated depressed subjects with bipolar disorder.Bipolar Disorders. 2009; 11(2): 178–189. Publisher Full Text | PubMed Abstract | , PMCID: Free Full Text\n\nRosvold HE, Mirsky AF, Sarason I, et al.: A continuous performance test of brain damage. J. Consult. Psychol. 1956; 20(5): 343–350. Publisher Full Text\n\nRubinsztein JS, Michael A, Paykel ES, et al.: Cognitive impairment in remission in bipolar affective disorder. Psychol. Med. 2000; 30(5): 1025–1036. PubMed Abstract | Publisher Full Text\n\nSackeim HA, Decina P, Malitz S, et al.: Dr. Sackeim and Associates Reply. Am. J. Psychiatr. 1983; 142(4): 522–523. Publisher Full Text\n\nSavard RJ, Rey AC, Post RM: Halstead-Reitan Category Test in Bipolar and Unipolar Affective Disorders. J. Nerv. Ment. Dis. 1980; 168(5): 297–304. PubMed Abstract | Publisher Full Text\n\nSparding T, Joas E, Clements C, et al.: Long-term trajectory of cognitive performance in people with bipolar disorder and controls: 6-year longitudinal study.BJPsych Open. 2021; 7(4). Publisher Full Text\n\nSweeney JA, Kmiec JA, Kupfer DJ: Neuropsychologic impairments in bipolar and unipolar mood disorders on the CANTAB neurocognitive battery. Biol. Psychiatry. 2000; 48(7): 674–684. PubMed Abstract | Publisher Full Text\n\nSax KW, Strakowski SM, Zimmerman ME, et al.: Frontosubcortical Neuroanatomy and the Continuous Performance Test in Mania. Am. J. Psychiatr. 1999; 156(1): 139–141. PubMed Abstract | Publisher Full Text\n\nRaust A, Daban C, Cochet B, et al.: neurocognitive performance As An Endophenotype For Bipolar disorder. Frontiers in Bioscience-Scholar. 2014; 1(E6): 89–103. Publisher Full Text\n\nShaw ED, Stokes PE, Mann JJ, et al.: Effects of lithium carbonate on the memory and motor speed of bipolar outpatients. J. Abnorm. Psychol. 1987; 96(1): 64–69. PubMed Abstract | Publisher Full Text\n\nSigurdsson E, Fombonne E, Sayal K, et al.: Neurodevelopmental antecedents of early-onset bipolar affective disorder. Br. J. Psychiatry. 1999; 174(2): 121–127. Publisher Full Text\n\nSimonsen C, Sundet K, Vaskinn A, et al.: Neurocognitive profiles in bipolar I and bipolar II disorder: differences in pattern and magnitude of dysfunction. Bipolar Disord. 2008; 10(2): 245–255. PubMed Abstract | Publisher Full Text\n\nStoll AL, Pillay SS, Diamond L, et al.: Dr. Stoll and Colleagues Reply. J. Clin. Psychiatry. 1996; 57(11): 548. Publisher Full Text\n\nStrakowski SM, Adler CM, Almeida J, et al.: The Functional Neuroanatomy Of Bipolar Disorder: a Consensus Model. Bipolar Disord. 2012; 14(14): 313–325. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStrakowski SM, DelBello MP, Adler CM: The Functional Neuroanatomy Of Bipolar Disorder: a Review Of Neuroimaging Findings. Mol. Psychiatry. 2004; 1(10): 105–116. Publisher Full Text\n\nTham A, Engelbrektson K, Mathe AA, et al.: Impaired Neuropsychological Performance in Euthymic Patients With Recurring Mood Disorders. J. Clin. Psychiatry. 1997; 58(1): 26–29. PubMed Abstract | Publisher Full Text\n\nThompson JM, Monkst PJ, Lloyd AJ, et al.: Functional MRI of verbal working memory in prospectively verified euthymic bipolar patients. NeuroImage. 2001; 13(6): 1106. Publisher Full Text\n\nThompson JM, Gray JM, Hughes JH, et al.: Impaired working memory monitoring in euthymic bipolar patients. Bipolar Disord. 2007; 9(5): 478–489. PubMed Abstract | Publisher Full Text\n\nThompson JM, Hamilton CJ, Gray JM, et al.: Executive and visuospatial sketchpad resources in euthymic bipolar disorder: Implications for visuospatial working memory architecture. Memory. 2006; 14(4): 437–451. PubMed Abstract | Publisher Full Text\n\nTohen M: Two-Year Syndromal and Functional Recovery in 219 Cases of First-Episode Major Affective Disorder With Psychotic Features. Am. J. Psychiatr. 2000; 157(2): 220–228. PubMed Abstract | Publisher Full Text\n\nTohen M, Waternaux CM, Tsuang MT, et al.: Four-year follow-up of twenty-four first-episode manic patients. J. Affect. Disord. 1990; 19(2): 79–86. PubMed Abstract | Publisher Full Text\n\nTorres IJ, Boudreau VG, Yatham LN: Neuropsychological functioning in euthymic bipolar disorder: a meta-analysis.Acta Psychiatrica Scandinavica. 2007; 116(s434): 17–26. Publisher Full Text\n\nvan Gorp WG , Altshuler L, Theberge DC, et al.: Declarative and procedural memory in bipolar disorder. Biol. Psychiatry. 1999; 46(4): 525–531. Publisher Full Text\n\nvan Gorp WG , Altshuler L, Theberge DC, et al.: Cognitive Impairment in Euthymic Bipolar Patients With and Without Prior Alcohol Dependence. Arch. Gen. Psychiatry. 1998; 55(1): 41–46. PubMed Abstract | Publisher Full Text\n\nWilder-Willis KE, Sax KW, Rosenberg HL, et al.: Persistent attentional dysfunction in remitted bipolar disorder. Bipolar Disord. 2001; 3(2): 58–62. Portico. PubMed Abstract | Publisher Full Text\n\nZarate CA Jr, Tohen M, Land M, et al.: Psychiatry Q. 2000; 71(4): 309–329. Publisher Full Text"
}
|
[
{
"id": "210876",
"date": "12 Oct 2023",
"name": "Andrew Sortwell",
"expertise": [],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntroduction: The introduction of the research paper offers a clear and engaging overview of neuropsychology, highlighting its focus on understanding the brain-mind-behavior relationship. The emphasis on psychological phenomena such as language, motivation, and memory sets the stage for discussing the relevance of neuropsychology in the context of bipolar disorder.\n\nResearch Gap: The paper effectively addresses the limited attention given to neuropsychological changes in individuals diagnosed with bipolar disorder compared to other psychiatric conditions like schizophrenia. By identifying this research gap, the authors underscore the importance of studying cognitive abnormalities in bipolar disorder, thus establishing a compelling rationale for the review.\n\nScope and Objectives: The paper defines its scope and objectives succinctly, aiming to compile and analyze existing research on the association between cognitive abnormalities and bipolar disorder. The comprehensive approach, including various stages of the condition and comparative studies with schizophrenia, reflects the thoroughness and relevance of the study.\n\nMethodology: Although the paper does not explicitly outline its methodology, it successfully reviews and synthesizes existing research, providing a cohesive analysis of the available literature. The inclusion of diverse studies enhances the credibility of the findings and enriches the discussion.\n\nFindings and Analysis: The review delves into the cognitive abnormalities associated with bipolar disorder, exploring research across different stages of the condition. The comparison with schizophrenia adds depth to the analysis, offering a broader perspective on neuropsychological aspects. Additionally, the consideration of psychopharmaceutical interventions contributes to a comprehensive understanding of potential treatment implications.\n\nImplications and Future Directions: The authors effectively discuss the etiological implications, therapies, preventions, and prognostic factors related to social competence and quality of life for patients with bipolar disorder. This section offers valuable insights for future research, highlighting the importance of further investigation in this area.\n\nConclusion: The conclusion succinctly summarizes the key findings and emphasizes the critical need for continued research in neuropsychology concerning bipolar disorder. The paper successfully advocates for a heightened focus on cognitive abnormalities, thereby contributing to a deeper understanding of the condition and its potential therapeutic implications.\n\nOverall Evaluation: Overall, this research paper offers a comprehensive and insightful review of the association between cognitive abnormalities and bipolar disorder. The study effectively identifies a significant research gap, analyzes existing literature, and provides valuable insights for future research and clinical practice. This contribution is essential for advancing our understanding of the neuropsychological aspects of bipolar disorder and improving the lives of affected individuals.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": []
},
{
"id": "220344",
"date": "08 Feb 2024",
"name": "Elias Kourkoutas",
"expertise": [
"Reviewer Expertise Clinical Psychology",
"Education",
"Clinical Interventions",
"School Psychology",
"Psychotherapy",
"Counseling"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article is a comprehensive review of current literature in the fields of clinical psychology and neuropsychology of psychosis particularly bipolar disorder. It comprises several key areas of study in bipolar disorder, describing the patterns of each one: memory, executive functions, attention, and language.\nThe article's language is accessible and the cognitive parameters are described analytically. The article consists of extended literature on the topic.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1235
|
https://f1000research.com/articles/12-1234/v1
|
27 Sep 23
|
{
"type": "Review",
"title": "Pathophysiology of risk factors for post operative complications",
"authors": [
"Pankaj Gharde",
"Roshani S Manekk",
"Pramita Muntode Gharde",
"Shalinder Koul",
"Pankaj Gharde",
"Pramita Muntode Gharde",
"Shalinder Koul"
],
"abstract": "Postoperative complications lead to an increase in morbidity and mortality, increase in hospital length of stay and costs for health care. Understanding the pathophysiology of various risk factors causing post-operative complications, helps in better understanding of the subject and perioperative patient assessment. The risk factors selected for the purpose of the study include modifiable risk factors and includes results from various single centre and multi-centre cohort studies, and systematic reviews and data from various meta-analysis by various authors on different subjects. The importance of optimizing the modifiable risk factors like hypoalbuminemia, anemia, obesity and smoking can be understood from the above study. It is important to remember that morbidity is multifactorial and taking into account only a single risk factor will not improve the outcomes. This signifies the importance of multidisciplinary approach when treating the patient.",
"keywords": [
"post-operative",
"complications",
"risk factors",
"pathophysiology"
],
"content": "Introduction\n\nPostoperative complications lead to an increase in morbidity and mortality, increase in hospital length of stay and costs for health care.1 Clavien and his colleagues, defined complications as “any deviation from the normal postoperative course.” The basic T92 model was revised by Clavien and his colleagues in the year 2004 which was later named as “Clavien-Dindo Classification”.2 The T92 model also known as the Clavien classification system described IV grades of complications, which was then classified into V grades in 2004 model as shown in Table 1. Currently peri-operative care has been standardized as per ERAS (enhanced recovery after surgery) protocols.3 This provides guidelines for improvement in the peri-operative care of patients. This is beneficial only when, the screening is focused on modifiable risk factors, which can be partially reversed for example nutritional support along with physiotherapy. Many of the studies are focused on decreasing the complications by improving the surgical techniques; but, very few studies emphasize on improvement of peri-operative care.1 Understanding the pathophysiology of various risk factors causing post-operative complications, helps in better understanding of the subject and perioperative management of patient to decrease the morbidity and mortality in the patient. The aim of this review is to understand the pathophysiology of various important risk factors responsible for post-operative complications (Table 1).\n\n* Acceptable drugs – antiemetics, antipyretics, analgesics diuretics, electrolytes. Therapeutic regimens allowed-Physiotherapy.\n\n\nMethods\n\nThe risk factors selected for the purpose of the study include modifiable risk factors like anemia, hypoalbuminemia, obesity, smoking and non-modifiable risk factors related to demographic characteristics of the patient for example age and gender and other non-modifiable factors include history of previous abdominal surgery. A set of key words was selected for example pathophysiology, pre operative risk factors, post-operative complications and related literature was studied and narrated in the present study. The literature includes results from various single centre and multi-centre cohort studies, and systematic reviews and data from various meta-analysis by various authors on different subjects. A total of 21 studies were included in the following study to stratify the data pertaining to pathophysiology of various risk factors. No specific exclusion criteria were made.\n\n\nDiscussion\n\nThere are numerous risk factors associated with occurrence of post-operative complications like age, gender, comorbidities, hypoalbuminemia, anemia, obesity, smoking, higher ASA score, etc. Also, there are specific risk factors for certain surgeries for example, laparoscopic surgeries, where history of previous abdominal surgeries play an important role in conversion of a laparoscopic procedure to open. The purpose of this article is to discuss the pathophysiology of common risk factors we encounter in day-to-day life in detail.\n\nThere is a higher incidence of post-operative complications in elderly patients, when compared to younger age groups.4 A systematic review and meta-analysis published in 2018 notes that although more post operative complications are noted after elective surgery in older age groups (age >60 years) with an incidence of 25.17%, it is not the sole prognostic factor responsible for those complications. Frailty was responsible for doubling of the complications in older age group with odds ratio of 2.16.5 As per the to the reports of GOSAFE study (Geriatric Oncology Surgical Assessment and Functional recovery after surgery study), frailty is common in elderly patients who undergo cancer surgery. The goal of this study was to gather prospective data on both functional recovery (FR) and quality of life (QoL) in these patients after surgery.6\n\nGenetic, physiological, and environmental factors play an important role in creating health differences between females and males. Gender-related discrepancies in outcomes after a surgery have been reported in many studies. Males are usually seen to have higher mortality rates, after surgeries like lung resection, hip replacement surgery and sepsis, while females experience higher complication rates secondary to endovascular repair of abdominal aortic aneurysms and bear a negative effect on morbidity following cardiovascular procedures and CNS-related complications after surgical procedures.7 Females have reduced red cell mass and have lower circulating blood volumes of RBC’s compared to males, and significant amounts of blood loss was noted in females undergoing certain procedure. Thus, there was higher relative loss of red cell mass and higher rates of transfusion in females.8\n\nFrom a surgeon’s point of view, anemia is viewed as a non-specific sign for disease associated with low haemoglobin levels. Blood loss leads to decreased blood pressure and thus leads to release of catecholamines. There is vasoconstriction, increase in contractility of cardiac muscles which leads to increased cardiac output and normalizes the oxygen delivery to tissue by increasing the blood flow. Impaired oxygen delivery to tissues leads to membrane instability at cellular level, this sodium (Na+) and water flow into the cells and potassium (K+) moves out followed by cellular oedema which leads to cell death. During surgery, a fresh wound is created and the anaerobic environment in the wound is augmented by the presence of anaemia. This makes the local conditions ideal for growth of microorganisms, leading to infection of wound and delay in wound healing. An elderly patient is unable to compensate for loss of haemoglobin due to inability to increase cardiac output. This can result in poor tissue perfusion and stroke in such patients or myocardial infarction (MI). However, pre-operative blood transfusion may decrease this risk. Hypoxemia can also be associated with post-operative mental confusion.9\n\nIt is imperative to know the causes of pre-operative anaemia for appropriate management of anemia, the commonest cause being Iron deficiency worldwide. The other causes include parasitic infestation by either hookworms, malaria and schistosomiasis, pregnancy and gynaecological diseases, anemia associated with chronic renal disease and haemoglobinopathies.8 Anemia is defined by WHO on the basis of Hb concentration and has defined various thresholds for Hb and anemia as per age, gender and its severity are graded as mild, moderate or severe As per WHO it was noted that in a case of Iron Deficiency Anemia (IDA), the term “mild” is a misnomer because the anemia is very severe by the time it is detected, and its consequences are not apparent clinically. Also, adjustments of thresholds for level of Hb pertaining to altitude and smoking are necessary.8\n\nICC-PBM (International Consensus Conference on Patient Blood Management) meeting in Frankfurt, stated that “perioperative anemia is an important risk factor for peri-operative morbidity (acute myocardial infarction, ischemic stroke or kidney injury) and hospital and 30-day mortality”. Thus, it is essential to detect as well as classify anemia well in advance of major elective surgery. The leading causes of preoperative anemia include absolute iron deficiency and iron sequestration, whereas surgical blood loss and inflammation lead to postoperative anemia. In February 2018, WHO gave gender and age specific non-anemic values of haemoglobin as described in Table 2.10\n\nConcept of post-operative anemia\n\nPost-operative anemia can be a consequence of anemia present pre-operatively, anemia due to intraoperative blood loss or due to coagulopathy or phlebotomies in the perioperative period and also due to surgical stress which leads to decreased rate of erythropoiesis due to inflammatory cytokines, decreased uptake of iron from the gastrointestinal tract (GIT) due to inflammation and diminished response of RBCS to erythropoietin. It is also noted that pre-operative anemia renders the patient at increased need of intra-operative blood transfusions and its complications.11\n\nResearch data analysis\n\nA retrospective study published by Xu et al. in 2022 in patients undergoing pancreatoduodenectomy (PD), noted that after propensity score matching (PSM) in the groups having anemia the prevalence of postoperative complications was higher especially related to cerebrovascular and cardiac events in these patients. The complications in this particular study were recorded using the Clavien-Dindo Classification system.12 To understand this further, anemia decreases the oxygen (O2) carrying capacity of the blood is reduced, thus affecting the myocardial oxygen supply. When this factor gets combined with tachycardia, hypotension and ionotropic supports being used during peri-operative period there is mismatch in O2 supply and demand, thus leading to myocardial injury in non-cardiac surgeries. The study also reported that the optimal cut-off values of prediction of major post-operative complications in male was 10.45 g/dl and in females was 9.05 g/dl.13 A meta-analysis published by Fowler et al. in 2015 confirms that despite the heterogenicity between the studies in the review, pre-operative anemia was associated with poor outcomes after surgery. The meta-analysis has included data from 24 observational studies including both cardiac and non-cardiac surgeries. In patients undergoing cardiac surgeries, anemia association was noted with increase in the risk of stroke with p value of 0.009.14\n\nPatients having malnutrition have a higher rate of morbidity and mortality. Serum albumin (Sr Albumin) level proves to be a good indicator of presence of severity of malnutrition and thus is an indirect indicator for surgical risk. Hypoalbuminemia causes delay in recovery of function of bowel and thus is responsible for complications after gastrointestinal (GI) surgeries. The common complications seen due to hypoalbuminemia are wound infections, anastomotic leak, pneumonia etc.15\n\nAlbumin protects the body from inflammatory processes and also it acts a carrier molecule for the purpose of elimination and distribution of drugs in the body. Hypoalbuminemia can be due to inflammation, damage to hepatocytes, insufficiency of dietary amino acids, decreased synthesis of albumin and increased albumin excretion. It is well known that hypoalbuminemia is an independent risk factor for developing Surgical site infections (SSI’s), in patients undergoing GI surgeries. In a study done on 524 patients of GI surgeries, pre operative hypoalbuminemia, especially albumin levels of <3 g/dl was associated with increase in rate of deep SSI’s compared to Superficial SSI’s. It has also been seen that low albumin levels are associated with poor outcomes in patients having Covid -19 infection.16\n\nResearch data analysis\n\nAs per literature, serum albumin level was a much better predictor of sepsis and major infections and thus better in predicting outcomes of surgery compared to other preoperative patient characteristics.17 As per a study cohort data compiled using the ACS NSQIP database (American College of Surgeons, National Surgical Quality Improvement Program), a pre-operative serum albumin of 3.4 g/dl predicts death in 30-days post-operatively. The secondary outcomes studied which had high odds in relation to hypoalbuminemia were, death, stroke, cardiac arrest, and reoperation.18 A systematic review of literature published by Joliat et al in 2022 emphasises that serum albumin levels decline post-operatively and this decline of serum albumin levels can be used as a valuable biomarker in predicting outcomes after GI surgeries with a sensitivity of 63% - 84% and a specificity of 61% - 86%. There were total 16 studies included in the review out of which 9 studies recorded a threshold of decline of serum albumin to be in the range of 0.5-1.1 g/dl.19\n\nFrom a surgeon’s point of view, obesity has always been considered as a risk factor for post operative outcomes. The common complications seen post operatively due to obesity include respiratory complications like obesity hypoventilation syndrome, sleep apnoea, pulmonary embolism, atelectasis of lungs, pneumonia, etc.; cardiovascular complications like atrial fibrillation especially after cardiac surgeries, and wound related complications like wound dehiscence, SSI’s. The metabolic and immune response of body to any injury or trauma, initiates a response known as “acute phase” response. The activation of this response stimulates the antimicrobial response, reduces the damage to tissues, and promotes healing of wound. In support to this response the protein metabolism shifts i.e., there is increased loss of proteins from the gut, skeletal muscle and connective tissue and an increased synthesis of liver “acute phase proteins”. Whole body turnover of protein increases thus there is increase in nitrogen excretion, which leads to negative nitrogen balance in the body. When uncontrolled and in excess it can lead to loss of lean body mass, decreased immunity, impaired pulmonary function and increase in risk of mortality. Obese patients have decreased efficiency of protein synthesis, and the body undergoes changes which indicate muscle catabolism. They have decrease in “rate of lipolysis per unit fat mass” and increased level of free fatty acids (FFA) in the plasma. This means that obese patients do not use their fat stores effectively and rely on endogenous protein sources. Thus, pulmonary related complications and MOF are more, after major trauma in these patients.\n\nObesity and wound related complications\n\nThe proposed theory for wound dehiscence due to obesity is that “obesity directly effects the traction at the fascial edges at the time of closure and this in-turn increases the risk of wound infections, which can lead to wound dehiscence.” Adipose tissue is relatively avascular in nature thus leads to hypoperfusion of the tissue and also decrease in oxygen tension. The bactericidal action of neutrophils is by oxidative killing of the surgical pathogens. Now this decreased oxygen tension at the surgical site in an obese individual will lead to reduced bactericidal activity of neutrophils, leading to increase in risk of SSI’s. When obesity is present in association with insulin resistance, there is impaired function of macrophages, impaired collagen accumulation, also angiogenic response and production of growth factor is impaired which causes impaired healing of wound and finally there is increase in risk of wound infection.20\n\nLonger operation time in obese individuals is a strong predictor of wound infections post-operatively. Furthermore, elevated levels of blood glucose, impaired immunity and traction at surgical site are also the factors leading to impaired wound healing. The evidence existing regarding the effect of obesity on postoperative complications following gastrointestinal surgery are conflicting. There are studies suggestive of obesity paradox i.e moderate obesity decreases an adverse event, while patients who are underweight have higher propensity to develop complications. Some studies suggest that a patient with obesity is at increased risk to develop surgical-site infection (SSI) and deep venous thrombosis and thromboembolism.21\n\nIt is known that smoking has strong association with cancer, pulmonary diseases and cardiovascular diseases. A study done by Yoshikawa R et al. shows that, the risk of complications and that of mortality in the 30 days post operative period may increase due to smoking.22 Smoking can cause poor postoperative outcomes like impaired wound healing, wound infections, and cardiopulmonary complications. It has been noted that, smoking affects the transport as well as production of mucus within the pulmonary tract, ameliorates the immune system, can facilitate pulmonary inflammation thus resulting in respiratory dysfunction and pneumonia. Carbon monoxide and nicotine which are carried by smoking have effects on platelet function and vascular tone thus causing cardiac complications or wound related complications by causing impaired wound healing due to smoking-induced ischaemia. The Japanese Society of Anaesthesiologists have issued guidelines for cessation of smoking perioperatively, which suggest that cessation of smoking at least 4 weeks prior to elective surgery reduce the risk of postoperative complications.”22\n\nPrevious abdominal surgery was noted a risk factor, the rationale for it being that, it leads to more intra-abdominal adhesions thus increase in operative time, as well as postoperative ileus.23 This is the cause of increased morbidity in patients who have undergone previous abdominal surgery. Other complications of previous surgical scar include wound dehiscence and weakening of the abdominal wall muscles, thus leading to increase in incidence of incisional hernias in post-operative period.\n\n\nConclusion\n\nThe importance of optimizing the modifiable risk factors like hypoalbuminemia, anemia, obesity and smoking can be understood from the above study. Especially, factors like anemia not only need transfusions to optimize the haemoglobin levels but the primary cause of anemia should also be treated to prevent post-operative morbidity. The knowledge of current guidelines for threshold of Hb needed for elective surgeries, help in preventing over correction of anemia thus, preventing blood and blood products transfusion reactions. It is important to remember that morbidity is multifactorial and taking into account only a single risk factor will not improve the outcome, as seen with respect to age where age was not an independent risk factor but associated with frailty and other factors. In the era of modern medicine, which focuses on improved postoperative outcomes, it is always necessary to revisit the basics, thus more such articles are needed in future.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nvan Kooten RT , Bahadoer RR, Peeters KCMJ, et al.: Preoperative risk factors for major postoperative complications after complex gastrointestinal cancer surgery: A systematic review. Eur. J. Surg. Oncol. 2021 Dec; 47(12): 3049–3058. PubMed Abstract | Publisher Full Text\n\nManekk RS, Gharde P, Gattani R, et al.: Surgical Complications and Its Grading: A Literature Review. Cureus. 2022 May; 14(5): e24963. PubMed Abstract | Publisher Full Text\n\nWainwright T. ERAS® Society: The SAGES/ERAS Society Manual of Enhanced Recovery Programs for Gastrointestinal Surgery.2015 [cited 2023 Jul 12]. Reference Source\n\nYokozuka K, Tomita K, Nakagawa M, et al.: New risk factors of postoperative complications in elective gastrointestinal surgery of elderly patients: a prospective cohort study. BMC Surg. 2021 Dec; 21(1): 173. Publisher Full Text\n\nMayor S: Age is not a risk factor for complications after surgery in older patients, review finds. BMJ. 2018 Jan 12; (360): k187. Publisher Full Text\n\nMontroni I, Rostoft S, Spinelli A, et al.: GOSAFE - Geriatric Oncology Surgical Assessment and Functional rEcovery after Surgery: early analysis on 977 patients. J. Geriatr. Oncol. 2020 Mar 1; 11(2): 244–255. PubMed Abstract | Publisher Full Text\n\nAl-Taki M, Sukkarieh HG, Hoballah JJ, et al.: Effect of Gender on Postoperative Morbidity and Mortality Outcomes: A Retrospective Cohort Study. Am. Surg. 2018 Mar; 84(3): 377–386. Publisher Full Text\n\nGómez-Ramirez S, Jericó C, Muñoz M: Perioperative anemia: Prevalence, consequences and pathophysiology. Transfus. Apher. Sci. 2019 Aug; 58(4): 369–374. PubMed Abstract | Publisher Full Text\n\nGreenburg AG: Pathophysiology of anemia. Am. J. Med. 1996 Aug; 101(2): 7S–11S. Publisher Full Text\n\nPasricha SR, Colman K, Centeno-Tablante E, et al.: Revisiting WHO haemoglobin thresholds to define anaemia in clinical medicine and public health. Lancet Haematol. 2018 Feb 1; 5(2): e60–e62. PubMed Abstract | Publisher Full Text\n\nKalra SK, Thilagar B, Khambaty M, et al.: Post-operative Anemia After Major Surgery: a Brief Review. Curr. Emerg. Hosp. Med. Rep. 2021 Sep; 9(3): 89–95. Publisher Full Text\n\nXu JY, Tian XD, Yang YM, et al.: Preoperative Anemia Is a Predictor of Worse Postoperative Outcomes Following Open Pancreatoduodenectomy: A Propensity Score-Based Analysis. Front. Med. 2022 May 13; 9: 818805. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKwon JH, Park J, Lee SH, et al.: Pre-operative anaemia and myocardial injury after noncardiac surgery: A retrospective study. Eur. J. Anaesthesiol. 2021 Jun; 38(6): 582–590. PubMed Abstract | Publisher Full Text\n\nFowler AJ, Ahmad T, Phull MK, et al.: Meta-analysis of the association between preoperative anaemia and mortality after surgery. Br. J. Surg. 2015 Sep 9; 102(11): 1314–1324. Publisher Full Text\n\nLalhruaizela S, Lalrinpuia B, Dilip GV: Serum Albumin is a Predictor for Postoperative Morbidity and Mortality in Gastrointestinal Surgeries. JCDR. 2020 [cited 2022 Jan 23]. Publisher Full Text Reference Source\n\nWiedermann CJ: Hypoalbuminemia as Surrogate and Culprit of Infections. IJMS. 2021 Apr 26; 22(9): 4496. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGibbs J: Preoperative Serum Albumin Level as a Predictor of Operative Mortality and Morbidity: Results From the National VA Surgical Risk Study. Arch. Surg. 1999 Jan 1; 134(1): 36. Publisher Full Text\n\nNipper CA, Lim K, Riveros C, et al.: The Association between Serum Albumin and Post-Operative Outcomes among Patients Undergoing Common Surgical Procedures: An Analysis of a Multi-Specialty Surgical Cohort from the National Surgical Quality Improvement Program (NSQIP). JCM. 2022 Nov 4; 11(21): 6543. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJoliat GR, Schoor A, Schäfer M, et al.: Postoperative decrease of albumin (ΔAlb) as early predictor of complications after gastrointestinal surgery: a systematic review. Perioper. Med. 2022 Dec; 11(1): 7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDoyle SL, Lysaght J, Reynolds JV: Obesity and post-operative complications in patients undergoing non-bariatric surgery: Obesity and post-operative complications. Obes. Rev. 2010 Dec; 11(12): 875–886. PubMed Abstract | Publisher Full Text\n\nTjeertes EEKM, Hoeks SSE, Beks SSBJC, et al.: Obesity – a risk factor for postoperative complications in general surgery? BMC Anesthesiol. 2015 Dec; 15(1): 112. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYoshikawa R, Katada J: Effects of active smoking on postoperative outcomes in hospitalised patients undergoing elective surgery: a retrospective analysis of an administrative claims database in Japan. BMJ Open. 2019 Oct; 9(10): e029913. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSeetahal S, Obirieze A, Cornwell EE, et al.: Open abdominal surgery: a risk factor for future laparoscopic surgery? Am. J. Surg. 2015 Apr; 209(4): 623–626. Publisher Full Text"
}
|
[
{
"id": "238155",
"date": "18 Apr 2024",
"name": "Terry Feldheim",
"expertise": [],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article while it does talk about some of the pathophysiology and modifiable risk factors it appears very superficial. It glances over some key words and does not provide depth to these factors. It has some superficial merit but it lacks detailed discussion of its key topics.\nThe methods section needs some expansion. How were these studies selected still seems nebulous to me. How did they get to the 21 total studies? How many studies came up when these key words were searched and how was this narrowed to 21 studies? There should also be some exclusion criteria for studies that did not meet their criteria of what information the authors are looking for?\nIn the discussion the section Age the term frailty is used but without context and not defined here. It would be good to know how frailty was measured, this is important and speaks to the author glancing over key wording and details.\nThe discussion on anemia is a stretch. The claim that \" An elderly patient is unable to compensate for loss of hemoglobin due to inability to increase cardiac output.\" Is partly true yes there is less reserve but to claim that an elderly patient has no ability to increase cardiac output is categorically false. The ideas need to be defined and expanded upon it reads as a flight of ideas. There are only minor details that are incorrect the overall idea of the paper is sound however it needs some major fleshing out of the ideas presented.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Partly\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1234
|
https://f1000research.com/articles/12-1233/v1
|
27 Sep 23
|
{
"type": "Case Report",
"title": "Case Report: Tuberculosis in hydrocele of the spermatic cord in an older adult",
"authors": [
"Pankaj Gharde",
"Shalinder Koul",
"Yeshwant Lamture",
"Nitesh Badwaik",
"Shalinder Koul",
"Yeshwant Lamture",
"Nitesh Badwaik"
],
"abstract": "Background: Antibioma is a loculated collection in the spermatic cord, which is generally a transparent sterile fluid located above the testis in the inguinal region. It is an acquired congenital anomaly that is commonly observed in infants and children. Infected spermatic cord hydrocele has been reported on previously, but to the best of our knowledge, antibioma of spermatic cord hydrocele in adults has not yet been reported. In specific cases of long-standing abscesses, cartridge-based nucleic acid amplification test (CBNAAT) is used as the final diagnostic tool and can determine whether they are of tubercular pathology. Case: Here we are presenting a case of a 72-year-old male patient reporting to the surgery Outpatient Department, with complaints of swelling in the left inguinal region since birth, along with intermittent pain in the swelling for one year. It was diagnosed as antibioma and was confirmed to be of tubercular origin by CBNAAT following surgical exploration. The patient was started on anti-tubercular management as per the National Tuberculosis Elimination Programme protocol. Conclusions: Long standing abscesses are mostly tuberculous. We must look into whether they need urgent attention or can be managed conservatively as a routine procedure.",
"keywords": [
"Spermatic Cord",
"Infected Cyst",
"Antibioma",
"Tubercular cavity"
],
"content": "Introduction\n\nCongenital hydrocele, hernia and hydrocele of cord are generally seen in infants and young adults, but it is a rare finding in older adults. A lot of people do not come to clinics or take consultations as the swellings are symptomless and the disease does not affect them in their day-to-day activities. Hydrocele of cord is the fusion of patent processus vaginalis on both ends with the presence of fluid inside. The fluid present is usually sterile as there is no breach in continuity of the peritoneum and hence it does not get infected.1 The fluid inside the sac generally remains sterile and very rarely surgeons come across infected hydrocele. Long-term use of antibiotics can convert this fluid into sterile pus known as antibioma.2\n\nThe differential diagnosis of such swellings can be done using various modalities of investigations. Literature suggests that the best investigations are ultrasonography for differential diagnosis, color doppler to rule out arteriovenous malformation, computed tomography (CT) scan and magnetic resonance imaging (MRI) to rule out obstructed hernia, abdominal communication and pathologies leading to abscess.3\n\nThese investigations when done in tandem or subsequently, can help in finalizing the treatment modality, based on the findings. In specific cases of long-standing abscesses, cartridge-based nucleic acid amplification test (CBNAAT) is used as the final diagnostic tool.4\n\nHydrocele of cord is symptomless until and unless there is any trauma or infection. In the case of older men, we also have to rule out obstructed or Richter hernia. For this purpose, ultrasonography and CT scan can be highly useful.3\n\n\nCase report\n\nA72 year old male patient, farmer by occupation, resident of rural area of Wardha District, Maharashtra, Central India, presented to the Surgery Outpatient Department of Acharya Vinoba Bhave Rural Hospital at Wardha, with a mild painful swelling in the left inguinal region that had been present for one year and chronic infection of hydrocele of cord. The swelling in the left inguinal region was present since birth, but the patient did not experience any disturbing symptoms until the previous year. In February 2022, the patient experienced sudden pain associated with this swelling and a fever of 102°F. He visited a local physician, and was prescribed tablet pantoprazole 40 mg OD, tablet diclofenac sodium 50 mg BD and tablet amoxicillin + clavulanic acid 500 mg + 125 mg for five days, and was given a referral to a higher center for diagnosis and management. However, as he felt better the next morning, he delayed his visit to the higher center. The pain subsided and according to the history given by patient, recurred just once or twice every two months. The patient continued with the symptomatic management prescribed by his clinician without any repeat consultations. He took over-the-counter medications. Finally in April 2023, the patient came to us with complaints of pain with swelling since the last one year. On examination, the patient had a swelling measuring 7 × 10 cm in the left inguinal region (Figure 1). It was soft cystic, had restricted mobility and was mobile only on pulling the testis downwards, clearly indicating hydrocele of cord. The swelling was not tender and the temperature over the swelling was not raised.\n\nThe transillumination test on the swelling was absent, indicating that the fluid present in the swelling is turbid and light cannot pass through it. The scrotum was normal and no inguinal lymph nodes were palpable on either sides of the inguinal region. Patient’s vitals were normal and all the laboratory investigations came to be within the normal limits. Ultrasonography report showed infected cystic collection in the spermatic cord. Abdominal ultrasound was normal. We decided to explore it, for which the fitness for the surgery was obtained from the Anesthesia Department. On exploration, the sac was adhered to the spermatic cord. While exploring the sac, we found that the cyst was adhered to the spermatic cord (Figure 2), it ruptured during handling (Figure 3). We excised the remnants of the sac. The remnants of the sac were excised, pus was sent for culture and sensitivity analysis while the cyst wall was sent for histopathology reporting. The wound was kept open with the intention of secondary healing. After a few days when it became clean and covered with red granulation tissue, we closed the cavity with polyglactin 2-0 and Nylon 3-0 (Figure 3). Pre-operative and post-operative antibiotics were administered. The report for culture sensitivity came to be sterile and the histopathological report showed chronic granulomatous infection.\n\nConsidering the chronicity of the swelling and the presence of abscesses we decided to rule out tuberculosis, hence CBNAAT was our choice. CBNAAT reporting confirmed that the swelling and abscess was tubercular in origin. As the reports confirmed our diagnosis of antibioma and tubercular cavity, the patient was started on with antitubercular management. The sutures were removed on the 10th and 11th post-operative days and the discharge of the patient was without any immediate surgical complications. As documented, tuberculous cavities, ulcers and wounds do not heal without any anti-tubercular treatment, but in this case the patient showed good early healing, to our surprise.\n\nThe patient was satisfied and comfortable with our management and decided to extend his hospital stay until the stitch removal, although we wanted to discharge him on the fourth post-operative day.\n\n\nDiscussion\n\nCongenital swelling, that is hydrocele of cord presenting in a 72-year-old male patient is rare by itself. While a diagnosed antibioma confirmed to be of tuberculous origin by CBNAAT is an additional unusual finding.\n\nInfected hydrocele of cord may result from the intrabdominal infection through patent processus vaginalis. It may also be a result of lower urinary tract infection, epididymo-orchitis, incarcerated inguinal hernia, appendicitis or any other abdominal infection. In routine cases it cannot be treated by conservative management and surgery is a must in all the cases of hydrocele of cord.5 It may remain dormant for years if not treated and only in very few cases it may convert into abscesses. As we are in a developing country, the socioeconomically poor patients in rural areas may never attend the hospital until or unless they suffer from major discomfort or are scared of malignancy or death.6 This is exactly what happened in this case as the patient was lingering on the disease but when it did not subside even after conservative treatment for about a year, that is when he decided to come to the surgery outpatient department. Clearly indicating the lack of health seeking behavior in low and middle-income countries. We could not find any primary cause of infection leading to this abscess.\n\nThe team looked at the condition from different angles and narrowed down on tuberculosis considering the presentation and chronicity. Taking a decision to explore the antibioma and suspecting an infection of tubercular origin helped us diagnose and manage the case appropriately.\n\nThe complications of inguinal hernia area such as incarcerated hernia, abscess, malignant lymph nodes and cellulitis should be attended on priority basis as some times they may be underdiagnosed, some cases may need urgent consideration otherwise they may prove fatal.7\n\nAs mentioned, hydrocele of cord is detected in early life and patients usually get operated at an early age. Very rarely would you come across an older patient presenting with this condition. As the swelling was present since birth i.e., most probably congenital in origin, it must have caused discomfort to the patient, but peculiarly the patient went through adulthood without any seemingly obvious discomfort that would have initiated seeking any medical assistance.\n\nThe investigations needed for the swelling in this region include CT scan and MRI of the abdomen to rule out hernia, especially an obstructed one. Second line of investigations must be ultrasonography to differentiate between a cystic swelling or solid swelling. If it turns out to be solid; fine needle aspiration cytology (FNAC) or excision biopsy is needed. If it is cystic, either aspiration or excision should be done. A CT scan and MRI are essential for ruling out abdominal pathologies too, which may lead to infected hydrocele of cord.2\n\nFor the control of infection, systemic antibiotics can be given along with analgesics, anti-inflammatories along with other symptomatic management.8 In pyogenic abscess, the treatment of choice is incision and drainage, but in cases of tubercular abscess an anti-gravity aspiration of the abscess followed by antitubercular management will suffice.9 Any chronic abscess present for a long duration should raise suspicions of tuberculosis. CBNAAT examination of fluid is a test that gives a report within two hours and is available at many centers, it is a useful test to diagnose extrapulmonary tuberculosis. Tuberculoma and antibioma of spermatic cord is a rare presentation that we wanted to highlight, as clinicians should also keep it as a differential diagnosis in such types of cases. Furthermore, it is an inspiration for a surgeon to explore the unresolved mysteries in human bodies.\n\n\nConclusions\n\nLong standing abscess are mostly tuberculous. In a case of inguinal or inguinoscrotal swelling it is necessary to diagnose it properly. We must look into whether it needs urgent attention or can be managed conservatively as a routine procedure. Every aspect must be scrutinized with necessary investigations and appropriate decisions should be taken and followed by definitive management so that nothing is neglected. Medical science is vast and knowledge must be shared amongst the medical professionals to build their opinions and for the best possible management. The patient was notified to the District Tuberculosis Centre and was started on anti-tuberculosis drugs under the National Tuberculosis Elimination Programme.\n\n\nConsent\n\nWritten informed consent for publication of their clinical details and clinical images was obtained from the patient.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReferences\n\nCostantino E, Ganesan GS, Plaire JC: Abdominoscrotal hydrocele in an infant boy. BMJ Case Rep. 2017 May 27; 2017: bcr2017220370. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPatel RV, Brown LM, More B, et al.: Neonatal-perforated appendix forming antibioma masquerading as duodenal duplication. BMJ Case Rep. 2013 Jul 29; 2013: bcr2013200067. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShadbolt CL, Heinze SB, Dietrich RB: Imaging of groin masses: inguinal anatomy and pathologic conditions revisited. Radiographics. 2001 Oct; 21: S261–S271. 21 Spec No:S261-71. PubMed Abstract | Publisher Full Text\n\nSachdeva K, Shrivastava T: CBNAAT: A Boon for Early Diagnosis of Tuberculosis-Head and Neck. Indian J. Otolaryngol. Head Neck Surg. 2018 Dec; 70(4): 572–577. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKohlhauser M, Pirsch JV, Maier T, et al.: The Cyst of the Canal of Nuck: Anatomy, Diagnostic and Treatment of a Very Rare Diagnosis-A Case Report of an Adult Woman and Narrative Review of the Literature. Medicina (Kaunas). 2022 Sep 27; 58(10): 1353. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDean L, Tolhurst R, Nallo G, et al.: Neglected tropical disease as a ‘biographical disruption’: Listening to the narratives of affected persons to develop integrated people centred care in Liberia. PLoS Negl. Trop. Dis. 2019 Sep 6; 13(9): e0007710. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWani I, Rather M, Naikoo G, et al.: Encysted hydrocele of cord in an adult misdiagnosed as irreducible hernia: a case report. Oman Med. J. 2009 Jul; 24(3): 218–219. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTiveron AP, Rosalen PL, Franchin M, et al.: Chemical Characterization and Antioxidant, Antimicrobial, and Anti-Inflammatory Activities of South Brazilian Organic Propolis. PLoS One. 2016 Nov 1; 11(11): e0165588. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNatali D, Cloatre G, Brosset C, et al.: What pulmonologists need to know about extrapulmonary tuberculosis. Breathe (Sheff.). 2020 Dec; 16(4): 200216. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "243136",
"date": "21 Feb 2024",
"name": "Muhammad Asykar Palinrungi",
"expertise": [
"Reviewer Expertise urology",
"pediatric urology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbstract: first talk about hydrocele, then explain about antibioma. case reports; explain how you diagnose and act as well as follow up on patients\n1. Because this is a single case report, it limits the generalizability of the findings. 2. It is necessary to compare other cases that have existed, both in terms of diagnosis and therapy in patients with cases like this. 3. The use of anti-gravity aspiration for tubercular abscesses is a unique approach that may not be widely applicable or feasible in all clinical settings. 4. Need to explain a detailed description of the patient's follow-up and long-term outcomes, which could provide valuable information for future research and practice. 5. This report does not discuss any potential limitations or biases in the study design or methodology, which could impact the validity of the findings. 6. It's best to use references from the last 5-10 years.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "11144",
"date": "13 Apr 2024",
"name": "Pankaj Gharde",
"role": "Author Response",
"response": "Dear Sir, I am humbly responding to it one by one in sequence in Italiacs below each query. Abstract: first talk about hydrocele, then explain about antibioma. case reports; explain how you diagnose and act as well as follow up on patients. 1. First of all, it is not a primary hydrocele, it is a Hydrocele of the cord, described appropriately in the 4th and 5th lines of 'background' 1. Because this is a single case report, it limits the generalizability of the findings. 2. Hydrocele of the cord is found commonly in Indian scenarios, it is taught in almost every teaching encounter of congenital hernia and hydrocele, yet we can't suspect Tuberculosis in every case, especially if it is a congenital swelling. In this case it was not expected to be tuberculosis of hydrocele of the spermatic cord in the initial stages, only after the swelling ruptured and we found mild exudate fluid instead of clear fluid. 2. It is necessary to compare other cases that have existed, both in terms of diagnosis and therapy in patients with cases like this. As far as we have searched the literature we could not find a single case of Tuberculosis of hydrocele of cord. 3. The use of anti-gravity aspiration for tubercular abscesses is a unique approach that may not be widely applicable or feasible in all clinical settings. 3. Dear Sir, we don't do incision and drainage of tubercular abscesses, as recommended in the management of tuberculous abscess, we perform anti-gravity aspiration for tubercular abscesses, and for aspiration, we should be confirmed of it. In our case, it was not suspected to be a tubercular abscess, as a doubt in our mind, the fluid was turbid, and it was having room temperature which usually happens in a tubercular abscess in contrast to a pyogenic abscess. It was confirmed after 2 days of surgery as we sent its sample for CBNAAT(because of our doubt), but it was not a confirmed case of Tuberculosis. secondly, if it is a confirmed case of Tuberculosis, in that case, we do antigravity aspirate otherwise it may form a continuous draining sinus, which does not heal easily. 4. Need to explain a detailed description of the patient's follow-up and long-term outcomes, which could provide valuable information for future research and practice. 4. As we operated the case and when the CBNAAT of the sample came positive, we started with DOTs, the wound is healed patient was taking DOTs treatment for it, we started writing this case report on the third day of the operation and the follow up could not be mentioned here. 5. This report does not discuss any potential limitations or biases in the study design or methodology, which could impact the validity of the findings. As it is not a research article, it needs an aim, objectives, methodology study design, data collection, data entry in master chart, statistical analysis, and then limitations( All these are part of the Original article, not a Case report. so it is not possible here to mention in case report) 6. It's best to use references from the last 5-10 years. Except for reference No. 7 which is from 2009, the rest are recent ones, kindly confirm. Thanks for your queries, I think my humble replies are enough to clear your doubts. Is the background of the case’s history and progression described in sufficient detail? Partly Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes Is the case presented with sufficient detail to be useful for other practitioners? Yes"
}
]
},
{
"id": "243130",
"date": "28 Feb 2024",
"name": "Rabea Ahmed Gadelkareem",
"expertise": [
"Reviewer Expertise Rare urological cases",
"Kidney transplantation",
"stones and endourology."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors presented a case of tuberculous pyocele of the encysted hydrocele of the spermatic cord in a 72-year-old patient. The swelling was dated since birth, but pain and fever occurred only within the last year. Relative to the long-standing history of swelling, a high index of suspicion of tuberculosis was prominent. Surgical excision was performed, using CBNAAT. Many concerns and errors need to be addressed: 1) The title needs to be re-designed. I suggest re-writing as Tuberculous pyocele complicating a hydrocele of the spermatic cord in an adult: a case report. 2) Abstract-Background: The definition of antibioma is not correct. 3) The description (acquired congenital) should be corrected. There is no acquired congenital at the same time. 4) Case report: A 72 year should be corrected to be: A 72-year-old. 5) Revise the methods: there are many unsuitable terms (adhered to be adherent; the patient was started to be the patient started the anti-tuberculous regimen. 6) Laboratory workups, such as Complete blood count, blood sugar, and other organ function tests should be provided. 7) Workups to investigate the origin of this TB infection: Exclusion of pulmonary TB needs to be provided. 8) Discussion: You may provide a discussion about the other TB forms of the spermatic cord. 9) Conclusion: The last sentence is not suitable for this part. It would be better to be transferred to the section of the Case report.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1233
|
https://f1000research.com/articles/9-371/v1
|
18 May 20
|
{
"type": "Brief Report",
"title": "Analyses of spike protein from first deposited sequences of SARS-CoV2 from West Bengal, India",
"authors": [
"Feroza Begum",
"Debica Mukherjee",
"Dluya Thagriki",
"Sandeepan Das",
"Prem Prakash Tripathi",
"Arup Kumar Banerjee",
"Upasana Ray",
"Feroza Begum",
"Debica Mukherjee",
"Dluya Thagriki",
"Sandeepan Das"
],
"abstract": "India has recently started sequencing SARS-CoV2 genome from clinical isolates. Currently only few sequences are available from three states in India. Kerala was the first state to deposit complete sequence from two isolates followed by one from Gujarat. On April 27, 2020, the first five sequences from the state of West Bengal (Eastern India) were deposited on GISAID, a global initiative for sharing avian flu data. In this study, we have analysed the spike protein sequences from all five isolates and also compared their similarities or differences with other sequences reported in India and with isolates of Wuhan origin. We report one unique mutation at position 723 and another at 1124 in the S2 domain of spike protein of the isolates from West Bengal only. There was one mutation downstream of the receptor binding domain at position 614 in S1 domain which was common with the sequence from Gujarat (a state of western India). Mutation in the S2 domain showed changes in the secondary structure of the spike protein at region of the mutation. We also studied molecular dynamics using normal mode analyses and found that this mutation decreases the flexibility of S2 domain. Since both S1 and S2 are important in receptor binding followed by entry in the host cells, such mutations may define the affinity or avidity of receptor binding.",
"keywords": [
"Spike",
"India",
"West Bengal",
"Mutations"
],
"content": "Introduction\n\nThe SARS-CoV2 (a member of Coronaviruses) outbreak occurred in Wuhan, China in the year 2019, and was recently declared a pandemic, which has affected countries worldwide. To design antiviral therapeutics/vaccines it is important to understand the genetic sequence, structure and function of the viral proteins. When a virus tries to adapt to a new environment, in a new host, in a new geographical location and a new population, it may make changes to its genetic make-up which in turn bring slight modifications in viral proteins. Such variations would help the virus to utilize the host’s machinery to best in favour virus survival and propagation. Since the host’s immune system eventually learns to identify an infecting pathogen and starts producing protective antibodies, a virus often changes its structural proteins so that it escapes the host’s immune system and continues to infect the host cells. Coronaviruses have been long known to undergo rapid mutations in its RNA genome1. Such mutations are reflected in changes in the amino acid sequences of its structural and non-structural proteins.\n\nThe spike protein is a structural protein of SARS-CoV2 that forms a homotrimer on the surface of the vital lipid envelope2. This trimer is made up of monomers consisting of S1 and S2 subunits. S1 subunit helps in attachment to the host cell receptor, while S2 subunit helps in fusion to host cell and entry. Thus, the spike protein has been an area of interest for designing vaccine and antiviral candidates against SARS-CoV2. Since the spike protein tends to mutate, it is important to obtain a broad mutation profile of this protein from extensive genome sequencing from different geographical locations of the world. Targeting areas of the spike protein that do not undergo mutation, i.e. conserved regions, would be the key to designing effective broad spectrum antivirals or vaccine.\n\n\nMethods\n\nWe downloaded the five new SARS-CoV2 sequences from West Bengal (EPI_ISL_430468; EPI_ISL_430467; EPI_ISL_430465; EPI_ISL_430464; EPI_ISL_430466) from the GISAID database under the EpiCov icon by specifying location as India and the spike protein sequences corresponding to Kerala isolates (QIA98583 and QHS34546)3, Gujarat isolate (QJC1949.1)4 and Wuhan isolate (QIS29982.1) from the NCBI virus database. Wuhan isolate was used as the original SARS-CoV-2 sequence for sequence comparisons. For this study we have considered only the complete sequences (>29,000bp) with high coverage.\n\nFor the West Bengal isolates, the nucleotide sequences corresponding to the spike protein were selected and then translated on ExPASY Translate tool to obtain the protein sequences.\n\nAll the spike protein sequences were aligned using the multiple sequence alignment platform of CLUSTAL Omega. The alignment file was viewed using MView and differences in the sequence or the amino acid changes were recorded.\n\nCFSSP (Chou and Fasman secondary structure prediction) server was used to predict secondary structures of SARS-CoV2 spike protein.\n\nTo study the effect of mutation on the conformation, stability and flexibility of the spike protein, the SARS-CoV-2 structure was downloaded from RCSB PDB. We used the available SARS-CoV-2 spike ectodomain structure (open state) (PDB ID: 6VYB). The 6VYB structure was uploaded on DynaMut software (University of Melbourne, Australia)5 and changes in vibrational entropy and the atomic fluctuations and deformation energies due to mutation were determined. For atomic fluctuation and deformation energy calculations, calculations were performed by the software over first ten non-trivial modes of the molecule.\n\n\nResults and discussion\n\nThe first set of five sequencing data from clinical isolates of SARS-CoV2 from the state of West Bengal, India was submitted on 27/2/2020 by the National Institute of Biomedical Genomics (NIBMG) in collaboration with ICMR-National Institute of Cholera and Enteric Diseases (ICMR-NICED). The sequences were submitted to the GISAID database.\n\nWe downloaded all the sequences from West Bengal (Table 1) and performed a nucleotide translation to obtain respective spike protein sequences. All these spike protein sequences were first aligned in CLUSTAL Omega to check for similarities or differences. We found that at position 723, all the isolates from West Bengal except EPI_ISL_430466 had ‘T’ (other isolates had ‘I’). Also, at position 1124, two of the isolates (EPI_ISL_430468 and EPI_ISL_430464) showed mutation from ‘G’ to ‘V’. We used spike protein sequence translated from one of these sequences (EPI_ISL_430468) as representative of SARS-CoV2 spike from West Bengal for our further comparison with other states.\n\nSince, we had access to sequences for SARS-CoV2 only from three states in India (Kerala, Gujarat and now West Bengal), we compared all those sequences to detect possible changes (Figure 1). We considered the original Wuhan sequence as the wild type for comparison. We found six different amino acid positions that were mutated in these isolates overall. We had recently published the details with respect to the spike protein mutations in Kerala3 and Gujarat isolates4.\n\n(A) Multiple sequence alignment of Spike protein sequence of Kolkata isolate with sequences obtained from other parts of India. Sites of mutation are showed in Red. (B) Tabulation of amino acid mutations among isolates from kolkata. Mutations are shown in red. Number/s in parenthesis show number of osolates that showed the amino acid type. (C) Tabulation of amino acid present at the points of mutation for isolates from different parts of india.\n\nHere, we report that in West Bengal isolates there were three mutations in the spike protein. One of these mutations was D614G in the S1 domain. This lies near the receptor bending domain at a downstream position. Another mutation, T723I lie further downstream in the S protein in the S2 domain. Mutation G1124V is the third mutation and lie in the S2 domain. While D614G was also found in the isolate from Gujarat but not in Kerala isolates, T723I and G1124V mutation were exclusively found in the isolates of West Bengal. None of the isolates from other parts of India had this mutation.\n\nAlthough T723I was also exclusive for West Bengal, it appeared only in one isolate. Thus, we characterized mutation G1124V which appeared in two of the isolates. Both glycine (G) and valine (V) are non-polar amino acids with aliphatic R groups. Glycine has no side chain whereas valine is bulkier due to its side chain. A change from glycine to valine can thus potentially disrupt the local folding of the protein. For example, it was shown that G to V change in a P-glycoprotein changed its drug specificities6.\n\nSecondary structure prediction showed changes in and around the site of mutation (Figure 2). In the mutant spike there was a loss of turn structure from position 1124 and addition of four helices at positions 1123, 1124, 1125 and 1126. This change in secondary structure might lead to change in function of S2. S2 helps in fusion process of the spike protein and thus mutation in S2 may have altered receptor spike interactions and thus infectivity.\n\n(A) Secondary structure of Spike protein of Wuhan isolate (the area around the residue 1124 has been shown); (B) secondary structure of Spike protein of Kolkata isolate showing effect of mutation on the secondary structure.\n\nTo correlate if changes in secondary structure are also reflected in the dynamics of the protein in its tertiary structure, we performed normal mode analyses and studied protein stability and flexibility. Change in vibrational entropy energy (ΔΔSVib ENCoM) between the wild type Wuhan isolate and the West Bengal isolate was -4.445 kcal.mol-1.K-1 (Figure 3). The ΔΔG was 0.905 kcal/mol and the ΔΔG ENCoM was 4.756 kcal/mol. All these suggested a stabilizing mutation in this type of spike. The interatomic interactions have been shown in Figure 4.\n\nΔ Vibrational Entropy Energy Between Wild-Type and Mutant ΔΔSVib ENCoM: -4.445 kcal.mol-1.K-1. Amino acids were coloured as per the vibrational entropy change due to mutation. Blue represents rigidification of structure.\n\nWild-type and mutant residues are coloured in light-green and are also represented as sticks alongside with the surrounding residues which are involved on any type of interactions.\n\nAnalyses of atomic fluctuations and deformation energies showed visible changes (Figure 5). Atomic fluctuations calculate the measure of absolute atomic motion whereas deformation energies detect the measure of flexibility of a protein. Figure 5 shows the visual representations of the atomic fluctuation and deformation energies where positions that could be visibly detected to be different have been marked.\n\nMagnitude of (A) atomic fluctuation and (B) deformation has been shown using thin to thick lines coloured blue (low), white (moderate) and red (high).\n\nThis is the first report of mutations of such types in the isolates of the state of West Bengal and further sequencing followed by sequence analyses would help expanding the knowledge about variations of spike protein in human SARS-CoV. These variations might lead to virus diversification and eventual emergence of variants, antibody escape mutants, strains and serotypes. Also, mutations might help the virus to expand its tissue tropism and adjust with the host environment better. Therefore, elaborate studies on sequence variations should be done, which would in turn help in better therapeutic targeting.\n\n\nData availability\n\nAccession numbers for sequences used in this study can be found in Table 1 and the test. GSAID is a free-to-use resource, but requires registration prior to accessing.\n\nFigshare: Figure F1000corrected.pdf, https://doi.org/10.6084/m9.figshare.12254033.v27.\n\nThis project contains the following extended data:\n\n- Images raw images as created on DynaMut software:\n\n○ Deformation_protein_158809623989_wild_type\n\n○ Deformation_protein_G943V_158809623989_mutant_1124\n\n○ Diff_A_G943V_158809623989_Kolkata_1124_mutation_6VYB23805-V1-1-fluctuation_protein_158809623989wild_type\n\n○ Fluctuation_protein_G943V_158809623989_mutant_1124\n\n○ Protein_cleanedcontacts_A_943_158809623989_wild_type\n\n○ Protein_G943Vcontacts_A_943_158809623989_Mutant_Kolkata_1124",
"appendix": "Acknowledgements\n\nWe thank NIBMG, Kalyani, West Bengal and ICMR-NICED for depositing the sequences in public database and making it openly available. We thank CSIR, AcSIR and North Bengal Medical College and Hospital for other necessary support and input.\n\nA previous version of this article is available on bioRxiv: https://biorxiv.org/cgi/content/short/2020.04.28.066985v1\n\n\nReferences\n\nWu F, Zhao S, Yu B, et al.: A new coronavirus associated with human respiratory disease in China. Nature. 2020; 579(7798): 265–269. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTai W, He L, Zhang X, et al.: Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol. 2020. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSaha P, Banerjee AK, Tripathi PP, et al.: A virus that has gone viral: Amino acid mutation in S protein of Indian isolate of Coronavirus COVID-19 might impact receptor binding and thus infectivity. BioRxiv. 2020. Publisher Full Text\n\nBanerjee AK, Begum F, Thagriki D, et al.: Novel Mutations in the S1 domain of COVID 19 Spike Protein of Isolate from Gujarat Origin, Western India. Preprints. 2020. Publisher Full Text\n\nRodrigues CH, Pires DE, Ascher DB: DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability. Nucleic Acids Res. 2018; 46(W1): W350–W355. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChoi KH, Chen CJ, Kriegler M, et al.: An altered pattern of cross-resistance in multidrug-resistant human cells results from spontaneous mutations in the mdr1 (P-glycoprotein) gene. Cell. 1988; 53(4): 519–29. PubMed Abstract | Publisher Full Text\n\nRay U: Figure F1000corrected.pdf. figshare. Figure. 2020. http://www.doi.org/10.6084/m9.figshare.12254033.v2"
}
|
[
{
"id": "63545",
"date": "26 May 2020",
"name": "Pawan Kumar Maurya",
"expertise": [
"Reviewer Expertise Clinical Biochemistry"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript submitted reports mutations in newly sequenced SARS-CoV-2 isolates of West Bengal origin. The information presented here is a useful addition to the ongoing COVID 19 research. While the manuscript is well written and sufficiently documented, the authors should consider adding the following additional information.\n\nMutation 614 D to G has been in discussion in recent times extensively. The authors could add few lines in the discussion about the possible importance of this mutation as they also report the same in West Bengal’s sequences.\n\nDynaMut analysis for only G1124V has been done. Since mutation at the 723 position is also unique, a similar analysis for the same should also be included.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Yes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "63544",
"date": "02 Jun 2020",
"name": "Jalaj Gupta",
"expertise": [
"Reviewer Expertise Host-pathogen interaction",
"Biochemical characterization of mutant versions of proteins",
"Cancer biology using organoid and mouse models"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nBegum et al. submitted the manuscript ‘Analyses of spike protein from first deposited sequences of SARS-CoV2 from West Bengal, India’ where COVID19 virus sequences retrieved from GISAID database have been studied for possible mutations. Authors report three mutations out of which two are unique (T723I and G1124V) and one shared (D614G) with other geographical locations. This is a timely study, unrevealing two unique mutations that can be useful for further studies on the behavior of COVID19. However, the authors did not clarify why they characterized only one mutant but not the other.\n1) The two mutations (T723I and G1124V) discussed in the manuscript should be similarly presented. Authors have described detailed analysis of G1124V mutation while T723I mutation is not discussed in detail. Therefore entropy calculations, interatomic interactions, deformation energy, and atomic fluctuation studies should also be done for mutation T723I.\n\nWhat is the effect of T723I mutation on the secondary structure? This analysis should also be done and included in Figure 3. This will further improve the quality of the manuscript.\n\nAuthors claim that the two mutations (T723I and G1124V) are unique in the West Bengal region of India. Are they prevalent elsewhere in the World as well? Authors should expand their analysis and include more COVID19 isolates from different continents/countries.\n\nMinor comments:\nThe accession number of Gujarat isolate in method and figure 1 do not match. Correction needed.\n\nAccession number EPI_ISL_430465 in Table 1 is duplicated. One should be EPI_ISL_430466.\n\nParameters for calculation of vibrational entropy, atomic fluctuations, and deformation energies should be described in more detail.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "63543",
"date": "18 Jun 2020",
"name": "Nicolas Cuburu",
"expertise": [
"Reviewer Expertise I have limited expertise on computational approaches for protein structure prediction"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article from Begum et al. entitled “Analyses of spike protein from first deposited sequences of SARS-CoV2 from West Bengal, India\" reports a detailed analysis spike protein sequences deposited in GSIAD repository from clinical isolates of SARS-CoV2. The report relies on algorithms to predict the secondary structure of the SARS-CoV2 spike protein variant from Bengal and proposes that novel mutations in the SARS-CoV2 S2 domain could result in changes in the virus infectivity and escape mutants.\n\nBecause the structures were all based on the CFSSP algorithm it would be important to show how these structures relate to the known crystal structure of SARS-CoV2 spike from Wuhan. Also, the authors compared the sequences to Wuhan's original virus, but more mutations in S2 notably have been reported in clinical isolates from other parts of the world. An important question is whether the mutations from Bengal are new and unique or whether they are found also in the circulating virus in North America and Europe for instance.\n\nOverall the observation and the hypothesis are interesting but at this point, it is purely speculative and these mutations could be passengers with no consequence on virus natural infection and transmission. These questions could only be solved by infection experiments in vitro or in animal models.\n\nThe authors have used the CFSSP method, but many other algorithms are available for secondary structure prediction. What was the rationale for choosing this specific algorithm? Would other algorithms yield similar predictions?\n\nIn the introduction, the authors mention that the CoV undergo rapid mutations but compared to other RNA viruses CoV tends to mutate more slowly due to the proofreading exonuclease.\n\nFigure 1: it is not clear what consensus 100% 90% etc… represent.\n\nMinor comments: few typos (osolate instead of isolate etc…)\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/9-371
|
https://f1000research.com/articles/12-84/v1
|
23 Jan 23
|
{
"type": "Research Article",
"title": "Drugs prescribed for Phelan-McDermid syndrome differentially impact sensory behaviors in shank3 zebrafish models.",
"authors": [
"Robert A. Kozol",
"Julia E. Dallman",
"Robert A. Kozol"
],
"abstract": "Background: Altered sensory processing is a pervasive symptom in individuals with Autism Spectrum Disorders (ASD); people with Phelan McDermid syndrome (PMS), in particular, show reduced responses to sensory stimuli. PMS is caused by deletions of the terminal end of chromosome 22 or point mutations in Shank3. People with PMS can present with an array of symptoms including ASD, epilepsy, gastrointestinal distress, and reduced responses to sensory stimuli. People with PMS are often medicated to manage behaviors like aggression and/or self-harm and/or epilepsy, and it remains unclear how these medications might impact perception/sensory processing. Here we test this using zebrafish mutant shank3ab PMS models that likewise show reduced sensory responses in a visual motor response (VMR) assay, in which increased locomotion is triggered by light to dark transitions. Methods: We screened three medications, risperidone, lithium chloride (LiCl), and carbamazepine (CBZ), prescribed to people with PMS and one drug, 2-methyl-6-(phenylethynyl) pyridine (MPEP) tested in rodent models of PMS, for their effects on a sensory-induced behavior in two zebrafish PMS models with frameshift mutations in either the N- or C- termini. To test how pharmacological treatments affect the VMR, we exposed larvae to selected drugs for 24 hours and then quantified their locomotion during four ten-minute cycles of lights on-to-off stimuli. Results: We found that risperidone normalized the VMR in shank3 models. LiCl and CBZ had no effect on the VMR in any of the three genotypes. MPEP reduced the VMR in wildtype (WT) to levels seen in shank3 models but caused no changes in either shank3 model. Finally, shank3 mutants showed resistance to the seizure-inducing drug pentylenetetrazol (PTZ), at a dosage that results in hyperactive swimming in WT zebrafish. Conclusions: Our work shows that the effects of drugs on sensory processing are varied in ways that can be highly genotype- and drug-dependent.",
"keywords": [
"Shank3",
"Phelan-McDermid Syndrome",
"autism spectrum disorders",
"zebrafish",
"Risperidone",
"Carbamazepine",
"Lithium",
"MPEP",
"anti-epileptic"
],
"content": "Introduction\n\nAltered sensory processing affects the majority (69-97%) of people with autism and is one of the core diagnostic symptoms in the Diagnostic and Statistical Manual V (Leekam et al., 2007; Tomchek and Dunn, 2007; Lane et al., 2011; Green et al., 2016; Tavassoli et al., 2016; Siper et al., 2017). Such symptoms includes hypo- and hyper-reactivity to stimuli, and sensory fixation (Robertson and Baron-Cohen, 2017). Consistent with this, genotype by symptom meta-analyses identified sensory hyporeactivity/increased-pain-tolerance in over 80% of individuals with Phelan-McDermid syndrome (PMS) (Mieses et al., 2016; Tavassoli et al., 2016; De Rubeis, 2018). PMS is a syndromic form of ASD, that can be caused by a chromosome 22 terminal deletion that encompasses the SHANK3 gene or a mutation in the SHANK3 gene specifically (Phelan and McDermid, 2012; De Rubeis, 2018). In addition to sensory hyporeactivity, SHANK3 mutations are correlated with a range of symptoms, that include epilepsy, sleep disturbances, and gastrointestinal distress (Soorya et al., 2013; De Rubeis, 2018; Frank, 2021; Smith-Hicks et al., 2021). This range of symptoms makes prescribing medications challenging (Costales and Kolevzon, 2015; Harony-Nicolas et al., 2015), with many individuals experiencing a prescription carousel: when one drug fails to maintain control of a symptom and/or side-effects become intolerable. Therefore, to achieve more effective symptom management, it is critical to better understand how medications impact the range of symptoms found in individuals with PMS.\n\nZebrafish provide characteristics that are ideal for studying how small molecules impact sensory-motor behaviors. Zebrafish sensory-motor circuits are established and become active a few days after fertilization because precocial behavioral development is essential for the survival of freely swimming larvae (Kimmel et al., 1974; Portugues and Engert, 2009; Fero et al., 2011; Kinkhabwala et al., 2011; Warp et al., 2012; Marques et al., 2018). Predator avoidance and prey capture require visual acuity, sensitive hearing, and multimodal sensory integration to activate the appropriate swimming circuits (Fero et al., 2011; Koyama et al., 2011). Importantly, sensory-motor deficits provide a proxy for circuit pathology, that can be used to identify neuropathological critical periods (Kozol, 2018; Sakai et al., 2018; Kozol et al., 2021). Finally, due to their small size and large clutch sizes (100-200 embryos), zebrafish can be screened in large numbers and also absorb most small molecules dissolved in the water that houses them. Therefore, zebrafish provide a vertebrate model that is poised to identify how small molecules influence sensorimotor behaviors in ASD models (Sakai et al., 2018).\n\nTo investigate how drugs impact SHANK3-associated hyporeactivity, zebrafish shank3a and shank3b (shank3ab) mutants were exposed to drugs and screened for sensorimotor behavior using a the well-established visual-motor-response (VMR) assay (Burgess and Granato, 2007). shank3ab mutants exhibit hyporeactivity and sustained hypoactivity in response VMR stimuli, repeated lights-on to lights-off transitions (Kozol et al., 2021). To determine the effects of small molecules on this sensorimotor deficit, we exposed larval zebrafish to the commonly prescribed medications risperidone (Nyberg et al., 1993; McDougle et al., 2005; Gencer et al., 2008; Lemmon et al., 2011), lithium chloride (LiCl) (Malhi et al., 2013; Verhoeven et al., 2013; Serret et al., 2015; Egger et al., 2017; Malhi et al., 2020), and carbamazepine (CBZ) (Mattson et al., 1992; Verhoeven et al., 2013; Jia et al., 2022). We also tested 2-methyl-6-(phenylethynyl) pyridine (MPEP), which normalized anxiety and striatal synaptic transmission in a shank3 mouse model (Wang et al., 2016) and pentylenetetrazole (PTZ), used in animal models to better understand susceptibility to seizures (Baraban et al., 2005; Hoffman et al., 2016; Liu and Baraban, 2019) (Table 1).\n\nBelow we describe the varied ways these drugs impacted the VMR sensorimotor behavior, from having no effect to suppressing or enhancing the VMR in a shank3-genotype-specific manner.\n\n\nMethods\n\nZebrafish were housed and maintained at 28°C in system-water on a 14:10 hour circadian light:dark cycle in the zebrafish core facility at the University of Miami where they were fed twice a day using a combination of dry fish food and brine shrimp. Adult and larval zebrafish used in this study were handled in accordance with NIH guidelines and experiments were approved by the University of Miami Institutional Care and Use Committee protocol #’s 15-128 (approval date 9/22/2015) and 18-128 (approval date 9/27/2018). To limit harm to the animals and ensure experimental reproducibility, after natural spawnings, unfertilized eggs were removed and embryos were maintained in 10 cm dishes with ~50 larvae per dish until behavioral observations. Embryos were raised with the same 14:10 light cycle as their parents. Zebrafish lines used in this study were; ABTL wildtype (WT), shank3abN-/- (Kozol et al., 2021) and shank3abC-/- (James et al., 2019).\n\nThis study is reported in line with the Animal Research: Reporting of in vivo Experiments (ARRIVE) guidelines (Kozol & Dallman, 2023).\n\nSample\n\nAll exact sample sizes can be found in the figure legends. Sample sizes were derived from a previous study based on the same VMR behavioral endpoint (Kozol et al., 2021).\n\nHigh-throughput behavioral screens\n\nExperimental plans were developed and refined during weekly meetings but there was no protocol registered prior to initiation of experiments. The DanioVision systemtm (Noldus, Wageningen, NTD) with the DanioVision observation chamber (DVOC-0040) was used to record videos of larval behaviors during experiments using the following settings: 25 fps, 1280 × 960 resolution using a Basler acA1300-60 gm camera fitted with a 12 mm Megapixel lens. White light for the visual motor response assay was set at 12% intensity on the high-power setting. Larvae were pipeted into an ANSI-SBS-compatible 96 well microtiter plate at a density of one larva per well, at a depth of 10 mm. Six-day-old larvae were acclimated to the observation chamber at 28 °C in the dark for at least 1 hr. Larval sex is unknown at this stage. Larvae were monitored during behavioral recordings, to ensure no signs of distress were exhibited during light cycles. DanioVision EthoVision XT software version 11.5 (Noldus) was used to set up data collection and for preliminary analyses. Visual motor response (VMR) experiments consisted of four cycles of alternating lights-on (five min.)/lights-off (five min.) for a total of 40 minutes. All behavioral experiments were conducted between 11 am and 3 pm, with 2-5 independent trials. Larvae were randomly assigned across each 96-well plate, blinded to experimenters, then were genotyped following behavioral experiments using restriction digest assays previously described (James et al., 2019; Kozol et al., 2021), allowing larvae to be binned by genotype for subsequent analyses. Following experiments, larvae were humanely euthanized using MS222.\n\nDrug screening\n\nZebrafish were exposed to drugs dissolved in 0.1% DMSO system water (water from the system that houses the adult fish) 24 hours prior to running VMR assays. A range of risperidone, MPEP, CBZ and LiCl concentrations were derived from previously published papers (Tucker et al., 2006; Bruni et al., 2016; Hoffman et al., 2016), then dose-response curves were generated to determine an effective dose in relation to the VMR response of WT zebrafish. Concentrations used for comparing WT and shank3 larvae were 10 μM Risperidone (Bruni et al., 2016; Hoffman et al., 2016), 5 mM LiCl and 200 μM CBZ, and 5 μM MPEP (Tucker et al., 2006). Genotype controls were exposed to DMSO (0.1%) in system water.\n\nFor PTZ trials, larvae were initially acclimated in 1 mL of system water at 28 °C in the Daniovision behavioral box for 30 minutes. Larvae were then recorded for 10 minutes to establish baseline behavior. Following a baseline recording, larvae were either exposed to 3 mM PTZ in 0.1% DMSO system water or 0.1% DMSO system water for ten minutes, before capturing ten minutes of behavior following drug exposure. Baseline and PTZ/DMSO data was then binned as total distance moved for 10 minutes pre and post PTZ exposure.\n\nData were analyzed using PRISM 9 (graphpad, inc.); these same analyses could be conducted using R. Videos were manually screened before running data analyses, to determine that tracking software accurately captured individuals’ movements; if discrepancies between tracks and videos were noted, videos were retracked. No individuals or data points were excluded from behavioral analyses. Significance was assessed using the non-parametric Wilcoxon rank score test (Mann-Whitney rank scores). When there were more than two groups, a Kruskal-Wallis rank score test was first calculated and, if p<0.05, was followed by a Dunn’s multiple comparisons test to compare all treatments and genotypes. See Tables 2-41.\n\nSee Figure 1c.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 1c.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 1d.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 1d.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 1e.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 1e.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 2a.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 2a.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 2a.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 2a.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 2b.\n\nSee Figure 2b.\n\nSee Figure 2c.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 2c.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 2c.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 2c.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 2d.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 2d.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 2d.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 2d.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 3a.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 3a.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 3b.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 3b.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 4a.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 4a.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 5b.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 5b.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 5a.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 5a.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 5b.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 5b.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 6a.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 6a.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 6b.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 6b.\n\n* p < 0.05,\n\n** p < 0.01,\n\n*** p < 0.001,\n\n**** p < 0.0001.\n\nSee Figure 7b.\n\nSee Figure 7b.\n\nSee Figure 7b.\n\nSee Figure 7b.\n\n\nResults\n\nWe previously showed that both shank3abN and shank3abC mutants exhibit sensory hyporeactivity (activity during first 30 seconds in dark) and hypoactivity (activity over full 5 minutes in dark) in a light to dark transition paradigm, the VMR assay (Kozol et al., 2021). Here we repeat this assay, but this time in the presence of the drug carrier 0.1% DMSO. In comparison to WT (Figure 1a & b, Tables 2 & 3), both shank3abN-/- and shank3abC-/- models exhibited hyporeactivity and hypoactivity (Figure 1c-e, Tables 4-7). These results provide a reliable sensorimotor phenotype that can be quantified following exposure to selected drugs (Kozol & Dallman, 2023).\n\na) shank3ab N-terminal and C-terminal mutants were designed to target regions with known deleterious mutations in individuals with PMS. b) Trace line graphs showing four cycles of 5 minutes lights-on to lights-off. Checkered boxes on the x-axis represent lights on and off. c) Lights on to off paired comparison, highlighting no significant change in activity of shank3ab N terminal mutants during the first 30 sec lights-off. d) Box plots showing first 30 sec lights-off activity. e) Box plots showing activity across the full 5 minutes lights-off. Box plots represent 25th and 75th percentile, and median, with min to max whiskers. Sample sizes: WT = 50, shank3 N = 65, shank3 C = 44. p values; * = p < 0.05, ** = p < 0.01, *** = p < 0.001, **** = p < 0.0001.\n\nDose-response curves for small molecules were performed to investigate how these drugs impact the VMR in WT larvae. Risperidone did not affect the VMR at 1 μM, while at 10 and 20 μM doses, the VMR was decreased (Figure 2a, Tables 8-11). LiCl did not impact the VMR in WT larvae, despite exceeding previously published concentrations (Figure 2b, Tables 12-13). In contrast, CBZ had varying effects on both reactivity and activity: 40 μM and 120 μM CBZ concentrations showed no effect a, while 200 μM caused larvae to be hypo-reactive (Figure 2c, Tables 14-17). Similarly, 1 μM of MPEP did not affect the VMR, while 5 and 10 μM the VMR was decreased (Figure 2d, Tables 18-21). These results provide the lowest effective concentrations for each drug, risperidone (10 μM), CBZ (200 μM) and MPEP (5 μM), that caused a significant decrease in WT activity and reactivity; for LiCl we proceeded with the high dose of 5 mM. We next used these small molecule concentrations to compare how each would impact sensorimotor behavior in shank3ab-/- mutants.\n\na) Risperidone exposure of WT larvae in 1, 10 and 20 μM doses. b) LiCl salt exposure of 0.5, 1 and 5 mM doses. c) CBZ exposure of WT larvae in 80, 120 and 200 μM doses. d) MPEP exposure of WT larvae in 1, 5 and 10 μM doses. Box plots represent 25th and 75th percentile, and median, with min to max whiskers. Sample sizes: WT = 23, WT + risperidone = 24, shank3 N = 33, shank3 N + risperidone = 31, shank3 C = 19, shank3 C + risperidone = 23. p values; * = p < 0.05, ** = p < 0.01, *** = p < 0.001, **** = p < 0.0001.\n\nRisperidone is commonly prescribed in ASD for aggressive, self-injurious and hyperactive behavior (Lemmon et al., 2011). In shank3ab-/- mutants, 10 μM risperidone exacerbated hyporeactivity, but normalized hypoactivity, with shank3ab mutants achieving wild-type levels of swimming over the full duration of lights-off conditions (Figure 3, Tables 22-25). These results show that risperidone both reduced shank3 stimulus reactivity, and normalized overall stimulus-driven behaviors in shank3ab mutants.\n\na) Activity during the first 30 seconds of lights-off of larvae exposed to 10 μM risperidone. b) Activity during the full 5 minutes lights-off of larvae exposed to 10 μM risperidone. Box plots represents 25th and 75th percentile, and median, with min to max whiskers. Sample sizes: WT = 31, WT + risperidone = 29, shank3 N = 24, shank3 N + risperidone = 23, shank3 C = 25, shank3 C + risperidone = 23. p values; * = p < 0.05, ** = p < 0.01, *** = p < 0.001, **** = p < 0.0001.\n\nLithium chloride (LiCl) has been prescribed for several neuropsychological disorders, including bipolar disorder, depression, and ASD (Malhi et al., 2020). LiCl has been prescribed to individuals with PMS that exhibit bipolar depression, psychosis, and catatonic behavior (Verhoeven et al., 2013; Egger et al., 2017). Exposure to 5 mM LiCl caused no change in shank3ab-/- VMR (Figure 4, Tables 26-29). Therefore, LiCl does not impact visual processing in either WT zebrafish or shank3 mutant larvae.\n\na) Activity during the first 30 seconds of lights-off of larvae exposed to 5 mM LiCl. b) Activity during the full 5 minutes lights-off of larvae exposed to 5 mM LiCl. Box plots represent 25th and 75th percentile, and median, with min to max whiskers. Sample sizes: WT = 20, WT + risperidone = 16, shank3 N = 18, shank3 N + risperidone = 18, shank3 C = 16, shank3 C + risperidone = 16. p values; * = p < 0.05, ** = p < 0.01, *** = p < 0.001, **** = p < 0.0001.\n\nCarbamazepine (CBZ) is commonly prescribed to control seizures in individuals with epilepsy (Mattson et al., 1992). For individuals with PMS, CBZ has been prescribed following symptom resistance to common mood stabilizers, such as lithium and valproic acid (Verhoeven et al., 2013). WT and shank3abN-/- mutants VMR reactivity trended reduced with CBZ exposure but did not reach p < 0.05 (Figure 5, Tables 30-33). By contrast, shank3ab C-terminal VMR reactivity was unaffected by CBZ exposure. These results suggest that CBZ could have differential impacts on sensorimotor circuits depending on the location of the mutation in the shank3 gene.\n\na) Activity during the first 30 seconds of lights-off of larvae exposed to 200 μM CBZ. b) Activity during the full 5 minutes lights-off of larvae exposed to 200 μM CBZ. Box plots represent 25th and 75th percentile, and median, with min to max whiskers. Sample Sizes, WT = 35, WT + CBZ = 37, shank3ab N = 24, shank3ab N + CBZ = 19, shank3ab C = 27, and shank3ab C + CBZ = 34. p values; * = p < 0.05, ** = p < 0.01, *** = p < 0.001, **** = p < 0.0001.\n\nWhile the molecules described above have been prescribed for ASD and epilepsy, we were also interested in investigating compounds used to rescue behavioral deficits in Shank3 mouse models (Wang et al., 2016). We found that MPEP did not affect the VMR in shank3ab mutants however, MPEP was sufficient to cause hyporeactivity and hypoactivity in WT larvae (Figure 6, Tables 34-37). Therefore effects of MPEP on sensory-induced behaviors were genotype-dependent.\n\na) Activity during the first 30 seconds of lights-off of larvae exposed to 5 μM MPEP. b) Activity during the full 5 minutes lights-off of larvae exposed to 5 μM MPEP. Box plots represent 25th and 75th percentile, and median, with min to max whiskers. Sample Sizes, WT = 23, WT + MPEP = 24, shank3ab N = 33, shank3ab N + MPEP = 31, shank3ab C = 19, and shank3ab C + MPEP= 24. p values; * = p < 0.05, ** = p < 0.01, *** = p < 0.001, **** = p < 0.0001.\n\nA standard approach used in animal models to test for susceptibility to seizures related to reduced GABAergic inhibition is to test responses to the GABAA receptor antagonist pentylenetetrazole (PTZ) (Baraban et al., 2005; Hoffman et al., 2016; Liu and Baraban, 2019). In response to 3 mM PTZ, both N and C shank3ab-/- larvae fail to exhibit WT level of hyperactivity suggesting altered GABAergic signaling in the shank3ab mutant models (Figure 7, Tables 38-41).\n\na) Behavioral traces of larvae exposed to 3 mM PTZ. b) Activity of WT, shank3ab N and shank3ab C larvae for 10 minutes following exposure to 3 mM of PTZ. Box plots: box represents 25th and 75th percentile, and median, with min to max whiskers. Sample sizes for shank3 N trials, WT = 30, shank3 N = 30; for shank3 C trials, WT = 31, shank3 C = 28. p values; * = p < 0.05, ** = p < 0.01, *** = p < 0.001, **** = p < 0.0001.\n\n\nDiscussion\n\nHere we show both drug- and genotype- specific effects on sensory-evoked VMR behavior in shank3ab zebrafish models of Phelan-McDermid Syndrome. The array of symptoms experienced by people with Phelan-McDermid Syndrome is likely a consequence of the diverse developmental and physiological roles played by SHANK3 (Sheng and Kim, 2000; Grabrucker, 2014; Harony-Nicolas et al., 2015; Kozol et al., 2015, 2021; Harris et al., 2016; Engineer et al., 2018; James et al., 2019; Breen et al., 2020; Lutz et al., 2020). Here we tested how drugs targeting aggressive behavior, catatonia, and/or epilepsy affect sensorimotor VMR behaviors in zebrafish shank3 models of PMS. We found that drugs were neutral, enhanced or suppressed sensory-induced behavior in a genotype- and drug-dependent manner.\n\nZebrafish, in particular, provide a cost-effective and high-throughput way to test how medications impact behaviors (Rihel et al., 2010; Kokel and Peterson, 2011; Rihel and Schier, 2013; Jordi et al., 2015; Bruni et al., 2016; Hoffman et al., 2016). We previously validated shank3ab N and C zebrafish models and showed a shank3ab mutant dose-dependent reduction in the VMR (James et al., 2019; Kozol et al., 2021). Because the VMR phenotype is strongest in shank3ab homozygous larvae, we focused on this genotype for our small drug screen.\n\nWidely-prescribed, mood-stabilizing medications risperidone and LiCl had distinct effects on the VMR. Risperidone exacerbated shank3 VMR hyporeactivity and rescued overall activity to be to WT levels; by contrast, LiCl had no effect on the VMR in any of the three genotypes tested. In addition to the beneficial effects of risperidone however, this medication is associated with weight-gain in humans and reduced gastrointestinal motility in zebrafish (de Alvarenga et al., 2017; Guber et al., 2022). Consistent with this, risperidone D2 and 5-HT2 receptor targets (Nyberg et al., 1993) are expressed and regulate function in both brain and gut (Taniyama et al., 2000; Eliassi et al., 2008; Feng et al., 2020). Therefore, risperidone creates known symptom trade-offs in addition to improving mood in people and visual processing in zebrafish.\n\nTreatment-resistant epilepsy in Phelan-McDermid Syndrome is one of the most difficult symptoms to manage and also one for which there are many drug options (Chakraborty et al., 2022). CBZ, a sodium channel blocker, has been used in patients with PMS who were resistant to mood stabilizers (Mattson et al., 1992; Verhoeven et al., 2013, 2020). CBZ reduced reactivity to dark transitions in WT and shank3abN-/- larvae (though VMRs in neither genotype reached p<0.05) but had no effect on median VMR values in shank3abC-/- larvae, indicating possible shank3 allele-specific differences in the way CBZ impacts the VMR. Consistent with shank3 allele-specific differences, whole brain activity mapping in these same models showed a greater activity in mid and hindbrain circuits in response to dark transition in shank3abN than shank3abC alleles (Kozol et al., 2021). Another drug that addresses seizure susceptibility is PTZ, a GABAA receptor antagonist that is used to test seizure susceptibility in zebrafish and murine models. Our findings that shank3ab models are resistant to doses that make WT larvae hyperactive suggest that these models might have fewer GABAA receptors targets for PTZ to act upon. As with the mood stabilizers, the effects of CBZ and PTZ were both drug- and genotype-dependent.\n\nFinally, our findings that MPEP made WT behave like shank3ab-/- larvae in the VMR assay suggest that blocking mGluR5 may affect sensory processing. MPEP blocks mGluR5 and improves excessive grooming and striatal synaptic plasticity in a mouse shank3 model (Wang et al., 2016). GluR5 continues to show promise as a regulator of excitatory/inhibitory balance in the striatum where a negative correlation between mGluR5 and GABA was measured in autistic people using fMRI; mouse Cntnap2 mutants showed a similar negative mGluR5 and GABA correlation that was not found in either Shank3 or 16p11.2 deletion models (Carey et al., 2022).\n\n\nSummary/conclusions\n\nOur findings highlight the genotype-, drug-, and phenotype-specific challenges of designing treatment strategies for Phelan-McDermid Syndrome. These include trade-offs that can occur when a drug like risperidone improves sensory-processing and mood at the expense of gut function and differential effects of drugs on different symptoms.",
"appendix": "Data availability\n\nDRYAD: Drugs prescribed for Phelan-McDermid syndrome differentially impact sensory behaviors in shank3 zebrafish models. https://doi.org/10.5061/dryad.hqbzkh1kn (Kozol & Dallman, 2023).\n\nDRYAD: ARRIVE checklist for ‘Drugs prescribed for Phelan-McDermid syndrome differentially impact sensory behaviors in shank3 zebrafish models.’ https://doi.org/10.5061/dryad.hqbzkh1kn (Kozol & Dallman, 2023).\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgements\n\nWe would like to thank the Phelan-McDermid Syndrome Foundation for including us in their scientific/family conferences where we learned about the challenges families face in managing multiple symptoms. 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Publisher Full Text\n\nMarques JC, Lackner S, Felix R, et al.: Structure of the zebrafish locomotor repertoire revealed with unsupervised behavioral clustering. Curr. Biol. 2018; 28: 181–195.e5. PubMed Abstract | Publisher Full Text\n\nMattson RH, Cramer JA, Collins JF: A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. N. Engl. J. Med. 1992; 327: 765–771. PubMed Abstract | Publisher Full Text\n\nMcDougle CJ, Scahill L, Aman MG, et al.: Risperidone for the core symptom domains of autism: results from the study by the autism network of the research units on pediatric psychopharmacology. Am. J. Psychiatry. 2005; 162: 1142–1148. PubMed Abstract | Publisher Full Text\n\nMieses AM, Tavassoli T, Li E, et al.: Brief Report: Sensory Reactivity in Children with Phelan-McDermid Syndrome. J. Autism Dev. Disord. 2016; 46: 2508–2513. PubMed Abstract | Publisher Full Text\n\nNyberg S, Farde L, Eriksson L, et al.: 5-HT2 and D2 dopamine receptor occupancy in the living human brain. A PET study with risperidone. Psychopharmacology. 1993; 110: 265–272. PubMed Abstract | Publisher Full Text\n\nPanizzutti B, Bortolasci CC, Spolding B, et al.: Biological Mechanism(s) Underpinning the Association between Antipsychotic Drugs and Weight Gain. J. Clin. Med. 2021; 10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPhelan K, McDermid HE: The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome). Mol. Syndromol. 2012; 2: 186–201. PubMed Abstract | Publisher Full Text\n\nPortugues R, Engert F: The neural basis of visual behaviors in the larval zebrafish. Curr. Opin. Neurobiol. 2009; 19: 644–647. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRihel J, Schier AF: Sites of action of sleep and wake drugs: insights from model organisms. Curr. Opin. Neurobiol. 2013; 23: 831–840. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRihel J, Prober DA, Arvanites A, et al.: Zebrafish behavioral profiling links drugs to biological targets and rest/wake regulation. Science. 2010; 327: 348–351. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRobertson CE, Baron-Cohen S: Sensory perception in autism. Nat. Rev. Neurosci. 2017; 18: 671–684. Publisher Full Text\n\nSakai C, Ijaz S, Hoffman EJ: Zebrafish models of neurodevelopmental disorders: past, present, and future. Front. Mol. Neurosci. 2018; 11. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSerret S, Thummler S, Dor E, et al.: Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports. BMC Psychiatry. 2015; 15: 107. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSheng M, Kim E: The Shank family of scaffold proteins. J. Cell Sci. 2000; 113(Pt 11): 1851–1856. Publisher Full Text\n\nSiper PM, Kolevzon A, Wang AT, et al.: A clinician-administered observation and corresponding caregiver interview capturing DSM-5 sensory reactivity symptoms in children with ASD. Autism Res. 2017; 10: 1133–1140. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSmith-Hicks C, Wright D, Kenny A, et al.: Sleep Abnormalities in the Synaptopathies-SYNGAP1-Related Intellectual Disability and Phelan-McDermid Syndrome. Brain Sci. 2021; 11. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSoorya L, Kolevzon A, Zweifach J, et al.: Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Mol. Autism. 2013; 4: 18. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTaniyama K, Makimoto N, Furuichi A, et al.: Functions of peripheral 5-hydroxytryptamine receptors, especially 5-hydroxytryptamine4 receptor, in gastrointestinal motility. J. Gastroenterol. 2000; 35: 575–582. PubMed Abstract | Publisher Full Text\n\nTavassoli T, Bellesheim K, Siper PM, et al.: Measuring Sensory Reactivity in Autism Spectrum Disorder: Application and Simplification of a Clinician-Administered Sensory Observation Scale. J. Autism Dev. Disord. 2016; 46: 287–293. PubMed Abstract | Publisher Full Text\n\nTomchek SD, Dunn W: Sensory processing in children with and without autism: a comparative study using the short sensory profile. Am. J. Occup. Ther. 2007; 61: 190–200. PubMed Abstract | Publisher Full Text\n\nTu JC, Xiao B, Naisbitt S, et al.: Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron. 1999; 23: 583–592. PubMed Abstract | Publisher Full Text\n\nTucker B, Richards RI, Lardelli M: Contribution of mGluR and Fmr1 functional pathways to neurite morphogenesis, craniofacial development and fragile X syndrome. Hum. Mol. Genet. 2006; 15: 3446–3458. PubMed Abstract | Publisher Full Text\n\nVerhoeven WM, Egger JI, Cohen-Snuijf R, et al.: Phelan-McDermid syndrome: clinical report of a 70-year-old woman. Am. J. Med. Genet. A. 2013; 161A: 158–161. PubMed Abstract | Publisher Full Text\n\nVerhoeven WMA, Egger JIM, de Leeuw N : A longitudinal perspective on the pharmacotherapy of 24 adult patients with Phelan McDermid syndrome. Eur. J. Med. Genet. 2020; 63: 103751. PubMed Abstract | Publisher Full Text\n\nVucurovic K, Landais E, Delahaigue C, et al.: Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion. Eur. J. Med. Genet. 2012; 55: 625–629. PubMed Abstract | Publisher Full Text\n\nWang X, et al.: Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism. Nat. Commun. 2016; 7: 11459. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWarp E, Agarwal G, Wyart C, et al.: Emergence of patterned activity in the developing zebrafish spinal cord. Curr. Biol. 2012; 22: 93–102. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "164132",
"date": "09 Mar 2023",
"name": "Fumihito Ono",
"expertise": [],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper by Kozol and Dallman studied the effects of small molecule drugs on the behavior of shank3 mutant zebrafish, using it as a model of PMS. Specifically, authors examined their response to the change of illumination. The experiments were reasonably designed and the analysis was rigorously executed. Small molecules examined in the study also have clinical significance.\nI have several suggestions listed below.\nPlease provide the definition of “activity” and “reactivity” in Introduction or Methods. I presumed that the former corresponds to the overall activity during the dark 5 min while the latter to that of first 30 seconds. Because this concept is central to the study design and the analysis, it may be worthwhile to highlight it in Fig.1.\n\nThe difference of reactivity and activity between N-term and C-term mutants in CBZ is intriguing. Is it known whether human patients with either mutation show distinct response to CBZ?\n\nConcentration of each drug in the bath solution was determined by making a dose response curve first in Wild type fish (Fig.2). The concentration in the CNS may reach that of the bath solution depending on the chemical property of the drug, while some drugs may display disparity between CNS and bath. It will be difficult to directly measure the concentration of each drug in the brain. Therefore, I suggest adding some discussion on pharmacokinetics (absorption, excretion, blood brain barrier etc.) in the text.\n\nIn Fig.1c and d, please put labels on the horizontal axes. While readers can identify three groups based on their colors, labeling will make the identification easier.\n\nIn Fig.2C, please include data for 200 microM.\n\nIf allowed in the journal format, please consider moving most of the tables to supplement. It is definitely good that readers can directly look at all the analysis. On the other hand, having 41 tables in the middle of the main text is somewhat distracting.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10178",
"date": "27 Sep 2023",
"name": "Julia Dallman",
"role": "Author Response",
"response": "First, we would like to thank Dr. Ono for his careful and insightful review of our paper. We respond (our responses are in italics) to each suggestion below. Please provide the definition of “activity” and “reactivity” in Introduction or Methods. I presumed that the former corresponds to the overall activity during the dark 5 min while the latter to that of first 30 seconds. Because this concept is central to the study design and the analysis, it may be worthwhile to highlight it in Fig.1. Response: We agree with the reviewer that we omitted the definitions for activity and reactivity. We have since edited the text of both the introduction and the methods to read, Introduction: ”During the VMR, sudden changes in illumination from light to dark evoke abrupt increases in swimming behavior as larvae search the well for a way to return to the light (Horstick et al. 2017); we capture the abrupt response by quantifying swimming in the first 30 seconds right after the transition to dark, referred to hereafter as reactivity, but the larvae sustain their search for the full 5 minutes, referred to hereafter as activity”. Methods: “Behavior was analyzed by binning the raw ethovision movement data into 30 second and 5 minute bins. We then defined behaviors in the first 30 seconds after dark transitions as reactivity and behaviors sustained across the full five minutes of darkness as activity. Therefore, a statistical increase or decrease in swimming during the first 30 seconds was defined as hyperreactive or hyporeactive respectively; a statistical increase or decrease in swimming during the full five minutes was defined as hyperactive or hypoactive respectively” The difference of reactivity and activity between N-term and C-term mutants in CBZ is intriguing. Is it known whether human patients with either mutation show distinct response to CBZ? Response: We appreciate the reviewer’s curiosity in how our results relate to the literature. We know that CBZ is used to treat intractable epilepsy in some individuals with PMS. However, information regarding medication is usually a portion of meta analyses for clinical reviews or perspectives. Therefore, they do not indicate how CBZ impacts other symptoms of the patients. Concentration of each drug in the bath solution was determined by making a dose response curve first in Wild type fish (Fig.2). The concentration in the CNS may reach that of the bath solution depending on the chemical property of the drug, while some drugs may display disparity between CNS and bath. It will be difficult to directly measure the concentration of each drug in the brain. Therefore, I suggest adding some discussion on pharmacokinetics (absorption, excretion, blood brain barrier etc.) in the text. Response: Thank you for pointing this out. We have added a paragraph to the discussion: “It should be noted that the concentration of the drug reported here corresponds to that in the bath solution surrounding the larvae. This bath concentration may differ substantially from the brain concentration due to differences in on a drug by drug basis related to pharmacokinetic differences. These include the drug’s ability to cross the skin and/or blood brain barrier as well as differences in kinetics of drug breakdown and excretion (Skiba et al., 2023; Windell et al., 2023). Also, this route of administration differs fundamentally from that in people and therefore drug dosage in zebrafish does not correspond to that in people.” In Fig.1c and d, please put labels on the horizontal axes. While readers can identify three groups based on their colors, labeling will make the identification easier. Response: We have added labels to the bottom of the box plots in Figure 1. In Fig.2C, please include data for 200 microM. Response: We apologize for the error in labeling our graph. The initial submission has an incorrect dose response that has now been changed to, 80, 120 and 200 microM. The numbers in the methods, figure legend and statistical tables are all correct and have remained the same. If allowed in the journal format, please consider moving most of the tables to supplement. It is definitely good that readers can directly look at all the analysis. On the other hand, having 41 tables in the middle of the main text is somewhat distracting. Response: We agree with the reviewer and have moved the tables detailing statistics to the end of the paper that comes just before the references."
}
]
},
{
"id": "178147",
"date": "17 Jul 2023",
"name": "Sara Moir Sarasua",
"expertise": [
"Reviewer Expertise Phelan-McDermid syndrome"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for the opportunity to review this interesting and timely research. The authors present a study in which they use the zebrafish model of two shank3ab mutants (affecting either the N or C terminus of shank3a and shank3b) to measure sensory-motor behaviors by subjecting larvae to one of 3 medications for 24 hours and then measuring response to light/dark cycles. The authors find that risperidone, but not LiCl or Carbamazepine, affects the response to light. They also find that the shank3ab models are resistant to the seizure-inducing drug PTZ. The methods presented will be helpful to others using the zebrafish model for Phelan-McDermid syndrome related research. This research is important because it models commonly used therapies in the zebrafish model with the hope of better understanding effective treatments in people with Phelan-McDermid syndrome due to SHANK3 haploinsufficiency or SHANK3 pathogenic variants. As such it will be of interest both to researchers investigating animal models as well as clinical researchers. With an interdisciplinary audience in mind, there are places where additional information would be most helpful.\nOur specific comments follow:\nAbstract:\nThe authors state in the Results that “risperidone normalized the VMR in shank3 models”. In the Results section, the authors state that “risperidone exacerbated hyporeactivity, but normalized hypoactivity.” Would the authors clarify?\nIntroduction:\nThe authors provide a sound justification for the use of the zebrafish model in measuring sensory motor behavior.\nThe authors do not indicate why PTZ trials were included in the experiments. This should be added to the introduction. Because epilepsy and seizures are important phenotypes in PMS, it is reasonable to look at this phenotype, thus it should be included in the introduction.\nMethods:\nPage 3 (of the pdf version of the article). It would help the reader to state that these mutants include both shank3a and shank3b deletions of either the C or N terminus regions. Please direct the reader to the shank3a and shank3b model in Figure 1a. While this information is in the Figure, it is not mentioned in text. And because the figures and tables are located some distance from the text, the information is not as accessible as it could be.\nTable 1. It is somewhat unclear whether the “Effect on VMR” in this table derives from the cited literature or from the results of the research. After reading the manuscript, it would be helpful to have a table to summarize the results of the research in a table similar to Table 1, but based just on the present research results. A lot of work and many many statistical analyses were performed in this research study, and the results get somewhat lost. A summary table with an interpretation of what they mean would be very helpful to the reader.\nPage 4.\nWhat is the dosage used for the MS222 to euthanize the larvae?\n\nHigh-throughput behavioral screens – what is the outcome measured in the VMR experiments? Is it the same as described for the PTZ trials – total distance moved for 10 minutes?\n\nPlease define in the methods how activity/hypoactivity was defined or measured. Please define how reactivity/hyporeactivity was defined. Does VMR include both of these measures? Or only the reactivity?\n\nIn the “Drug Screening” section, the system water needs more detail of quality measures i.e.. breakdown of the monitored levels of alkalinity, hardness, carbon dioxide, dissolved oxygen, pH, and anything else that is measured per-period or weekly.\nIn the statistical analysis section, please tell the reader how the analyses were to be interpreted. By this we mean that normalization or rescue of a response was determined by comparing WT to mutant and finding no statistically significant difference, or a reduced difference. A challenge we discovered when interpreting the figures which display the statistical significance levels between WT-DMSO and mutants or WT drug and mutants, is that it was the lack of significance (lack of stars) that led to the interpretation of results. For instance, in Figure 3 describing response to risperidone, the caption says that risperidone normalizes the response. The reader can observe that the significant differences observed in the 30 second test, were no longer apparent in the 5 minute test. The 5 minute tests were similar between WT and mutants. We are so trained to look for the stars on graphs that it is hard to observe the lack of stars. Do the authors have suggestions to guide the reader in how to interpret these results? When the “biologically significant” finding is the non-statistically significant finding. It may also be of help to the reader to include a particular focus on the tables with statistical tests that much interest is given to such as the comparison of WT to mutant (showing difference) then WT to mutant-risp (showing no difference). Thus risperidone normalizing the outcome. Our first inclination was to suggest that the many tables be placed in a supplemental file, however, they are quite important. Is there a way to highlight these key comparisons that were used to come to the conclusions that the authors make?\nTable 2. Please tell the reader who is in Group A and who in Group B.\nTable 5, 2nd to last row. Why does it say ABTL instead of WT? Elsewhere sometimes ABTL is used and sometimes WT. Are they interchangeable? I suggest using just WT if they are the same. The methods section tells the reader that WT is ABTL.\nFigures. We appreciate the authors defining what is depicted in the box plots and inclusion of the sample sizes.\nFigure 2. Please label the 2 columns of the graph. Two graphs are shown for each drug. One for distance (mm/30 sec) and the other Distance (mm/5min). It would help the reader to label the two columns/graphs. It is defined in Figure 3 and would help the reader to define it in Figure 2. It would help the reader to label each column (Activity) and (Reactivity) so the reader more clearly understands which graph shows which outcome.\nFigures 3, 4, 5. The figures show statistical comparisons between WT DMSO vs. the 4 shank3ab genotypes and WT drug vs. the 4 shank3ab genotypes by indicating with stars whether the comparisons are statistically significant. However, it is the absence of a statistical difference that leads to the interpretation. This is a challenge in reading the graphs and requires a detailed review of the statistical tables. Do the authors have any suggestions?\nFigure 4. In this figure caption, it reads “reactivity or activity” rather than “hyporeactivity or hypoactivity” as in the previous figure. It helps the reader to be consistent in use of the terms across the written portion as well as figures/tables.\nFigure 7. panel b and c, label WT and N-/+ and N -/-. In panel a, it appears the investigators assessed N-/- and N-/+. However, in the accompanying graphics, it appears only the N-/- is graphed. Is that correct? Is N-/+ a heterozygote? I do not see assessment of heterozygotes in the methods or anywhere else in the manuscript. Please include the methods in the methods section.\nPage 26. It is understandable to model the strongest phenotypic response in the homozygous models. However, PMS is caused by a heterozygous deletion/variant in SHANK3. Would the authors comment on how their results might be applied to the case of heterozygous mutations and how this work translates to the human clinical condition? Would the authors also comment on how the fish paralogs shank3a and shank3b relate to the human SHANK3?\nIt would help the reader if the authors would help interpret the direction of effect that is to the benefit. For instance, if treated with risperidone, the activity in the mutants is less than when not treated with risperidone. The authors say this exacerbated the hyporeactivity. For clinical usage, is increased hyporeactivity (is that less reactivity?) a desired outcome? If treatment with risperidone normalized activity, is that a desired outcome? Back to an earlier comment, it would help the reader to provide a summary table telling the reader, for each drug and each genotype, what the effect was (no difference, Decreased activity, Increased activity, Normalized compared to WT, decreased reactivity, Increased reactivity, Normalized reactivity, And which direction is the desired direction)\nWhat does this study add to what was previously known?\nGeneral points\nThe flow of the manuscript is disrupted with the many figures and tables and the text is sometimes lost among the tables. It would help to have the Figures and Tables placed where referenced and include them all within the Results section rather than interspersed.\nDiscussion\nHow do the authors interpret the genotype-specific findings?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10192",
"date": "27 Sep 2023",
"name": "Julia Dallman",
"role": "Author Response",
"response": "First, we would like to thank Dr. Sarasua for her thorough and clear feedback for how to improve the presentation of our work. We respond (our responses are in italics) to each suggestion below. Our specific comments follow: Abstract: The authors state in the Results that “risperidone normalized the VMR in shank3 models”. In the Results section, the authors state that “risperidone exacerbated hyporeactivity, but normalized hypoactivity.” Would the authors clarify? Response: We agree that as written there seems to be a discrepancy between what is stated in the abstract and results/discussion. We decided not to include the terms and definitions of hypoactivivity and hyporeactivity in the abstract due to the need for brevity but in the current version, we edited the text in the abstract results section to read “We found that risperidone partially normalized the VMR in shank3 models.” Introduction: The authors provide a sound justification for the use of the zebrafish model in measuring sensory motor behavior. The authors do not indicate why PTZ trials were included in the experiments. This should be added to the introduction. Because epilepsy and seizures are important phenotypes in PMS, it is reasonable to look at this phenotype, thus it should be included in the introduction. Response: We edited the following sentence to more clearly introduce PTZ experiments “ Lastly, we quantified swimming before and after exposure to pentylenetetrazole (PTZ), a drug used in animal models to better understand susceptibility to seizures, at doses that normally cause hyperactivity in wild type larvae (Baraban et al., 2005; Hoffman et al., 2016; Liu and Baraban, 2019). Methods: Page 3 (of the pdf version of the article). It would help the reader to state that these mutants include both shank3a and shank3b deletions of either the C or N terminus regions. Please direct the reader to the shank3a and shank3b model in Figure 1a. While this information is in the Figure, it is not mentioned in text. And because the figures and tables are located some distance from the text, the information is not as accessible as it could be. Response: We agree that more information on the design of our mutations provides clarity for the reader. We have since added the text, “Readers should note that each model includes a mutation in both the a and the b ohnolog of the shank3 gene and therefor mutants are referred to as shank3ab; mutations in shank3abN are located near the N-terminus while those in shank3abC are located near the C-terminus of the predicted Shank3 protein product (Figure 1a).” Table 1. It is somewhat unclear whether the “Effect on VMR” in this table derives from the cited literature or from the results of the research. After reading the manuscript, it would be helpful to have a table to summarize the results of the research in a table similar to Table 1, but based just on the present research results. A lot of work and many many statistical analyses were performed in this research study, and the results get somewhat lost. A summary table with an interpretation of what they mean would be very helpful to the reader. Response: We agree with the reviewer that clarity on the content of table 1 would help direct the reader’s attention to the important summaries from our study. This table includes the drug, drug classification, receptors that the drug targets, the summary of how the drug effected VMR in our study and references that provided mechanism of action and/or helped us determine dosages to test for our dose response assays. We have since edited the last sentence of the introduction to read “Results of the above experiments are summarized in the column entitled ‘effect on VMR’ in Table 1.” And the table description to read, “Drugs used in this study are listed to the left followed by indication and target(s)/mechanism of action. These are based on relevant references in the rightmost column. Drug effects on VMR in are based results from this study.” Page 4. What is the dosage used for the MS222 to euthanize the larvae? Response: We thank the reviewer for finding this concentration omission. We have since added to the text, “200 mg/L”. High-throughput behavioral screens – what is the outcome measured in the VMR experiments? Is it the same as described for the PTZ trials – total distance moved for 10 minutes? Response: We thank the reviewer for finding this omission in the methods. We have added the definition of activity and reactivity, along with the measurement units that were compared. The text now reads, “Behavior was analyzed by binning the raw ethovision movement data into 30 second and 5 minute bins. We then defined behaviors in the first 30 seconds after dark transitions as reactivity and behaviors sustained across the full five minutes of darkness as activity.” Please define in the methods how activity/hypoactivity was defined or measured. Please define how reactivity/hyporeactivity was defined. Does VMR include both of these measures? Or only the reactivity? Response: We thank the reviewer for finding this omission in the methods. We have added the definition of hyper- and hypo- following the above mentioned definition of baseline activity and reactivity. The manuscript now reads, “Therefore, a statistical increase or decrease in swimming during the first 30 seconds was defined as hyperreactive or hyporeactive respectively; a statistical increase or decrease in swimming during the full five minutes was defined as hyperactive or hypoactive respectively.” In the “Drug Screening” section, the system water needs more detail of quality measures i.e.. breakdown of the monitored levels of alkalinity, hardness, carbon dioxide, dissolved oxygen, pH, and anything else that is measured per-period or weekly. Thank you for pointing out this oversight. We have added the following to the methods section. “The water in which the adult fish are housed are tested for pH and conductivity by probes that are always sampling, ‘system water’. System water is tap water that goes through a water softener, a charcoal filter, and reverse osmosis membranes to make the water less hard/alkaline, remove contaminants and ions respectively. This purified water is stored on a 100 gallon storage tank and used for 10% daily water exchanges that are controlled by a solenoid. pH 7.0-8.1 and conductivity 350-800 µS are kept within range by two dosers, one with sodium bicarbonate (pH) and the other with instant ocean (conductivity). We also track room humidity and temperature on a daily basis. These values are important to track because the temperature of the water is regulated by air temperature.” In the statistical analysis section, please tell the reader how the analyses were to be interpreted. By this we mean that normalization or rescue of a response was determined by comparing WT to mutant and finding no statistically significant difference, or a reduced difference. A challenge we discovered when interpreting the figures which display the statistical significance levels between WT-DMSO and mutants or WT drug and mutants, is that it was the lack of significance (lack of stars) that led to the interpretation of results. For instance, in Figure 3 describing response to risperidone, the caption says that risperidone normalizes the response. The reader can observe that the significant differences observed in the 30 second test, were no longer apparent in the 5 minute test. The 5 minute tests were similar between WT and mutants. We are so trained to look for the stars on graphs that it is hard to observe the lack of stars. Do the authors have suggestions to guide the reader in how to interpret these results? When the “biologically significant” finding is the non-statistically significant finding. It may also be of help to the reader to include a particular focus on the tables with statistical tests that much interest is given to such as the comparison of WT to mutant (showing difference) then WT to mutant-risp (showing no difference). Thus risperidone normalizing the outcome. Our first inclination was to suggest that the many tables be placed in a supplemental file, however, they are quite important. Is there a way to highlight these key comparisons that were used to come to the conclusions that the authors make? Response: We agree that it might be confusing to have the lack of significance indicate rescue. We have edited the figure legend to now state, “No statistical significance between drug exposed mutant and control was interpreted as normalization.” Table 2. Please tell the reader who is in Group A and who in Group B. Response: We agree with the reviewer that these labels were arbitrary and did not define the categories analyzed. We have updated these labels to “lights-on” for “Group A” and “lights-off” for “Group B”. Table 5, 2nd to last row. Why does it say ABTL instead of WT? Elsewhere sometimes ABTL is used and sometimes WT. Are they interchangeable? I suggest using just WT if they are the same. The methods section tells the reader that WT is ABTL. Response: We agree with the reviewer that multiple names is confusing. We have since taken ABTL out of all instances, besides the initial definition of WT in the “Ethics, fish maintenance and husbandry” section. Figures. We appreciate the authors defining what is depicted in the box plots and inclusion of the sample sizes. Response: We thank the reviewer for the compliment. Figure 2. Please label the 2 columns of the graph. Two graphs are shown for each drug. One for distance (mm/30 sec) and the other Distance (mm/5min). It would help the reader to label the two columns/graphs. It is defined in Figure 3 and would help the reader to define it in Figure 2. It would help the reader to label each column (Activity) and (Reactivity) so the reader more clearly understands which graph shows which outcome. Response: Thank you for this suggesting this change. We have revised both Figure 1 and Figure 2 accordingly. Figures 3, 4, 5. The figures show statistical comparisons between WT DMSO vs. the 4 shank3ab genotypes and WT drug vs. the 4 shank3ab genotypes by indicating with stars whether the comparisons are statistically significant. However, it is the absence of a statistical difference that leads to the interpretation. This is a challenge in reading the graphs and requires a detailed review of the statistical tables. Do the authors have any suggestions? Response: We agree with the reviewer that the submitted version did not explicitly state how to interpret the graphs. We have since edited the figure legends of Figures 4-5 to read, “No statistical significance between drug exposed mutant and control was interpreted as normalization.” Figure 4. In this figure caption, it reads “reactivity or activity” rather than “hyporeactivity or hypoactivity” as in the previous figure. It helps the reader to be consistent in use of the terms across the written portion as well as figures/tables. Response: Our figure legend title, “Figure 4. LiCl does not impact lights-off activity or reactivity behaviors in wildtype and shank3ab mutants.” Referred to the finding that no behavior changed when exposed to LiCL, wildtype or mutant. We have tried to address this issue by changing the figure legend title to be, “Figure 4. LiCl does not impact lights-off VMR behaviors in wildtype and shank3ab mutants.” Figure 7. panel b and c, label WT and N-/+ and N -/-. In panel a, it appears the investigators assessed N-/- and N-/+. However, in the accompanying graphics, it appears only the N-/- is graphed. Is that correct? Is N-/+ a heterozygote? I do not see assessment of heterozygotes in the methods or anywhere else in the manuscript. Please include the methods in the methods section. Response: We agree that the figure is confusing when seeing the inconsistencies in genotype titles for the image and graph. We decided to focus on the homozygote data, because heterozygotes were not tested or analyzed for the other drugs used in the study. We have edited the text for the “Drug Screening” section to now include clarity about our analysis. The text now reads, “Both heterozygote and homozygote larvae were tested for seizure susceptibility, however to remain consistent with the other genotypes analyzed in the study, we chose to focus on the homozygotic data for statistical analyses to be consistent with the rest of the paper.” Page 26. It is understandable to model the strongest phenotypic response in the homozygous models. However, PMS is caused by a heterozygous deletion/variant in SHANK3. Would the authors comment on how their results might be applied to the case of heterozygous mutations and how this work translates to the human clinical condition? Would the authors also comment on how the fish paralogs shank3a and shank3b relate to the human SHANK3? Response: We assessed heterozygotes in previous research for VMR and other phenotypes, see Kozol et al. 2015 Human Molecular Genetics, James et al. 2019 Molecular Autism, and Kozol et al. 2021 Nature Communications Biology. In our previous work, we found that the homozygotes provided the most pronounced version of a phenotype and therefore an ideal choice for determining how drugs impact these phenotypes. Because homozygotes are viable in zebrafish, we believe the model provides an opportunity to screen a relatively strong phenotype that is qualitatively similar to the heterozygous phenotype for drug rescue that could be translatable for genetic forms of ASD. For instance, recently a clinical assessment of individuals with PMS found that a large minority suffer visual hyporeactivity, see Walinga et al. 2022, European Journal of Medical Genetics. Therefore, our shank3 gene models may provide a phenotype that is similar to visually initiated hyporeactive symptoms present in individuals with shank3 variant PMS. We believe further research determining secondary effects of commonly prescribed drugs for any condition would benefit the knowledgebase of clinical researchers and doctors. In terms of the relationship between human and zebrafish gene paralogs, we previously published a study that has an analysis that describes how conserved shank3 genes are in fish. We found that both ohnologs are highly conserved with humans, with both copies maintaining all of the major conserved protein interacting domains. Finally, we found shank3a was more highly conserved, with higher percent pairwise comparisons and inclusion of smaller single protein interacting domains. See Kozol et al. 2015, Human Molecular Genetics for more details. It would help the reader if the authors would help interpret the direction of effect that is to the benefit. For instance, if treated with risperidone, the activity in the mutants is less than when not treated with risperidone. The authors say this exacerbated the hyporeactivity. For clinical usage, is increased hyporeactivity (is that less reactivity?) a desired outcome? If treatment with risperidone normalized activity, is that a desired outcome? Back to an earlier comment, it would help the reader to provide a summary table telling the reader, for each drug and each genotype, what the effect was (no difference, Decreased activity, Increased activity, Normalized compared to WT, decreased reactivity, Increased reactivity, Normalized reactivity, And which direction is the desired direction) Response: We understand that our original interpretation of the relationship between our results and how they relate to the human condition was not clear. This study was looking to see how drugs prescribed for one symptom, such as aggressive behavior or epilepsy, impacted sensory perception, with a focus on sensory hyporeactivity that is found in our models. Therefore, our results provide evidence that many non-selective molecules used to treat core symptoms, can in reality exacerbate or help medicate sensory symptoms that may not have been tested yet in a clinical study. We strongly believe that normalizing or medicating a sensory deficit to baseline should be a primary goal for a clinician, seeing that sensory deficits are one of several quality of life ailments for individuals with PMS. Finally, table 1 provides the primary results for each drugs effect on VMR and we have provided clarity in the text to direct the reader to this information. See previous response. What does this study add to what was previously known? Response: As stated above, this study provides evidence that many commonly prescribed drugs for core symptoms of Phelan-Mcdermid Syndrome may be unintentionally impacting sensory symptoms, whether positively (risperidone) or negatively. General points The flow of the manuscript is disrupted with the many figures and tables and the text is sometimes lost among the tables. It would help to have the Figures and Tables placed where referenced and include them all within the Results section rather than interspersed. Response: We understand the frustration for the reader that the layout of the paper makes the manuscript hard to read. However, we disagree and would prefer that the tables be added after the main body and before the references. This makes the reading flow easiest visually and maintains the tables for readers to reference if they are interested in specific metrics not mentioned in the text or figure legends, such as t and p values."
}
]
}
] | 1
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https://f1000research.com/articles/12-84
|
https://f1000research.com/articles/12-1045/v1
|
29 Aug 23
|
{
"type": "Case Report",
"title": "Case Report: IgG4-related kidney disease complicated by interstitial pneumonia",
"authors": [
"Akira Mima",
"Rina Lee",
"Ami Murakami",
"Hidemasa Gotoda",
"Ryosuke Akai",
"Shinji Lee",
"Rina Lee",
"Ami Murakami",
"Hidemasa Gotoda",
"Ryosuke Akai",
"Shinji Lee"
],
"abstract": "Immunoglobulin G4 (IgG4)-related disease is a systemic inflammatory disorder characterized by tubulointerstitial nephritis with IgG4-positive plasma cell infiltration. We report the case of an 84-year-old male who presented with a history of dyspnea on exertion and cough. The lymph nodes were palpated in the axilla. Urinalysis revealed mild proteinuria and increased levels of NAG and β2-microglobulin. Blood tests showed hyperglobulinemia with a marked elevation of serum IgG4 levels. Chest computed tomography showed bilateral ground-glass and reticular opacities in the lower and peripheral portions of the lungs. Ga-67 scintigraphy showed kidney uptake. The patient was diagnosed with IgG4-related kidney disease based on the renal pathology indicative of typical tubulointerstitial nephritis with extensive IgG4-positive plasma cell infiltration. The patient was treated with prednisolone and showed a prompt response in his clinical condition. The patient achieved normalization of serum IgG4 levels 6 months after the initiation of treatment. Although IgG4-related disease is thought to be potentially associated with organ fibrosis, there are few reports on combination of interstitial pneumonia and IgG4-related kidney disease. Our case report presents a possible pattern of IgG4-related disease.",
"keywords": [
"IgG4-related kidney disease",
"tubulointerstitial nephritis",
"interstitial pneumonia",
"prednisolone"
],
"content": "Introduction\n\nImmunoglobulin G4 (IgG4)-related disease is a systemic inflammatory disease characterized by extensive lymphoplasmacytic infiltration of IgG4-positive cells in various organs.1–3 Renal involvement has been reported in approximately 10% of patients with IgG4-related disease.4 Respiratory organ lesions have also been recognized; however, their rate is low and they are often only detected during close examination.5 Clinical symptoms vary depending on the organs affected by IgG4-related disease; however, they are usually mild. Thus, IgG4-related disease should be diagnosed based on a combination of clinical, serological, and radiological findings, and pathological features.6 There have only been a few reports on the coexistence of interstitial pneumonia and IgG4-related kidney disease.7 In this report, we describe the case of a patient who presented with interstitial pneumonia and was diagnosed with IgG4-tubulointerstitial nephritis and IgG4-related kidney disease. Treatment with prednisolone was initiated soon after diagnosis and the patient responded well.\n\n\nCase presentation\n\nAn 84-year-old unemployed Japanese man presenting with dyspnea on exertion and cough was referred to our hospital. The patient had a history of hypertension and hypothyroidism, but an unremarkable family history of any related pathology. Examination results of the patient were found to be negative for arthralgia, skin rash, macrohematuria, and hemoptysis. Upon admission, body temperature was recorded to be 36.5 °C; blood pressure, 128/72 mmHg; heart rate, 72 bpm; oxygen saturation, 98%; weight, 60.5 kg; height, 164.9 cm; and BMI, 21.1 kg/m2. Initial laboratory and diagnostic workup revealed blood urea nitrogen 18 mg/dL (normal range: 8-20 mg/dL), creatinine 0.98 mg/dL (normal range: 0.65-1.07 mg/dL), estimated glomerular filtration rate 56 mL/min/1.73 m2 (normal range: ≥ 60 mL/min/1.73 m2), calcium 9.4 mg/dL (normal range: 8.8-10.4 mg/dL), total protein 9.1 g/dL (normal range: 6.5-8.0 g/dL), albumin 3.6 g/dL (normal range: 3.9-4.9 g/dL), alkaline phosphatase 60 IU/L (normal range: 50-350 IU/L), aspartate transaminase 27 IU/L (normal range: 7-38 IU/L), alanine transaminase 11 IU/L (normal range: 4-44 IU/L), total cholesterol 182 mg/dL (normal range: 120-220 mg/dL), triglyceride 175 mg/dL (normal range: 50-149 mg/dL), WBC 11.5×103/μL (normal range: 3.1-8.4×103/μL), RBC 3.97×106/μL (normal range: 4.2-5.7×106/μL), hemoglobin 12.5 g/dL (normal range: 14-18 g/dL), platelets 200×103/μL (normal range: 150-330×103/μL), eosinophils 3% (normal range: 0-5%), and urinalysis negative for protein, RBC, and cell casts. Urinary N-acetyl-beta-D-glucosaminidase (NAG)/creatinine 17.1 IU/gCr (normal range: 1.6-5.8 IU/gCr) and urinary β2 microglobulin 371 mg/L (normal range: ≤289 mg/L). Antineutrophil cytoplasmic antibodies screening was found to be negative, with low C3=68 mg/dL, low C4=7.4 mg/dL, and negative for anti-SSA, anti-SSB, anti-RNP, Scl-70, anti-Sm, and ds-DNA antibodies. Antinuclear antibodies (ANA) antibodies were found to be ×1280. Hyperglobulinemia was determined with an IgG level of 3719 mg/dL (normal range: 870-1700 mg/dL) and an IgG4 level of 1290 mg/dL (normal range: 4-108 mg/dL). Rheumatoid factor (≤15 IU/mL) was elevated at 24 IU/mL, and KL-6 (<500 IU/mL) was significantly increased at 623 IU/mL. Computerized tomography (CT) revealed bilateral ground-glass and reticular opacities predominantly in the lower and peripheral portions of the lungs (Figure 1a). Furthermore, bronchial wall thickening, and enlarged cervical, mediastinal, and axillary lymph nodes were identified. However, renal, pancreatic, or salivary gland inflammation was not observed. Ga-67 scintigraphy revealed accumulation in the kidneys (Figure 2). Consequently, the patient was diagnosed with IgG4-related kidney disease based on the renal pathology with massive tubulointerstitial nephritis, characteristic fibrosis (bird’s eye pattern) (Figure 3a and b), and IgG4-positive cell infiltration, wherein the number of IgG4 positive plasma cells was >10/hpf, and IgG4/IgG ratio was 61.9% (Figure 3c). Deposition of globulin or complement, and evidence of glomerular sclerosis were not observed in the glomeruli. Treatment was initiated by administering oral prednisolone at 30 mg/day for one month, followed by prompt alleviation of cough and dyspnea on exertion. With a subsequent decrease (after one month prednisolone treatment) in urinary NAG and β2 microglobulin and IgG4 levels, prednisolone was decreased from 2.5 to 5 mg every 2 to 4 weeks for 4 weeks. One year after the initiation of treatment, the patient achieved normalization of serum IgG4 levels, and chest CT revealed the interstitial pattern was found to have nearly disappeared (Figure 1b). Figure 4 shows the clinical course of this patient.\n\n(a) Plain chest CT showing the reticular pattern and bronchial dilatation in the bilateral lower lung fields before therapy; (b) After therapy, the interstitial pattern nearly disappeared from the bilateral lung fields. CT: computed tomography.\n\nUptake by kidney revealed using Ga-67 scintigraphy.\n\n(a) The interstitium shows mononuclear cell infiltration and interstitial fibrosis with tubular atrophy with Masson’s trichrome stain (×40); (b) PAM stain in the interstitium shows bird’s eye pattern of fibrosis (×200); (c) Immunohistochemical analysis for IgG4 shows dominant IgG4+ plasma cell filtration, with an IgG4+/IgG+ ratio of >40% (×100).\n\nClinical course treatment was initiated by administering prednisolone at 30mg/day, followed by prompt alleviation of the dyspnea on exertion and cough. Urinary NAG and β2 MG, and serum IgG4 were significantly decreased after prednisolone treatment. NAG, N-acetyl-β-D-glucosaminidase; β2 MG, β2 microglobulin; PSL, prednisolone.\n\n\nDiscussion\n\nIgG4-related diseases should be differentiated from diseases caused by excessive inflammatory cytokine production, such as interleukin-6 (IL-6)-produced Castleman’s disease and autoimmune disorders.8 Usually, IgG4-related diseases are observed in middle-aged men. Most patients with this disease present with associated extrarenal lesions, such as in the salivary glands, lymph nodes, and pancreas.9 Therefore, the clinical manifestations of the disease vary according to the organ involved. The most characteristic features of IgG4-related kidney disease are presence of IgG4 positive plasma cell-rich tubulointerstitial nephritis and fibrosis, which are sometimes concurrent with glomerular lesions.10,11\n\nSimilar to the present case, approximately 30% of the patients diagnosed with IgG4-related kidney disease do not show any abnormality on a CT scan. In contrast, previous reports indicated that approximately 70% of patients with IgG4-related kidney disease show some kind of abnormality.9,12 The discrepancy between these findings can be owing to the presence or absence of contrast-enhanced CT, which is necessary within renal function tolerance. Ga-67 scintigraphy and FDG-PET have been reported to be useful for its diagnosis. However, contradictory to the present case, positive accumulation in the kidney during Ga-67 scintigraphy has been reported to be only 11%.9 Another useful method of analysis for IgG4-related kidney disease is T2-weighted and diffusion-weighted MR imaging.13\n\nCT imaging findings of the lungs in IgG4-related diseases have been classified into four types: ground-glass opacity, diffuse reticular, bronchial wall thickening, and nodular patterns.14 The ground-glass opacity and diffuse reticular patterns potentially suggest lymphocyte and plasma cell infiltration of the alveoli and interstitium. Bronchial wall thickening pattern indicates plasma cells infiltration of the bronchial vascular bundles, alveoli, and interstitium. Finally, nodular sclerosing inflammation of the bronchial glands was prominently observed to be associated with the nodular pattern.14 Although we did not perform a lung biopsy in the present case, the CT findings of diffuse reticular and bronchial wall thickening confirmed pulmonary involvement in IgG4-related diseases.\n\nInflammatory cytokines, such as IL-5 and tumor necrosis factor (TNF)-α, reportedly correlate with IgG4-related diseases.15,16 Furthermore, our previous reports also indicate that the inflammatory cytokines play a potentially pivotal role in the development of renal fibrosis.17 T helper cells type 2 (Th2) and regulatory T cells (Tregs) have been reported to be involved in IgG4-related tubulointerstitial fibrosis.18 Treg cells can increase the regulatory cytokines, such as transforming growth factor-β (TGF-β), which has also been identified in renal fibrosis signaling.18,19 However, many aspects of this disease, especially complications caused by interstitial pneumonia, remain unclear with limited reports on this disease type; hence, further studies are warranted.\n\nThe optimal treatment for IgG4-related kidney disease has not been established; however, most patients, including the one in the present case, respond to prednisolone. Saeki et al. showed that the induction of prednisolone led to rapid improvement in renal function and serological abnormalities 1 month after the initiation of therapy, and that maintenance therapy with low-dose prednisolone successfully resulted in long-term suppression of disease activity in 43 Japanese patients with IgG4-related kidney disease.9\n\nSimilar to the present case, even in patients without diagnosis of renal localized IgG4-related disease, favorable outcomes can be achieved with the same treatment modalities as those employed for the patients diagnosed with the disease.\n\nIgG4-related kidney disease is an emerging disease with recently identified pathological features. Generally, patients respond rapidly to prednisolone and present a relatively favorable prognosis. The present case of IgG4-related kidney disease associated with interstitial pneumonia provides a novel rationale for its pathophysiology.\n\n\nConsent\n\nWritten informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.\n\nThe study protocol for the patient record review was reviewed and the need for approval was waived by Institutional Review Board of Osaka Medical and Pharmaceutical University, as a retrospective review of patient data did not require ethical approval in accordance with local guidelines.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nAcknowledgements\n\nThe author thanks Dr. Yoshinobu Hirose and Dr. Tatsuhiko Mori (Osaka Medical and Pharmaceutical University) for valuable discussions on the case pathology. We would like to thank Honyaku Center Inc. for English language editing.\n\n\nReferences\n\nHamano H, Kawa S, Horiuchi A, et al.: High serum IgG4 concentrations in patients with sclerosing pancreatitis. N. Engl. J. Med. 2001; 344: 732–738. Publisher Full Text\n\nStone JH: IgG4-related disease: nomenclature, clinical features, and treatment. Semin. Diagn. Pathol. 2012; 29: 177–190. PubMed Abstract | Publisher Full Text\n\nUmehara H, Okazaki K, Masaki Y, et al.: Research Program for Intractable Disease by Ministry of Health, Labor and Welfare (MHLW) Japan G4 team. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod. Rheumatol. 2012; 22: 1–14. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSaeki T, Nishi S, Imai N, et al.: Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis. Kidney Int. 2010; 78: 1016–1023. PubMed Abstract | Publisher Full Text\n\nMasaki Y, Dong L, Kurose N, et al.: Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann. Rheum. Dis. 2009; 68: 1310–1315. PubMed Abstract | Publisher Full Text\n\nDeshpande V, Zen Y, Chan JK, et al.: Consensus statement on the pathology of IgG4-related disease. Mod. Pathol. 2012; 25: 1181–1192. PubMed Abstract | Publisher Full Text\n\nAdachi H, Okuyama H, Yamaya H, et al.: A case of IgG4-related kidney disease complicated by eosinophilic lung disease. CEN Case Rep. 2015; 4: 162–168. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNishimoto N, Terao K, Mima T, et al.: Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008; 112: 3959–3964. PubMed Abstract | Publisher Full Text\n\nSaeki T, Kawano M, Mizushima I, et al.: The clinical course of patients with IgG4-related kidney disease. Kidney Int. 2013; 84: 826–833. Publisher Full Text\n\nSaeki T, Kawano M: IgG4-related kidney disease. Kidney Int. 2014; 85: 251–257. Publisher Full Text\n\nRaissian Y, Nasr SH, Larsen CP, et al.: Diagnosis of IgG4-related tubulointerstitial nephritis. J. Am. Soc. Nephrol. 2011; 22: 1343–1352. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKawano M, Saeki T, Nakashima H, et al.: Proposal for diagnostic criteria for IgG4-related kidney disease. Clin. Exp. Nephrol. 2011; 15: 615–626. Publisher Full Text\n\nOno H, Murakami T, Mima A, et al.: Successful treatment of highly advanced immunoglobulin G4-related kidney disease presenting renal mass-like regions with end-stage kidney failure: a case study. BMC Nephrol. 2017; 18: 261. PubMed Abstract | Publisher Full Text | Free Full Text\n\nInoue D, Zen Y, Abo H, et al.: Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology. 2009; 251: 260–270. PubMed Abstract | Publisher Full Text\n\nTakekawa M, Imai K, Adachi M, et al.: Hypereosinophilic syndrome accompanied with necrosis of finger tips. Intern. Med. 1992; 31: 1262–1266. PubMed Abstract | Publisher Full Text\n\nCampbell HD, Tucker WQ, Hort Y, et al.: Molecular cloning, nucleotide sequence, and expression of the gene encoding human eosinophil differentiation factor (interleukin 5). Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 6629–6633. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMima A: Inflammation and oxidative stress in diabetic nephropathy: new insights on its inhibition as new therapeutic targets. J. Diabetes Res. 2013; 2013: 248563.\n\nNakashima H, Miyake K, Moriyama M, et al.: An amplification of IL-10 and TGF-beta in patients with IgG4-related tubulointerstitial nephritis. Clin. Nephrol. 2010; 73: 385–391. PubMed Abstract | Publisher Full Text\n\nMima A, Abe H, Nagai K, et al.: Activation of Src mediates PDGF-induced Smad1 phosphorylation and contributes to the progression of glomerulosclerosis in glomerulonephritis. PLoS One. 2011; 6: e17929. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "203749",
"date": "11 Sep 2023",
"name": "Masaru Matsui",
"expertise": [
"Reviewer Expertise CKD"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis case report focuses on the topic that interstitial pulmonary diseases are a rare complication of IgG4-related diseases. As the authors acknowledge, lung biopsy was required for showing IgG4 cells infiltration in interstitium of lungs, and therefore the pathological association between lung and kidney may not be evident. This reviewer was curious about changes in KL-6 after steroid treatment.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "10217",
"date": "06 Oct 2023",
"name": "AKIRA MIMA",
"role": "Author Response",
"response": "We appreciate reviewer's careful review ."
}
]
},
{
"id": "203747",
"date": "11 Sep 2023",
"name": "Tomohito Gohda",
"expertise": [
"Reviewer Expertise diabetic kidney disease"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis case report is well written. However, I suggest the authors to respond to the following comments:\nThe quality of microscopy findings of renal biopsy seems to be poor.\n\nPlease describe in more detail how to differentiate normal IP from IgG4-related lung disease in the absence of lung biopsy findings.\n\nPlease describe any differences from previous reports in cases of IgG4-related renal and respiratory disease.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "10265",
"date": "06 Oct 2023",
"name": "AKIRA MIMA",
"role": "Author Response",
"response": "Reviewer: The quality of microscopy findings of renal biopsy seems to be poor. Authors’ response: First of all, we would like to thank the reviewer’s careful review. As the reviewer points out, the image quality is not good. We are very sorry; this is a limitation of the image capture machine. However, we believe the images are sufficient for pathological diagnosis. Reviewer: Please describe in more detail how to differentiate normal IP from IgG4-related lung disease in the absence of lung biopsy findings. Authors’ response: The reviewer raised important question regarding features of IgG4-RD-induced IP. Pathologically, characteristic findings such as lymphocyte and IgG4-positive plasma cell infiltrates have been reported to have the same distribution as the imaging findings. However, in some lymphoproliferative diseases other than IgG4-RD, similar findings are seen on chest imaging or histopathology, and it is difficult to differentiate them from respiratory involvement of IgG4-RD, suggesting that respiratory involvement of IgG4-RD should be diagnosed comprehensively from the clinical picture, imaging findings and pathological aspects. Reviewer: Please describe any differences from previous reports in cases of IgG4-related renal and respiratory disease. Authors’ response: It has been reported that most imaging studies of the lungs in IgG4-RD showed a variety of pathologic patterns, including solid nodule density, ground-glass opacity, bronchiectasis, honeycombing, and bronchiolar vesicle thickening. Our case showed the reticular pattern and bronchial dilatation. Hence, our case is considered a pulmonary lesion similar to those reported in the past, although there have been only a few reports to date."
}
]
},
{
"id": "203748",
"date": "20 Sep 2023",
"name": "Seiji Kishi",
"expertise": [
"Reviewer Expertise kidney disease",
"acute kidney injury",
"chronic kidney disease"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis case report presents an IgG4-related disease complicated by pulmonary involvement. The association with pulmonary lesions is discussed as a novel finding.\nPlease allow me to ask the following questions to improve the paper and make it more meaningful to the reader:\nAre there any other findings besides imaging that can be evaluated in relation to steroid therapy? Physical examination, walking distance, oxygen saturation, pulmonary function tests, and even other blood tests would be acceptable.\n\nCan you discuss more about IgG4-related diseases and pulmonary involvement? For example, the classification and frequency of interstitial pneumonia, the prediction of steroid response, and whether the findings are predictive of recovery of renal function.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "10268",
"date": "06 Oct 2023",
"name": "AKIRA MIMA",
"role": "Author Response",
"response": "Reviewer: Are there any other findings besides imaging that can be evaluated in relation to steroid therapy? Physical examination, walking distance, oxygen saturation, pulmonary function tests, and even other blood tests would be acceptable. Authors’ response: The reviewer raised important question regarding evaluation of steroid therapy in our case. Oxygen saturation was quickly restored to 100% when started steroid therapy. We have added this information to the “Case Presentation” section. Reviewer: Can you discuss more about IgG4-related diseases and pulmonary involvement? For example, the classification and frequency of interstitial pneumonia, the prediction of steroid response, and whether the findings are predictive of recovery of renal function. Authors’ response: The reviewer asked more detailed information for IgG4-RD. From a pathological perspective, it has been observed that certain distinct features, such as the presence of lymphocytes and IgG4-positive plasma cells, exhibit a distribution pattern consistent with the findings in imaging. Nevertheless, in certain lymphoproliferative disease unrelated to IgG4-RD, comparable findings are evident in both CT imaging and histopathology. This similarity poses a challenge in distinguishing them from the respiratory manifestations of IgG4-RD should consider clinical presentation, imaging results, and pathological characteristics. Relatively good response to corticosteroid has been reported for the treatment of IgG4-RD lung lesions. These pieces of information are added to the “Discussion” section."
}
]
}
] | 1
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https://f1000research.com/articles/12-1045
|
https://f1000research.com/articles/12-1231/v1
|
27 Sep 23
|
{
"type": "Study Protocol",
"title": "A cross-sectional study to assess the morbidity pattern among female agricultural workers in the rural area of Central India: a study protocol",
"authors": [
"Deepika Yadav",
"Ashok Mehendale",
"Komal Muneshwar",
"Ashok Mehendale",
"Komal Muneshwar"
],
"abstract": "Agriculture serves as the primary source of income for a substantial number of agricultural workers, with a significant portion of the Indian population, especially in rural areas, engaged in this occupation. However, the health status of female agricultural workers is often adversely affected by various factors, including working conditions, environmental exposure, and other morbidities. As a result, they are at risk of developing several diseases, such as tuberculosis, diabetes, hypertension, lung disease, muscle pain, joint pain, and pesticide poisoning, which constitute the main occupational health concerns in this sector. Unfortunately, despite the prevalence of these health risks, many female agricultural workers do not prioritize their own health and wellbeing. According to the latest survey data by the National sample survey office (NSSO), around 54% of the Indian workforce is engaged in agriculture, mainly in rural areas. There are no unions for female agricultural workers, and they cannot receive occupational health facilities and social security schemes provided to them. This study aims to understand female agricultural workers and health-seeking behaviours and morbidities. Objectives- This study assesses the morbidity pattern among female agricultural workers and the health-seeking behaviour of female agricultural workers. It also identifies the utilization of social security schemes among female agricultural workers in villages. The study focuses on assessing the morbidities among female agricultural workers aged 18 and above residing in the villages of Wardha district of Maharashtra. For this purpose, A pretested questionnaire covering sociodemographic data, morbidity profile, socioeconomic variables, family, education, and social security measures will be utilized. The study aims to conduct a community-based cross-sectional survey among 131 female agricultural workers from the specified region.",
"keywords": [
"morbidity profile",
"female agricultural worker",
"health"
],
"content": "Introduction\n\n“Morbidity is defined using three dimensions: the number of individuals affected by illnesses, the types of diseases they have, and duration of the illness (in days, weeks, etc.)” as stated by the WHO expert committee on health statistics. Agriculture poses unique challenges that put the health of its workers at risk, including exposure to excessive chemicals, organic products, long working hours, awkward postures, and the operation of dangerous machinery and equipment. furthermore, farmers living in villages face additional public health issues such as communicable diseases, inadequate nutrition, and unhygienic surroundings, which significantly influence their health and susceptibility to illnesses. The factors should be addressed, and efforts to sensitize people about these issues should be intensified.1\n\nIn India, female agricultural workers face various occupational health issues due to their involvement in various challenging manual tasks. While musculoskeletal injuries, coal workers’ pneumoconiosis lung diseases, pesticide poisoning, and noise-induced hearing loss are recognised as significant concerns, other critical health issues affecting agricultural workers, such as animal bites, exposure to harmful chemicals, insect bites, physical risks under harsh conditions, and respiratory problems like occupational asthma, often do not receive adequate attention due to lack of awareness about their health.2 Although Female agricultural workers, whether working in their own fields or as day labourers, face various forms of exploitation, making them more vulnerable and uncertain about their future. They typically labour long hours, both in agriculture and housekeeping, which puts them at risk of developing musculoskeletal conditions. While it has been observed that women perform farm tasks better than men, pay inequalities still persist.3\n\nHowever occupational health risks in the agricultural sector can be mitigated by providing employees with a safe working environment. This includes the provision and proper use of personal protective equipment, along with adequate guidance and training on its correct usage and significance. However, farming-related health issues often arise due to the significant gap between agricultural health policymaking.4\n\nA woman undertakes a wide range of demanding tasks within household roles, rural women play a crucial and active part in various farming related activities. Furthermore, especially in wealthier and well- resourced rural areas, There has been seen that the involvement of an Indian women in agricultural businesses and operations increases in recent times.5 This unorganised sector encompasses various areas of the economy, including agriculture, trade, transportation, communication, services, healthcare, education, building, and construction. Women are more likely to obtain jobs in the informal economy due to their lower education and skill levels.\n\nHowever, working in this sector exposes them to additional risks as there are no formal occupational health and safety regulations, and they may be more susceptible to sexual assault.6\n\nAgricultural workers, in general, face challenges such as unstable employment, lack of workplace safety, irregular income, and insufficient social security protection. The National Commission on self- employed conducted a study to assess the severity of occupational health issues among women in the unregulated industry. They found that women working in this sector suffer from various illnesses, including postural problems, communication issues involving hazardous substances, continuous work-related issues, lack of rest, and an unfavourable work environment.7 Women in agriculture may experience generalized body aches, respiratory problems and other associated health-related morbidities. Women’s likelihood of obtaining jobs in the informal economy is influenced by their lower levels of education and skills, as well as the availability of flexible work hours, which can be beneficial for mothers with young children.8 In conclusion, addressing the health and safety issues faced by agricultural workers, especially women in the informal economy, requires significant attention from policymakers and relevant authorities to implement measures that protect their well-being and ensure fair working conditions.\n\nAgricultural women often face life-threatening health issues, yet they remain unaware and suffer from various diseases, including gynaecological problems, mental illnesses, skin diseases, occupational hazards, and other co-morbidities. Despite existing laws, research and studies focused on their specific health needs are lacking. These women are typically part of the underdeveloped segment of society, both economically and in terms of health, due to factors such as limited education, lack of awareness, inadequate access to healthcare, physical strain, pesticide exposure, and lack of resources and transportation options.9\n\nTo address these challenges, a comprehensive approach is needed. This approach should encompass improved education and training for female agricultural workers, enhanced access to healthcare services, and robust regulations to protect them from pesticide exposure and other hazards. Conducting a study on the prevalent morbidities affecting agricultural women is crucial to identify knowledge gaps and understand the significance of these health issues. It is essential to determine the level of investment agricultural workers make in their health and to assess the specific health problems they encounter. This study aims to equip them with the necessary knowledge to prevent and treat these health issues effectively when they arise. Additionally, the study seeks to provide insights into various social security measures available to them and guide them on accessing these benefits.\n\nBy conducting this research and taking a proactive approach, we can empower agricultural women with better health awareness and help to improve their overall well being. Addressing their specific health needs will contribute to a more equitable and healthier society.\n\nThis study aim to assess the morbidity pattern of female agricultural workers.\n\nThe primary objective is to assess the morbidity pattern among female agricultural workers, identifying prevalent health issues they face in their occupational settings.\n\nSecondary objectives is to explore the health seeking behaviour of female agricultural workers and to identify the utilization of social security schemes available to female agricultural workers.\n\n\nMethods\n\nThis survey will be conducted as a community-based cross-sectional survey to assess the morbidity pattern of female agriculture workers in villages of Wardha district, Maharashtra which includes 5 villages of Wardha carrying 131 households.\n\nThe study participants will be female agricultural workers aged 18 and above who live in a village of the Wardha district Maharashtra. The selection of this population was made because of the numerous health-related issues that female agricultural workers deal with daily as a result of the nature of their employment in the fields.\n\nFemale agricultural workers who are above 18 years and working on an agricultural field.\n\n\n\n1) We will exclude women who will be breastfeeding at that time or pregnant women.\n\n2) Migrant female agriculture workers who are not from Maharashtra.\n\n3) Farmers who are not working in agriculture and doing some other jobs.\n\n4) Houses that are locked during our visits.\n\n\n\n1. Sociodemographic data of female agricultural workers.\n\n2. Morbidity profiles of female agricultural workers.\n\n3. Social security measures and healthcare utilization.\n\nThe study tool will consist of a self-made structured questionnaire with a quantitative component for the data collection on social demographic variables and the morbidity profile of female agricultural workers in rural areas.\n\nIt will be administered in four types:\n\nSection A: The sociodemographic profile of the study participant includes information on their age, sex, family status, religion, level of education, type of employment, length of employment, time between jobs, number of working hours, number of days worked per week, income, other sources of income, and other sociodemographic characteristics.\n\nSection B: It include s a morbidity profile of female agriculture workers which covers factors like diabetes, hypertension, T. B, any injury, trauma, muscleor joint pain, rash, itching, diarrhoea, eye-related problems, dental problems, menstrual-related problems, skin burn (sunburn), skin-related conditions (allergy) injuries caused by dangerous machinery and equipment. Injuries caused by sharp objects, insect bites, electric current, psycho-social issues, waterborne diseases, gynaecological issues, and other general issues.\n\nSection C: Documents related Sociodemographic status like pan card, ration card, Aadhar card, health insurance card.\n\nSection D: Utilisation of social security scheme-(yes/no).\n\nData analysis plan\n\nThe data will be input into Microsoft Excel (MS Excel) /Epi-info software and analysed by SPSS (Statistical Product and Service Solution). Frequency and percentage will be presented using tables and graphs.\n\nIn the context of the study on morbidity among female agricultural workers, recall bias could impact the accuracy and completeness of the data collected on their health issues. In this study, participants are likely to be asked about their past health conditions, symptoms, and health-seeking behaviours.\n\nAccording to NFHS 5, the prevalence of rural areas of India is 21.7%, with confidence the limit is 10%; this total sample size calculated is 131. This sample size is estimated from Epi-info software.\n\nThe sample size was calculated using the following formula:\n\nPopulation size -100000\n\nFrequency of outcome factor in the population-21.7% Confidence limits as % of 100(absolute +/-%)(d)-10% Design effect (DEFF)-2.\n\nConfidence levels-95% Hence a sample size of 131 will be used for data collection.\n\nThe study will be conducted using a simple random sampling method in which we randomly select 5 villages nearby Wardha district, Maharashtra. From each village, we will select 30 households. Inclusion only those households in which have females 18 years old or above working in the field/farm. written consent will be obtained, and data will be collected using a questionnaire on morbidity among female agricultural workers. The data will be gathered in the form of a kobo toolbox. The collected information is entered for analysis in Microsoft Excel.\n\nThis information is analysed by victimization EPI info software. While frequency distributions were generated for divided variables, descriptive statistics (mean and standard deviations) were utilized to explain continuous variables.\n\nSome factors should be taken into consideration when evaluating. In the first instance, the study will begin after taking approval from the institutional ethical committee carried out under Datta Meghe Institute Of Higher Education And Research (DMIHER) approval number is DMIHER (DU)/IEC/2023/637. The participants will be treated with respect. Before starting the survey, all participants will be informed of the research’s purpose and methodology using the “written consent” procedure. Since the participants are young adults, and we will ensure that they feel comfortable. The data recorded will be confidential. There won’t be any identifying features in the presentation of our final results. If our study proves fulfilling, the following anonymized information will be used to generalise the basic information and knowledge related to morbidity among female agricultural workers.\n\nThe study findings will provide valuable insights into the health challenges faced by female agricultural workers, who work in villages of Wardha district. And also, understanding their health seeking behaviour will help to design targeted interventions and policies to improve their access to healthcare services. Moreover, by assessing the utilization of social security schemes.\n\nThe current status of my study is that I am preparing a questionnaire tool for data collection.\n\n\nDiscussion\n\nIndia is renowned for its agricultural sector, and it has made significant strides in improving the health of its female population. While there has been a general decline in mortality leading to increased life expectancy, it remains uncertain whether there have been any changes in morbidity patterns. India has entered the fourth stage of health transition, characterized by the prevalence of various illnesses among females. According to the international labour organization, women constitute about 60% of the agricultural workforce in India, yet their work often goes unrecognized and undervalued. They face discrimination in terms of wages, working conditions, and access to resources. Many women work for long hours in agricultural or other fields to secure a stable income, but this has resulted in a higher likelihood of developing chronic illnesses such as respiratory issues, musculoskeletal problems, joint diseases, hypertension, diabetes, common cold, asthma, neurological disorders, cardiovascular disorders and joint diseases.\n\nFemale susceptibility to diseases starts in the early working years, peaks in the late working years, declines in older ages, and their health tends to deteriorate earlier than that of men.10\n\nAlthough women stand to gain significant benefits from automation in farming, the majority of tools and equipment have been designed with a male oriented approach. This design orientation comes with both advantages and disadvantages. Many agricultural machinery, systems, and tools used for tasks such as field treatment, ridging, plucking, grain processing, culinary burners, and freshwater conveyance, especially in Asia, are characterized by their massive, bulky, weighty, and challenging to maintain nature which develop musculoskeletal conditions and other illness.11\n\nDue to lack of awareness or education among females, they are often unaware of the various government schemes designed for their health and wellbeing. The Indian government has implemented several schemes and programs to address these issues and enhance agricultural workers’ livelihoods, including women. For instance, the Pradhan Mantri Fasal Bima Yojana provides crop insurance coverage to farmers, including women farmers, while the Pradhan Mantri Kisan Samman Nidhi offers direct income support to small and marginal farmers, including women farmers.12\n\nThe primary objective of the study was to evaluate the morbidity profile of female agricultural workers in rural areas of central India, with an emphasis on creating awareness about social security schemes available to them. By understanding the prevalent health issues and increasing awareness of the support available. The study seeks to contribute to the betterment of female agricultural workers’ overall health and wellbeing.\n\n\n\n1. In order to enhance policy frameworks and systems, it is crucial to compile province level information on the comprehensive healthcare issues and workplace hazards experienced among female agricultural workers.13\n\n2. Establish mobile clinics or healthcare centers in rural are as to provide easy access to medical services for female agricultural workers.\n\n3. A holistic approach should be integrated into rural development initiatives to address occupational healthcare issues and workplace hazards experienced among female agricultural workers.14\n\n4. Government funding could be allocated to initiate programs focused on agricultural and environmental healthcare in collaboration with leading educational and professional institutions.\n\n5. Offer regular health check-ups, screenings, and immunisations to address health issues proactively.\n\n6. Our Government should require every company to provide essential protective equipment, such as suitable footwear, gloves, masks, and skull coverings, in order to reduce occupational health risk.15\n\nThe present study will help to assess the morbidity pattern among female agricultural workers that can impact various aspects of their lives and the agricultural sector as a whole.\n\nUnderstanding and addressing these implications are crucial for promoting the health and wellbeing of female agricultural workers and fostering sustainable agricultural practices.16\n\nIn comparison to urban labourers, female agricultural workers are not much educated and unaware of health problems and government advantages. Therefore, the majority of state measures aimed at reducing rural economic conditions haven’t had any positive effects on women’s lives.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nExecutive Board 23: Expert Committee on Health Statistics: sixth report. World Health Organization; 1959 [cited 2023 Jul 17]. Report No.: EB23.R19. Reference Source\n\nGhosh J: Unseen Workers: Women in Indian agriculture Frontline.2015. Googlescholar\n\nPark PSM 26th Edition PDF [Download]: [cited 2023 Jul 30]. Reference Source\n\nMeenakshi JR, Panneer S: Occupational Health of Agricultural Women Workers in India. Indian J. Community Med. 2020; 45(4): 546–549. PubMed Abstract | Publisher Full Text\n\nMurty: Socio-economic participation of women in informal… - Google Scholar: [cited 2022 Sep 3]. Reference Source\n\nShramshakti: Report of the National Commission on Self Employed Women and Women in the Informal Sector (Book Review) - ProQuest.[cited 2023 Aug 13]. Reference Source\n\nHawkes C, Ruel M: The links between agriculture and health: an intersectoral opportunity to improve the health and livelihoods of the poor. Bull. World Health Organ. 2006 Dec; 84(12): 984–990. PubMed Abstract | Publisher Full Text | Free Full Text\n\nUnorganisedWorkersSocialSecurityAct2008.pdf.[cited 2023 Aug 13]. Reference Source\n\nNayak J, Singh SP, Moharana G: Occupational Health Hazard of Farm Women. Director National Research Centre for Women in Agriculture Bhubaneswar; 2013. Google Scholar\n\nResolution concerning statistics of employment in the informal sector.1993 [cited 2023 Aug 13]. Reference Source\n\nNag A, Vyas H, Nag P: Occupational health scenario of Indian informal sector. Ind. Health. 2016; 54(4): 377–385. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPunekar: Social Security Scheme for Farmers. Punekar News.2015 [cited 2022 Jan 27]. Reference Source\n\nNational Institute of Occupational Health (NIOH), Ahmedabad|India Science, Technology & Innovation - ISTI Portal.[cited 2023 Aug 13]. Reference Source\n\nThresia CU: Women Workers in Agriculture: Gender discrimination, working conditions, and health status.2004 [cited 2023 Aug 13]. Reference Source\n\nAgricultural Health and Safety|Recent Advances|Kelley J. Donham, R.[cited 2023 Aug 13]. Reference Source\n\nKulkarni RK, Shivaswamy MS, Mallapur MD: A CROSS-SECTIONAL STUDY OF MORBIDITY PATTERN OF RURAL AGRICULTURAL WORKERS IN SOUTH INDIA.2012 Dec 16."
}
|
[
{
"id": "221516",
"date": "29 Nov 2023",
"name": "Demet Ünalan",
"expertise": [
"Reviewer Expertise Public Health"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn which sub-fields of agriculture do women workers work, e.g. field agriculture, greenhouse?\n\nSituations such as whether there is exposure to harmful chemicals.\n\nThe provision of preventive health services and personal protective equipment (mask, gloves, etc.) for female agricultural workers should be explained.\n\nIt is also important to compare the working conditions of female employees across the country or in other sectors in the region where the study is conducted.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": [
{
"c_id": "10899",
"date": "16 Jan 2024",
"name": "Deepika Yadav",
"role": "Author Response",
"response": "1- field agriculture 2- yes 3- yes 4- yes I do in my original article by associating morbidity with different type of disease"
},
{
"c_id": "11614",
"date": "25 Jun 2024",
"name": "Deepika Yadav",
"role": "Author Response",
"response": "Womens work in the field of agriculture. Our study emphasis the morbidity pattern among female agriculture workers so we concluded the study with provide them a preventive treatment on exposing with harmful chemicals. I explained the reason in my original article. I have done association of morbidity with the diseases(eye related problem, hypertension, diabetes, knee pain, menstrual hygiene. we aim to access to resources, healthcare and safety measures which can significantly impact the morbidity pattern among female agricultural workers."
}
]
},
{
"id": "303081",
"date": "31 Jul 2024",
"name": "Nosimilo Mlangeni",
"expertise": [
"Reviewer Expertise Public Health",
"worker's health",
"agricultural workers",
"HIV and TB",
"occupational health"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI congratulate the authors for deciding to conduct a study in such an important field and topic. However, there are several improvements that can be done in the paper.\n1. The authors should do grammatic revision in some sections of the papers 2. Study rationale: The authors use the phrase 'agricultural women' which is rather confusion as it can have different meanings. The most common phrases could be women in agriculture. If authors prefer current phrase they can add a definition for the purposes of the study. Secondly the first sentence in this section mentions that they face life-threatening issues. Were the authors referring to work-related issues? If so they can update the sentence to state that these are occupational exposures, so that the reader can be able to differentiate this phrase from general life-threatening issues that even those in different walks of life may face. There is a mention of knowledge gap in the last sentence of page 3, it is a bit confusing whether knowledge gap on morbidities, or authors are referring to gaps in literature. The authors also refer to 'the significance of these health issues' in the same sentence - which health issues? So it is best for the writing to be clear so that the reader is not left to make their own conclusions. Revising this sentence my improve the readers' understanding of the communication made. First paragraph of page 4 is still study rationale. Authors should be careful here as they mention 'this study aim...', and yet this is different from the study aim mentioned below. This is confusing, and what is mentioned on this particular sentence sounds like the authors intend to conduct a program rather than a research study.\nMethods: I recommend rephrasing of the study design first sentence 'this survey...' may be a bit misplaced as this is the first time you are introducing your intention to conduct a survey\n\nMeasurements: this section (data analysis plan) is expected below after the sampling and sample size has been mentioned.\nStatistical methods: Authors start by referring to the random sampling, which is expected before analysis. Then in the same section they add analysis information, which should be part of data analysis plan...\nStudy status: Be careful of first person expressions...\nDiscussion: The first paragraph reads like it belongs to the introduction. The discussion actually feels like an extension of the introduction. Perhaps the authors could consider moving most of the information here to the introduction, then changing this section to conclusion and only leave what would sound as a conclusion of their proposal, such as the last paragraph of the section.\nSuggestions to decrease the morbidity pattern...: This reads as recommendations, and thus cannot be offered before conducting the study, and even then, they should be based on your study findings. The authors sound positively passionate about the study but should not provide recommendations in a protocol.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
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https://f1000research.com/articles/12-1231
|
https://f1000research.com/articles/12-1229/v1
|
27 Sep 23
|
{
"type": "Research Article",
"title": "Analysis of time-domain indices, frequency domain measures of heart rate variability derived from ECG waveform and pulse-wave-related HRV among overweight individuals: an observational study",
"authors": [
"Sinha Mukesh Kumar",
"K. Vaishali",
"G. Arun Maiya",
"K.N. Shivashankar",
"U. Shashikiran",
"Sinha Mukesh Kumar",
"G. Arun Maiya",
"K.N. Shivashankar",
"U. Shashikiran"
],
"abstract": "Background: Research on the compatibility of time domain indices, frequency domain measurements of heart rate variability obtained from electrocardiogram (ECG) waveforms, and pulse wave signal (pulse rate variability; PRV) features is ongoing. The promising marker of cardiac autonomic function is heart rate variability. Recent research has looked at various other physiological markers, leading to the emergence of pulse rate variability. The pulse wave signal can be studied for variations to understand better changes in arterial stiffness and compliance, which are key indicators of cardiovascular health. Methods: 35 healthy overweight people were included. The Lead II electrocardiogram (ECG) signal was transmitted through an analog-to-digital converter (PowerLab 8/35 software, AD Instruments Pty. Ltd., New South Wales, Australia). This signal was utilized to compute Heart Rate Variability (HRV) and was sampled at a rate of 1024 Hz. The same AD equipment was also used to capture a pulse signal simultaneously. The right index finger was used as the recording site for the pulse signal using photoplethysmography (PPG) technology. Results: The participants' demographic data show that the mean age was 23.14 + 5.27 years, the mean weight was 73.68 + 7.40 kg, the mean body fat percentage was 32.23 + 5.30, and the mean visceral fat percentage was 4.60 + 2.0. The findings revealed no noticeable difference between the median values of heart rate variability (HRV) and PRV. Additionally, a strong correlation was observed between HRV and PRV. However, poor agreement was observed in the measurement of PRV and HRV. Conclusion: All indices of HRV showed a greater correlation with PRV. However, the level of agreement between HRV and PRV measurement was poor. Hence, HRV cannot be replaced with PRV and vice-versa.",
"keywords": [
"Pulse Signal",
"Electrocardiogram",
"pulse rate variability",
"Adiposity",
"Cardiac autonomic function",
"sympathetic nervous system",
"parasympathetic nervous system"
],
"content": "Introduction\n\nAssessing the cardiac autonomic nervous system’s functioning, heart rate variability (HRV) obtained from electrocardiographic (ECG) signals is a useful tool. Over the past decade, HRV measures have been used in a variety of clinical contexts as indicators of sympathovagal interaction and to diagnose various clinical and functional conditions.1,2 Analysis of the time and frequency domains can be used to quantify heart rate variability.1 Statistics such as mean heart rate, SDNN (standard deviation of normal-to-normal intervals), RMSSD (root mean square of successive differences), and pNN50 (percentage of successive normal-to-normal intervals that differ by more than 50 millisecond) are among the time domain measures of HRV. The primary time-domain measure used to calculate the vagally mediated changes indicated in HRV is the RMSSD, which reflects the beat-to-beat variance in HR.1,3 The pNN50 is closely correlated with peripheral nervous system activity and it is correlated with the RMSSD and high frequency (HF) power. Frequency domain of HRV is measured using spectrum analysis of ECG signal. High frequency (HF) and low frequency (LF) are the two primary sub-bands of the HRV frequency spectrum.1,3 HF power reflects parasympathetic activity, whereas LF power may indicate both sympathetic and parasympathetic activity.1,3 The LF/HF power ratio is often employed as a measure of sympathovagal balance and total power (TP) represents overall variability.1,3,4\n\nAtherosclerosis development, myocardial infarction, and heart failure have all been associated with low HRV indices. Studies have shown that the reduced HRV value is also associated with conditions like coronary artery disease, diabetes mellitus, pain, acute and chronic stress, metabolic syndrome, hypertension, and physical inactivity.5–7 An autonomic nervous system that is more adaptable and resilient is indicated by a higher HRV.3 Also the use of HRV as a social interaction, athletic performance, and emotional state marker is also common.8,9\n\nThe ECG signal is frequently used to estimate HRV. The use of physiological signals other than the ECG to produce HRV data has been established in a number of research during the past few years.10 The data on HRV derived from pulse wave signals; thus it is referred to pulse-wave-related HRV or pulse rate variability (PRV).10–12 Variations in the pulse wave pressure are indicative of changes in arterial stiffness and compliance, two pivotal facets of cardiovascular well-being.13 Elevated arterial stiffness, commonly observed in cardiovascular disorders, can precipitate modifications in the pulse wave pressure, underscoring its importance in assessing cardiovascular health.13–15\n\nThe term compatibility between PRV and HRV characteristics is a subject of interest for current research, due to its frequent use in clinical and everyday situations, researchers have tried to extract as much information as possible from pulse signals to understand the similarity between PRV and HRV characteristics.10,16 For instance, the findings from a study by Wong JS17 showed that the time-varying spectral indices generated from HRV and PRV have a few minor differences. This suggests that PRV can be considered as an alternate measurement to HRV. When they compared the results from the healthy subject during regular breathing, they came to similar conclusions. According to the study cited by Ahsan H. Khandoker,18 PRV does not accurately reflect HRV in individuals with obstructive sleep apnea. The accuracy of PRV as a substitute for HRV has recently been the subject of numerous studies, but it has not been examined in overweight individuals, who appear to have lower heart rate variability than healthy normal individuals. The purpose of this study was to determine whether healthy overweight individuals’ PRV can serve as a substitute for HRV.\n\n\nMethods\n\nA study was conducted in the Cardiopulmonary Physiotherapy Laboratory at Kasturba Hospital in Manipal, Karnataka, India. This is a cross-sectional study, which is part of a large intervention trial. The study protocol was approved by the Institutional Research Committee (IRC), and Institutional Ethics Committee of Kasturba Medical College and Kasturba Hospital Manipal (IEC/155/2018). The trial has been registered under the Clinical Trials Registry (CTRI number: CTRI/2018/08/015523).\n\nThis study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. This study included 35 healthy overweight individuals (20 women and 15 men, aged 23.13 ± 5.27 years). Upon verbal advertising, willing individuals were screened for eligibility. Each participant signed a written informed consent form before the study’s process started. Participants received detailed information about the study’s objectives, procedures, and rights to withdraw at any time. Participation in the study was entirely voluntary. Prior to the HRV recording, participants were asked to abstain from drinking anything alcoholic or caffeinated for at least 12 hours.\n\nThe study enrolled participants with any genders, aged between 18 and 40 years, with a body mass index (BMI) ranging from 25 to 29.9 kg/m2, and assessed to have low risk based on the AHA/ACSM Health/Fitness Facility Preparticipation Screening Questionnaire.19 The study excluded participants who had been diagnosed with cardiopulmonary disease, diabetes mellitus, hypertension, metabolic disorder or were taking any regular prescribed medication for renal and liver disease.\n\nThe participants were instructed to avoid consuming caffeine, alcohol, or other stimulants for at least 12 hours before the test. They were also advised to avoid any strenuous activity for at least 2 hours before the test. A properly calibrated instrument from AD Instruments Pty. Ltd. (New South Wales, Australia) was used to record the ECG signal. Electrodes were placed on the subject’s chest to record the ECG signal. The participants were asked to lie down in a quiet, comfortable room (temp- 22-24oC was maintained during HRV recording). The ECG signal was recorded for 15 minutes while the subject was at rest. The recorded ECG signal was processed using software PowerLab 8/35 in LabChart (AD Instruments, PowerLab 8/35 on LabChart for Windows version) that is designed to analyze HRV. Also simultaneously pulse signal was recorded with the help of same AD Lab instrument (AD Instruments Pty. Ltd.) and signal acquisition was obtained on the AD instrument. The pulse signal was recorded using photoplethysmography (PPG) from the right index finger. The recorded pulse signal was processed using the PowerLab 8/35 software to synchronise the event in LabChart (Alternatively, Kubios HRV Standard software can also be used for HRV analysis). The analysis involves identifying the time domain and frequency domain measures of PRV. Time domain analysis includes SDNN (Standard deviation of NN intervals), RMSSD (Root mean square of successive RR interval differences), and pNN50 (Percentage of successive RR intervals that differ by more than 50 ms). The frequency domain analysis includes High frequency (HF), low frequency (LF), LF/HF ratio, and total power.\n\nAll participants performed the cardiopulmonary exercise test using the Bruce protocol.19 Participants were screened for eligibility and informed of the testing procedures. A heart rate monitor (Polar FT1 heart rate monitor watch with polar T31- CODED transmitter) and a blood pressure cuff (Diamond Dial Deluxe Blood Pressure Apparatus) were connected to the patient to record the vitals. The participants were asked to warm up for 2-3 minutes by walking on a treadmill (Runner 7410, Runner Srl, Cavezzo, Italy) at a slow pace, with a 0% grade. The test was started with the treadmill set at a 10% grade and a speed of 2.7 km/h. The participants were asked to walk at this pace for 3 minutes. Thereafter every 3 minutes’ treadmill speed and inclination was increased as per standard Bruce protocol.19 Exercise test termination was considering as per standard recommendation.19 The test was terminated if the individual reached volitional fatigue or about 85% of age-predicted HRmax, displayed adverse signs or symptoms, requested to stop. An adequate cool-down/recovery interval was provided in the form of continuous walking at a work rate equal to that of the first stage of the exercise test protocol or lower.19 Throughout the test, heart rate, blood pressure, and Spo2 was monitored and recorded. The participants were also asked to rate their perceived exertion at the end of each stage using the Borg Rating of Perceived Exertion scale.19 No adverse event was noted during or following the exercise test.\n\nStatistical Package for the Social Sciences (SPSS) version 15.0 was used to analyse the data (SPSS for Windows, Version 15, SPSS, Inc., Chicago, IL, USA). Also Jamovi software20 was used for Bland-Altman analysis. Descriptive statistics was used to summarize the data. Measures such as mean, standard deviation, median, minimum, maximum, and range were calculated for HRV and PRV data separately. Correlation analysis was used to examine the relationship between HRV and PRV. Spearman rank correlation coefficient was used as data was not normality distributed. Mann-Whitney U test was performed to determine difference between HRV and PRV. Also, Bland-Altman analysis was carried out between HRV and PRV for level of agreement in measurement.\n\n\nResults\n\nA total of 35 participants (20 females and 15 males) data were analyzed in this study. Table 1 describes the demographic details of the participants, where the mean age was 23.14 ± 5.27 years, weight was 73.68 ± 7.40 kg, body fat % was 32.23 ± 5.30 and visceral fat % was 4.60 ± 2.0. Table 2 describes comparison of time domain indices, frequency domain measures (absolute parameter) of HRV and PRV of the participants. The Mann Whitney U test was performed to compare HRV and PRV for absolute parameter, the results showed no significant difference between the median HRV and PRV values (p-value ≥ 0.05).\n\nTable 3 describes comparison of time domain indices, frequency domain measures (Log transformed parameter) of HRV and PRV of the participants. A t-test was performed to compare HRV and PRV. The results showed no significant difference between the mean HRV and PRV values (p-value ≥ 0.05). Table 4 depicts Bland-Altman plot of Total Power measures of HRV and PRV.\n\nThe study found no significant correlation with the frequency domains variables of HRV/PRV with VO2 Peak (Depicted in Figures 1 and 2). The results from the correlation analyses between HRV and PRV are shown in Figure 3. Also Figures 4 and 5 represent Bland-Altman plots comparing HRV and PRV measurements.\n\nLF - Power in the low-frequency range (0.04–0.15 Hz); HRV - Heart rate variability; PRV - Pulse rate variability.\n\nHF - Power in the high-frequency range (0.15–0.4 Hz); HRV - Heart rate variability; PRV - Pulse rate variability.\n\n\nDiscussion\n\nThe primary objective was agreement analysis, commonly performed using a method like Bland-Altman analysis, assesses the level of agreement or consistency between two measurement methods or variables. It focuses on quantifying the degree of agreement between HRV and PRV by examining the magnitude of the differences between the two measures. The analysis helps determine if the two variables can be used interchangeably or if there are systematic differences or biases between them. In the context of HRV and PRV comparison, agreement analysis investigates the consistency in the measurements of the two variables and whether they can be substituted for one another. In our study Bland-Altman analysis demonstrated the lack of consistency in the measurement of PRV and HRV.\n\nWe examined the time-domain measures and frequency-domain metrics of HRV obtained from ECG waveforms and pulse-wave-related HRV (PRV) among overweight individuals. Interestingly, no significant difference were observed between these measures. Additionally, when the HRV and PRV variables were subjected to a log transformation, there were no discernible effects on the study outcomes.\n\nThe study revealed that there were no disparities between the HRV and PRV variables, which were concurrently measured for all participants. This suggests that potential confounding factors like age, sex, recording time, temperature, and BMI were similar among the individuals.\n\nAlthough the study found no statistically significant differences between the HRV and PRV variables, it does not always follow that they are always interchangeable, especially when examining different temperature settings. According to Shin H’s21 study findings, ambient temperature significantly influences PRV compared to HRV, and the difference increases with increasing ambient temperature. The autonomic nervous system, which controls heart rate and affects both HRV and PRV, can be impacted by temperature.21 PRV may contain distinct information that is not available through HRV alone. According to a study report by Mejía-Mejía E,10 PRV reacts to exposure to cold differently than HRV, notably in peripheral areas like the finger and toe, and may contain additional information that HRV does not. In order to evaluate the autonomic activity on many body sites and in various situations, a multi-site PRV assessment is warranted. Further investigations are required to gain a better understanding of the contribution of the sympathetic nervous system to PRV measurements following exposure to varying temperatures.\n\nHRV measures are impacted mainly by heart rate fluctuations brought on by exercise or stress.22 Conversely, PRV reflects the interaction between the heart and peripheral vascular resistance, providing information that HRV does not capture. Different factors cause several significant differences between HRV and PRV. One such distinction is that PRV is assessed by catching the mechanical waves passed from the heart to the fingertips. In contrast, HRV is quantified using the electrical waves recorded in an ECG.10,23\n\nChanges in temperature can also result in a short lag in the pulse wave’s peak and the R wave on the ECG. Following the electrical current discharge from the sinoatrial (SA) node to the ventricles, the mechanical force produced by the heart’s contraction undergoes substantial attenuation and change as it moves from the left ventricle to the fingertips. In addition, blood viscosity, osmolarity, regulation by the autonomic nervous system, blood vessel size and shape, and individual physical features all have a role in the discrepancy between PRV and HRV.24,25\n\nThe second objective of the current study was to examine the correlation between HRV and PRV. Our main finding displayed that, across all analyzed indices, HRV showed greater associations with PRV. This result is in line with Bulte CS report, 2011.26 The advantage of using pulse wave signals to obtain the PRV is that the technology is less complex and more user-friendly than ECG equipment. Consequently, it can be a suitable option for routine monitoring and serve as an alternative to ECG-based HRV analysis.27\n\nStudies have demonstrated that short recordings of at least 5 minutes can reliably analyze the frequency domain measures of heart rate variability derived from ECG waveform in healthy individuals.3,28 In our research, we expanded upon previous investigations by employing a broader range of statistical tests, such as mean difference, correlation, and Bland-Altman methods. Additionally, we adhered strictly to comprehensive assessment criteria, thereby enhancing the reliability of our findings. Our results indicate that HRV parameters derived from ECG signals exhibit poor measurement consistency with PRV, but they do exhibit a strong correlation with both sources. Despite the significant correlation between PRV and HRV, caution should be used when substituting PRV with HRV, especially in overweight persons, as inconsistent levels of agreement found in the measurement of PRV and HRV in this study.\n\n\nConclusions\n\nThe findings showed no noticeable difference between the median heart rate variability (HRV) and pulse rate variability (PRV). Furthermore, a correlation analysis showed that there was a significant correlation between HRV and PRV. However, there was a poor level of agreement found in the measurement of PRV and HRV. While additional studies are required, it is to shed light on how sympathetic and parasympathetic nervous systems affect PRV. Additionally, PRV measurements from each finger can be compared with HRV.\n\nThis cross-sectional study is a component of a large intervention trial. This work constitutes a sub-analysis derived from the above-mentioned large intervention trial. The study protocol was approved by the Institutional Research Committee (IRC), and Institutional Ethics Committee of Kasturba Medical College and Kasturba Hospital Manipal (IEC/155/2018). The trial has been registered under the Clinical Trials Registry (CTRI number: CTRI/2018/08/015523). The participants provided their written informed consent to participate in this study.",
"appendix": "Data availability\n\nHarvard dataverse. Dataset for Heart rate variability and Pulse rate variability analysis, https://doi.org/10.7910/DVN/ONPYF1. 29\n\n- Dataset for HRV and PRV.xlsx (This dataset comprises of participant data heart rate variability and pulse rate variability for Total of 35 participants (20 females and 15 males)\n\nHarvard dataverse, “Checklist: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies”, https://doi.org/10.7910/DVN/FIXXRS, Harvard Dataverse, V1. 30\n\n- STROBE checklist.docx- This file comprises of table depicting The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nHeart rate variability: standards of measurement, physiological interpretation and clinical use: Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996; 93(5): 1043–1065.\n\nSieciński S, Kostka PS, Tkacz EJ: Heart Rate Variability Analysis on Electrocardiograms, Seismocardiograms and Gyrocardiograms on Healthy Volunteers. Sensors (Basel). 2020; 20(16). PubMed Abstract | Publisher Full Text | Free Full Text\n\nShaffer F, Ginsberg JP: An Overview of Heart Rate Variability Metrics and Norms. Front. Public Health. 2017; 5: 258. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStrüven A, Holzapfel C, Stremmel C, et al.: Obesity, Nutrition and Heart Rate Variability. Int. J. Mol. Sci. 2021; 22(8). PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchroeder EB, Liao D, Chambless LE, et al.: Hypertension, blood pressure, and heart rate variability: the Atherosclerosis Risk in Communities (ARIC) study. Hypertension. 2003; 42(6): 1106–1111. Publisher Full Text\n\nDekker JM, Crow RS, Folsom AR, et al.: Low heart rate variability in a 2-minute rhythm strip predicts risk of coronary heart disease and mortality from several causes: the ARIC Study. Atherosclerosis Risk In Communities. Circulation. 2000; 102(11): 1239–1244. PubMed Abstract | Publisher Full Text\n\nKubota Y, Chen LY, Whitsel EA, et al.: Heart rate variability and lifetime risk of cardiovascular disease: the Atherosclerosis Risk in Communities Study. Ann. Epidemiol. 2017; 27(10): 619–25.e2. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDong JG: The role of heart rate variability in sports physiology. Exp. Ther. Med. 2016; 11(5): 1531–1536. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPham T, Lau ZJ, Chen SHA, et al.: Heart Rate Variability in Psychology: A Review of HRV Indices and an Analysis Tutorial. Sensors (Basel). 2021; 21(12). PubMed Abstract | Publisher Full Text | Free Full Text\n\nMejía-Mejía E, Budidha K, Abay TY, et al.: Heart Rate Variability (HRV) and Pulse Rate Variability (PRV) for the Assessment of Autonomic Responses. Front. Physiol. 2020; 11: 779. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen YS, Lin YY, Shih CC, et al.: Relationship Between Heart Rate Variability and Pulse Rate Variability Measures in Patients After Coronary Artery Bypass Graft Surgery. Front. Cardiovasc. Med. 2021; 8: 749297. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBánhalmi A, Borbás J, Fidrich M, et al.: Analysis of a Pulse Rate Variability Measurement Using a Smartphone Camera. J. Healthc. Eng. 2018; 2018: 1–15. Publisher Full Text\n\nMitchell GF, Hwang SJ, Vasan RS, et al.: Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation. 2010; 121(4): 505–511. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSaid MA, Eppinga RN, Lipsic E, et al.Relationship of arterial stiffness index and pulse pressure with cardiovascular disease and mortality. J. Am. Heart Assoc. 2018 Jan 22; 7(2): e007621. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChandra P, Sands RL, Gillespie BW, et al.: Relationship between heart rate variability and pulse wave velocity and their association with patient outcomes in chronic kidney disease. Clin. Nephrol. 2014; 81(1): 9–19. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchäfer A, Vagedes J: How accurate is pulse rate variability as an estimate of heart rate variability? A review on studies comparing photoplethysmographic technology with an electrocardiogram. Int. J. Cardiol. 2013; 166(1): 15–29. PubMed Abstract | Publisher Full Text\n\nWong JS, Lu WA, Wu KT, et al.: A comparative study of pulse rate variability and heart rate variability in healthy subjects. J. Clin. Monit. Comput. 2012; 26(2): 107–114. Publisher Full Text\n\nKhandoker AH, Karmakar CK, Palaniswami M: Comparison of pulse rate variability with heart rate variability during obstructive sleep apnea. Med. Eng. Phys. 2011; 33(2): 204–209. Publisher Full Text\n\nPescatello LS; Medicine ACoS: ACSM’s Guidelines for Exercise Testing and Prescription. Wolters Kluwer Health; 2014.\n\nThe jamovi project: jamovi (Version 2.3) [Computer Software].2023. Reference Source\n\nShin H: Ambient temperature effect on pulse rate variability as an alternative to heart rate variability in young adult. J. Clin. Monit. Comput. 2016; 30(6): 939–948. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKim HG, Cheon EJ, Bai DS, et al.: Stress and Heart Rate Variability: A Meta-Analysis and Review of the Literature. Psychiatry Investig. 2018; 15(3): 235–245. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMejía-Mejía E, May JM, Torres R, et al.: Pulse rate variability in cardiovascular health: a review on its applications and relationship with heart rate variability. Physiol. Meas. 2020; 41(7): 07tr1. Publisher Full Text\n\nPeng RC, Li Y, Yan WR: A correlation study of beat-to-beat R-R intervals and pulse arrival time under natural state and cold stimulation. Sci. Rep. 2021; 11(1): 11215. Publisher Full Text\n\nKiran Kumar C, Manaswini M, Maruthy KN, et al.: Association of Heart rate variability measured by RR interval from ECG and pulse to pulse interval from Photoplethysmography. Clin. Epidemiol. Glob. Health. 2021; 10: 100698. Publisher Full Text\n\nBulte CS, Keet SW, Boer C, et al.: Level of agreement between heart rate variability and pulse rate variability in healthy individuals. Eur. J. Anaesthesiol. 2011; 28(1): 34–38. PubMed Abstract | Publisher Full Text\n\nPinheiro N, Couceiro R, Henriques J, et al.: Can PPG be used for HRV analysis? Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. 2016; 2016: 2945–2949.\n\nMelo HM, Martins TC, Nascimento LM, et al.: Ultra-short heart rate variability recording reliability: The effect of controlled paced breathing. Ann. Noninvasive Electrocardiol. 2018; 23(5): e12565. Publisher Full Text\n\nMukesh KS: Dataset for Heart rate variability and Pulse rate variability analysis. V1 ed. [Data]. Harvard Dataverse. 2023. Publisher Full Text\n\nMukesh KS: Checklist: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. V1 ed. Harvard Dataverse. 2023. Publisher Full Text"
}
|
[
{
"id": "210177",
"date": "03 Oct 2023",
"name": "Aishwarya Nair",
"expertise": [
"Reviewer Expertise Pulmonary Rehabilitation",
"Cardiac Rehabilitation",
"Critical care",
"neonates",
"pediatric"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article is written very well.\nIn Introduction, the time domain indices, and frequency domain measurements may be elaborated on more so that therapists of various professional grade may understand and apply.\n\nIn Participant recruitment, kindly provide reference for the sentence regarding abstinence from alcohol and caffeine. Why these two drinks are considered above others, can be clarified.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "210175",
"date": "03 Oct 2023",
"name": "Saumya Srivastava",
"expertise": [
"Reviewer Expertise Musculoskeletal conditions",
"LBP",
"Sacroiliac dysfunctions"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbstract - Result - correlation value should be added along with p value.\n\nIntroduction - can be made elaborate to explain the need for the study.\n\nMethods - how was the sample size calculated? Mention the validity and reliability of the equipment and tools used in the study.\n\nDiscussion - can be backed with a few more studies and reasoning.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "210176",
"date": "10 Oct 2023",
"name": "Sanjay Tejraj Parmar",
"expertise": [
"Reviewer Expertise OVER WEIGHT AND CARDIAC FUNCTION"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nHighlight the other cardiac autonomic markers in the introduction.\n\nJustify why PRV can serve as a substitute for HRV in the intro section.\n\nAdd on how adiposity alter the HRV and PRV in intro.\nMethods: Kindly mention all exclusions.\nDiscussion:\nPreferably mention log transformed Bland-Altman plots comparing HRV and PRV for log transformed data.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "210173",
"date": "10 Oct 2023",
"name": "Sanyog Rawat",
"expertise": [
"Reviewer Expertise Antenna Technology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nJustify increase or decrease in heart rate variability and pulse rate variability significance in the introduction section.\n\nExplain how being overweight is going to affect heart rate variability and pulse rate variability.\n\nClinical significance may be needed to be strengthened in the discussion section.\n\nThe authors need to highlight several confounders such as diet, sleep, stress in the discussion section.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1229
|
https://f1000research.com/articles/12-1228/v1
|
27 Sep 23
|
{
"type": "Review",
"title": "Oleogel-based drug delivery for the treatment of periodontitis: current strategies and future perspectives",
"authors": [
"Shaswata Karmakar",
"Shashikiran Shanmugasundaram",
"Baishakhi Modak",
"Shaswata Karmakar",
"Baishakhi Modak"
],
"abstract": "Periodontitis is the chronic inflammation of tooth-supporting tissues that leads to loss of tooth support if untreated. Conventional therapy for periodontitis (mechanical removal of microbial biofilm and oral hygiene enforcement) is augmented by anti-microbial and anti-inflammatory drugs. These drugs are frequently delivered locally into the periodontal pocket for maximum efficiency and minimum adverse effects. The potential of oleogels for periodontal drug delivery has been discussed and further, the future scope of oleogel-based drug delivery systems in dentistry. An oleogel-based local drug delivery system offers several advantages over other systems. Superior mechanical properties (firmness and compressibility), muco-adhesion, shear thinning, thixotropy, controlled drug release and the ability to incorporate water-insoluble drugs clearly distinguish and highlight the potential of oleogels as periodontal local drug delivery systems. Bigels can combine the qualities of both hydrogels and oleogels to provide a more promising option for drug delivery. However, there is limited evidence concerning oleogels as local drug delivery agents in periodontics. Further studies are needed to discern the clinical efficacy of oleogel-based drug delivery systems.",
"keywords": [
"Oleogels",
"Gels",
"Hydrogels",
"Local drug delivery",
"Periodontitis",
"Periodontics"
],
"content": "Introduction: Drug delivery in periodontics\n\nPeriodontics is the branch of dentistry that deals with the prevention, diagnosis and treatment of diseases affecting the tissues that surround and support the teeth. The World Health Organization (WHO) estimates that periodontal diseases affect around 19% of adults around the world.1 Periodontitis is the chronic inflammation of the alveolar bone and other soft tissues surrounding the teeth that leads to gradual loss of tooth support, ultimately leading to tooth loss, if untreated.2 This chronic inflammation is triggered by dysbiotic microbial biofilm accumulating around the teeth. Periodontitis often results in periodontal pockets (deepening of the gingival sulcus) around the teeth (Figure 1). These areas act as biofilm retentive niches that are inaccessible to hygiene procedures (brushing and flossing) where biofilm continues to accumulate leading to a slow but continuous destruction of tissues.3 The host immuno-inflammatory mediators such as cytokines and prostaglandins also play a significant role in the disease progression and tissue damage.4\n\nThe microbial biofilm that accumulates on the teeth causes chronic inflammation of tissues around the tooth leading to the formation of periodontal pockets and a gradual loss of tooth support. The oral cavity encounters a constant flow of saliva and frequent physical movements due to talking and chewing. The oral cavity also hosts a diverse microbiome. Created with BioRender.com.\n\nPeriodontal therapy aims to remove the accumulated biofilm (mechanical debridement), disinfect the pocket region, resolve inflammation, and enforce optimal hygiene habits in the patients. The main goal of periodontal therapy is to eliminate or control the microbial biofilm and restore the health and function of the periodontium (Figure 1). Various antimicrobial and anti-inflammatory drugs have been used along with mechanical debridement (professional removal of microbial biofilm) for the treatment of periodontitis; and delivering these drugs locally into the pocket region provides the best efficiency in terms of drug concentration at the site while eliminating systemic side effects in patients. Oral administration of drugs has some inherent drawbacks such as reduced bioavailability of the drug at the required site (due to first-pass metabolism in the liver) and systemic side effects. To overcome these drawbacks, clinicians often choose to locally deliver the drugs into the inflamed sites.5\n\nThe periodontal pocket is a narrow crevice encircling the tooth. The region is bounded by soft tissue on one side and hard tissue (tooth) on the other.6 The therapeutic agents delivered into the periodontal pocket must be retained in the region for a long time without getting displaced by the continuous flow of saliva and the constant physical movements of the oral cavity. Hence, the delivery system needs to be adhesive to the pocket wall (Figure 2). Also, the release of the drug into the region should be slow and sustained to resolve inflammation.6 One of the major challenges in periodontics is to efficiently deliver therapeutic agents to the inflamed sites around the teeth and maintain their concentration for sufficient time. The oral cavity is a physically dynamic environment with a constant flow of saliva, which makes local delivery of drugs into the periodontal environment a challenge (Figure 1). Therefore, there is a need for developing novel drug delivery systems that can provide sustained and controlled release of drugs in this dynamic environment.5\n\nThe periodontal pocket is a deep narrow space around the tooth affected by periodontitis. The pocket is bounded on one side by the tooth and the other side by the gingival soft tissue. Therapeutic agents (anti-microbial or anti-inflammatory) loaded in either of the three gel systems are delivered locally into the periodontal pocket to control the inflammation. Created with BioRender.com.\n\nAmong the various types of local drug delivery systems, gels have received considerable attention for periodontal applications.7 Gels are semi-solid systems that consist of a liquid phase entrapped within a three-dimensional network of cross-linked polymers or solid particles.7,8 Gels are biocompatible, can be administered easily, and can adapt to different shapes in the periodontal region.7 Depending on the nature of the liquid phase, gels can be classified into hydrogels, oleogels and bigels (Figure 2). Hydrogels are gels that contain water as the liquid phase. They are widely used for drug delivery purposes, as they can swell and release drugs in response to various stimuli, such as pH, temperature, enzymes, or electric fields. However, hydrogels also have some drawbacks, such as rapid drug release, low mechanical strength, poor stability, and inability to incorporate hydrophobic drugs.8 Oleogels have oil as their liquid phase and have been explored for food, cosmetics, and pharmaceutical applications. Oleogels have shown potential for drug delivery due to their unique properties, such as high solubility and stability of lipophilic drugs, low water activity and microbial growth, tunable rheology, and texture, and injectability with a needle.9 Bigels are gels that contain both water and oil as the liquid phases. They are relatively new gels that combine the benefits of hydrogels and oleogels while overcoming their drawbacks.\n\nIn this review, we explore the current state of knowledge on oleogels for drug delivery in periodontics; provide an overview of the recent advances in oleogels as local drug delivery systems for periodontitis; and discuss the challenges and future perspectives of oleogel-based drug delivery systems.\n\n\nOleogels in periodontics\n\nGel formulations, particularly hydrogels, have drawn a lot of attention among these local delivery systems for the treatment of periodontitis. Non-steroidal anti-inflammatory drugs (NSAIDs) and antibacterial agents are frequently delivered via hydrogels made of sodium carboxymethyl cellulose, chitosan, polyethene oxide, xanthan gum, and polyacrylic acid to treat periodontitis. The ability of hydrogels to adhere to the mucosa in the periodontal pocket and then be quickly removed by typical catabolic routes demonstrates their excellent biocompatibility and mucoadhesive qualities.10,11 However, the major drawback of using hydrogels is that they are less compatible with lipophilic drugs.\n\nOleogels are formed by adding a structuring agent to an edible oil to create a three-dimensional network that entraps the oil molecules. The structuring agent can be either a low-molecular-weight gelator, such as fatty acids or waxes, or a high-molecular-weight gelator, such as polymers or proteins. Bigels can be synthesized by mixing organogel (oil phase) and hydrogel (aqueous phase) components in different proportions and methods. Bigels can provide improved drug loading capacity, release kinetics, rheological properties and biocompatibility compared to hydrogels or oleogels alone.12 Oleogels can enhance the penetration of drugs due to their lipophilic nature. They have been used to deliver water-insoluble drugs like tetracycline, metronidazole, metronidazole benzoate, and their combinations.13 Bigels, another system of drug delivery, is a biphasic system created by combining water-based hydrogels and oil-based oleogels. So, it is possible to incorporate and deliver both lipophilic and hydrophilic drugs at the same time.\n\nIn the past, oleogels have been used for periodontal drug delivery. One study evaluated “Elyzol® 25%” dental gel (Colgate-Palmolive (UK) Limited), which contains sesame oil, glyceryl monooleate, and metronidazole benzoate.14 When the pocket was filled with it, it flowed smoothly via the applicator to the location. This offers a simple and efficient method of administration.14 “ATRIDOX® gel” (Atrix Lab, USA), another local drug delivery agent is composed of poly-dl-Lactide dissolved in a biocompatible solvent N-methyl-2-pyrrolidone loaded with 10% doxycycline hyclate. Sol-gel transition and the formation of a semisolid structure on encountering Gingival Crevicular Fluid (GCF) is a characteristic of this system that is based on water-free mixtures of lipids such as glycerol monooleate and sesame oil. Studies were conducted using this gel for the treatment of periodontitis and the results showed that 250 mg/ml of drug was present in GCF for seven days indicating sustained drug delivery.15,16 A study developed and evaluated a metronidazole gel and reported adequate muco-adhesiveness and controlled drug release.17 Another recent study evaluated a thermoreversible metronidazole gel and reported sustained antibacterial action.18 The delivery of a combination of amoxicillin and metronidazole using a lipid-based gel system showed sustained anti-bacterial efficacy19 (Table 1).\n\nSRP (Scaling and Root Planing); GCF (Gingival Crevicular Fluid).\n\nThere are a limited number of studies comparing different types of gel systems that can be used for local drug delivery for periodontitis. Hamed et al., conducted a study investigating the local delivery of NSAIDs to treat periodontitis using different gel formulations.12 Gel formulations were characterized in terms of their various properties (flow behavior, viscoelasticity and bio-adhesive properties, in vitro drug release). The results of the study showed that rheological and bio-adhesive properties were greatly influenced by the type of gel formulations. Oleogels and bigels showed superior properties such as viscoelasticity, bio-adhesion and controlled-drug release when compared to hydrogels. The study concluded that bigels and oleogels showed the greatest promise as a potential local drug delivery system for treating periodontitis.12 Promising results have also been obtained with several oleogels for the delivery of 2.5% tetracycline, 25% metronidazole, 40% metronidazole benzoate, as well as a combination of tetracycline and metronidazole benzoate.20\n\nAnother study compared the efficacy of hydrogels, oleogels, and bigels loaded with metronidazole for treating periodontitis.21 Bigels and Oleogels showed superior properties like shear-thinning (a property that enables the gel to form thin layers and to be injected by syringes), thixotropy (the gel is rendered more viscous under stress and less viscous in the absence of stress), bio-adhesiveness (the ability of the gel to adhere to the mucosa). Oleogels showed better mechanical properties like firmness, compressibility, and adhesiveness when compared to bigels and hydrogels. However, among the three gel systems, oleogels showed the least drug release and bigels showed the highest drug release. The study concluded that bigels and oleogels are promising local drug delivery systems to treat periodontitis.21 A 2022 study formulated and evaluated olive oil and mustard oil-based oleogels as drug-delivery agents loaded with metronidazole. The prepared oleogels showed thermoreversible behavior, shear-thinning, and pseudo-plasticity. The gels also showed pH-responsive controlled drug release. The study concluded that these gels could serve as excellent tools for drug delivery.22 Overall, the superior properties of oleogels and bigels can potentially enable a more efficient and robust drug delivery to the periodontal region and aid in successful therapy.\n\n\nOther applications of oleogels in dentistry\n\nOil-based or lipid-based formulations can be used to treat many other mucosal and inflammatory dental diseases and conditions and have been employed more frequently during the past few decades for their applicability in a variety of treatment aspects such as gene delivery, cancer therapy, and infectious disorders.23 They are preferred drug carriers due to their capacity to enclose, transport and safeguard molecules with a variety of physical and chemical properties.23 Liposomes, being the active component of lipid-based compounds, are tiny, adaptable lipid-based vesicles that can enclose hydrophilic, lipophilic, and amphiphilic substances. Increased biocompatibility and site-specificity, increased therapeutic index and less toxicity are some of its important properties, making it suitable for drug administration in dentistry.24 In recent years, a great number of lipid-based formulations have been developed for oral drug delivery to treat various diseases, including diseases of oral-dental origin.25\n\nSeveral diseases of the oral mucosa like erythema multiforme, pemphigus vulgaris, lichen planus, and bullous pemphigoid of the oral mucosa need topical steroid delivery.26–28 Oleogels can provide a superior alternative to currently existing steroid-delivery systems. Local anesthetic gels containing Lidocaine or Benzocaine are frequently used for the symptomatic treatment of oral ulcers.29 An oleogel-based delivery system, with improved bio-adhesiveness and controlled release, could provide sustained action at ulcerated sites.\n\nOral cancer is one of the most prevalent health concerns around the globe. Chemotherapeutic drugs frequently have unfavorable side effects on noncancerous tissues when used to treat oral cancer. Drug resistance and metastasis result from cancer therapies’ being unable to completely eradicate malignant cells.30 However, lipid-based drugs can dispense an appropriate amount of drug to the tumor cells, making treatment more effective.30 Doxil® was the first FDA (Food and Drug Administration, USA)-approved liposomal doxorubicin for the treatment of oral cancer. Additionally, lipid-based drugs may enhance the activity of certain drugs, bypass drug-resistance mechanisms, and reduce the toxicity associated with them, especially for drugs like antibiotics.30 A wide range of antibiotics are used in dentistry. Rukavina et al., developed azithromycin-loaded liposomes that improved the antibiotic’s activity against various oral infections caused by Staphylococcus aureus. The formulation also retained the drug more efficiently and prevented oral biofilm formation.31 In a recent study, Ribeiro et al., showed their hybrid liposomal formulation’s improved in vitro antimicrobial activity against various drug-resistant bacterial strains.32\n\n\nCurrent challenges and future perspectives\n\nOleogel-based drug delivery systems seem to offer numerous advantages such as delivery of water-insoluble drugs, enhanced muco-adhesiveness, sustained delivery, shear thinning, and thixotropy; oleogels have the potential to serve as a superior alternative to hydrogel-based drug delivery. However, the formulation of oleogels needs to be standardized and optimized for oral drug delivery and should be tailored for specific drugs. The choice of the appropriate oil phase and gelator can enhance the qualities of the oleogel. The safety of oleogels needs to be studied further; biodegradability, biocompatibility, and potential for toxicity and adverse reactions need to be elucidated before clinical use. Future clinical trials need to study the efficacy of oleogel-based drug delivery systems in humans.\n\nBigels can be a significant improvement over the characteristics of oleogels as they can combine the benefits of both hydrogels and oleogels. But the ideal ratios and proportions of aqueous and oil phases need to be studied in the future as they can significantly influence the behavior and characteristics of these gel systems.12 Temperature-sensitive and pH-sensitive smart oleogel systems (like their hydrogel counterparts) can greatly enhance the treatment of diseases like periodontitis as the periodontal pocket region has variable temperature and pH in accordance with health and disease states.33 Nanogels can significantly increase the drug loading capacity with increased permeability.34 The development of stimuli-responsive smart oleogel systems and oil-based nano-gels (nano-oleogels) in the future can augment the potential of oleogels for drug delivery.\n\n\nConclusions\n\nPreliminary evidence suggests that oleogels and bigels offer several advantages over hydrogels. The ability to incorporate water-insoluble drugs, higher muco-adhesion, controlled drug release, and superior mechanical properties highlights the potential of oleogels to be used as an alternative drug delivery system in periodontics. Oleogels and bigels also show shear-thinning and thixotropic behavior that can aid in their placement and retention in the periodontal pocket. However, several aspects of the formulation such as the ideal choice of the oil phase, gelators and other additives, especially for oral mucosal drug delivery need to be studied. The biodegradability of oleogels and the possibility of toxicity also need further research. Currently, there is limited evidence concerning oleogels and their efficacy in periodontal drug delivery. Future research needs to focus on the knowledge gaps in the literature and should address the safety and efficacy of oleogel-based periodontal drug delivery in humans.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nOral health: [cited 2023 Jul 11]. Reference Source\n\nCekici A, Kantarci A, Hasturk H, et al.: Inflammatory and immune pathways in the pathogenesis of periodontal disease. Periodontol. 2000. 2014 Feb [cited 2023 Jul 11]; 64(1): 57–80. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWei Y, Deng Y, Ma S, et al.: Local drug delivery systems as therapeutic strategies against periodontitis: A systematic review. J. Control. Release. 2021 May 10; 333: 269–282. PubMed Abstract | Publisher Full Text\n\nBelstrøm D, Damgaard C, Nielsen CH, et al.: Does a causal relation between cardiovascular disease and periodontitis exist? Microbes Infect. 2012 May [cited 2023 Jun 30]; 14(5): 411–418. Publisher Full Text Reference Source\n\nAmato M, Santonocito S, Polizzi A, et al.: Local Delivery and Controlled Release Drugs Systems: A New Approach for the Clinical Treatment of Periodontitis Therapy. Pharmaceutics. 2023 Apr 1 [cited 2023 Jul 11]; 15(4). PubMed Abstract | Publisher Full Text | Free Full Text\n\nDonos N: The periodontal pocket. Periodontol. 2000. 2018 Feb 1 [cited 2023 Jul 11]; 76(1): 7–15. PubMed Abstract | Publisher Full Text\n\nYadav R, Kanwar IL, Haider T, et al.: In situ gel drug delivery system for periodontitis: an insight review. Future J. Pharm. Sci. 2020 Jul 17 [cited 2023 Jul 11]; 6(1): 1–13. Publisher Full Text\n\nRebaka V, Rachamalla A, Batra S, et al.: State of the art and new perspectives in oleogels and applications. Springer; 2020 [cited 2023 Jun 30]. Publisher Full Text\n\nDavidovich-Pinhas M: Oleogels: a promising tool for delivery of hydrophobic bioactive molecules. Future Sci. 2015 Dec 10 [cited 2023 Jul 11]; 7(1): 1–3. Publisher Full Text\n\nNguyen S, Hiorth M: Advanced drug delivery systems for local treatment of the oral cavity. Ther. Deliv. 2015 May 1 [cited 2023 Jun 30]; 6(5): 595–608. Publisher Full Text Reference Source\n\nRehman K, Amin MCIM, Zulfakar MH: Development and physical characterization of polymer-fish oil bigel (hydrogel/oleogel) system as a transdermal drug delivery vehicle. J. Oleo Sci. 2014 Sep 10 [cited 2023 Jun 30]; 63(10): 961–970. PubMed Abstract | Publisher Full Text\n\nHamed R, AbuRezeq A, Tarawneh O: Development of hydrogels, oleogels, and bigels as local drug delivery systems for periodontitis. Drug Dev. Ind. Pharm. 2018 Sep 2; 44(9): 1488–1497. PubMed Abstract | Publisher Full Text\n\nRehman K, Zulfakar MH: Recent advances in gel technologies for topical and transdermal drug delivery. Drug Dev. Ind. Pharm. 2014 [cited 2023 Jun 30]; 40(4): 433–440. PubMed Abstract | Publisher Full Text\n\nGriffiths GS, Smart GJ, Bulman JS, et al.: Comparison of clinical outcomes following treatment of chronic adult periodontitis with subgingival scaling or subgingival scaling plus metronidazole gel. J. Clin. Periodontol. 2000 [cited 2023 Jul 1]; 27(12): 910–917. Publisher Full Text Reference Source\n\nJavali MA, Vandana KL: A comparative evaluation of atrigel delivery system (10% doxycycline hyclate) Atridox with scaling and root planing and combination therapy in treatment of periodontitis: A clinical study. J. Indian Soc. Periodontol. 2012 Jan [cited 2023 Jul 3]; 16(1): 43–48. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPolson AM, Garrett S, Stoller NH, et al.: Multi-center comparative evaluation of subgingivally delivered sanguinarine and doxycycline in the treatment of periodontitis. I. Study design, procedures, and management. J. Periodontol. 1997 Feb [cited 2023 Jul 3]; 68(2): 110–118. PubMed Abstract | Publisher Full Text\n\nSallam AS, Hamudi FF, Khalil EA: Effect of ethylcellulose and propylene glycol on the controlled-release performance of glyceryl monooleate-mertronidazole periodontal gel. Pharm. Dev. Technol. 2015 Mar 1 [cited 2023 Jul 8]; 20(2): 159–168. PubMed Abstract | Publisher Full Text\n\nYadav E, Sebastian S, Gupta MK: Aminopyridinyl Tricosanamide Based Pseudoplastic and Thermoreversible Oleogels for pH-Dependant in vitro Release of Metronidazole. ChemistrySelect. 2022 Oct 26 [cited 2023 Jul 8]; 7(40): e202203014. Publisher Full Text\n\nLéber A, Szȕcs MB, Urbán E, et al.: Combination of Zinc Hyaluronate and Metronidazole in a Lipid-Based Drug Delivery System for the Treatment of Periodontitis. Pharmaceutics. 2019 Mar 1 [cited 2023 Jul 8]; 11(3). PubMed Abstract | Publisher Full Text | Free Full Text\n\nJoshi D, Garg T, Goyal AK, et al.: Advanced drug delivery approaches against periodontitis. Drug Deliv. 2016 Feb 12 [cited 2023 Jul 1]; 23(2): 363–377. PubMed Abstract | Publisher Full Text\n\nWróblewska M, Szymańska E, Szekalska M, et al.: Different Types of Gel Carriers as Metronidazole Delivery Systems to the Oral Mucosa. Polymers. 2020 Mar 19 [cited 2023 Jul 7]; 12(3): 680. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source\n\nYadav E, Sebastian S, Gupta MK: Aminopyridinyl Tricosanamide Based Pseudoplastic and Thermoreversible Oleogels for pH-Dependant in vitro Release of Metronidazole.ChemistrySelect [Internet].2022 Oct 26 [cited 2023 Jul 7];7(40):e202203014.Publisher Full Text Reference Source\n\nObuobi S, Julin K, Fredheim EGA, et al.: Liposomal delivery of antibiotic loaded nucleic acid nanogels with enhanced drug loading and synergistic anti-inflammatory activity against S. aureus intracellular infections. J. Control. Release. 2020 Aug 10 [cited 2023 Jul 5]; 324: 620–632. PubMed Abstract | Publisher Full Text\n\nLeszczyńska A, Buczko P, Buczko W, et al.: Periodontal pharmacotherapy - an updated review. Adv. Med. Sci. 2011 Dec 1 [cited 2023 Jul 5]; 56(2): 123–131. Publisher Full Text Reference Source\n\nLi L, Xu ZP, Gbian DL, et al.: Lipid-Based Drug Delivery Systems for Diseases Managements. Biomedicine. 2022 Aug 31 [cited 2023 Jul 6]; 10(9): 2137. Publisher Full Text Reference Source\n\nIngen-Housz-Oro S, Valeyrie-Allanore L, Cosnes A, et al.: First-line Treatment of Pemphigus Vulgaris With a Combination of Rituximab and High-Potency Topical Corticosteroids. JAMA Dermatol. 2015 Feb 1 [cited 2023 Sep 8]; 151(2): 200–203. PubMed Abstract | Publisher Full Text Reference Source\n\nSandhu S, Klein BA, Al-Hadlaq M, et al.: Oral lichen planus: comparative efficacy and treatment costs—a systematic review. BMC Oral Health. 2022 Dec 1 [cited 2023 Sep 8]; 22(1): 121–161. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKiran M, Vidya S, Aswal G, et al.: Systemic and Topical Steroids in the Management of Oral Mucosal Lesions. J. Pharm. Bioallied Sci. 2017 Nov 1 [cited 2023 Sep 8]; 9(Suppl 1): S1–S3. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAltenburg A, El-Haj N, Micheli C, et al.: The Treatment of Chronic Recurrent Oral Aphthous Ulcers. Dtsch. Arztebl. Int. 2014 Oct 3 [cited 2023 Sep 8]; 111(40): 665–673. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSonju JJ, Dahal A, Singh SS, et al.: Peptide-functionalized liposomes as therapeutic and diagnostic tools for cancer treatment. J. Control. Release. 2021 Jan 10 [cited 2023 Sep 8]; 329: 624–644. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRukavina Z, Šegvić Klarić M, Filipović-Grčić J, et al.: Azithromycin-loaded liposomes for enhanced topical treatment of methicillin-resistant Staphyloccocus aureus (MRSA) infections. Int. J. Pharm. 2018 Dec 20 [cited 2023 Jul 6]; 553(1–2): 109–119. PubMed Abstract | Publisher Full Text\n\nRibeiro LN d M, de Paula E , Rossi DA, et al.: Hybrid Pectin-Liposome Formulation against Multi-Resistant Bacterial Strains. Pharmaceutics. 2020 Aug 1 [cited 2023 Jul 6]; 12(8): 1–15. Publisher Full Text | Free Full Text\n\nSathian A, Vijay N, Joshy KS, et al.: Hydrogels: Smart Materials in Drug Delivery. Hydrogels - From Tradition to Innovative Platforms with Multiple Applications.2022 Jul 13 [cited 2023 Jul 10]. Reference Source\n\nDalir Abdolahinia E, Barati G, Ranjbar-Navazi Z, et al.: Application of nanogels as drug delivery systems in multicellular spheroid tumor model. J. Drug Deliv. Sci. Technol. 2022 Feb 1; 68: 103109. Publisher Full Text\n\nBeg S, Dhiman S, Sharma T, et al.: Stimuli Responsive In Situ Gelling Systems Loaded with PLGA Nanoparticles of Moxifloxacin Hydrochloride for Effective Treatment of Periodontitis. AAPS PharmSciTech. 2020 Apr 1 [cited 2023 Jul 10]; 21(3). Publisher Full Text Reference Source\n\nToskić-Radojicić M, Nonković Z, Loncar I, et al.: Assessment of the feasibility of the formulation of preparation for the growth inhibition of metronidazole-resistant strains isolated from the periodontal pockets. Vojnosanit. Pregl. 2005; 62(6): 453–459. Publisher Full Text"
}
|
[
{
"id": "216725",
"date": "19 Oct 2023",
"name": "Dhirendra Kumar Singh",
"expertise": [
"Reviewer Expertise Periodontology",
"Periodontal microbiology",
"Oral Implantology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript is well formulated, and structured with comprehensive information on the topic, as the non-invasive and non-surgical periodontal treatments are the need of the hour. The present manuscript will definitely help future researchers in gathering the cumulative information on local drug delivery systems from just one article.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": []
},
{
"id": "253604",
"date": "29 Apr 2024",
"name": "Shikha Sharma",
"expertise": [
"Reviewer Expertise periodontics"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nA comprehensive review regarding the ole gel as local drug delivery agent has been discussed. the indications, advantages and disadvantages have been elaborated. The article provides an insight into the dental and periodontal indications of the oleo gels. oleo gels forms a promising future for the treatment of periodontitis as a local drug delivery agent.\nThe article clearly draws the importance of the lipophilic nature of the oleogels and their importance in delivering some of the drugs used in the treatment of periodontitis like metronidazole etc. The Article comprehensively describes the use of oleogels in dentistry including in periodontics .The article briefs about the current trends, challenges and future perspective of olegels in periodontics\nMajor The article doesn't discuss the comparison between the mechanism, advantages, indications of different mode of the delivering of LDD apart from olegel ,just name has been mentioned i.e. Hydrogel and bigels , further elaboration about the same can be done , to bring about the importance and point of interest in regards with the oleogels proving it be more beneficial than the counter parts. The article has in depth beautifully explained about the oleogels , describing its features , structures , researches done in periodontics and general dentistry\n\nminor article in depth has described the used of oleogels from past till present .\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": []
},
{
"id": "267725",
"date": "06 May 2024",
"name": "Dana Gabriela Budală",
"expertise": [
"Reviewer Expertise prosthodontics"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOleo gels are emerging as a promising option for the localized treatment of periodontitis. A thorough examination of oleo gels as local drug delivery agents has been conducted, highlighting their uses, advantages, and limitations. The article provides a deeper understanding of the role of oleo gels in dental and periodontal care. Oleo gels show significant potential for future use in the targeted treatment of periodontitis.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1228
|
https://f1000research.com/articles/12-1225/v1
|
27 Sep 23
|
{
"type": "Clinical Practice Article",
"title": "An early Indian experience with benralizumab - A compendium on severe asthma cases: a case series",
"authors": [
"Deepak Talwar",
"Manoj Yadav",
"Nagarjuna Maturu",
"Rahul Sharma",
"Priti Meshram",
"Soumya Das",
"Manoj Yadav",
"Nagarjuna Maturu",
"Rahul Sharma",
"Priti Meshram",
"Soumya Das"
],
"abstract": "Background: Severe eosinophilic asthma (SEA), one of the phenotypes of asthma that is characterized by elevated blood eosinophil counts, is a common cause of uncontrolled asthma. Patients with SEA often experience severe persistent symptoms and have frequent exacerbations despite optimal inhaler therapy. They also have poor lung function and quality of life (QoL). Benralizumab (Fasenra), a monoclonal antibody, has been approved for managing cases of SEA. This series of six cases, the first of its kind from India, aims to add to the real-world evidence of benralizumab in India. Methods: Benralizumab 30 mg (once in four weeks for the first three doses followed by a dose every eight weeks for two years) was administered in six patients with symptoms of cough, breathlessness on exertion, and wheezing, diagnosed with SEA. The following were the endpoints assessed: (i) overlap between high immunoglobulin E (IgE) and eosinophilic asthma; (ii) reduction of exacerbations; (iii) withdrawal of oral corticosteroids; and (iv) improvement in lung function and QoL. Results: In all cases, management with benralizumab resulted in optimal clinical and functional improvement, a decline in systemic steroid use, and improved QoL. Conclusions: The cases presented here are the first of their kind in the Indian asthmatic population with all SEA patients demonstrating significant improvement in symptoms with the use of benralizumab.",
"keywords": [
"Asthma",
"benralizumab",
"eosinophilia",
"interleukin-5",
"monoclonal antibodies"
],
"content": "Introduction\n\nAsthma is a chronic inflammatory condition defined by symptoms of breathlessness, tightness of the chest, wheezing, and cough. Globally, approximately 300 million people are affected by asthma and this number is projected to increase to 400 million by 2025.1 Based on the Global Initiative for Asthma (GINA) global strategy for asthma management and prevention 2022 update, 3.7% of asthma patients have severe asthma.2\n\nThe number of people living with asthma in India exceeds that of human immunodeficiency virus and tuberculosis and stands at 3,79,00,000.3 More than 6% of adults with asthma have severe asthma. Repeated exacerbations and persisting symptoms of asthma which require management with repetitive bursts of oral glucocorticoids and/or maintenance therapy with oral glucocorticoids, and asthma which persists despite adequate therapy with long-acting muscarinic antagonists, long-acting β2-agonists, and high-dose inhaled glucocorticoids, is termed as severe asthma.4 In these patients, add-on treatment including biological therapy helps to reduce the disease burden. Benralizumab (Fasenra) is administered at a dose of 30 mg subcutaneously every 4 weeks, for three doses, followed by a dose every 8 weeks according to the scheduled regimen.5 Benralizumab, a cytosolic monoclonal antibody directed against the α-chain of the IL-5 receptor, induces direct, rapid, and nearly complete depletion of eosinophils via enhanced, antibody-dependent, cell-mediated cytotoxicity.6\n\nReal-world evidence on the safety and efficacy of benralizumab is limited with no studies from the Indian subcontinent. These cases present an early real-world experience with benralizumab in Indian patients with severe asthma.\n\n\nCase report\n\nThe patients included in this case-series are males and females, in the age range of 51–83 years, and of Indian origin.\n\nA 58-year-old, non-smoking male was admitted to the hospital with acute exacerbation of asthma and was seen in the outpatient department for further management. He had a body mass index (BMI) of 22 kg/m2 and had recurrent asthma exacerbations requiring courses of oral corticosteroids (OCS) 4–6 times/year. The attacks were mostly precipitated by viral upper respiratory tract infections and weather changes. He was on a maintenance dose of oral prednisolone 10 mg/day. The patient had a history of chronic sinusitis with nasal polyposis and functional endoscopic sinus surgery (FESS) was performed twice, out of which one surgery was performed 10 years ago and the other surgery was performed 8 months ago. He also had non-insulin–dependent diabetes mellitus for which he was on oral hypoglycemic agents for the last 12 years. He had a cerebrovascular accident more than 20 years ago with resultant mild weakness of the left side, in addition to osteoporosis. At the time of presentation, the patient was on formoterol and budesonide (400 μg/4.5 μg) 2 puffs twice a day (BD), tiotropium inhaler (18 μg) 2 puffs once daily (OD), montelukast 10 mg daily, oral prednisolone 10 mg/day, fluticasone furoate nasal spray 2 doses daily, and azithromycin 500 mg thrice a week. Despite being on optimal inhaler therapy as per GINA step 5, the patient had poor asthma control. He had severe symptoms daily, and his asthma control test (ACT) score was 17. Despite being on OCS, he was unable to work. His adherence to treatment and inhaler technique was good. This patient’s baseline investigation details are presented in Table 1.\n\nA diagnosis of severe T2 asthma with overlap phenotype (high eosinophils and IgE levels with insect sensitization) was made and benralizumab 30 mg subcutaneously every 4 weeks, for three doses, followed by a dose every 8 weeks was prescribed to this patient.\n\nIn adults with asthma, when the IgE levels are very high (>700 IU/mL) as in this patient (1404 IU/mL), omalizumab is usually not recommended as there is insufficient data to recommend a dose.7 Subsequently, the patient reported a significant improvement in his condition with no notable side effects. He began working again and stopped oral medication (prednisolone, theophylline, and montelukast). He was on only a long-acting beta-agonist (LABA) and a medium dose of inhalational corticosteroids (ICS) (formoterol and budesonide 200 μg two puffs BD).\n\nBenralizumab treatment resulted in the elimination of OCS use in this patient. Eosinophils dropped to 0 from 1460 and lung function forced expiratory volume in the first second (FEV1) improved from 1.02 L to 2.50 L, 12 months after the initiation of benralizumab.\n\nTable 2 shows the improvement in vital parameters at 6 and 12 months.\n\nThe forced vital capacity (FVC) before the benralizumab first dose and after six months of benralizumab treatment was 1.97 L (55% of predicted normal) and 3.08 L (86% of predicted normal), respectively. Figure 1 shows the changes in FEV1 after benralizumab therapy.\n\nFEV1: Forced expiratory volume in the first second.\n\nA 51-year-old male with asthma with no comorbidities was on standard care for more than 10 years and had symptoms of cough, breathlessness on exertion, and wheezing. The patient was being treated with optimal doses of salmeterol 50 μg and fluticasone 500 μg twice daily, montelukast 10 mg, fexofenadine 120 mg, and theophylline (as per GINA step 5).\n\nAlthough he adhered to the controller medications, he experienced a gradual worsening of symptoms over the years, along with a progressive decline in lung function and an increasing number of exacerbations that required OCS bursts.\n\nAt the time of presentation to the specialist in 2018, the patient had severe asthma with an overlap phenotype, eosinophils were estimated to be at 1100 cells/μL, and IgE levels were 419 UI/mL. The levels of Aspergillus fumigatus antigen were raised. In vitro allergy testing showed sensitization to different allergens. The patient was prescribed omalizumab (300 mg every 2 weeks, i.e. 600 mg/month injection in two divided doses). The response to therapy was suboptimal with intermittent relapses.\n\nIn 2019, due to the suboptimal response to omalizumab, the patient was switched to mepolizumab as his blood eosinophil count (EOS) was high. After mepolizumab initiation, he reported an improvement in symptoms, and eosinophil levels dropped to around 328 cells/μL from around 1000 cells/μL. Additionally, there was no or minimal improvement in FEV1 (lung functions). In February 2021, the patient was given mepolizumab and a short course of OCS which dramatically improved his QoL with subjective improvement in physical endurance and a feeling of well-being. In March 2021, after testing positive for severe acute respiratory syndrome coronavirus 2, the biologics were withheld.\n\nAfter recovery from coronavirus disease 2019, the patient reported improvement after a small OCS dose despite regular mepolizumab, which implied an incomplete depletion of eosinophils. Thus, benralizumab was administered in May 2021. The patient felt better within the first two weeks of initiating benralizumab.\n\nAfter two doses, the eosinophil level was reduced to zero, and the ACT score improved from 20 to 25 after a month of initiating benralizumab. There was a significant improvement in FEV1 as well, from 1.51 L (pre-benralizumab) to 1.98 L at six months. Peak flows improved from 300 mL to 400 mL. The patient felt better and skipped the subsequent two doses of benralizumab due to financial constraints. Four months after the last dose of benralizumab, his EOS was still found to be zero, and the patient had a good QoL. Figure 2 illustrates the variation in eosinophil levels after treatment with benralizumab after 6 months of benralizumab initiation.\n\nAEC: Absolute eosinophil count.\n\nA 63-year-old female presented with complaints of progressively worsening symptoms of cough, breathlessness, wheezing, and tightness in her chest over the last five years. Diurnal variations in symptoms were present with worsening of symptoms at night. Initially, symptoms were episodic but became persistent over the years. The triggers for these symptoms included dust, viral infection, cold weather, exercise, and strong odor. She was diagnosed with asthma at 33 years of age. The patient was obese and suffered from obstructive sleep apnea, which was optimally controlled with continuous positive airway pressure therapy. She had a history of two hospitalizations due to exacerbations that required burst doses of oral corticosteroids in the last year. Two years ago, she had undergone bronchial thermoplasty for her uncontrolled asthma with a suboptimal outcome. At the time of presentation, she was on high-dose ICS/LABA, long-acting muscarinic antagonists (LAMA), and oral seratrodast.\n\nInvestigations revealed an elevated eosinophil count of 360 cells/μL, but the serum total IgE and fractional exhaled nitric oxide (FeNO) were within normal limits. She was also not sensitized to any of the aeroallergens tested. At baseline, the patient had a very low FEV1 value (27% of the predicted normal value and FVC of 960 mL). The ACT revealed a score of 13, indicating uncontrolled asthma.\n\nShe was prescribed benralizumab 30 mg subcutaneously. The patient was on regular benralizumab every 8 weeks and demonstrated an increase in the ACT score from 13 to 23 at the 6-month follow-up, which was a clinically meaningful increase (Figure 3a). Absolute eosinophil counts gradually reduced from 360 cells/μL to 0 by the sixth month (Figure 3b). During the same period, there was also a clinically meaningful improvement in FEV1 (200 mL) and FVC (300 mL).\n\nThe therapy was well tolerated without any clinically relevant adverse event.\n\nA 31-year-old female with a history of asthma for the last 10 years presented with an exacerbation that necessitated hospitalization and the use of OCS bursts. The patient had comorbidities such as sinusitis and rhinitis. Despite good treatment adherence and inhaler technique, she had a history of frequent exacerbations and required bursts of OCS to manage the symptoms. She had been on optimal doses of inhalers as per GINA step 5 recommendations. Her average short-acting beta agonist (SABA) usage was 2–4 puffs per day. She was also using intranasal steroids and proton pump inhibitors for gastric reflux.\n\nThe initial assessment showed high eosinophil levels and IgE levels of 1400/μL and 381 IU/mL, respectively; FEV1 was 1.25 L and FEV% was 66%. Her QoL was poor, with an ACT score of 10/25.\n\nBenralizumab was initiated as she had a history of frequent exacerbations requiring OCS bursts, and her blood eosinophils were high. After benralizumab treatment, FEV1 increased to 78% and the ACT score increased to 17, demonstrating improved lung function and QoL (Figure 4). The patient had well-controlled asthma while on benralizumab, but it was discontinued owing to her pregnancy.\n\nFEV1: Forced expiratory volume in the first second; FVC: Forced vital capacity.\n\nA 79-year-old male presented with severe uncontrolled asthma. He had this condition for the last 50 years and required around 3–4 bursts of OCS every year for acute exacerbations. He was on oral medications previously but later switched to inhaled medications. Over the last few years, he was on a dual combination inhaler of 500 μg fluticasone propionate and 50 μg salmeterol BD along with other inhaled medications, ipratropium bromide, and levosalbutamol 3–4 times/day along with inhaled glycopyrronium. Despite the optimum therapy, he had daytime symptoms, limitations of daily activities, poor lung functions (FEV1-0.59 L, FEV1% -27.2%), and had 3–4 episodes of exacerbation that required short bursts of OCS, usually a dose of 40 mg of oral prednisolone for 5 to 7 days, which impacted his QoL.\n\nThe patient was prescribed omalizumab for high IgE levels (120 IU/mL) but this was discontinued after two doses as he developed rashes.\n\nConsidering these factors and reports of persistent increased blood eosinophils levels (290 cells/μL), an anti-eosinophilic biologic therapy, benralizumab, was initiated. After only a few weeks of the first injection, the patient started to feel better with improved daytime symptoms and lesser activity limitation. The ACT score improved gradually from 11 at baseline to 16 after the 5th dose of benralizumab. The requirement for fluticasone propionate came down from 500 μg BD to 250 μg BD with no additional controller medications required for the last two months.\n\nThe patient’s blood eosinophil count was reduced to 0, without any reported clinically relevant adverse events, and he did not experience an exacerbation requiring an OCS burst for a duration of around 7 months which was observed after starting benralizumab.\n\nAn 83-year-old male presented with longstanding asthma for more than 18 years and was on optimized inhaler therapy including budesonide (800 μg), formoterol (12 μg), glycopyrronium (50 μg), tablet montelukast (10 mg OD) and mometasone nasal spray 2 sprays (50 μg of mometasone furoate in each spray) in each nostril once daily (total daily dose of 200 mcg).\n\nThe patient had five exacerbations between April 2020 and August 2021 and received six courses of oral prednisolone 40 mg for 5–7 days.\n\nThe FEV1 was 61% and the patient was categorized as having severe asthma based on history and presentation after reassessing the diagnosis and adherence to the inhaler therapy. Phenotyping interventions showed the baseline eosinophil absolute blood count of 250 cells/μL and IgE levels of 504 IU/mL. Attributes such as a high number of exacerbations (>2/year), adult-onset of asthma (>18 years of age), relatively higher EOS count, frequent steroid consumption, and higher IgE levels were considered to phenotype asthma as potential overlap asthma.\n\nThe patient was treated with benralizumab in August 2021 and received six doses to date. There was a significant improvement in the QoL (ACT improved from 17 to 20, Figure 5) with minimal changes in lung function. There were no asthma exacerbations during the six months after initiation of benralizumab (100% reduction in exacerbation rate).\n\nACT: Asthma control test.\n\n\nDiscussion\n\nThese cases in Indian patients demonstrate the efficacy of benralizumab in the management of SEA in terms of an improvement of symptoms and pulmonary function (clinically significant gain in FEV 1), reduction in episodes of exacerbation, reduction of concomitant use of oral corticosteroids and improved patient QoL.\n\nThe cases included in the study were assessed for the efficacy of benralizumab on parameters such as:\n\n1. Reduction in exacerbations: Usually severe asthma patients with elevated eosinophils have frequent exacerbations and poor asthma control, which require frequent OCS use. Even in the present cases, at the time of presentation to the specialist, all the patients had frequent episodes of exacerbations, some even requiring hospitalization.\n\nThe use of benralizumab in the current cases (though the follow-up was short) resulted in no new episodes of exacerbations, improved asthma control (ACT), and decreased hospitalizations. Similar findings were observed in randomized controlled trials (RCTs), which showed up to 70% reduction in annual asthma exacerbation rate as per the Zonda trial,8 and 63%, 74%, and 87% of patients on benralizumab were completely exacerbation free at 1, 2, and 5 years, respectively.9,10\n\nBenralizumab is the only respiratory biologic that leads to rapid and near-complete depletion of eosinophils within 24 hours, which is critical for controlling inflammation and clinical consequences in SEA.11 Benralizumab promotes lung function through the rapid resolution of bronchial eosinophilic inflammation.5 Something similar was seen in case 2, wherein a patient on mepolizumab when switched to benralizumab showed additional improvement in the reduction of EOS, lung function, and symptom control. The residual eosinophils, which were suspected to cause exacerbations, were effectively treated using benralizumab. The findings of case 2, which showed zero exacerbations following the switch to benralizumab, match the results of a previous study where switchers from mepolizumab to benralizumab experienced significant reductions in exacerbations.12\n\n2. Improvement in lung function: Despite adherence to treatment and optimal doses of inhaler therapy as per GINA step 5 recommendations, a progressive decline in lung functions was reported in the included cases at baseline.\n\nBenralizumab showed clinically meaningful improvement in lung function in these patients. For example, in case 1, FEV1 increased from 26% to 87%. In case 2, FEV1 improved from 1.51 L (pre-benralizumab) to 1.98 L at six months. Peak flows improved from 300 mL to 400 mL in case 2 and showed improvement in the other cases as well. Similar findings were observed in RCTs (Sirocco, Calima, and Bora) where benralizumab showed significant improvement in lung function, which was sustained over long-term use. Improvement in FEV1 can be observed as early as 4 weeks.13–15 These real-world cases and RCTs depict that by rapid and almost complete depletion of eosinophils, benralizumab reduces eosinophilic inflammation and improves airway obstruction and lung function (FEV1).16\n\n3. Corticosteroid tapering effect: In the present cases, the use of oral corticosteroids was tapered/discontinued in all six cases. Corticosteroids are used intermittently to treat severe asthma exacerbations or chronically to maintain asthma control.17 There is, however, a well-known risk of chronic side effects and an increase in mortality associated with OCS. Based on recent evidence, this risk is related to cumulative lifetime exposure to OCS, suggesting that even short courses repeated several times may have a substantial impact on mortality.18 Real-world tertiary asthma center studies have shown a 70% reduction in maintenance OCS dose by week 16 in patients on benralizumab.11 The PONENTE trial demonstrated that the majority of OCS-dependent patients (62.2%) achieved a 100% reduction in the median OCS daily dosage and 91.3% of patients reduced a daily OCS dosage ≤5 mg.19\n\nStudies have reported that patients with asthma receiving OCS treatments of >6 mg/day (prednisolone equivalent) had significantly higher rates of infections and cardiovascular, metabolic, psychiatric, and ocular complications than those receiving OCS treatments <6 mg/day.20 It has been previously reported that taking 5 mg prednisolone-equivalent per day for a year is associated with a 40% increase in mood problems, 45% increase in sleep problems, 40% increase in skin bruising, and 60% increase in weight gain.20 A proportional increase in adverse effects was noted with higher doses of corticosteroid.20 A study compared the mean reduction in OCS dose from baseline to 28 weeks following the administration of mepolizumab and benralizumab. With mepolizumab, the median reduction in OCS dose was 50% and complete steroid withdrawal was seen in 14% of the patients. With benralizumab, the median reduction in OCS dose was 75%, and complete steroid withdrawal was achieved in >50% of the patients.12 In case 1, the patient was on maintenance prednisolone and was able to completely taper off OCS after initiating benralizumab with good control of asthma and better QoL. In the other cases as well, the requirement for burst OCS was reduced to nil.\n\nThese findings are in line with RCTs in which benralizumab treatment in severe OCS-dependent, eosinophilic, asthma patients resulted in the elimination or reduction of OCS use in more than 52% and 63% of patients, respectively, without compromising asthma control (Zonda and Ponente studies).9,21\n\n4. Safety and improvement in QoL: Benralizumab demonstrated a good safety profile in the present cases, having less than a year of follow-up time. Previously, the MELTEMI-integrated analysis has shown similar results in individuals with SEA on benralizumab followed up for 5 years.10 Benralizumab has not been associated with an increased risk of serious infections or any new safety signals in patients with severe, uncontrolled eosinophilic asthma receiving benralizumab for up to 5 years, as reported in the MELTEMI study.10 The QoL dramatically improved after benralizumab therapy. An improvement of ACT scores from 10 to 14, 16, and 17 were seen from dose 1 to dose 4 of benralizumab in the current cases. This mirrors the findings of Scioscia et al., wherein a significant improvement in patient’s perception of QoL and ACT scores was noted.22\n\nReal-world data that includes patients with diverse characteristics differ widely from clinical trials as there are various predictors of response to benralizumab, such as:\n\n1. Enhanced effect with benralizumab is seen in patients with a history of nasal polyps (NP), OCS dependence, frequent exacerbations, decreased lung function, and late onset of disease, irrespective of eosinophil count.23–26\n\n2. When eosinophil counts were <300 cells/μL: OCS dependence, history of NP, and decreased lung function continued to predict an enhanced exacerbation reduction response.24–27\n\n3. NP history alone continued to predict an enhanced FEV1 response.28,29\n\n4. Atopic/IgE status was not a predictor of clinical outcomes.7\n\nThe results of the current cases are in line with the key benralizumab studies SIROCCO, CALIMA, and ZONDA.13,14,30 The reduction in exacerbations vary from 51% per year at 48 weeks in the SIROCCO trial to 70% in the Zonda trial at week 28, when beralizumab was given every 8 weeks (following the first 3 doses at a 4-week interval).13,30 In contrast, in the current study, the number of exacerbations reduced to zero in the respective follow-up period after the initiation of benralizumab treatment. Benralizumab improved ACT (>40%), lung function (>30% improvement in FEV1 and >14% improvement in FVC), and reduced exacerbations (from 2–4 exacerbations to zero exacerbation) in patients with severe asthma treated with benralizumab for up to six months. This is similar to the findings by Bona et al. and Padillo-Galo et al.31,32\n\nThe present cases included patients with comorbidities such as chronic rhinosinusitis with nasal polyps, sinusitis, rhinitis, diabetes mellitus, hypertension, osteoporosis, obesity, sleep apnea, and prostatic hyperplasia. In one case (case 4), the patient was pregnant and, hence, benralizumab was discontinued as pregnant patients are excluded from phase 3 trials.13,14,33 Ethnic variations with biologics may result from genetic, cultural, environmental, and socioeconomic factors. A study has demonstrated that the eligibility for biologic therapies for asthma differs across races based on specific blood parameters and the predominant asthma subtype.34 The discussed cases are therefore important as they provide real-world data on the Indian population. The other strength of this report is the heterogeneity of the clinical characteristics of each case.\n\n\nConclusion\n\nThe cases presented here are the first of their kind in the Indian asthmatic population. The results of this series reveal that benralizumab reduced asthma exacerbations in patients with SEA and demonstrated significant improvement in SEA management with a reduction in OCS use and improvement in lung function and QoL. Studies in larger cohorts and comparisons of biologics where more than one biologic is indicated would add to the pool of literature and assist clinicians in the management of SEA.\n\n\nConsent\n\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the patient/parent/guardian/relative of the patient.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nOpen Science Framework: CARE checklist for ‘An early Indian experience with benralizumab - A compendium on severe asthma cases: a case series’, https://doi.org/10.17605/OSF.IO/XYDHQ.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgements\n\nThe authors would like to thank BioQuest Solutions for medical writing and editorial support, which was funded by AstraZeneca India. The manuscript building was done in accordance with GPP 2022 guidelines (https://www.ismpp.org/gpp-2022).\n\n\nReferences\n\nFarne HA, Wilson A, Powell C, et al.: Anti-IL5 therapies for asthma. Cochrane Database Syst. Rev. 2017; 9(9): CD010834. PubMed Abstract | Publisher Full Text\n\nGINA Global Initiative for Asthma: Global strategy for asthma management and prevention. Global Initiative for Asthma; 2017 May 3. [accessed 2022 August 02]. Updated: 03 May 2022. Accessed on: 01 August 2022. Reference Source\n\nKrishna MT, Mahesh PA, Vedanthan PK, et al.: The burden of allergic diseases in the Indian subcontinent: barriers and challenges. Lancet Glob. 2020; 8(4): e478–e479. Publisher Full Text\n\nBackman H, Jansson S, Stridsman C, et al.: Severe asthma among adults: Prevalence and clinical characteristics. Eur. Respir. J. 2018; 52: 3918.\n\nPelaia C, Busceti MT, Vatrella A, et al.: Real-life rapidity of benralizumab effects in patients with severe allergic eosinophilic asthma: Assessment of blood eosinophils, symptom control, lung function and oral corticosteroid intake after the first drug dose. Pulm. Pharmacol. Ther. 2019; 58: 101830–101834. PubMed Abstract | Publisher Full Text\n\nLaviolette M, Gossage DL, Gauvreau G, et al.: Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J. Allergy Clin. Immunol. 2013; 132(5): 1086–1096.e5. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJackson DJ, Humbert M, Hirsch I, et al.: Ability of serum IgE concentration to predict exacerbation risk and benralizumab efficacy for patients with severe eosinophilic asthma. Adv. Ther. 2020; 37(2): 718–729. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBusse WW: Biological treatments for severe asthma: A major advance in asthma care. Allergol. Int. 2019; 68(2): 158–166. PubMed Abstract | Publisher Full Text\n\nMenzies-Gow A, Hoyte FL, Price DB, et al.: Clinical remission in severe asthma: A pooled post hoc analysis of the patient journey with benralizumab. Adv. Ther. 2022; 39(5): 2065–2084. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKorn S, Bourdin A, Chupp G, et al.: Integrated safety and efficacy among patients receiving benralizumab for up to 5 Years. J. Allergy Clin. Immunol. Pract. 2021; 9(12): 4381–4392.e4. PubMed Abstract | Publisher Full Text\n\nMenzella F, Bonavia M, Bonini M, et al.: Real-world experience with benralizumab in patients with severe eosinophilic asthma: A case series. J. Asthma Allergy. 2021; 14: 149–161. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChung Y, Katial R, Mu F, et al.: Real-world effectiveness of benralizumab: Results from the ZEPHYR 1 Study. Ann. Allergy Asthma Immunol. 2022; 128(6): 669–676.e6. PubMed Abstract | Publisher Full Text\n\nBleecker ER, FitzGerald JM, Chanez P, et al.: Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016; 388(10056): 2115–2127. Publisher Full Text\n\nFitzGerald JM, Bleecker ER, Nair P, et al.: Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016; 388(10056): 2128–2141. PubMed Abstract | Publisher Full Text\n\nBourdin A, Shaw D, Menzies-Gow A, et al.: Two-year integrated steroid-sparing analysis and safety of benralizumab for severe asthma. J. Asthma. 2021; 58(4): 514–522. PubMed Abstract | Publisher Full Text\n\nMenzella F, Ruggiero P, Galeone C, et al.: Significant improvement in lung function and asthma control after benralizumab treatment for severe refractory eosinophilic asthma. Pulm. Pharmacol. Ther. 2020; 64: 101966–101971. PubMed Abstract | Publisher Full Text\n\nBoulet LP, Godbout K: Oral corticosteroids tapering in severe asthma. Am. J. Respir. Crit. Care Med. 2021; 203(7): 795–796. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEkström M, Nwaru BI, Hasvold P, et al.: Oral corticosteroid use, morbidity and mortality in asthma: A nationwide prospective cohort study in Sweden. Allergy. 2019; 74(11): 2181–2190. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMenzies-Gow A, Gurnell M, Heaney L, et al.: Elimination of oral corticosteroids (OCS) with benralizumab treatment in OCS-dependent asthmatics using a rapid, personalized algorithm: The PONENTE trial. J. Allergy Clin. Immunol. 2021; 147(2): AB249. Publisher Full Text\n\nVolmer T, Effenberger T, Trautner C, et al.: Consequences of long-term oral corticosteroid therapy and its side-effects in severe asthma in adults: a focused review of the impact data in the literature. Eur. Respir. J. 2018; 52(4): 1800703. PubMed Abstract | Publisher Full Text\n\nPhase III ZONDA trial for benralizumab shows ability to reduce oral steroid use in severe asthma patients. Astrazeneca; 2017 May 22. [accessed 2022 August 02]. Updated: 22 May 2017. Accessed on: 02 August 2022. Reference Source\n\nScioscia G, Carpagnano GE, Quarato CMI, et al.: Effectiveness of benralizumab in improving the quality of life of severe eosinophilic asthmatic patients: Our real-life experience. Front. Pharmacol. 2021; 12: 631660–631668. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCanonica GW, Harrison TW, Chanez P, et al.: Benralizumab improves symptoms of patients with severe, eosinophilic asthma with a diagnosis of nasal polyposis. Allergy. 2022; 77(1): 150–161. PubMed Abstract | Publisher Full Text\n\nKroes JA, Zielhuis SW, Van Roon EN, et al.: Prediction of response to biological treatment with monoclonal antibodies in severe asthma. Biochem. Pharmacol. 2020; 179: 113978–113992. Publisher Full Text\n\nCriner GJ, Celli BR, Singh D, et al.: Predicting response to benralizumab in chronic obstructive pulmonary disease: Analyses of GALATHEA and TERRANOVA studies. Lancet Respir. Med. 2020; 8(2): 158–170. PubMed Abstract | Publisher Full Text\n\nEger K, Kroes JA, Ten Brinke A, et al.: Long-term therapy response to anti–IL-5 biologics in severe asthma—A real-life evaluation. J. Allergy Clin. Immunol. Pract. 2021; 9(3): 1194–1200. PubMed Abstract | Publisher Full Text\n\nMallah N, Rodriguez-Segade S, Gonzalez-Barcala FJ, et al.: Blood eosinophil count as predictor of asthma exacerbation. A meta-analysis. Pediatr. Asthma Allergy Immunol. 2021; 32(3): 465–478. PubMed Abstract | Publisher Full Text\n\nMatsuno O, Minamoto S: Rapid effect of benralizumab for severe asthma with chronic rhinosinusitis with nasal polyps. Pulm. Pharmacol. Ther. 2020; 64: 101965–101968. PubMed Abstract | Publisher Full Text\n\nGudiseva A, Ramaswamy B, Singh R, et al.: Comparative study of nasal symptoms and pulmonary function tests post FESS in ethmoidal polyposis. Indian J. Otolaryngol. Head Neck Surg. 2019; 71(3): 2000–2003. Publisher Full Text\n\nNair P, Wenzel S, Rabe KF, et al.: Oral glucocorticoid–sparing effect of benralizumab in severe asthma. N. Engl. J. Med. 2017; 376(25): 2448–2458. PubMed Abstract | Publisher Full Text\n\nDi Bona D, Minenna E, Albanesi M, et al.: Benralizumab improves patient reported outcomes and functional parameters in difficult-to-treat patients with severe asthma: Data from a real-life cohort. Pulm. Pharmacol. Ther. 2020; 64: 101974–101978. PubMed Abstract | Publisher Full Text\n\nPadilla-Galo A, Levy-Abitbol RC, Olveira C, et al.: Real-life experience with benralizumab during 6 months. BMC Pulm. Med. 2020; 20(1): 163–176.\n\nFerguson GT, FitzGerald JM, Bleecker ER, et al.: Benralizumab for patients with mild to moderate, persistent asthma (BISE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. Respir. Med. 2017; 5(7): 568–576.\n\nLee YW, Kim CW: Dupilumab treatment for asthma: On the road to a new horizon beyond ethnic differences? Allergy, Asthma Immunol. Res. 2022; 14(2): 147–150. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "216716",
"date": "31 Oct 2023",
"name": "Arjun Khanna",
"expertise": [
"Reviewer Expertise Asthma",
"Biological therapy",
"COPD"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nA very well written case series. All aspects of biological therapy have been discussed very well. Everyone, right from beginners to advanced prescribers will benefit from this article.\nIt should be accepted for indexing without modifications. Any change in the text will dilute the subject and the article should be accepted without modification.\n\nIs the background of the cases’ history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the conclusion balanced and justified on the basis of the findings? Yes",
"responses": []
},
{
"id": "237756",
"date": "08 Feb 2024",
"name": "Sourabh Pahuja",
"expertise": [
"Reviewer Expertise Interventional Pulmonology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nCongratulations to the author for their work. Case series related to use of Biologicals are very few in number. Authors have highlighted the role of benralizumab in different case scenarios nicely. However there are few doubts regarding these cases which I would request the authors to please have a look.\nCase 1, Case 3 and Case 5: - Why was mepolizumab not considered in this case and any particular reason for giving preference to benralizumab over mepolizumab\nCase 2: - Was there bronchiectasis in this case on CT scan and was treatment for ABPA done in past for this particular case as he had raised IgE, AEC and Aspergillus fumigatus antigen was positive\nCase 4: - Patient is young asthmatic with overlap phenotype of severe asthma. Anti IgE and anti-eosinophilic both therapies could have been given to patient. Any particular reason for selecting benralizumab in this case over omalizumab which is much cheaper than benralizaumab.\n\nIs the background of the cases’ history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the conclusion balanced and justified on the basis of the findings? Yes",
"responses": [
{
"c_id": "11574",
"date": "28 Jun 2024",
"name": "Deepak Talwar",
"role": "Author Response",
"response": "Case 1, Case 3 and Case 5: - Why was mepolizumab not considered in this case and any particular reason for giving preference to benralizumab over mepolizumab” Response: Benralizumab was preferred over Mepolizumab to the patient as it is more efficacious. Case 2: - Was there bronchiectasis in this case on CT scan and was treatment for ABPA done in past for this particular case as he had raised IgE, AEC and Aspergillus fumigatus antigen was positive Response : 1. There was no evidence of bronchiectasis on HRCT chest 2. No ABPA specific treatment was given. Case 4: - Patient is young asthmatic with overlap phenotype of severe asthma. Anti IgE and anti-eosinophilic both therapies could have been given to patient. Any particular reason for selecting benralizumab in this case over omalizumab which is much cheaper than benralizaumab. Response : As the patient had a history of frequent exacerbations requiring OCS bursts, and her blood eosinophils were high apart from high IgE, so Benralizumab was initiated for the patient"
}
]
}
] | 1
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https://f1000research.com/articles/12-1225
|
https://f1000research.com/articles/12-807/v1
|
10 Jul 23
|
{
"type": "Research Article",
"title": "Comparison of vitreous/retinal pigment epithelium relative intensity in proliferative vitreoretinopathy and uveitis ",
"authors": [
"Ari Djatikusumo",
"Andi Arus Victor",
"Alida Roswita Harahap",
"Heri Wibowo",
"Rina La Distia Nora",
"Rianto Setiabudy",
"Iwan Sovani",
"Lukman Edwar",
"Annisa Citra Permadi",
"Seruni Hanna Ardhia",
"Ari Djatikusumo",
"Andi Arus Victor",
"Alida Roswita Harahap",
"Heri Wibowo",
"Rina La Distia Nora",
"Rianto Setiabudy",
"Iwan Sovani",
"Annisa Citra Permadi",
"Seruni Hanna Ardhia"
],
"abstract": "Background: Quantitative measurements of vitreous inflammation using vitreous/retinal pigment epithelium-relative intensity (VIT/RPE-Relative Intensity) have been described recently. In proliferative vitreoretinopathy (PVR), inflammation plays a central role in the pathogenesis, inducing retinal fibrosis and contraction. However, no attempts have yet to be made to analyze the severity of inflammation in PVR progression. Methods: A cross-sectional study was conducted by reviewing OCT image sets obtained from patients divided into four groups: (1) proliferative vitreoretinopathy, (2) intermediate and posterior uveitis, (3) panuveitis, (4) normal healthy eyes in Cipto Mangunkusumo Kirana Eye Hospital between April 2021 – December 2021. OCT images were then analyzed in the ImageJ software for VIT/RPE-relative intensity. Results: A total of 19 PVR eyes, 12 intermediate-posterior uveitis eyes, 16 panuveitis eyes, and 28 normal healthy eyes were recruited for this study. The VIT/RPE-Relative Intensity was significantly higher in PVR eyes (0.415±0.178) than in intermediate-posterior uveitis (0.236±0.043, p=0.002) and panuveitis eyes (0.30±0.07, p=0.023). Compared to the normal eyes, PVR and both uveitis groups have significantly higher VIT/RPE relative intensity (p = <0.001 in each group). Conclusions: VIT/RPE-relative intensity may offer quantitative measurements of vitreous inflammation in the role of the pathogenesis of PVR. Comparison with cellular inflammation in the vitreous is required to validate this finding.",
"keywords": [
"Vitreous/Retinal Pigment Epithelium-Relative Intensity",
"Proliferative Vitreoretinopathy",
"Uveitis"
],
"content": "Introduction\n\nRhegmatogenous retinal detachment (RRD) can produce some degree of vitreous haziness that may be associated with its severity and prognosis.1,2 RRD causes neurosensory retina and retinal pigment epithelium (RPE) separation, which leads to retinal ischemia and blood-retinal barrier disruption.3,4 These two events serve as initiating inflammatory factors of the pathogenesis of proliferative vitreoretinopathy (PVR).5 Exposure of RPE cells to the vitreous results in the migration of cytokines, inflammatory cells, and growth factors into the vitreous cavity to further stimulate cellular responses that lead to a turbid vitreous. Inflammation plays a central role in stimulating the development of epiretinal membranes and retinal fibrosis, latter findings in PVR.5,6\n\nAccording to the updated Retina Society Classification, PVR is classified into grades; A, B, and C. Grade A is defined as the presence of vitreous haziness and pigment clumping. Grade B is defined as surface retinal wrinkle, rolled edges of retinal breaks, retinal stiffness, and artery-venous tortuosity; and grade C is full-thickness retinal folds and/or subretinal bands.2 However, most clinicians use this classification only as prognostic hints and a guideline in which vitreous substitute is used, i.e. gas or silicone oil. It does not address the role of inflammation that generates during RRD development. Vitreous haze caused by inflammation is not specific to PVR, as it can also be present in uveitis or a retinal detachment without PVR.7,8 Furthermore, this classification does not offer any information regarding the severity of inflammation, which plays an essential role in the pathogenesis and disease severity in PVR.2,9\n\nOptical coherence tomography (OCT) is a non-invasive diagnostic procedure that provides cross-sectional images of ocular tissue, allowing qualitative assessment of retinal diseases and automated retinal thickness measurements. Recently, OCT has been described to visualize vitreous haziness in patients with uveitis10–12 Quantitative measurements of vitreous haze or inflammation using OCT images were obtained by measuring the vitreous intensity relative to retinal pigmented epithelium intensity, which is termed VIT/RPE-relative intensity. Studies have reported that the VIT/RPE relative intensity is significantly higher in uveitis eyes than in eyes without vitreous haze; furthermore, validation analysis shows a positive correlation with Nussenblatt vitreous haze scale.10\n\nThis study aims to objectively measure vitreous haziness in PVR compared to uveitis and normal eyes by measuring vitreous intensity relative to retinal pigment epithelium intensity captured through OCT.\n\n\nMethods\n\nWe obtained OCT image sets from four groups of consecutive patients in Cipto Mangunkusumo Kirana Eye Hospital between April 2021 and December 2021.\n\nThe participants were identified during their visit to Cipto Mangunkusumo Kirana Eye Hospital. Those who met the inclusion criteria and provided informed consent were included. The procedures were done during routine appointments.\n\nThe first group of data included images from eyes with RRD and PVR. The inclusion criteria for the RRD and PVR group were patients with macula-off RRD and PVR with grade A or B, age of 18 or above, and RRD onset upon examination of 7 days to 1 month. The exclusion criteria of the RRD and PVR group were patients with media opacification (i.e., cataracts, vitreous hemorrhage), a history of intraocular surgery in less than 3 months, and patients with other eye disease comorbidities (i.e., macular hole, age-related macular degeneration, intraocular tumor).\n\nThe second and third groups were obtained from uveitis patients, which were divided into two groups; (1) intermediate and posterior uveitis; (2) panuveitis. We excluded uveitis patients with vitreous hemorrhage, retinal pigment epithelial irregularity such as in age-related macular degeneration, intraocular tumor, and choroidal neovascularization, history of triamcinolone acetate intravitreal within 6 months, and vitrectomized eyes.\n\nThe fourth group was the control group, which included image sets from normal eyes that did not show signs of intraocular inflammation or any ocular disease. We only include patients in each group with goodand readable OCT imaging quality, defined as clear visualization of the vitreous cavity, neurosensory layer, and RPE layer in one OCT image.\n\nThe estimation sample size for the present study was calculated using correlation coefficient (r) based on the previous study of Keane et al.10 (r=0.566). By implementing this method, the sample size would be 29 for the uveitis group. The sample size for the PVR and control group will be adjusted with the uveitis group.\n\nThis study was conducted based on the Declaration of Helsinki and was approved by the Ethics Committee of the Faculty of Medicine, Universitas Indonesia and Cipto Mangunkusumo Hospital (KET-87/UN2.F1/ETIK/PPM.00.02/2021) on 8th February 2021. All subjects provided written informed consent.21\n\nAll participants underwent a complete ocular examination. Clinical data collected from each patient during recruitment and examination include age, sex, and best-corrected visual acuity (BCVA) using Snellen chart and converted into LogMAR. Etiology of uveitis patient was obtained from further work-ups. OCT Image was obtained by OCT Cirrus HD 4000 (Carl Zeiss Meditec, Dublin, CA) with HD-line raster scan protocol system in grayscale. This system has a 27,000 A-scans per second imaging speed and an axial resolution of 3.9 mm. Volume scans were centered on the fovea in each OCT image. The OCT images were taken by experienced staff nurses. Each patient will have 4 to 5 images taken until the best image is obtained.\n\nVIT/RPE Relative Intensity was measured with ImageJ software version 1.53 (National Institutes of Health, Bethesda, MD, USA). The image was manually segmented by a polygonal selection tool. OCT images were measured independently by two graders (ASA and FI). The value that will be included in the correlation analysis is the highest value of VIT/RPE-Relative Intensity obtained from the measurements. All images were randomized and the OCT image graders were masked from patient data and diagnosis to reduce the risk of bias.\n\nOCT images were obtained from OCT and imported into free access software ImageJ. This software enables manual segmentation and measurements of OCT images for the intensity of the vitreous and retinal pigment epithelium area. We measured vitreous inflammation or hazziness using the Vitreous/RPE Relative Intensity. Images were set to 8-bit type before measurement. The boundaries definition for measurements was based on the previous study by Keane et al.10 Boundaries of the vitreous area consist of (1) “vitreous top”, the upper limit of the vitreous area visible in OCT; (2) internal limiting membrane (ILM), the inner border of the neurosensory retina. Vitreous absolute intensity is defined as the intensity of the vitreous area, which is the area between the vitreous top and internal limiting membrane. Boundaries for the RPE area consisted of (1) inner-retinal pigment epithelium (RPE), the inner border of RPE; and (2) outer-RPE, the outer boundary of the RPE. The RPE intensity is described as the space between the RPE’s inner and outer boundaries.\n\nClinical and imaging data were analyzed using descriptive statistics. T-independent test was used for the VIT/RPE relative intensity mean value between groups. P values<0.05 were considered statistically significant. All analyses were performed using IBM SPSS, version 26 (IBM Corp), and GraphPad Prism 9.0 (GraphPad Software, Inc., San Diego, CA).\n\n\nResults\n\nA total of 29 eyes in the uveitis group and 37 eyes in the RRD-PVR group were eligible for the study.19,20 However, there were only 28 eyes in the uveitis group and 19 eyes in the RRD-PVR group that met the criteria of good and readable OCT. A finaltotal of 19 PVR eyes, 28 uveitis eyes (12 intermediate-posterior uveitis eyes and 16 panuveitis eyes), and 28 normal healthy eyes were recruited for this study. The mean age of patients was 43±11.95 years in the PVR group with 63.16% male patients. In the intermediate-posterior uveitis group, the mean age was 36.58±12.17 years with an equal of six male and female patients, and in the panuveitis group, the mean age was 34.75±10.88 years with 62.5% female patients. Visual acuity in the three groups ranged between 0 to 2.5 LogMAR units. The clinical characteristics of each group are described in Table 1.\n\nCharacteristics of patients in the rhegmatogenous retinal detachments and proliferative vitreoretinopathy group are described in Table 2. RRD duration upon examination was mostly 0-7 days (52.6%). All patients included in the study were PVR grade B.\n\nFrom 28 uveitis patients that were included in the study, the most common etiologies were toxoplasma (28.6%) and sifilis (25%). The characteristics of uveitis patients were summarized in Table 3.\n\nThe VIT/RPE-Relative Intensity of each group (“proliferative vitreoretinopathy”, “intermediate-posterior uveitis”, “panuveitis”, and “normal eyes”) are described in Figure 1. The VIT/RPE-Relative Intensity index in the PVR eyes (0.415±0.178) was found to be significantly higher in PVR than in intermediate-posterior uveitis (0.236±0.043) (p=0.002) and in panuveitis eyes (0.30±0.07) (p=0.023). A significant difference was also found between the intermediate-posterior uveitis and panuveitis groups (p=0.008). Compared to the healthy controls, PVR and both uveitis groups have significantly higher VIT/RPE relative intensity (p≤0.001 in each group).\n\n\nDiscussion\n\nVitreous haze is defined as the accumulation of inflammatory cells and protein exudate in the vitreous cavity, resulting in the decreased visibility of the retina and optic nerve. In uveitis, vitreous haziness is one of the important clinical outcomes in disease evaluation.7,13 OCT imaging enables direct visualization of vitreous haze.14 Recent studies have developed an objective, quantitative measurement of vitreous signal intensity, compared to RPE-absolute intensity. VIT/RPE-Relative Intensity is used to acquire quantitative measurements of vitreous haze in uveitis eyes, as studies reported to be significantly higher compared with normal eyes.10,11\n\nPrevious studies reported increased levels of cytokines, growth factors, and inflammatory cells in the vitreous of RRD-PVR eyes, including macrophages, transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6 and IL-8.6,15–18 These inflammatory cells, pro-inflammatory cytokines, and growth factors facilitate RPE cell migration, proliferation, and epithelial-mesenchymal transition, which leads to the development of retinal fibrosis and contraction.17\n\nOur study showed that VIT/RPE-Relative Intensity in the PVR group is significantly higher than intermediate-posterior uveitis, panuveitis, and normal eyes. We also compared intermediate-posterior uveitis with panuveitis, with the result of the value of VIT/RPE Relative Intensity in the panuveitis group being significantly higher than the intermediate-posterior uveitis (p=0.008). Both uveitis groups also are significantly higher compared to normal eyes. These results may indicate that the inflammation and protein exudate into the vitreous cavity of PVR is higher than in uveitis cases. This study also showed similar findings for the VIT/RPE-Relative Intensity of uveitis eyes described in previous studies.10–12\n\nThese results are a preliminary finding in validating the VIT/RPE-Relative Intensity use for measuring vitreous inflammation objectively in the role of the pathogenesis of PVR and may be useful to obtain a new standard classification of PVR that corresponds to the inflammatory status of the disease. The higher value of VIT/RPE-Relative Intensity in PVR than in uveitis may indicate the need for anti-inflammatory drug use in PVR, in addition to surgery, to decrease disease severity.\n\nWe understand that this study had some limitations regarding the subject number, with only 19 subjects in the PVR group. A larger study comparing the VIT/RPE-Relative Intensity index and vitreous inflammatory cells, cytokines, and growth factors in PVR patients will be required to validate our significant findings.",
"appendix": "Data availability\n\nFigshare: Comparison of Vitreous/Retinal Pigment Epithelium Relative Intensity in Proliferative Vitreoretinopathy and Uveitis. https://doi.org/10.6084/m9.figshare.22632715.v1. 19\n\n• Characteristics of Proliferative Vitreoretinopathy, Uveitis, and Normal Patients\n\nMendeley Data: OCT images of Proliferative Vitreoretinopathy, Intermediate+Posterior Uveitis, Panuveitis, and Normal Eyes. https://doi.org/10.17632/hbr5pwk5w5.1. 20\n\n• OCT images of Proliferative Vitreoretinopathy, Intermediate+Posterior Uveitis, Panuveitis, and Normal Eyes\n\nFigshare: Informed Consent – Comparison of VIT/RPE-Relative Intensity in PVR and Uveitis (Translated to English). https://doi.org/10.6084/m9.figshare.22707988.v1. 21\n\n• Informed Consent – Comparison of VIT/RPE-Relative Intensity in PVR and Uveitis (Translated to English)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nThe authors wish to thank all healthcare providers in the Faculty of Medicine – Cipto Mangunkusumo Kirana Eye Hospital that was involved in the completion of the study.\n\n\nReferences\n\nNi Y, Qin Y, Huang Z, et al.: Distinct Serum and Vitreous Inflammation-Related Factor Profiles in Patients with Proliferative Vitreoretinopathy. Adv. Ther. 2020; 37(5): 2550–2559. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMachemer R, Aaberg T, Freeman HM, et al.: An Updated Classification of Retinal Detachment with Proliferative Vitreoretinopathy. Am J. Ophthalmol. 1991; 112(2): 159–165. PubMed Abstract | Publisher Full Text\n\nMurakami Y, Notomi S, Hisatomi T, et al.: Photoreceptor cell death and rescue in retinal detachment and degenerations. Prog. Retin. Eye Res. 2013; 37: 114–140. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChidlow G, Chan WO, Wood JPM, et al.: Investigations into photoreceptor energy metabolism during experimental retinal detachment. Front. Cell. Neurosci. 2022; 16(November): 1–25. Publisher Full Text\n\nPastor JC, Rojas J, Pastor-Idoate S, et al.: Proliferative vitreoretinopathy: a new concept of disease pathogenesis and practical consequences. Prog. Retin. Eye Res. 2016 Mar; 51: 125–155. PubMed Abstract | Publisher Full Text\n\nDai Y, Dai C, Sun T: Inflammatory mediators of proliferative vitreoretinopathy: hypothesis and review. Int. Ophthalmol. 2020; 40: 1587–1601. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStandardization of Uveitis Nomenclature (SUN) Working Group: Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am. J. Ophthalmol. 2005; 140: 509–516. Publisher Full Text\n\nHoog JD, Berge JCT, Groen F, et al.: Rhegmatogenous retinal detachment in uveitis. J. Ophthal. Inflamm. Infect. 2017; 7(22): 22. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDi Lauro S, Kadhim MR, Charteris DG, et al.: Classifications for Proliferative Vitreoretinopathy (PVR): An Analysis of Their Use in Publications over the Last 15 Years. J. Ophthalmol. 2016; 2016: 1–6. Publisher Full Text\n\nKeane PA, Karampelas M, Sim DA, et al.: Objective Measurement of Vitreous Inflammation Using Optical Coherence Tomography. Ophthalmology. 2014; 121: 1706–1714. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZarranz-Ventura J, Keane PA, Sim DA, et al.: Evaluation of Objective Vitritis Grading Method Using Optical Coherence Tomography: Influence of Phakic Status and Previous Vitrectomy. Am. J. Ophthalmol. 2016; 161: 172–180.e4. PubMed Abstract | Publisher Full Text\n\nZicarelli F, Ometto G, Montesano G, et al.: Objective Quantification of Posterior Segment Inflammation: Measuring Vitreous Cells and Haze Using Optical Coherence Tomography. Am. J. Ophthalmol. 2023; 245: 134–144. PubMed Abstract | Publisher Full Text\n\nDavis JL, Madow B, Cornett J, et al.: Scale for photographic grading of vitreous haze in uveitis. Am. J. Ophthalmol. 2010; 150(5): 637–641.e1. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSaito M, Barbazetto IA, Spaide RF: Intravitreal cellular infiltrate imaged as punctate spots by spectral-domain optical coherence tomography in eyes with posterior segment inflammatory disease. Retina. 2013; 33: 559–565. PubMed Abstract | Publisher Full Text\n\nSong Y, Liao M, Zhao X, et al.: Vitreous M2 Macrophage-Derived Microparticles Promote RPE Cell Proliferation and Migration in Traumatic Proliferative Vitreoretinopathy. Invest. Ophthalmol. Vis. Sci. 2021; 62(12): 26. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKita T, Hata Y, Arita R, et al.: Role of TGF-beta in proliferative vitreoretinal diseases and ROCK as a therapeutic target. Proc. Natl. Acad. Sci. U. S. A. 2008; 105(45): 17504–17509. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHasanpour H, Kenney MC, Kuppermann BD, et al.: Vitreal Concentrations of Vascular Endothelial Growth Factor in Patients with Rhegmatogenous Retinal Detachment. J. Clin. Med. 2023; 12(4): 1259. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHinton DR, He S, Jin ML, et al.: Novel growth factors involved in the pathogenesis of proliferative vitreoretinopathy. Eye. 2002; 16: 422–428. PubMed Abstract | Publisher Full Text\n\nDjatikusumo A, Ardhia SH: Characteristics of Proliferative Vitreoretinopathy, Uveitis, and Normal Eyes. [Dataset]. figshare. 2023. Publisher Full Text\n\nDjatikusumo A, Hanna S: Optical Coherence Tomography (OCT) Images of Proliferative Vitreoretinopathy, Uveitis, and Normal Eyes. [Dataset]. Mendeley Data. 2023; V1. Publisher Full Text\n\nDjatikusumo A, Ardhia SH: Informed Consent - Comparison of VIT/RPE-Relative Intensity in PVR and Uveitis (Translated to English). figshare. Media.2023. Publisher Full Text"
}
|
[
{
"id": "185983",
"date": "26 Jul 2023",
"name": "Paisan Ruamviboonsuk",
"expertise": [
"Reviewer Expertise retinal imaging",
"AI",
"wet AMD and DR"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a small study about detecting vitreous haze using OCT images in patients with RRD and early PVR compared to patients with uveitis. The study had a small sample size though the size was estimated based on data from the previous study.\nThe objective of this study is good since OCT device is ubiquitous. Early detection of PVR from OCT may have a role in managing RRD in encouraging sooner surgery. The results are convincing that patients with PVR had the highest vitreous haze compared to uveitis patients and normal. However, there are some limitations which have not yet been discussed.\nThe authors are not yet clear on how they measured the vitreous/RPE-Relative Intensity (VRI). I understand that they took the measurement method from the previous study but it should be clear here as well. The best thing is to show the VRI with figures.\n\nAnother major limitation that should be discussed is no comparison between RRD with and without PVR. It may be possible that those cases without PVR may still have vitreous haze from vitreous detachment (PVD). It would be great if the comparison between RRD with and without PVR showed similar results as this study. The procedure of detecting vitreous haze in this study would be very useful if the authors could demonstrate that the detection of PVR using this procedure is also better than clinical examination.\n\nIt is great that there are OCT images of the cases showing vitreous haze from PVR, the two uveitis groups, and normal, available as underlying data. It would be great if the authors can list the value of VRI for each case.\nNormally RPE cells would drop down by gravity to present at the inferior part of the eye. However, the OCT images are only from the macula area. It would be great if there are clinical examinations documenting the inferior vitreous of these eyes. Is obtaining only macula OCT images would be a limitation of applying this procedure in clinical practice since vitreous haze/RPE cells may be present inferiorly? I saw that some OCT images with high retinal detachment might have a much smaller area of vitreous to measure the VRI. Would this also be a limitation on applying this procedure in clinical practice?\n\nAnother potential bias is how the authors controlled the measurement of VRI on OCT by the two graders. Were there any agreement measurements between the two of them?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10008",
"date": "27 Sep 2023",
"name": "Ari Djatikusumo",
"role": "Author Response",
"response": "We would like to thank you for agreeing to be our article reviewer. We appreciate your suggestions and revisions to improve our article. We would also like to address certain aspects regarding the review. The protocol for VRI measurement was described in the method section of “Quantitative measurements of the vitreous Inflammation using ImageJ.” In the article revision, we will incorporate figures demonstrating the process of obtaining VRI (Vitreous/Retinal Pigment Epithelium Relative Intensity) using ImageJ in the Method section. In our inclusion criteria, we specifically enrolled patients with RRD and PVR, considering that PVR is correlated with vitreous inflammation and is a significant contributor to surgical failure in RRD repair. PVR grading through clinical examination is subjective and can vary between clinicians. Measuring VRI is expected to objectively provide vitreous inflammation, along with detecting PVR cases in RRD. We will add this issue in the Discussion section. We have uploaded the value of VRI for each case in the underlying data (figshare: https://doi.org/10.6084/m9.figshare.22632715.v1) We acknowledge that we did not obtain measurements of vitreous inflammation for the inferior vitreous. However, all patients were examined in the same position (seated position), ensuring that the location of the vitreous being examined was possibly consistent. We are also aware that in cases of RRD, there were cases with high retinal detachments, with a much smaller vitreous area to measure the VRI. However, these cases are inevitable and are commonly found. The results of high retinal detachments also consistently show higher VRI compared to uveitis or normal eyes. The two graders performed the VRI measurements using the same protocol described in the method section. Each grader measured the VRI twice. The highest VRI value among the two graders was taken as the result of VRI for each case. We will provide a more detailed explanation in the method section."
}
]
},
{
"id": "185981",
"date": "26 Jul 2023",
"name": "Augustinus Laude",
"expertise": [
"Reviewer Expertise medical retina and advanced optical imaging"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors describe a novel method using optical coherence tomography to evaluate and compare the images as a biomarker of different diseases of the eye. The aim of their study was to compare the OCT marker (vitreous/RPE relative intensity) between eyes with PVR, Uveitis and normal.\nThe title should be changed to reflect using OCT to evaluate and compare between different eye pathologies. The current title failed to mention the 'normal eyes' and should probably not include the term 'vitreous/retinal pigment epithelium relative intensity' (which is a technical term).\nThe abstract background needs to make clear the aim of the study which is comparing the different eyes with different pathologies, and not as stated 'to analyse the severity of inflammation in PVR progression'.\nThe power calculation was not well described and the authors instead chose to cite the paper by Keane, et al. This is not ideal and the author should describe in this paper their rationale for arriving at the sample size of '29 for the uveitis' group. If this was the case, I am assuming that they meant to have 29 eyes in each of the categories to be compared but in the paper, they have analysed 12, 16, 19 and 28 eyes. Therefore, this would significantly impact on the conclusions that can be drawn from their study. This limitation should be stated in the conclusion, not just for the PVR group but also for the uveitis groups.\nIn the results segment, the authors stated that only 28 eyes of the uveitis group and 19 eyes of the PVR group met the criteria of good and readable OCT. However, it was not clear why this was the case, especially when the authors took steps to exclude many factors that could have led to a poor OCT capture (e.g. media opacification, vitreous haemorrhage, etc.). More could be described as to why the images were ungradable.\nMore should be described about how the OCT images were processed and analysed. They mentioned in the 'Procedure' segment that the images were 'randomized'. I wasn't clear what this meant.\nThere was a spelling error for 'syphillis' in Table 3 and also in the Results segment.\nOverall, the manuscript writing could be improved a little from the language perspective.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "10026",
"date": "27 Sep 2023",
"name": "Ari Djatikusumo",
"role": "Author Response",
"response": "We would like to thank you for agreeing to be our article reviewer. We appreciate your suggestions for revisions of our article. We would also like to address certain aspects regarding your review. Regarding the title of the article, the authors believe that the term 'vitreous/retinal pigment epithelium relative intensity' should be included in the title, as it serves as the article's primary focus. The article primarily discusses the comparison of 'vitreous/retinal pigment epithelium relative intensity' as an objective measurement of vitreous inflammation in cases of PVR and uveitis, with normal eyes only as reference standards. We have changed the aim of the study in the abstract section to “analyze the vitreous inflammation of PVR.” The power calculation was achieved based on the correlation coefficient. We cite the paper by Keane et al of a previous study comparing the VRI measurement and Nussenblatt scale as a reference standard for diagnosing uveitis. The sample size obtained was 29 eyes. The number of subjects in the RRD-PVR and normal eyes were adjusted based on the sample size obtained (29 eyes for each case). However, during image acquisition and measurement of VRI, only 19 RRD cases and 28 uveitis cases and were considered as good and readable images, described as both vitreous area and RPE captured in one image and a clear view or visible RPE. We also divided the uveitis subjects into intermediate-posterior uveitis and panuveitis, to determine the vitreous inflammation in different types of uveitis. A total of 37 eyes with RRD-PVR have met the inclusion criteria. However, during the OCT image acquisition, 18 cases could not undergo VRI measurement due to a high retinal detachment, which made it infeasible to capture both the vitreous area and RPE in a single image. We will add and revise the result section. The protocol for VRI measurement from the OCT images was described in the method section of “Quantitative measurements of the vitreous Inflammation using ImageJ”. In the article revision, we will incorporate figures demonstrating the process of obtaining VRI (Vitreous/Retinal Pigment Epithelium Relative Intensity) using ImageJ from the OCT images. We have revised the spelling errors in our revised article."
}
]
}
] | 1
|
https://f1000research.com/articles/12-807
|
https://f1000research.com/articles/12-885/v1
|
26 Jul 23
|
{
"type": "Research Article",
"title": "Arterial blood analysis of healthy residents in Huamachuco, Peru (3,164 m): a cross-sectional study",
"authors": [
"Victor H. Bardales-Zuta",
"Lissett J. Fernández-Rodríguez",
"Cecilia Romero-Goicochea",
"Victor H. Bardales-Zuta",
"Cecilia Romero-Goicochea"
],
"abstract": "Background: Given that arterial blood gas is affected by altitude and ethnicity, establishing reliable reference standards for these values requires analysis of arterial blood at different elevations and locations. Our objective was to measure the arterial blood gases of healthy young volunteers in Huamachuco, Peru, at 3,164 m above sea level. This is likely the first study of arterial blood gas analysis of healthy Northern Peruvians living at high altitude. Methods: Healthy residents of Huamachuco were recruited for this cross-sectional convenience sample study and arterial blood was drawn by standard procedures. People with obesity, diabetes, high levels of physical activity and a history of using selected substances were excluded. The samples were analyzed on-site in less than 15 minutes using a Stat Profile Prime CCS analyzer (Nova Biomedical). Results: Data from 46 participants (17 male, 29 female) were included in the study. The median values for arterial blood pH, oxygen, carbon dioxide, ionized calcium, glucose, lactate, hematocrit, oxygen saturation, and bicarbonate were 7.42, 9.3 kPa (70 mmHg), 4.5 kPa (33.5 mmHg), 1.04 mM, 5.19 mM, 1.8 mM, 50 %, 94 %, and 21.6 mM, respectively. We also found a lower prevalence of diabetes among highlanders compared to the Peruvian population. Conclusions: The results determined here were comparable to other results determined at different altitudes in the Americas, although arterial blood oxygen was slightly higher than predicted. These results indicate that Northern Peruvians have an Andean-style adaptation to high altitude.",
"keywords": [
"blood gas",
"altitude",
"Andean",
"blood pH",
"blood calcium",
"blood glucose",
"hematocrit",
"Huamachuco"
],
"content": "Introduction\n\nApproximately 25.2 million people live at an altitude greater than 3,000 meters above sea level, in an environment marked by decreased atmospheric pressure1 which causes a series of downstream physiological effects that must be compensated to maintain homeostasis. Arterial blood gas analysis (ABGA) offers a window into these mechanisms for residents and sojourners at different altitudes.\n\nABGA is also an important tool for monitoring and diagnosing cardiopulmonary disfunction, which requires comparison of reference values to a result.2 However, establishing reference intervals is a significant challenge, especially for ABGA at high altitude, for three reasons: (1) few studies have examined reference intervals among healthy people because the test is frequently ordered for unwell patients,2,3 (2) obtaining arterial blood is a more difficult procedure that causes more pain to the patient than routine venous phlebotomy,4 and (3) different ethnic groups have different compensating mechanisms for life at high altitude: for instance, South American natives adapt by increasing hemoglobin, while Tibetan natives improve blood circulation.5,6\n\nTo provide additional ABGA values at high altitude and to better understand altitude adaptation mechanisms between ethnic groups, we performed arterial blood analysis on young healthy volunteers resident in Huamachuco, Peru (elevation 3,164 m) and compared them with published results at a variety of elevations and locations. We hypothesized that residents in Huamachuco will exhibit an Andean style of adaptation to high altitude, regardless of biological sex.5,6\n\n\nMethods\n\nAlthough the research took place at Instituto de Educación Superior Tecnológico Público de Huamachuco (IESTPH) due to its high-altitude location, none of the authors are affiliated with IESTPH, and IESTPH does not have, to the best of our knowledge, an ethics committee capable of approving the study. Because of this, The Training, Teaching and Research Committee (ethical approval committee) of Florencia de Mora – ESSALUD Hospital I approved this study, on 01 April 2019. We sought approval from the Florencia de Mora Hospital as the first author is a doctor based at this hospital. The administration of IESTPH was informed of the project with a formal letter. The National University of Trujillo Postgraduate School also ethically approved this study; VHBZ was affiliated with that institution at the time of the study.\n\nVolunteers were informed of the risks of arterial blood sampling and provided their written informed consent for arterial blood sampling and for the publication of the results. Participation in the study was strictly voluntary with no benefits provided, except for personal analysis results. There was one participant that was under the age of 18 (17 years old). In this case, the participant and the participant’s father signed the consent form for use with minors.\n\nThis cross-sectional convenience-sample study was not preregistered.\n\nIESTPH was chosen for the study site because it was high-altitude location that could accommodate the equipment necessary for arterial blood analysis. The GPS coordinates and altitude of the study location were measured using a Samsung Galaxy A3 with the “Precise Altimeter” application.\n\nA letter from the director or IESTPH was sent to students of the same institution inviting them to participate in the study. Recruitment took place between May to August 2019. On the day of the study, August 26, 2019, the fasting (>8 h) volunteers were informed of the risks of arterial blood sampling. Written informed consent for arterial blood sampling and for the publication of the results was obtained from all participants. Although the study took place in 2019, we are publishing this work now due to delays caused by the COVID-19 pandemic.\n\nInclusion criteria for the entire study were age between 17 and 30 years and residence in Huamachuco district for at least 5 consecutive years prior to the study. Exclusion criteria included self-report of strenuous exercise more than 60 minutes per day, use of tobacco, antiplatelet agents, anticoagulants, diuretics, corticosteroids, beta-blockers, or some beta-stimulants, or recent travel to low elevations. Exclusion criteria also included self-report or clinical signs upon evaluation of cardiovascular, pulmonary, or hematologic disease. Participants with self-reported diabetes and/or diabetes determined by arterial blood test (defined here as arterial blood glucose greater than 7.2 mM7,8), had BMI >30, or had abnormal axillary temperature (not between 35.5 and 37.0°C9) were allowed to continue their participation, but their ABGA results were not used in the aggregated data.\n\nVolunteers were questioned by a nurse from IESTPH to determine whether the participant met inclusion/exclusion criteria. The nurse measured the height, body mass, pulse rate, blood pressure, and axillary temperature of each participant. Volunteers were also asked to self-report their biological sex. Body mass index (BMI) was calculated by dividing body mass by the square of the height. If the volunteers wished to continue, physicians (authors VHBZ and/or LJFR) obtained one sample of arterial blood (1 mL) from the right brachial artery of the volunteers using standard sterile technique and a heparinized needle (Westmed Pulset 3cc syringe). Blood samples were stored on ice in a cooler prior to analysis.\n\nPersonnel from a commercial laboratory (BermanLab, Trujillo, Perú) analyzed blood gas parameters of the samples at IESTPH less than 15 minutes after sampling to avoid contamination during storage and transport. The blood gas analyzer (Stat Profile Prime CCS, Nova Biomedical) passed operational qualification in Huamachuco and was used to measure pH, partial pressure of oxygen (pO2) and carbon dioxide (pCO2), plasma ionized calcium (iCa2+), glucose (Glc), lactate (Lac), and hematocrit (Htc, %). Bicarbonate (HCO3-) and oxygen saturation (sO2) were calculated from the measured parameters.\n\nThe most likely experimental source of bias in this experiment is air contamination of the sample before or during analysis. Air contamination of the sample would artificially elevate pO2 without causing large changes in other parameters. This bias was addressed by careful sampling technique, rapid analysis of the sample, and removal of suspiciously high pO2 measurements by statistical methods. A second source of possible bias is due to the inclusion of unhealthy individuals in the ABGA, such as those with diabetes, obesity, or abnormal axillary temperature. If ABGA results were from a patient with diabetes, obesity, or abnormal axillary temperature or if the ABGA results were suspected of air contamination, the results were eliminated from the aggregated arterial blood analyses. However, these results were included in our analysis of the prevalence of diabetes and impaired fasting glucose.\n\nABGA results with pO2 outlier values were eliminated from the dataset (Tukey’s fence, k = 1.3). Shapiro-Wilk normality tests, Mann Whitney U tests, and linear regression analyses were used to analyze the dataset, compare different groups, and compare these results with previously reported data at a significance level of p < .05 using a Bonferroni correction where appropriate. Quantitative variables were reported as means and standard deviations or by quartile depending on the distribution. If the Mann Whitney U test revealed a significant difference between the sexes, data was reported for males and females separately. We used Microsoft Excel for Mac version 16.73 and R version 4.3.0 to analyze the data. Since all participants completed a single blood test on the same day, there was no missing data.\n\n\nResults\n\nHuamachuco district has an area of 424 km2, and a 2017 population of 66902.10 A topographic analysis of the district indicates that it varies from 2,200 to 4,600 m, but most of the population lives below 3,400 m. The largest city, also named Huamachuco, is located at about 3,200 m. IESTPH, where the samples were taken, is located at 7.815833 S, 78.03917 W and had a GPS altitude of 3,164 m.\n\nThe study size was based on available IESTPH students that volunteered and met acceptance criteria. A total of 56 participants (21 male and 35 female) volunteered for the study. Ten participants (4 male and 6 female) were excluded from ABGA after blood sampling because they had diabetes, unusual body temperature, obesity, or outlier arterial pO2. Some participants excluded at the interview, axillar temperature, or by excessive BMI freely decided to have their blood sampled and analyzed to know their results.\n\nThe 46 participants included in our ABGA analysis were between 17 and 28 years old, with a median age of 20 years. Ages were skewed toward lower values: the Shapiro-Wilk tests showed a significant departure from normality for age, W(46) = .885, p < .001. Body height was greater in males than females (Mann Whitney U test, p < 0.001): females had a median height of 1.51 m, and males had a median height of 1.60 m. Statistically significant differences between the sexes in other anthropomorphic parameters were not found. Body mass index had a normal distribution (Shapiro-Wilk, W(46) = .97, p = .31) and had an average of 23.4 and a standard deviation of 2.8. No participant had a BMI > 30, high blood pressure or diabetes. The median blood pressure was 100/60 mmHg, with a variation of less than 20 mmHg. The median pulse rate was 67 with a range of 55 to 89 min-1. Most of the participants had an axillar temperature of 36.6°C, but the range was 36.0 to 37.0°C.\n\nThe summary values of the resulting analyses are recorded in Table 1.\n\nValues are expressed as minimum, first quartile, median, third quartile, and maximum, as some results showed a statistically significant departure from normality. Males and females are separated where a statistically significant difference was found.\n\nThere were significant differences for Htc % (Mann Whitney U test, p < 0.001) and HCO3- (Mann Whitney U test, p = 0.0019). Other ABGA parameters failed to reach statistical significance between sexes with Bonferroni correction.\n\nWe compared 21 combinations between pH, pO2, pCO2, iCa2+, Glc, Lac, and Htc using regression analysis and Bonferroni correction. Only one comparison achieved statistical significance: glucose (mM) predicted lactate (mM) (R2 = .24, F(1,44) = 13.96, p < .001. β = .42, p < .001, α = -0.34, p = .57). pH and pCO2 and pH and glucose had inverse relationships that were close to reaching statistical significance.\n\n\nDiscussion\n\nLiving in the reduced atmospheric pressure of a high-altitude environment causes a series of physiological adaptations to maintain adequate blood oxygenation. These adaptations have been shown to vary between ethnic groups5,6 making it necessary to sample different healthy populations to establish reference intervals. To our knowledge, this is the first systematic ABGA of healthy northern Peruvians living at high altitudes. Furthermore, this study includes analysis of arterial iCa2+, Glc, and Lac, which are also not frequently measured among healthy high-altitude residents.\n\nA growing body of ABGAs of healthy residents of the Americas at different elevations makes a systematic comparison of pO2 and altitude possible. Figure 1A visualizes the published pO2 for healthy residents of the Americas living at different altitudes. The results collected over the past half century11–30 reveal that the inverse relationship between meters above sea level and pO2 (kPa) can be modeled with a linear equation up to about 4,500 m (R2 = 0.87, F(1,40) = 273.13, p < .001, β = -0.00133, p < .001, α = 12.5, p < .001). Inspection of Figure 1A reveals that there is a lack in published ABGA results between 100 to 1000 m. It is likely that data in this range will be useful in confirming or rejecting a linear model for pO2 and altitude. The median value of pO2 determined here is 1 kPa (7.50 mmHg) higher than the predicted value of the regression, although the data range overlaps the trendline and the point is within the spread of the data.\n\nEach panel represents a different blood parameter and its relationship to altitude (meters above sea level): (A) pO2 (kPa), (B) pCO2 (kPa), (C) pH, and (D) HCO3- (mM). Circle data points are averages or medians from previously published results in the Americas; where possible, age range was considered to coincide with the age range in this study.11–30 The square data point is the median determined here, with whiskers representing the interquartile range. Data from native Tibetans are represented as diamonds.31,32 Previously published results from the Americas (circle data points) were used to calculate the regression lines in the figure and regression statistics in the text.\n\nOne possible explanation is that arterial blood oxygen decreases with age and the ages of the participants in this study were skewed toward young adults.2,11 When possible, only subjects that resembled the ages of the participants were included in the regression, but selection criteria and age range reporting differed between studies; older participants in the published studies included in the regression would systematically lower the regression line (Figure 1A). A second possibility was hyperventilation during sample acquisition, but breathing rate among participants was not monitored. Changes in equipment use over the years may also have added systematic errors to the data.\n\nAndeans have been shown to have elevated oxygen saturation compared to Tibetan highlanders.5,6 In fact, the results of this study confirm higher pO2 for Andean residents, as two studies that measured similar parameters in Tibet31,32 fell slightly below the regression line (Figure 1A, diamonds); the results from Tibet were approximately 2 kPa (15 mmHg) below our result. Therefore, these results suggest support for the hypothesis that Andeans have higher oxygen saturation than Tibetans at similar altitudes, although more experimental data from random population samples at different altitudes in Tibet and Peru more would help confirm this observation.\n\nBlood pH is tightly regulated through several buffering systems, the most important of which is the bicarbonate-carbonic acid system, which is derived from dissolved carbon dioxide. Like pO2, pCO2 (kPa) has an inverse relationship with altitude in m (R2 = .57, F(1,40) = 53.27, p < .001. β = -.0003, p < .001, α = 5.05, p < .001, Figure 1B), although the slope of the correlation is less steep and altitude explains less of the variation in pCO2 than it does with pO2 (Compare Figure 1A and B). This decrease in pCO2 as altitude increases is usually explained by hyperventilation to compensate for decreased oxygen partial pressure at high altitude. We find that our results largely follow this trend. Unlike some other studies,2,12,33 a statistically significant difference between sexes for pCO2 was not observed.\n\nAlthough altitude and pCO2 were moderately correlated, no such relationship is present for pH, which remains almost constant regardless of altitude in m (R2 = .025, F(1,40) = 1.01, p = .320, β = .00000264, p = .320, α = 7.41, p < .001, Figure 1C). The results determined here nearly exactly overlap the regression line. Given that dissolved CO2 has an inverse relationship with pH, the pH should also increase with altitude, but this is compensated by renal excretion of nonvolatile bases.34,35 These changes also require modification of the Siggard-Anderson acid-base chart to account for altitude. Our data support moving the normal target of a plot of pH vs pCO2 downward, but the variance of our results suggests a widening of the vertical size of the target.34\n\nThis increased bicarbonate excretion is also reflected in an inverse relationship between HCO3- (mM) and altitude in m (Figure 1D; R2 = 0.43, F (1,27) = 20.13, p < .001, β = -.00095, p < .001, α = 23.16, p < .001). Since HCO3- is derived from pH and pCO2, it follows that if pH is relatively stable, HCO3- would also decrease. The HCO3- concentration determined here is higher than the regression line, but the spread of the data overlaps the trendline, and males had statistically significantly higher HCO3- than females.\n\nAmong healthy individuals, calcium is maintained within a narrow range. Departures from this range lead to several severe symptoms, including tetany, vomiting, coma, and neurological disturbances.36 The reference interval for iCa2+ is between 1.05 and 1.30 mM, which is slightly higher than the range (0.95 to 1.13 mM) found here.36 Similar studies in the Andes also reported average results below the lower limit of the reference range.13,14 Since iCa2+ is dependent on several factors, including albumin content, vitamin D, and blood pH, it is not yet possible to determine whether lower iCa2+ is a result of altitude or another confounding factor. Correcting iCa2+ for pH did not change values significantly: the largest adjustment was not greater than 0.02 mM.\n\nLac concentration is a measure of anaerobic respiration and tissue hypoxia and has a reference range of between 0.3-0.8 mM, but this has been called into question.36,37 The range of values determined here is both wider and has a higher median than the reference range. A study at higher altitude also reported higher Lac.14 These results may reflect a variety of activity levels among study participants, especially considering that the test site was in mountainous terrain. Alternatively, reduced oxygen at high altitude can promote anaerobic metabolism, but high-altitude residents have been shown to have Lac levels similar to those of lowlanders after exercise.38 We found a positive correlation with Lac and Glc concentration, which may be because of their relationship in the Cori cycle, but this hypothesis requires further testing.\n\nDue to the selection criteria, only subjects with normoglycemia and reasonable ABGA results were included in the data analysis. However, it is unlikely that fasting arterial blood Glc would be impacted by outlier ABGA results, which provides an opportunity to measure diabetes and impaired fasting blood glucose (IFBG) prevalence in the entire study population of 56 people. Using the entire dataset, we found 3 participants with diabetes (fasting blood glucose ≥ 7.0 mM) and 13 with IFBG (fasting blood glucose more than 5.6 mM, but less than 7.0 mM) using accepted criteria.7 However, diabetes and IFBG are usually defined in terms of glucose concentration in venous blood plasma; arterial blood was measured here. For fasting individuals, the arteriovenous glucose difference is on the order of 0.2 mM.8 Given this data, the true prevalence was 2/56 (3.6%) for diabetes, and 10/56 (17.9%) for IFBG, which also explains the 7.2 mM cutoff we used for ABGA selection criteria. Aggregated diabetes prevalence in Peru is approximately 6% and IFBG prevalence is approximately 15-20%. However, highland prevalence is lower for both diabetes and IFBG, where it is estimated to be approximately 4.5% and 17.4%, respectively.39 These results are almost exactly what we observe as well, indicating that living at high altitude correlates with lower diabetes prevalence.\n\nHtc. Htc, a measure of the red blood cell content of blood, has been shown to vary between biological males and females, as well as between different high-altitude resident populations. Andeans and acclimatized Europeans tend to respond to high altitude by increasing hemoglobin and Htc% in a dose-response manner.5,6,40 The hematocrit determined here (Table 1) falls on the high end of the sea-level reference interval (42-52% and 37-47% for males and females respectively), reflecting an Andean-style adaptation.5,6,36\n\n\nConclusions\n\nWe observe that in resident Andean highlanders pO2 and pCO2 decrease, Htc% increases, and pH and iCa2+ do not change very much with altitude. Thus, Northern Peruvians probably have the same adaptation profile as other Andeans. However, these results show higher than expected pO2 and pCO2 for the altitude of the analysis. This is likely due to the young age range of the participants and the small study sample.\n\nThis study used a convenience sample cross section of young and healthy Andeans, which means it is not likely applicable to older people or those with chronic conditions, as well as those with different altitude adaption profiles. Additional sample taking of a more demographically balanced cross section and controls preventing air exposure of the sample are necessary to confirm these results and make the generalizable to the population of Huamachuco. Furthermore, comparing the results as a function of barometric pressure rather than altitude can eliminate some variability.\n\nWe hope that these results can be helpful in further establishing altitude- and ethnicity-dependent data-supported values for ABGA as well as Glc, Lac, and iCa2+, which will aid in the diagnosis and treatment of cardiopulmonary disease at high altitude.",
"appendix": "Data availability\n\nFigshare: Dataset for “Arterial blood gas analysis of healthy residents in Huamachuco, Peru (3,164 m)”. https://doi.org/10.6084/m9.figshare.22720630. 41\n\nThis project contains the following underlying data:\n\n• Huamachuco-calculations-110623.xlsx (Dataset for the article “Arterial blood gas analysis of healthy residents in Huamachuco, Peru (3,164 m)”. All raw data collected and calculations are included in this spreadsheet.)\n\nFigshare: STROBE Checklist for “Arterial blood gas analysis of healthy residents in Huamachuco, Peru (3,164 m)”. https://doi.org/10.6084/m9.figshare.22720723. 42\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgements\n\nThe authors wish to thank the direction of Instituto de Educación Superior Tecnológico Público de Huamachuco. 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PubMed Abstract | Publisher Full Text\n\nPaulev PE, Zubieta-Calleja GR: Essentials in the diagnosis of acid-base disorders and their high altitude application. J Physiol Pharmacol. 2005; 56(Suppl 4): 155–170.\n\nZubieta-Calleja G, Zubieta-Castillo G, Zubieta-Calleja L, et al.: Do over 200 million healthy altitude residents really suffer from chronic acid-base disorders? Ind J Clin Biochem. 2011; 26(1): 62–65. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPagana KD, Pagana TJ: Mosby’s manual of diagnostic and laboratory tests. 6th ed.St. Louis: Elsevier; 2018.\n\nMerino MA, Sahuquillo J, Borrul A, et al.: ¿Es el lactato un buen indicador de hipoxia tisular? Resultados de un estudio piloto en 21 pacientes con un traumatismo craneoencefálico. Neurocirugía (Astur). 2010; 21(4): 289–300. PubMed Abstract | Publisher Full Text\n\nHochachka PW, Beatty CL, Burelle Y, et al.: The lactate paradox in human high-altitude physiological performance. News Physiol Sci. 2002; 17: 122–126. PubMed Abstract | Publisher Full Text\n\nVillena JE: Diabetes mellitus in Peru. Ann Glob Health. 2015; 81(6): 765–775. Publisher Full Text\n\nGonzales GF, Tapia V: Hemoglobina, hematocrito y adaptación a la altura: su relación con los cambios hormonales y el periodo de residencia multigeneracional. Rev Med. 2007; 15(1): 80–93.\n\nFernandez L: Dataset for “Arterial blood gas analysis of healthy residents in Huamachuco, Peru (3,164 m)”. [Dataset]. figshare. 2023. Publisher Full Text\n\nFernandez L: STROBE checklist for “Arterial blood gas analysis of healthy residents in Huamachuco, Peru (3,164 m)”. [Dataset]. figshare. 2023. Publisher Full Text"
}
|
[
{
"id": "198150",
"date": "04 Sep 2023",
"name": "Latika Mohan",
"expertise": [
"Reviewer Expertise High altitude physiology",
"Neurophysiology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article presents valuable data, is topical and useful. The study examines arterial blood gas analysis in adapted young adults residing at 3000m above sea level and discusses trends in ABGA with change in altitude. It is acknowledged that it is difficult to do such studies on normal subjects at altitude locations, but a larger sample size would have yielded more robust analysis. Was a sample size calculation done?\nThe methodology has been described in detail and all procedures documented well. Although the authors admit that most of the ABGA parameters failed to reach statistical significance, the trends can be observed in table 1, and follow the expected trends for pO2, pCO2. In contrast the pH and Bicarbonate values do not seem to follow the inverse relationship. This needs to be discussed in greater detail, as these are long term residents and there may be physiological compensatory mechanisms coming into play.\nThe regression model presented for predicting pO2 is very interesting, and larger population studies are required. As the altitude adaptation strategies are different in Tibetians and the Andeans, there may be merit in analysis of trends by ethnicity.\n\nOverall, well written and useful study.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "10274",
"date": "06 Oct 2023",
"name": "Lissett Fernández",
"role": "Author Response",
"response": "A sample size calculation was not done before the experiment because, as the reviewer points out, it is difficult to recruit healthy participants. Furthermore, sample size and power calculations are used for studies that compare groups; this study simply reported values from one group. Instead of a sample size calculation, we include a 95% confidence interval for blood gas parameters measured. The authors did an additional analysis of the data and found there was no statistically significant correlation between actual bicarbonate concentration and arterial blood pH, but there was one between pCO2 and bicarbonate. These results and their discussion were added to the text. We attempted to separate Andean and Tibetan blood gas results in figure 1 (diamonds and circles). We could only find 2 reports conducted in Tibet, but we could certainly add more if we were made aware of them. We also updated the figure to include color to better contrast the different groups presented."
}
]
},
{
"id": "198140",
"date": "08 Sep 2023",
"name": "Erica Heinrich",
"expertise": [
"Reviewer Expertise High-altitude medicine",
"pulmonary physiology",
"control of breathing"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe goal of this study was to evaluate arterial blood gas values in healthy Northern Peruvians living at high altitude. Arterial blood was collected and analyzed in 46 participants. The main findings are that the arterial pH, O2, CO2, and other factors are comparable to the expected values at this altitude, but that Northern Peruvians had slightly elevated arterial PO2, potentially indicating adaptation to high altitude.\nWhile these findings do not substantially move the field forward, these are valuable measurements that contribute to our larger understanding of the effect of high altitude on arterial blood gas values. The data presented in Figure 1, from many different studies, can serve as a useful reference for others as well.\nMinor comments:\n“However, these results were included in our analysis of the prevalence of diabetes and impaired fasting glucose.” How can this analysis be done if diabetes was an exclusion criteria? Clarify that these were exclusion criteria only for one part of all analyses.\nCan information be provided about how long participants had been at high altitude? Similarly, is the data in Figure 1 controlled for time spent at high altitude? These values will change with acclimatization and long-term adaptation.\n“The median blood pressure was 100/60 mmHg”. This is quite low for a median. Can the authors explain or speculate on why this may be?\nFigure 1: It is a bit difficult to see differences in the three point types for American, This Study, and Tibet. Can this figure be made in color or in some other way show the differences more clearly?\nI have some thoughts on the use of the term “Andean-style adaptation”. One could predict that some of the adaptations or maladaptations (such as excessive erythrocytosis and blunted ventilation/respiratory drive) in Andean high-altitude natives may be the normal response expected from other ancestral groups when exposed to a lifetime of high-altitude hypoxia, and not a specific phenotype expected only to appear in Andean individuals. However, since we don’t have much data from individuals of sea-level ancestry living for very long periods at high altitude, we can not test this idea yet. In my opinion, I would pull back from using this term and phrase this as something along the lines of “similar to adaptations seen in Andean high-altitude natives”, but it’s up to the authors.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10275",
"date": "06 Oct 2023",
"name": "Lissett Fernández",
"role": "Author Response",
"response": "We agree with the reviewer’s comments and recognize the limitations of this paper. It is our hope, too, that the compilation of blood gas results from the last several decades will be a useful reference for establishing reference parameters. Fasting arterial blood glucose was measured concurrently with blood gas. Therefore, the authors had access to blood glucose concentrations for all the participants for which a sample was drawn, even those who were later excluded from the blood gas results due to diabetes. Given that we still had the data, we felt reasonable to include it in an analysis of diabetes in the area to shed light on whether diabetes prevalence in Huamachuco was different than nearby lowlands. The authors recognize that this is somewhat difficult to follow, so the text was updated to be clearer about what participants were included at what stage of the study. One selection criterion was that the participant had to have resided in Huamachuco district for at least 5 years prior to the study, with no recent travel to lowland. As for the other papers cited, the authors tried, as much as possible, to include only residents, but each paper had their own criteria for what qualifies as resident. We added text in the conclusion that indicates that the results here are not applicable to sojourners to high altitude. The authors think that the blood pressure measured was reasonable, given the age of the study participants. A study from Cuzco, Peru, at a similar elevation, measured blood pressure to be 100/67 (Reference: Pereira, 2014). Additionally, a large study in Canada suggested a “normal” value for blood pressure in 20–29-year-old people to be approximately 105/68 (https://www150.statcan.gc.ca/n1/pub/82-625-x/2016001/article/14657-eng.htm). From these data, and considering the characteristics of the group we studied, the authors think that the measured blood pressure is reasonable. We updated the figure to take advantage of color to make the different groups clearer. Perhaps we were too bold in concluding Andean style adaptation, so we changed the wording where appropriate to suggest a greater level of uncertainty."
}
]
},
{
"id": "198146",
"date": "12 Sep 2023",
"name": "Niroj K. Sethy",
"expertise": [
"Reviewer Expertise Hypoxia",
"High altitude biology",
"Human response to hypoxia"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript reports arterial blood gas analysis of 17 males and 29 females from Huamachuco, Peru (3,164 m). Though the rationale of the study is interesting, I have reservations for number of participants, combining both the genders, and conclusions.\nNumber of participants are on lower side. The authors must do a power analysis for such clinical studies1.\n\nThe authors have excluded diabetic volunteers from the study. Hence, a comment like \"lower prevalence of diabetes among highlanders....\" is little misleading.\n\nThe conclusion statement \"Northern Peruvians have and Andean-style adaptation to high altitude\" based on arterial blood gas analysis a big claim.\n\nIn such field studies involving blood collection, I personally expect some other methods like ELISA/western blotting -based evidences for the original hypothesis.\n\nIt is now a well known fact that hypoxia response of males and females are distinct. Thus, combing male and female volunteer data sets for deciphering common hypoxia response is unwarranted.\n\nIs there any effect of elevation (Study location section of result section) on blood gas parameters? What are the authors opinion about the same parameters at 2,200 m or 4,600 m (the lowest and highest elevations of the studied district)?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "10276",
"date": "06 Oct 2023",
"name": "Lissett Fernández",
"role": "Author Response",
"response": "The authors agree that the study was small and that a larger sample size would have provided more reliable data. However, it is challenging to plan and execute a study in rural Peru, so this had to be considered. Power analyses are useful when two different groups are compared, but this paper describes a population sample. Nonetheless, we included a confidence interval calculation for the blood gas parameters in Table 1 and for diabetes prevalence. We think a confidence interval is a useful tool to describe how the data relates to the overall population’s blood gas parameters. Also, the cited article in this comment was retracted. The authors excluded participants with diabetes from the arterial blood gas analysis section of the study but included them to discuss diabetes prevalence. Participants with diabetes were allowed to have their blood tested and were included in our discussion of diabetes prevalence. Perhaps the authors were too bold in concluding Andean style adaptation. Instead, we have changed the wording to reflect uncertainty. We recognize that additional experiments could have supported our claims, but the logistical difficulties involved with transporting an arterial blood gas monitor to a mountain town in Peru was stretching the capabilities of the research team. Only data that did not show a significant difference using the Mann-Whitney U Test with Bonferroni correction between men and women were aggregated. Indeed, some parameters, like hematocrit and carbonate were different and were reported as different values for male and female participants (Table 1). Most everyone in the study lived in the city of Huamachuco or were present there for a few days, so the resident altitude range isn’t as large as all the possible altitudes in Huamachuco. Furthermore, the tests were completed in the same location, controlling for elevation."
}
]
}
] | 1
|
https://f1000research.com/articles/12-885
|
https://f1000research.com/articles/12-792/v1
|
06 Jul 23
|
{
"type": "Research Article",
"title": "Prevalence and risk factors associated with dysglycemia among overweight and obese Palestinian children in the Hebron governorate ",
"authors": [
"Diala Abu Al-Halawa",
"Stephanny Vicuna Polo",
"Radwan Qasrawi",
"Diala Abu Al-Halawa",
"Stephanny Vicuna Polo"
],
"abstract": "Background: The prevalence of dysglycemia among adolescents and younger children has been rising, yet health professionals are still unaware of the significance of this problem. According to the Palestinian Ministry of Health (MOH) records, most diabetic children under the age of 20 in Palestine are classified as type I; nonetheless, very limited data are available for policymakers to frame cost-effective screening programs. This study aims to determine the prevalence of dysglycemia in a sample of obese and overweight Palestinian children, identify risk factors associated with dysglycemia, and examine risk factors variance by gender. Methods: A cross-sectional sample of observed obese and overweight children was selected from public schools in the Hebron governorate. Informed consent, physical examination, anthropometric, and laboratory tests (Blood Glucose Level (BGL) and fasting BGL ) were performed on a sample of 511 students (44.6% boys and 55.4% girls) aged 13–18-years (13-15 years =46.2% and 16-18 years =53.8%). Results: The prevalence of confirmed overweight and obese cases was 73.2%, and dysglycemia prevalence among the confirmed cases was 3.7% (5.3% boys and 2.5% girls). The BMI classifications of the prediabetic children indicated that 42.1% were overweight and 31.1% were obese. Furthermore, 6.7% reported hypertension (both systolic and diastolic hypertension). Conclusions: The results of this study provide valuable information about the rising problem of dysglycemia among Palestinian children and underlines the need for rapid screening programs and protocols for early detection and classification of the disease, leading to initiation of early prevention and treatment plans.",
"keywords": [
"Dysglycemia1",
"schoolchildren2",
"Diabetes3",
"nutrition4",
"risk factors5",
"obesity6"
],
"content": "Introduction\n\nDiabetes is a metabolic disease involving glucose dysregulation that can result in serious and life-threatening complications such as nephropathy, neuropathy, retinopathy, and heart disease. The underlying mechanism is a defect in insulin secretion, action, or both. This defect affects mainly carbohydrate metabolism, although the metabolism of proteins and lipids is also affected.1–3 Recent estimates by the International Diabetes Federation (IDF) show that globally, 424.9 million of adults have diabetes with 79% of cases in low and middle-income countries, 9.2% of which are present in the middle east and north Africa region (MENA), including Palestine.4 The prevalence of type II diabetes, however, is not only increasing among adults but also spreading into younger age groups, such as adolescents and children.\n\nOriginally thought of as a disease of adults, type II diabetes has recently been appearing at increasing rates among adolescents and even younger children around the world.5–9 In the USA, the prevalence of prediabetes among adolescents was found to be 18%10; similarly, the prevalence of fully diagnosed type II diabetes in the US youth increased from 0.34/1000 in 2001 to 0.46/1000 in 2009.11 Wide variations in the prevalence of type II diabetes have been observed in different countries and within various ethnicities.4,12 In the Middle East, a study in Kuwait found that 34.9 per 100,000 children between 6-18 years old suffered from type II diabetes.13 Moreover, a study in Saudi Arabia reported a 9.04% prevalence of type II diabetes among overweight and obese Saudi children.14 In the same manner, a case series study of medical records from the Al Ain hospital in the UAE revealed that of 96 newly diagnosed diabetics aged 0-18 years, 11.5% fulfilled the criteria for type II diabetes diagnosis, most of which were females and 82% were obese.15 This alarming trend could be a consequence of or a corollary to the rising epidemic of obesity worldwide. Obesity is associated with and is antecedent to a variety of health conditions that extend beyond aesthetics and increased fat deposition. Obese adolescents are at increased risk of developing metabolic syndromes, cardiovascular disease, and diabetes later in life.16–18\n\nDespite the wide variations in prevalence, risk factors appear to occur commonly across nationalities in a similar manner to the rates present for adults, such as genetic and demographic factors, lifestyle factors, and metabolic and biological measures. Demographic and genetic risk factors include age, sex, family history, exposure to diabetes in utero, and race. Impaired glucose regulation appears more commonly in females and the risk increases with age, pubertal onset, and certain ethnicities.1,3 Nonetheless, obesity remains the most predisposing risk factor to type II diabetes as it is generally agreed upon that obesity increases the risk of type II diabetes mainly by increasing insensitivity of peripheral tissues to insulin. Abdominal obesity and visceral fat appear to be particularly detrimental.19 The rates of obesity have rapidly risen around the world, in such a way that, recently, an epidemic of obesity has been observed in many Middle Eastern countries.20,21\n\nSeveral studies have documented a strong association between physical activity and improved glucose regulation22,23; growing evidence suggests that even low to moderate physical activity could improve insulin sensitivity and decrease hepatic steatosis.24,25 Studies that were conducted on children show similar results to those in adults; thus, the Center for Disease Control and Prevention (CDC) recommend at least 60 minutes of physical activity for 6–17-year-old children and adolescents, including aerobic, muscle strengthening and bon strengthening activities to prevent type II diabetes.26,27 Similarly, diet plays an important role in the prevention of dysglycemia,28,29 nonetheless, relatively few studies have investigated the relationship between nutrition and dysglycemia in children. In a review of the diet strategies that could reduce the risk of type II diabetes among children, Gow et al. concluded that a diet low in carbohydrates, irrespective of the diet strategy, could decrease the risk factor for type II diabetes.30\n\nDysglycemia and type II diabetes are escalating worldwide with modern sedentary lifestyles and unhealthy diet habits, such as fast-food consumption, on the rise. The prevalence of these diseases is rapidly increasing in the MENA region, and thus determining their prevalence among Palestinian schoolchildren would support policy screening and enhanced regulations to prevent diabetes type II in the country. Although population-wide screening is costly and time-consuming,31 screening of high-risk children in the country is possible and cost-effective.32 Some countries (e.g., India, Finland, and the USA) have developed risk scores for screening purposes.32,33 Information on the prevalence and risk factors for diabetes in Palestine is needed to identify high-risk children in the country, as well as to raise awareness among health care professionals about the extent of the problem. Increased awareness will reduce cases of misdiagnoses, delayed diagnoses, or missed diagnoses. Therefore, this study aims be the first in the region to identify the prevalence of dysglycemia among a cohort of mainly overweight and obese children in the Hebron governorate, Palestine.\n\n\nMethods\n\nThe study received ethical approval from the Ministry of Education and Al-Quds University Institutional Review Board (IRB).\n\nSubjects were informed of the objectives, risks, and benefits of the study. The children and their parents signed informed consent forms detailing their rights to decline to continue participating in the study at any moment. Informed consent forms were written at the readability levels of each age group.\n\nThe Hebron Governorate is divided into four districts: the northern district, the southern district, Hebron city, and the Yatta district. Data from the Ministry of Education (MOE) shows that approximately 70000 students between the ages of 13-18 years attended public schools in the Hebron Governorate in the academic year 2018/2019. According to the online sample size calculator available from Creative Research Systems,34 the sample size of students required to estimate the prevalence of dysglycemia within a 4% margin of error and 95% confidence interval in all districts is 595 students.\n\nMultistage random sampling method was used to select the participants in this study. In the first stage, all public schools were enumerated in each of the four districts. Stratified random sampling was used to select two schools (one all-male and one all-female) in each district. In the second stage, a random sample of students from the selected schools was chosen, including those who were possibly overweight or obese. Therefore, a total number of 511 students between the ages 13 to 18 years constituted the final study sample. Obese patients with conditions known to cause diabetes such as steroid therapy, pancreatitis, pregnancy, and cystic fibrosis were excluded.\n\nAnthropometric and blood pressure measurements\n\nAnthropometric measurements included weight and height collected by trained nurses registered in the Ministry of Health. The Body Mass Index (BMI) was calculated as the weight divided by the square of the height in meter. BMI was expressed in standard deviations using the WHO standard curves for age and sex. Children were grouped into five categories: underweight, normal BMI, 1-2 SDs above the average line (overweight), and more than 2 SDs above the average line (Obese). Blood pressure measurements were taken for each student and categorized as normal or high. High blood pressure is defined as systolic or diastolic pressure more than 95th percentile for age, sex, or height based on standard tables.35\n\nStudy questionnaires\n\nStructured, self-administered questionnaires were distributed to students. The questionnaire included questions to be answered by the parents (e.g., family history of diabetes), and questions to be answered by the students themselves (e.g., food preferences).\n\nParents’ questionnaire: Specific questions that should be filled by a parent included education (less than secondary school, secondary to high school and higher than high school), place of residence, and family history of diabetes, hypertension, heart diseases and hypercholesterolemia. Family history of diabetes was recorded based on self-reports of no family history of diabetes in first degree relatives (mother, father, or sibling).\n\nStudent questionnaires: Physical activity and dietary patterns were assessed using standard questionnaires which are validated and appropriate for each age group. The questions concerning physical activity were based on the International Physical Activity Questionnaire (short form), which measures physical activity patterns during the last seven days,36 and The Youth Risk Behavior Surveillance Survey (YRBS), a recall questionnaire for children 10-21 years old.36 The questions concerning dietary habits were based on the Youth Risk Behavior Survey,37 and the Adolescent Food Habits Checklist.38 Healthy food intake included intake of fruits, vegetables, milk and derivatives, meat, and cereals. Unhealthy food intake included consumption of candies, cola and derivatives, sweetened fruit juices, energy drinks and fats. The variables were recoded according to 25th, 50th and 75th percentiles into: Low, moderate and high, respectively.\n\nLaboratory measures\n\nBlood samples were collected by MOH registered nurses and analyzed centrally at a nearby health facility. Glucose regulation measures were examined using standard laboratory procedures for collection of blood samples. Normal glucose regulation is fasting glucose <100 mg/dl and random plasma glucose (RPG) <140 mg/dl. Diabetes mellitus was defined as having fasting glucose ≥126 mg/dl, RPG≥200 mg/dl or Hemoglobin A1C>6.4% as per ISPAD clinical consensus guidelines for diabetes diagnosis in children and adolescents.39 Dysglycemia is the term that includes any abnormalities in glucose measures and therefore includes both prediabetes and diabetes.\n\nVariables were entered and analyzed using SPSS (version 21). Frequencies and percentages were used to describe the sociodemographic characteristics of the study participants. The risk factors associated with dysglycemia were explored by the three objectives. The first objective identified the most important risk factors, the second objective examined how these risk factors vary by BMI, and the third objective used the risk factors in a risk score based on (non-laboratory) clinical risk factors that identified high risk children who need further investigation through laboratory tests to confirm the diagnosis of dysglycemia. These objectives were analyzed using various statistical approaches. Univariate and bivariate analysis were conducted as appropriate to show the relationship between each of the risk factors with dysglycemia without adjusting for potential confounders. To adjust for potential confounders, multivariate logistic regressions were used and included all the variables that show statistically significant relationship with the outcome variable. Chi2 tests of comparisons were used for categorical variables. Multiple imputations were used to replace missing values.\n\n\nResults\n\nTable 1 represents the distribution of the study participants between the ages of 13-15 and 16-18 by their sociodemographic characteristics. Females constituted 50% of the younger students and 60% of the older students’ groups. Most of the students of both age groups lived in the city of Hebron (98.7% of younger students, 83.3% of older students). In both age groups, over half of the students’ fathers and 45% of their mothers had an education level less than secondary school (52.1%, 53.1%; and 45.3%, 45.5%) respectively. Parental employment status, across all ages, demonstrated that most of the students’ fathers had a job, while mothers did not (father employment: 94.5% of 13–15-year-old students, 90.2% of 16–18-year-old students; and for mother employment: 14% of 13–15-year-old students, 12% of 16–18-year-old students) respectively.\n\nN=511.\n\n1 BMI: Body Mass Index.\n\nThe body mass index (BMI) classification shows that in a sample of observed overweight and obese students, around 46% of 13-18-year-old students were overweight while 38.6% were obese, whereas among older students, 38.5% were overweight and 46.7% were obese.\n\nThe lifestyle characteristics including food consumption frequency and daily sports activity across students of different BMIs are displayed in Table 2. The food consumption frequency of students indicated that the consumption of most food groups didn’t differ significantly between normal, overweight, and obese students, except for candy, coke and derivatives, and sweetened fruit juices (p-value=0.000, p value=0.001, and p value=0.005 respectively). Interestingly, the results indicate that over one-third of students with a normal weight consume candy at least once daily, in comparison to 34.4% of overweight, and only 19.5% of obese students. In addition, 34.4% of overweight and 42.8% of obese students consume coke less than once a week, whereas 32.1% of normal-weight students consume coke 2-6 times a week. Moreover, over one-third of each group consumes fruit juices less than once a week (31.4% of normal weight, 33.5% of overweight, and 44% of obese students) respectively, however, around one-quarter of overweight and obese students consume fruit juices once a week. In contrast, around 30% of normal-weight students consume fruit juices two-six times a week.\n\nThe results show that most students consume fruits and vegetables two-six times a week (27.2%, 31.6% and 40% for fruits’ consumption; 42.3%, 32.1% and 40.9% for vegetables consumption), respectively. In terms of milk consumption, around one-quarter of students of each BMI group consume milk at least once daily (27.7% of normal weight, 25.6% of overweight, and 22.6% of obese students). Similarly, around one-third of students consume dairy products at least once daily (27%, 31.6%, and 33.3%). As for meat consumption, 56.2%, 49.3%, and 46.5% of normal, overweight, and obese students respectively consume meat two-six times a week. Additionally, 15.3% of normal-weight students consume fat daily, however there’s a higher percentage of daily consumption among overweight and obese students (20% and 22%), respectively.\n\nThe results for physical activity in the form of sports lasting over 60 minutes show that 40% of normal-weight students perform sports more than three times a week, however, most overweight, and obese students perform them one-three days a week (47.4% and 47.2% respectively). There is no statistically significant difference between in sports performance among students of different BMI groups.\n\nTable 3 shows the students’ personal health status and their family history of non-communicable diseases. When asked if they experience any symptoms of diabetes (e.g., increased thirst), over half of the students experienced at least one symptom (57.7% of normal weight, 53.5% of overweight, and 55.3% of obese students). No statistically significant difference was found among the groups (p-value=0.745).\n\n1 S: systolic blood pressure, D: diastolic blood pressure.\n\nThe students were examined for non-communicable diseases directly associated with obesity, such dysglycemia, and high blood pressure. The diagnosis of dysglycemia was found among 2.9%, 2.8% and 5.7% of normal-weight, overweight, and obese students respectively; however, no statistically significant association was found (p-value=0.297). The blood pressure measurements indicated that over 20% of normal-weight students, 28% of overweight students, and 45% of obese students had high systolic and/or diastolic blood pressure. The differences in probable hypertension were found to be significantly different among BMI groups (p value=0.000).\n\nIn terms of non-communicable diseases in first-degree relatives, around 12%, 25%, and 37% of normal-weight, overweight, and obese students respectively had at least one obese first-degree relative, which was significantly associated with students’ obesity levels (p value=0.000). Moreover, family diabetes was reported in around 22%, 25%, and 33% of normal-weight, overweight, and obese students respectively, albeit these differences are not statistically significant (p value=0.066). On the other hand, hypercholesterolemia and heart diseases were less reported by normal-weight students (6.6% and 4.4% respectively), whereas they were reported by a higher percentage of overweight and obese students (11.6%,12.1%; 14.5% and 11.9% respectively). The differences in having relatives with heart disease among students with different BMI groups were found to be statistically significant (p value=0.038), however, no significance was found in having hypercholesterolemia in first-degree relatives (p value=0.095).\n\nTable 4 demonstrates the results of binary logistic regression analysis of dysglycemia-related risk factors. In terms of sociodemographic characteristics, neither gender nor age were found to be significantly associated with dysglycemia (p value=0.08, p value=0.94), however, younger students presented a lower odd of dysglycemia (OR=0.96, 95%CI=0.33-2.79). In terms of parental education, the categories of parental education of secondary school education and above were summed for insertion to this model. Higher levels of paternal education were associated with an increased odds of dysglycemia, albeit not statistically significant (p value=0.56, OR=1.41, %CI=0.44-4.49). On the other hand, students with lower maternal education were less likely to have dysglycemia (p value= 0.29, OR=0.55, %CI=0/18-1.67). In terms of parental working status, paternal and maternal working status didn’t exhibit significant difference in children dysglycemia (OR=0.58, 95%CI=0.06-5.79, p value=0.65; OR=0.85, 95%CI=0.16-4.54, p value=0.85).\n\nPersonal health-related risk factors, such as lower intake of healthy foods, were found to increase the risk of dysglycemia (OR=1.61, 95%CI=0.17-15.33, p value=0.68 for moderate intake; and OR=2.81, 95%CI=0.29-27.33, p value=0.37 for low intake), however, higher intake of unhealthy foods didn’t increase the risk of dysglycemia (OR=0.021, 95%CI=0.04-1.06, p value=0.06 for moderate intake; and OR=0.89, 95%CI=0.25-3.1, p value=0.85 for high intake respectively). Moreover, sports activity of over 60 minutes one to three times a week showed higher dysglycemia prevalence as compared to sports activity over four days a week (OR=3.34, 95%CI=0.85-13.17, p value=0.09).\n\nHypertension was studied among schoolchildren. Systolic and diastolic hypertension significantly increased the risk of dysglycemia (OR=7.1, 95%CI=1.45-34.71, p value=0.02). First-degree relatives’ health showed that having an obese or diabetic relative was significantly associated with dysglycemia prevalence (OR=5.65, 95%CI=1.7-18.78, p value=0.01; OR=3.47, 95%CI=1.38-13.84, p value=0.01). Moreover, students who had a relative with hypercholesterolemia or heart disease were 2.97 and 1.05 times more likely to have dysglycemia (95%CI=0.65-13.51, p value=0.16; and 95%CI=0.21-5.15, p value=0.96). On the contrary, hypertension in first-degree relatives was not found to be significantly associated with dysglycemia prevalence (OR=0.23, 95%CI=0.05-1.11, p value=0.07).\n\n\nDiscussion\n\nNon-communicable diseases such as diabetes mellitus are increasing worldwide, particularly in the Middle East,9 however, there is a scarcity in the literature regarding children and adolescent dysglycemia and diabetes status in Palestine, including type II diabetes. The present study aimed to investigate the prevalence of dysglycemia and its associated risk factors among Palestinian schoolchildren. The results evidenced that among a cohort of seemingly overweight and obese children and adolescents, the average prevalence of dysglycemia was 3.7% overall, 5.3% in males, and 2.5% in females. Prevalence rates vary across the literature, depending on the region and selection criteria. For example, the ORANGE study in India found that 3.7% of 6–19-year-old children and adolescents had glucose intolerance.40 On the other hand, Al-Rubeaan et al. found that 6.12% of Saudi children and adolescents had dysglyecmia.41 Similarly, Nakiriba et al. reported the prevalence to be 6.4% among adolescent girls.37\n\nObesity is known to be strongly associated with dysglycemia. In fact, a recent review article states that obesity was found to quadruple the risk of type II diabetes among children and adolescents.5 In this study, 73.2% of apparently obese children were found to be overweight and obese by BMI classification. However, contrary to the literature, the prevalence of dysglycemia was not found significantly different across these groups,10,18 this can be justified due to the low number of dysglycemia cases in the BMI groups. Dysglycemia and obesity are also recognized to be associated with numerous non-communicable diseases, including hypertension, hyperlipidemia, cardiovascular diseases, and metabolic syndrome.17,42 In our study population, around 33% of students had probable hypertension, which differed significantly between normal, overweight, and obese students, and increased the odds of developing dysglycemia. These findings are consistent with a pediatric hypertension literature review done in Africa, which concluded that the prevalence of hypertension differed significantly across the different BMI groups.43\n\nDysglycemia and Type II diabetes are associated with increased morbidity, progression to adult diseases, and poor health in adulthood.44,45 Lifestyle behaviors, non-exclusively including dietary habits and physical activity, play a significant role in the development of obesity and dysglycemia.7,46,47 In this study, we aimed to assess the association between nutrition and physical activity to obesity and dysglycemia. The results revealed that dietary habits among children with distinct BMIs were somewhat similar with the exception of sweetened food items, such as coke, sweetened juices, and candy. However, the study found a discrepancy as normal-weight children in our sample population showed higher consumption levels of unhealthy food items than overweight or obese children. Similar results have been evidenced in other studies, such as in Ref. 48, where Viera et al. reported that normal-weight healthy Brazilian adolescents consumed more sugar and candy than obese adolescents. On the other hand, a study in Taiwan revealed that there was no association between sugar intake and obesity levels.49 The discrepancy in our study may be a result of the wide availability of these food items in cafeterias in Palestinian schools, and the higher scrutiny of overweight and obese students on lowering the consumption of these items. Furthermore, our results evidence that lower intake of healthy foods did not significantly correlate to impaired glucose tolerance. On the other hand, a higher intake of unhealthy foods showed to be associated with a higher prevalence of impaired glucose tolerance.\n\nIn terms of physical activity, normal, overweight, and obese weight students reported similar frequencies of sports performance. Moreover, contrary to our expectations, physical activity was not found significantly associated with dysglycemia. Similar results were found in Ref. 45, where Nakiriba et al. expressed that the level of physical activity was not significantly associated with dysglycemia among Ugandan adolescent girls. Additionally, Al Amiri et al. reported a similar finding among 11–17-year-old Emirati students.50 Nonetheless, several studies have demonstrated the impact of physical activity on blood glucose level management.22,23,51 The results obtained in this study could be attributed to the fact that our study participants had abnormal glucose readings rather than full-blown diabetes.\n\nAdditionally, this study examined participants’ family history of non-communicable diseases, including obesity, hypertension, hyperlipidemia, and cardiovascular diseases. The results demonstrate that obesity in first-degree relatives was the main factor associated with childhood obesity and dysglycemia. We found that around 61% of overweight and obese students had at least one obese first-degree relative. The findings are consistent with several previous studies that associated parental obesity and obesity, dysglycemia, and diabetes among children.48,52 Moreover, we found that diabetes in first-degree relatives is associated with dysglycemia among children and adolescents, however, it was not found significantly associated with childhood obesity. Various studies have demonstrated that children of diabetic parents are at increased risk for diabetes and obesity, independent of parental education.39,48,50\n\nThe results showed that other factors associated with dysglycemia prevalence among Palestinian children and adolescents included parental education and employment. Our results demonstrate paternal education higher than secondary school level was associated with decreased risk of dysglycemia. This finding is consistent with other studies that have found that parental education is positively associated with control of dysglycemia-related risk factors.53,54 However, contrary to the stated studies, lower maternal educational levels were not associated with increased risk of dysglycemia. In the Palestinian context, this could be attributed to the fact that the less educated mothers are usually stay-at-home mothers, who could have more control on home cooked meals and children eating habits. Parental employment on the other hand was not found to be significantly associated with dysglycemia among children.\n\nSymptoms of diabetes, mainly increased thirst, excessive urination, increased food cravings, and fatigue, were found to be positively correlated to dysglycemia prevalence.7 The results demonstrate that over half of the students suffered from at least one symptom related to diabetes. This study’s findings illustrate the importance of early screening for impaired glucose tolerance among students, particularly children and adolescents presenting diabetes-related symptoms.\n\nPotential limitations to this study include the small sample of dysglycemic patients, which we believe to be the reason for many of the non-significant associations in the regression model. Moreover, there were apparent cultural hindrances to the proper completion of blood testing. Many of the dysglycemic students’ parents refused to continue with a follow-up of blood glucose and lipids measurements, therefore we were unable to diagnose diabetes among children, and classify them as type I or type II. We believe this refusal could be attributed to the disease-related stigma present in the country. Parents believe that the diagnosis of diabetes could hinder their children’s progression in social and work life. Despite these limitations, this study highlights the presence of unrecognized dysglycemia among a cohort of Palestinian children and adolescents and offers a roadmap for further investigational studies on the status of dysglycemia and diabetes, particularly type II in the Palestinian pediatric population.",
"appendix": "Data availability\n\nHarvard Dataverse: Dysglycemia among Palestinian children. DOI: https://doi.org/10.7910/DVN/UPYHRR\n\nThis project contains the following underlying data:\n\n• Dysglycemia_data.tab\n\nZenodo Database: Dysglycemia_Palestinian_Children_questionnaires\n\n10.5281/zenodo.7766216\n\nThis database contains the following underlying data:\n\n• questionnaire-parent\n\n• questionnaire-student\n\n\nAcknowledgements\n\nWe wish to thank Prof. Akram Kharounbi for his work on designing and supervising this study. We would like to thank the Ministry of Education, Palestine for its permission to perform the study. We also thank all study participants, and field workers.\n\n\nReferences\n\nPunthakee Z, Goldenberg R, Katz P: Definition, Classification and Diagnosis of Diabetes, Prediabetes and Metabolic Syndrome. Can. J. Diabetes. 2018 Apr 1; 42: S10–S15. PubMed Abstract | Publisher Full Text\n\nMayer-Davis EJ, Kahkoska AR, Jefferies C, et al.: ISPAD Clinical Practice Consensus Guidelines 2018: Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr. Diabetes. 2018 Oct 1; 19: 7–19. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPetersmann A, Müller-Wieland D, Müller UA, et al.: Definition, Classification and Diagnosis of Diabetes Mellitus. Exp. Clin. Endocrinol. Diabetes. 2019; 127: S1–S7. PubMed Abstract | Publisher Full Text\n\nCho NH, Shaw JE, Karuranga S, et al.: IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract. 2018 Apr 1; 138: 271–281. PubMed Abstract | Publisher Full Text\n\nRao G, Jensen ET: Type 2 Diabetes in Youth. Glob. Pediatr. Health. 2020; 7: 2333794X2098134–2333794X2098139. Publisher Full Text\n\nLawrence JM, Divers J, Isom S, et al.: Trends in Prevalence of Type 1 and Type 2 Diabetes in Children and Adolescents in the US, 2001-2017. JAMA - Journal of the American Medical Association. 2021; 326: 717–727. American Medical Association. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDileepan K, Max FM: Type 2 diabetes mellitus in children and adolescents. Pediatr. Rev. 2013; 34(12): 541–548. Publisher Full Text\n\nCandler TP, Mahmoud O, Lynn RM, et al.: Continuing rise of Type 2 diabetes incidence in children and young people in the UK. Diabet. Med. 2018 Jun 1; 35(6): 737–744. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEl-Kebbi IM, Bidikian NH, Hneiny L, et al.: Epidemiology of type 2 diabetes in the Middle East and North Africa: Challenges and call for action. World J. Diabetes. 2021 Sep 15; 12(9): 1401–1425. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAndes LJ, Cheng YJ, Rolka DB, et al.: Prevalence of Prediabetes among Adolescents and Young Adults in the United States, 2005-2016. JAMA Pediatr. 2020 Feb 1; 174(2): e194498. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDabelea D, Mayer-Davis EJ, Saydah S, et al.: Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA. 2014 May 7; 311(17): 1778–1786. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSpanakis EK, Golden SH: Race/ethnic difference in diabetes and diabetic complications. Curr. Diab. Rep. 2013 Dec; 13(6): 814–823. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMoussa MAA, Alsaeid M, Abdella N, et al.: Prevalence of type 2 diabetes mellitus among Kuwaiti children and adolescents. Med. Princ. Pract. 2008 Jun; 17(4): 270–275. PubMed Abstract | Publisher Full Text\n\nal -Agha, N. Shata. : Prevalence of hyperinsulinism, type 2 diabetes mellitus and metabolic syndrome among Saudi overweight and obese pediatric patients. Minerva Pediatr. 2017; 64(6): 623–631. Reference Source\n\nPunnose J, Agarwal MM, Bin-Uthman S: Type 2 diabetes mellitus among children and adolescents in Al-Ain: a case series. East Mediterr. Health J. 2005; 11(4): 788–797. PubMed Abstract\n\nKansra AR, Lakkunarajah S, Jay MS: Childhood and Adolescent Obesity: A Review. Front. Pediatr. 2021 Jan 12; 8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPulgaron ER, Delamater AM: Obesity and type 2 diabetes in children: Epidemiology and treatment. Curr. Diab. Rep. 2014; 14(8): 508. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSkinner AC, Perrin EM, Moss LA, et al.: Cardiometabolic Risks and Severity of Obesity in Children and Young Adults. N. Engl. J. Med. 2015 Oct; 373(14): 1307–1317. PubMed Abstract | Publisher Full Text\n\nAl-Goblan AS, Al-Alfi MA, Khan MZ: Mechanism linking diabetes mellitus and obesity. Diabetes Metab. Syndr. Obes. 2014 Dec 4; 7: 587–591. PubMed Abstract | Publisher Full Text\n\nMusaiger AO: Overweight and obesity in Eastern Mediterranean Region: Prevalence and possible causes. J. Obes. 2011; 2011: 1–17. Hindawi Publishing Corporation. PubMed Abstract | Publisher Full Text | Free Full Text\n\nA systematic review of childhood obesity in the Middle East and North Africa (MENA) region: Prevalence and risk factors meta-analysis. Adv Pediatr Res. 2017.\n\nRiddell MC, Iscoe KE, Riddell MC, et al.: Physical activity, sport, and pediatric diabetes. Pediatr. Diabetes. 2006; 7: 60–70. Publisher Full Text Reference Source\n\nColberg SR, Sigal RJ, Yardley JE, et al.: Physical activity/exercise and diabetes: A position statement of the American Diabetes Association. Diabetes Care. 2016; 39: 2065–2079. American Diabetes Association Inc. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMedrano M, Arenaza L, Migueles JH, et al.: Associations of physical activity and fitness with hepatic steatosis, liver enzymes, and insulin resistance in children with overweight/obesity. Pediatr. Diabetes. 2020 Jun 1; 21(4): 565–574. PubMed Abstract | Publisher Full Text\n\nVäistö J, Haapala EA, Viitasalo A, et al.: Longitudinal associations of physical activity and sedentary time with cardiometabolic risk factors in children. Scand. J. Med. Sci. Sports. 2019 Jan 1; 29(1): 113–123. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCenters for Disease Control and Prevention: Prevent Type 2 Diabetes in Kids.[cited 2022 Oct 1]. Reference Source\n\nCenters for Disease Control and Prevention: How much physical activity do children need?Reference Source\n\nIsmail L, Materwala H, al Kaabi J : Association of risk factors with type 2 diabetes: A systematic review. Comput. Struct. Biotechnol. J. 2021; 19: 1759–1785. Elsevier B.V. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAdeva-Andany MM, Rañal-Muíño E, Vila-Altesor M, et al.: Dietary habits contribute to define the risk of type 2 diabetes in humans. Clin. Nutr. ESPEN. 2019; 34: 8–17. Elsevier Ltd. PubMed Abstract | Publisher Full Text\n\nGow ML, Garnett SP, Baur LA, et al.: The effectiveness of different diet strategies to reduce type 2 diabetes risk in youth. Nutrients. 2016; 8. MDPI AG. PubMed Abstract | Publisher Full Text | Free Full Text\n\nInternational Diabetes Federations: IDF Diabetes Atlas. 10th ed.Brussels, Belgium: 2021. Reference Source\n\nLindström J, Tuomilehto J: The Diabetes Risk Score A practical tool to predict type 2 diabetes risk. Diabetes Care. 2003; 26(3): 725–731. Publisher Full Text Reference Source\n\nLee JM, Gebremariam A, Woolford SJ, et al.: A risk score for identifying overweight adolescents with dysglycemia in primary care settings. J. Pediatr. Endocrinol. Metab. 2013 May 1; 26(5–6): 477–488. PubMed Abstract | Publisher Full Text\n\nSample Size Calculator: 2012. Reference Source\n\nKaelber DC, Pickett F: Simple table to identify children and adolescents needing further evaluation of blood pressure. Pediatrics. 2009 Jun; 123(6): e972–e974. PubMed Abstract | Publisher Full Text\n\nCraig CL, Marshall AL, Sjöström M, et al.: International physical activity questionnaire: 12-Country reliability and validity. Med. Sci. Sports Exerc. 2003 Aug 1; 35(8): 1381–1395. PubMed Abstract | Publisher Full Text\n\nEaton DK, Kann L, Kinchen S, et al.: Youth risk behavior surveillance - United States, 2011. MMWR Surveill. Summ. 2012; 6(41): 1–162.\n\nJohnson F, Wardle J, Griffith J: The Adolescent Food Habits Checklist: reliability and validity of a measure of healthy eating behaviour in adolescents. Eur. J. Clin. Nutr. 2002; 56: 644–649. PubMed Abstract | Publisher Full Text Reference Source\n\nMayer-Davis EJ, Kahkoska AR, Jefferies C, et al.: ISPAD Clinical Practice Consensus Guidelines 2018: Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr. Diabetes. 2018 Oct 1; 19: 7–19. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMehreen TS, Kamalesh R, Pandiyan D, et al.: Incidence and Predictors of Dysglycemia and Regression to Normoglycemia in Indian Adolescents and Young Adults: 10-Year Follow-Up of the ORANGE Study. Diabetes Technol. Ther. 2020 Dec 1; 22(12): 875–882. PubMed Abstract | Publisher Full Text\n\nColeman C, Wileyto EP, Lenhart CM, et al.: Multiple Health Risk Behaviors in Adolescents: An Examination of Youth Risk Behavior Survey Data. Am. J. Health Educ. 2014; 45(5): 271–277. Publisher Full Text\n\nShahwan MJ, Jairoun AA, Farajallah A, et al.: Prevalence of dyslipidemia and factors affecting lipid profile in patients with type 2 diabetes. Diabetes Metab. Syndr. 2019 Jul 1; 13(4): 2387–2392. PubMed Abstract | Publisher Full Text\n\nCrouch SH, Soepnel LM, Kolkenbeck-Ruh A, et al.: Paediatric Hypertension in Africa: A Systematic Review and Meta-Analysis. Lancet. 2022; 43.\n\nAl-Rubeaan K: National surveillance for type 1, type 2 diabetes and prediabetes among children and adolescents:a population-based study (SAUDI-DM). J. Epidemiol. Community Health. 2015; 69: 1045–1051. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNakiriba R, Mayega RW, Piloya T, et al.: Prevalence and factors associated with dysglycemia among girls in selected boarding secondary schools in Wakiso District, Uganda. Adolesc. Health Med. Ther. 2018 Oct; 9: 167–176. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGreenwood DC, Threapleton DE, Evans CEL, et al.: Association between sugar-sweetened and artificially sweetened soft drinks and type 2 diabetes: Systematic review and dose-response meta-analysis of prospective studies. Br. J. Nutr. 2014; 112: 725–734. Cambridge University Press. PubMed Abstract | Publisher Full Text\n\nte Morenga L , Mallard S, Mann J: Dietary sugars and body weight: Systematic review and meta-analyses of randomised controlled trials and cohort studies. BMJ (Online). 2013 Jan 19; 27(7891). Publisher Full Text\n\nVieira MV, del Ciampo IRL, del Ciampo LA: Food Consumption Among Healthy And Overweight Adolescents. J. Hum. Growth Dev. 2014; 24(2): 157–162. Publisher Full Text\n\nAbdul Rahim HF, Sibai A, Khader Y, et al.: Non-communicable diseases in the Arab world. Lancet. 2014; 383: 356–367. Elsevier B.V. Publisher Full Text\n\nAl Amiri E , Abdullatif M, Abdulle A, et al.: The prevalence, risk factors, and screening measure for prediabetes and diabetes among Emirati overweight/obese children and adolescents. BMC Public Health. 2015 Dec 24; 15(1): 1298. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRobertson K, Riddell MC, Guinhouya BC, et al.: Exercise in children and adolescents with diabetes. Pediatr. Diabetes. 2014; 15(SUPPL.20): 203–223. Publisher Full Text\n\nChen C, Min CY, Lin HK, et al.: Behavior, attitudes and knowledge about antibiotic usage among residents of Changhua, Taiwan.2005; pp. 53–59.\n\nChernausek SD, Arslanian S, Caprio S, et al.: Relationship between Parental Diabetes and Presentation of Metabolic and Glycemic Function in Youth with Type 2 Diabetes: Baseline Findings from the TODAY Trial. Diabetes Care. 2016 Jan 1; 39(1): 110–117. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZamora-Kapoor A, Fyfe-Johnson A, Omidpanah A, et al.: Risk factors for pre-diabetes and diabetes in adolescence and their variability by race and ethnicity. Prev. Med (Baltim). 2018 Oct 1; 115: 47–52. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "186872",
"date": "20 Jul 2023",
"name": "Huda Al Hourani",
"expertise": [
"Reviewer Expertise Overweight and obesity and its association with non-communicable diseases"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe most important suggestion for respected authors is to update some terms and definitions in the manuscript, such as using Arabic numerals for type 2 diabetes to avoid confusing the Roman numeral \"II\" with the Arabic number \"11.\" Also, using the updated Clinical practice guideline for screening and managing high blood pressure in children and adolescents in 2017. Furthermore, the diagnostic cutoff point for HbA1c (All articles are attached).\nThe age ranges between 13-18 years, so it is better to call the participants adolescents, not children.\nThe authors' methodology for measuring weight, height, and blood pressure (how many times it is measured) and classifying it needs to be expanded.\nThe authors must provide more information about the dysglycemic subjects included in this study (it makes a difference as usually, T1DM do not have overweight or obesity).\nThe conclusion must be expanded, not as in the abstract.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "10194",
"date": "26 Sep 2023",
"name": "Diala Abu Al Halawa",
"role": "Author Response",
"response": "Dear reviewer, Thank you greatly for your response. We made the suggested changes to the manuscript an updated the submission accordingly. Here is a point by point response to your comments: The most important suggestion for respected authors is to update some terms and definitions in the manuscript, such as using Arabic numerals for type 2 diabetes to avoid confusing the Roman numeral \"II\" with the Arabic number \"11.\" Also, using the updated Clinical practice guideline for screening and managing high blood pressure in children and adolescents in 2017. Furthermore, the diagnostic cutoff point for HbA1c (All articles are attached). - Thank you for your valuable feedback. We have updated the terms as suggested. As we updated the definition of high blood pressure, the percentage of adolescents who had high blood pressure readings increased to around 64%. Therefore, we have restudied the regression model. The were no major differences in the findings, and all changes are addressed in the results and discussion sections. The age ranges between 13-18 years, so it is better to call the participants adolescents, not children. - Thank you for your note. We have updated the term accordingly. The authors' methodology for measuring weight, height, and blood pressure (how many times it is measured) and classifying it needs to be expanded. We elaborated these specifics in the methodology section under (anthropometric and blood pressure measurements) section. The authors must provide more information about the dysglycemic subjects included in this study (it makes a difference as usually, T1DM do not have overweight or obesity). - In reference to the characteristics of the dysglycemic subjects, we added the total number of the cases and their distribution by gender, in addition to the distribution by the different BMI classes which was previously written in the article. However, due to the low number of cases, we believe that adding further information on the distribution of this group by the other sociodemographic variables won't contribute much value to the study. The conclusion must be expanded, not as in the abstract. - In reference to the conclusions, we extended the conclusions in the final paragraph of the discussion. However, we didn't further elaborate on the specifics of the conclusions supported by data since it's not a separate section but included in the discussion section."
}
]
}
] | 1
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https://f1000research.com/articles/12-792
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https://f1000research.com/articles/12-1221/v1
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26 Sep 23
|
{
"type": "Study Protocol",
"title": "Randomised control trial of epidural platelet rich plasma versus epidural steroids for low back pain",
"authors": [
"Adarsh Jayasoorya T.",
"Nitin Samal",
"Nitin Samal"
],
"abstract": "Background: Lower back pain (LBP) is a prevalent medical condition that frequently results in work-related disability and is one of the leading causes of missed workdays. Low back pain (LBP) struck 619 million people worldwide in 2020, and by 2050, it's predicted that there will be 843 million instances worldwide. 70 to 85% of people are predicted to suffer from LBP at some point of time in their lives. 90% of these people will experience multiple episodes, and an intervertebral disc prolapse accounts for a significant portion. Medications and lifestyle adjustments may be used as the first line of treatment. However, if the symptoms do not improve, minimally invasive procedures such as epidural steroid injection and epidural platelet-rich plasma injection may relieve the pain and lessen disability. We therefore aim to conduct a study to analyse the patient’s functional status and satisfaction after epidural platelet-rich plasma infiltration. Methods: Eligible patients with low back pain will be divided into two groups(Group A and Group B). Patients in group A will receive epidural steroid whereas Group B will receive epidural Platelet rich plasma. These patients will be monitored where visual analogue scale will be used to assess relief of pain before and after the procedure, Straight leg raising test will be used to understand the improvement of the patient clinically during examination pre and post procedure. Oswestry disability index will be used to compare the outcome in patient's day to day activities before and after the intervention. Patients will be evaluated with these methods pre-procedure and 1 hour after and later follow up evaluation will be done after 3 weeks and 3 months. The follow-up scores will be taken post one hour, three weeks and three months of the treatment. Protocol version: v1 dated 04/07/23 CTRI registration: REF/2023/06/068736 (12/06/2023)",
"keywords": [
"Low back pain",
"Platelet rich plasma",
"epidural PRP",
"Outcome analysis."
],
"content": "Introduction\n\nOne of the primary causes of lost workdays and a common medical ailment, low back pain (LBP), usually leads to work-related incapacity.1 Low back pain (LBP) is a multifactorial and the most prevalent musculoskeletal disorder, whose economic burden is of global concern.2 One of the most prevalent spinal degenerative disorder, lumbar disc herniation can cause radicular leg pain and low back pain (LBP).3 If lifestyle modifications and medication are inadequate, minimally invasive techniques, such as epidural steroid and platelet-rich plasma, may be used to manage the symptoms and lessen disability.\n\nLBP is described as pain that begins in the back and radiates to the legs. It is also known as sciatica, lumbar radiculopathy, or nerve root irritation Pathophysiological changes on intervertebral discs can lead to disc herniation, degenerative changes including canal stenosis, or chronic instability of the afflicted segments.4 According to some estimations, lumbar disc herniation is estimated to be the root cause of sciatica, which means that 90% of all cases of sciatica that have been reported have this problem.5 Treatment of this condition varies from conservative to surgical options.6 There are several nonsurgical treatments for low back pain, including oral or local analgesics, exercises, diet modification, and Physiotherapy; these conservative treatment modalities aim to delay or prevent surgery. In reality, conservative therapy or self- care can help LBP. Patients resistant to conservative managements are candidates for surgical management.\n\nAcute non-specific low back pain is defined as any pain lasting less than 6 weeks, subacute LBA is defined as lasting between 6 weeks - 3 months, and chronic pain is defined as lasting more than this. Pain is frequently the outcome of aberrant vertebral body motion or caused by instability at a specific motion segment. The loss of the spine's capacity to maintain the relationships between the vertebrae necessary to prevent injury to the spinal cord or irritation of the nerve roots, as well as the emergence of deformity or pain, is known as lumbar spinal instability.\n\nThe architecture of the intervertebral discs, which act as cushion between vertebrae and provide stability, flexibility, and some load-sharing, is disrupted in lumbar disc disease.4 This may result in a disc herniation that leads to pressure on the spinal cord, causing radiating pain and localized weakness.4 A 95 percent likelihood of herniated discs at L4-L5 or L5-S1 occurs in patients between 25 and 55 of age, causing compression at L4, L5, or S1 nerve root.6\n\nBhatia R and Chopra G suggested that there is a definitive role for PRP via lumbar epidural injection for chronic prolapsed intervertebral disc patients.7\n\nAkeda et al administered PRP into the lumbar discs of patients suffering from chronic low back pain and Degenerative Disc Disease affecting one or more lumbar segments. Notably, there was a significant improvement observed in VAS scores, decreasing from 7.1±1.2 to 1.8±2.0 (p<0.01), and this improvement persisted for a duration of 6 months.8\n\nAs per Bodor et al., positive outcomes were documented following a single intradiscal PRP treatment, and these benefits endured for a span of 6 to 12 months in approximately two-thirds of the patients. Among these patients, half exhibited an “excellent” response, while the other half experienced a “good” response, as determined by pain resolution and the ability to resume their daily activities and exercise routines.9\n\nEpidural steroid injection is a non-surgical treatment for managing lower back ache caused by herniated inter vertebral disc or degenerative changes in the vertebrae, which will relieve pain, improve function, and improve quality of life,10 whereas, Platelet-rich plasma (P.R.P.) is an emerging treatment modality that presents a unique opportunity for patients with the prolapsed intervertebral disc as it can bring down the symptoms and disabilities of the patient.7 P.R.P. has been used to improve both hard-tissue and soft-tissue healing. Hence a comparative study will help us to determine the potential of each treatment.\n\n\n\n• To compare the clinical outcome of chronic intervertebral disc prolapse in lumbar spine managed with epidural platelet rich plasma v/s epidural steroids.\n\n• To assess pain relief using visual analogue scale (VAS)\n\n• To assess relief in functional disability using Oswestry Disability Index (ODI)\n\n\nProtocol\n\nThis is a prospective randomized control study. The study will involve 64 participants during a duration of July 2023 to May 2024. (Figure 1) This protocol is reported in line with SPIRIT guidelines.11\n\nThe Ethics and screening Committee has approved the research proposal on 18/07/2022 Jawaharlal Nehru Medical College (JNMC), Datta Meghe Institute of Higher Education and Research (Ref.no. DMIMS (DU)/IEC/2022/47), to be carried out at Acharya Vinoba Bhave Rural Hospital (AVBRH), Sawangi, Wardha. Prior to their involvement in the study, each participants will receive a thorough explanation of the research’s objectives and procedures from a member of the research team. The participants have the right to withdraw at any time of the study and for any reason without any consequences. Written informed consent will be obtained from all participants to ensure their understanding and voluntary participation in the research. Ethics approval Ref. No. DMIMS (DU)/IEC/2022/47 dated 18/07/2022. This study has been registered at CTRI (REF/2023/06/068736) on 12/06/2023.\n\n\nParticipants\n\nAll Skeletally matured patients between the age of 18 – 70 years.\n\nDiagnosed cases of lumbar intervertebral disc prolapse.\n\nHaving back pain with radiation to lower limb for at least 4 weeks or more with straight leg raising test positive.\n\nPatient with infection, traumatic spine injuries, spinal tumors, spinal deformities and congenital spinal anomalies, bleeding disorders.\n\n32 Patients (Group A).\n\n32 Patients (Group B).\n\nSample size\n\nFormula Using Mean difference\n\nσ=std.dev= Pooled std. deviation = (1.2 +2)/2 =1.5\n\nPrimary Variable VAS (Visual Analogue scale) =\n\nMean Before = 7.1, Mean after = 1.8\n\nPotential participants of the study coming to the orthopedics OPD will be explained in detail about their condition its progression and all complications. They will be explained about these conservative treatment option and they will be assured that there will be strong rapport between the investigating team and the participants. In addition, customized care, including listening to the participant's problems, addressing their concerns and allowing them to contact investigators at any time of the day would be ensured for promoting participant retention and complete follow-up\n\nMicrosoft Excel, SSPS tests, analytical tests like the chi-square test and the Student's t-test will be performed. P 0.05 will be used as the level of significance for both primary and secondary outcomes in all statistical analyses. The study does not have any subgroups, hence the subgroup analysis will not be performed.\n\nPatients will be assessed on the basis of Visual analogue scale, Oswestry disability questionnaire score and Straight leg raising test scores one hour post procedure, after 3 weeks and 3 months and results will be documented for final analysis.\n\n\nProcedure\n\nAll adult patients with low back pain coming to the OPD of the Department of Orthopedics at Acharya Vinoba Bhave Rural Hospital (AVBRH), Sawangi, Wardha will be recruited if they satisfy the criteria. After explaining about the procedure, written informed consent will be signed. Prior to the procedure patients will be investigated with Complete Blood Count, Erythrocyte sedimentation rate, coagulation profile, blood sugar level, X-Ray anteroposterior and lateral view of Lumbosacral spine. Patients will be kept nill per oral 6 hours prior to the procedure. Oswestry disability questionnaire score, Visual Analogue Scale (VAS) score, SLRT before the procedure will be documented. Patients will be divided via computer generated random numbers using block randomization process into two groups, of 32 patients in each group. Mechanism of implementing the allocation sequence will be sequentially numbered, opaque, sealed envelopes. The principal investigator will generate the allocation sequence, will enrol participants, and will assign participants to interventions.\n\nUnder strict aseptic precautions, Group A will be receive a single injection of 1.5 ml of methylprednisolone and 1.5 ml of 2% lidocaine with 0.5 ml of saline at the affected lumbar intervertebral disc level.\n\nIn comparison, under strict aseptic precautions, Group B will receive a single injection of 3 ml autologous Platelet rich plasma, which will be prepared under the sterile condition. About 20 ml of the patient's blood will be taken, from median cubital vein which will be centrifuged to prepare 3 ml of platelet-rich plasma. 3 ml autologous P.R.P. will be administered under strict aseptic precautions in the epidural space via an interlaminar approach with an 18G needle.\n\nThis standard double spin method where 20 ml of blood is withdrawn from patient which is then transferred to 4 sterile sodium citrate vials each. These vials will be centrifuged at 2000 rpm for 15 minutes. Plasma will collect in the upper half of the test tube, while RBCs will settle in the lower part. Plasma is drawn out, collected in a different test tube, and centrifuged once more for 10 minutes at 1200 rpm. The platelet-poor plasma (PPP) in the upper buffy coat and the platelet-rich plasma (PRP) in the lower 2-4 mL layer of the plasma further separate. The simple noncooled REMI R-8C model centrifuge machine is used. The process is performed under sterile precaution at a room temperature of 24°C. This autologous PRP is utilized as the standard regenerative biological product.\n\nAll analgesics will be stopped, including NSAIDs, 2 weeks before starting the study. After the procedure, the hemodynamic status including blood pressure, heart rate, oxygen saturation and temperature of the patient will be monitored and recorded every 10 minutes for half an hour and patients will also be monitored for any complications. Patients will be evaluated after 1 hour post procedure, and will be discharged with advice to avoid excessive foreword bending, lifting heavy weights, or walking for prolonged duration, and told to follow up at 3 weeks and 3 months. VAS score (Table 1), MODQ (Table 2), and SLRT (Table 3) were noted at all times.\n\nAncillary and post trial care will be as follows, Post procedure patient will be kept inside the OT for 30 minutes for monitoring hemodynamic parameters including pulse rate, blood pressure, SP02 and then patient will be shifted to post op ICU to be observed for any complications including anaphylaxis, arrhythmia, hypotension or headache. There will be no special criteria for discontinuing or modifying allocated interventions. Strategies to improve adherence to interventions will include patient education verbally during each follow ups and reminder programs through phone calls. The participant timeline will be 18 July 2022 to 18 May 2024. Sequence generation will be done with Computer-generated random numbers. On-site computer system will be used as allocation concealment mechanism. The investigator will generate the allocation sequence, will handle participant enrolment and intervention assignment. Trial participants, outcome assessors, and data analysts will undergo blinding. In the event of an emergency requiring unblinding, the assignment will be determined through data analysis using randomized number spreadsheets. This process, devoid of human involvement, remains entirely concealed from both study investigators and potential participants until the assignment of the study arm.\n\nPatients data will be collected manually after clinical assessments of each participant using VAS score, MODQ and SLTR and will be documented manually before the intervention, 1 hour post procedure and 3 weeks and 3 months post procedure. A strong rapport will be build between the investigating team and the participants. In addition, customized care, including listening to the participant's problems, addressing their concerns and allowing them to contact investigators at any time of the day would be ensured for promoting participant retention and complete follow-up. Electronic data management will be done; the primary investigator will collect the data and will enter the data into the password protected database for screening and randomization purposes which can by access only by the principal investigator.\n\nThe Data Monitoring Committee (DMC) will consist of the institute's research lead and the department's research lead. In the event of adverse events or unintended consequences related to trial interventions or conduct, data collection, analysis, and immediate reporting will occur. A monthly review of the conducted trial will be conducted by the project management team. The trial steering group and the independent committee responsible for data monitoring and ethical considerations will convene to review and oversee the trial's progress until its conclusion.\n\nThe findings of this study will be made available to the scientific community through publication in peer reviewed journals.\n\nStudy yet to be started.\n\n\nDiscussion/conclusion\n\nThe main aim of this observational study done in Jawaharlal Nehru Medical College is to compare the efficacy of epidural PRP and epidural steroids in low back pain. As there is an increase in the incidence and prevalence of low back pain and its management options,12 it is essential to analyze and understand the outcome of low back pain managed with infiltration of epidural PRP and steroid and compare their efficacy.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\nZenodo: SPIRIT checklist for ‘Randomised control trial of epidural platelet rich plasma versus epidural steroids for low back pain’. https://doi.org/10.5281/zenodo.8192167. 11\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgements\n\nThe writer wishes to express gratitude to the personnel at the Department of Orthopedics in JNMC, AVBRH, Sawangi, Wardha, India for their assistance.\n\n\nReferences\n\nWami SD, Abere G, Dessie A, et al.: Work-related risk factors and the prevalence of low back pain among low wage workers: results from a cross-sectional study. BMC Public Health. 2019); 19: 1072. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKahere M, Ngcamphalala C, Östensson E, et al.: The economic burden of low back pain in KwaZulu-Natal, South Africa: A prevalence-based cost-of-illness analysis from the healthcare provider's perspective. PLoS One. 2022; 17(10): e0263204. Published 2022 Oct 13. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYang H, Liu H, Li Z, et al.: Low back pain associated with lumbar disc herniation: role of moderately degenerative disc and annulus fibrous tears. Int. J. Clin. Exp. Med. 2015 Feb 15; 8(2): 1634–1644. PubMed Abstract | Free Full Text\n\nDonnally CJ III, Hanna A, Varacallo M: Lumbar Degenerative Disk Disease. [Updated 2023 Aug 4]. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Reference Source\n\nKumar M: Epidemiology, pathophysiology and symptomatic treatment of sciatica: A review. nt. J. Pharm. Bio. Arch. 2011; 2.\n\nJordan J, Konstantinou K, O’Dowd J: Herniated lumbar disc. BMJ Clin. Evid. 2009; 2009: 1118.\n\nBhatia R, Chopra G: Efficacy of Platelet Rich Plasma via Lumbar Epidural Route in Chronic Prolapsed Intervertebral Disc Patients-A Pilot Study. J. Clin. Diagn. Res. 2016; 10(9): UC05-UC07. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAkeda K, et al.: Intradiscal injection of autologous serum isolated from platelet-rich-plasma for the treatment of discogenic low back pain: preliminary prospective clinical trial: GP141. Spine Journal Meeting Abstracts. LWW. 2011.\n\nBodor M, Toy A, Aufiero D: Disc regeneration with platelets and growth factors. Platelet-rich plasma: regenerative medicine: sports medicine, orthopedic, and recovery of musculoskeletal injuries. Berlin, Heidelberg: Springer Berlin Heidelberg; 2013; 265–279.\n\nPatel K, Chopra P, Upadhyayula S: Epidural Steroid Injections. [Updated 2023 Jul 3]. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Reference Source\n\nAdarsh JT: Randomised control trial of efficacy of epidural Platelet rich plasma v/s epidural steroids in low back pain (Version v1). Zenodo. 2023. Publisher Full Text\n\nAndersson GB: Epidemiological features of chronic low-back pain. Lancet. 1999; 354(9178): 581–585. Publisher Full Text"
}
|
[
{
"id": "251035",
"date": "02 Apr 2024",
"name": "King Hei Stanley Lam",
"expertise": [
"Reviewer Expertise Regenerative Injection Therapy",
"Pain Management and Pain Medicine",
"Musculoskeletal Medicine",
"Ultrasound and fluoroscopic-guided interventions. Dynamic ultrasound and -guided interventions of spine and nerves."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a prospective RCT to compare the efficacy of epidural platelet rich plasma injection vs epidural steroids for low back pain.\nIt is good to see more doctors around the world are paying more attention to the usage of PRP and other autograph biologics for treating disabilities due to chronic pain.\nMajor issue:\nThe blinding of the investigator and patients need to be elaborated and clearly defined. The protocol did not clearly state how would the patients be blinded; and it did not clearly describe how would the principal investigator and the assessors be blinded to the allocation. There is high chance the principal investigator cannot be blinded, which created a significant bias in the study. Procedure:\nWhy choose a particular form of steroid, methylprednisolone when we can choose non-particular form of steroid e.g. dexamethasone? Any justification(s)? What kind of needle, exactly, will be used for the steroid injection? Who will perform the procedure? What is(are) the experience of the interventionist(s)? What guidance will be used in the injection? Ultrasound or fluoroscope or CT? How to ensure the needle and injectate will be injected to the epidural space? How did you arrive at the protocol of 1.5ml steroid mixed with 1.5ml 2% lidocaine, please give a citation for this protocol. Why a 18G needle (what brand, what kind? Bevel of non-beveled?) will be used for PRP interlaminar injection? From my nearly 20 years’ experience of using PRP, I have no difficulty of injecting PRP using a needle bigger than 23Guage, the resistance will be more using a 25Guage needle, but is still feasible. Using a needle like 23G or 22G, there should be free flow without any resistance. Using a 18Guage needle means more damage to the ligamentum flavum and the whole tract of the trajectory, there is more chance of side effects from this procedure which is in fact preventable by using a smaller needle, e.g. 23G or 22G, or even a 25G spinal needle. What kind of system of PRP will be used? What brand/ which company? Have you checked the system and evaluate how many times from the baseline the system can concentrate with your listed procedures? What is the final concentration of the platelet, leukocytes and its differential, and red blood cells? Will the PRP be mixed with lidocaine? Please give a citation if you have. Same questions for steroid injection: Who will perform the procedure? What is(are) the experience of the interventionist(s)? What guidance will be used in the injection? Ultrasound or fluoroscope or CT? How to ensure the needle and injectate will be injected to the epidural space? Is the PRP itself or PRP lysate going to be injected, and why in each of the situation? Why post-procedure the patients need to be admitted to ICU? This procedure should not need ICU for post-procedure care.\n\nMinor issues:\nThe way this manuscript be written need to be edited.\n\nThe abstract should not contain to detailed prevalence of the LBP. “Low back pain (LBP) struck 619 million people worldwide in 2020, and by 2050, it's predicted that there will be 843 million instances worldwide. 70 to 85% of people are predicted to suffer from LBP at some point of time in their lives. 90% of these people will experience multiple episodes, and an intervertebral disc prolapse accounts for a significant portion.” These should be moved to introduction.\n\nPlease list the abbreviation when the word first appears, then keep using the abbreviation in the following content. Abbreviations in abstract and main content should be abbreviated separately.\n\n“We therefore aim to conduct a study to analyse the patient’s functional status and satisfaction after epidural platelet-rich plasma infiltration.” This statement, the aim should also contain: “pain relief”, not only the “functional status and satisfaction”. How will the satisfaction be assessed in this study? I cannot see definite data collection for this aspect.\n\n“subacute LBA is defined as lasting between 6 weeks - 3 months”, the “LBA” here should be “LBP” right? Please be consistent in using the short-forms.\n\nIn Discussion/conclusion session: “As there is an increase in the incidence and prevalence of low back pain and its management options,12” The conclusion should be drawn based on the results of your study, but not on the literature. This statement should be moved to introduction or your discussion and please separate discussion with conclusion. There should be one part in your discussion, there is NO TRUE control group in your study, which affects the validity of this study, or better think about the option of having a third group as true control group if you have not started the study.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
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https://f1000research.com/articles/12-1221
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https://f1000research.com/articles/12-1220/v1
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26 Sep 23
|
{
"type": "Case Report",
"title": "Case Report: Unexplained ascites can be constrictive pericarditis",
"authors": [
"Amol Lohakare",
"Priyanka Hampe",
"Dinesh V Hinge",
"R.J. Meshram",
"Amar Taksande",
"Amol Lohakare",
"Priyanka Hampe",
"R.J. Meshram",
"Amar Taksande"
],
"abstract": "Here we present a patient who had unexplained ascites despite a lengthy series of investigations. Extrathoracic manifestations of constrictive pericarditis such as re- solving ascites often cover the true situation and lead to a delayed diagnosis. A six-year-old boy was referred to our hospital due to a three-year history of abdominal distention, and difficulty in breathing. A chest x-ray revealed heart enlargement. The diameter of the induration of the tuberculin skin test was 14 mm. Echocardiography and cardiac magnetic resonance imaging showed constrictive pericarditis. The patient was diagnosed with a tuberculosis origin of pericarditis. Cardiac catheterization was performed, and pericardiectomy. The patient was started on an anti-tuberculosis drug leading to a complete cure of ascites.",
"keywords": [
"unexplained ascites",
"tuberculosis infection",
"constrictive pericarditis",
"pericardiectomy"
],
"content": "Introduction\n\nConstrictive pericarditis is a result of chronic pericardial inflammation characterized by fibrosis, calcification, and thickening of the pericardium leading to impaired cardiac dispensability and diastolic filling leading to right heart failure. Pericarditis can occur following causes like inflammatory conditions, non-inflammatory conditions, idiopathic disease, cardiac surgery, and radiation to the mediastinum for malignancy like Hodgkin’s disease or lymphoma.1 Malignancy is the least common cause of constrictive pericarditis.2 One to two percent of pulmonary tuberculosis (TB) patients and around 1% of all autopsied cases of TB had tuberculous pericarditis caused by Mycobacterium tuberculosis. It is the most common cause of pericarditis in a country like India, in which TB remains a major public health problem.3 Appropriate diagnosis and treatment of tuberculous pericarditis can prevent mortality. The primary pericarditis condition is rare and systemic, frequently a symptom of systemic illness, and can cause severe cardiac compromise that can be fatal.\n\n\nCase presentation\n\nA six-year-old male child born out of non-consanguineous marriage, second by birth order with normal birth and development history, no co-morbidities with no significant past medical, surgical, or family history presented to us with a complaint of distension of the abdomen for three years, and difficulty in breathing for one year. He was referred to our hospital, Acharya Vinoba Bhave Rural Hospital, in June 2022 before being referred to Jawaharlal Nehru Medical College, Wardha. The patient was apparently normal three years before, but he then developed a fever, which was low grade. The patient had three to four episodes every year and each episode lasted for several days. Later, he developed abdominal distension, which progressively increased but it was not associated with pain in the abdomen. The patient also complained of increased difficulty in breathing, aggravated by lying down but he was comfortable when sitting up. He went through extensive diagnostic workups in multiple hospitals for three years.\n\nThe patient had facial edema, a faint Kayser-Fleischer ring in both eyes, pallor, jugular vein distension, but haemodyanamically stable. On abdominal examination gross abdominal distension was observed with an everted umbilicus. The skin over the abdomen was stretched with a visible vein on the abdominal wall. On palpation, the abdomen was tense with mild hepatomegaly. On percussion fluid thrill was present. Cardiovascular examination showed jugular venous pressure (JVP) was raised, and muffled heart sounds were present. Respiratory and central nervous system examinations were normal. Anthropometry-wise was normal meaning weight and height were normal for age.\n\nIn a routine investigation, haemogram, erythrocyte sedimentation rate, renal and liver function were normal. Autoimmune workup including antinuclear antibody, double stranded DNA, and paraneoplastic markers like Carcinoembryonic antigen and cancer antigen 125 were normal, and serology for human immunodeficiency virus, hepatitis B surface antigen and hepatitis C virus were normal. (Detailed investigations are shown in Table 1). An electrocardiogram showed a low voltage QRS complex. A tuberculin skin test was performed, and the result three days later showed 14 mm induration. Ultrasonography of the abdomen showed increased echotexture, and irregularities suggestive of cirrhosis of the liver. There was no evidence of hepatic and portal vein thrombosis with gross ascites. Contrast-enhanced computed tomography of the abdomen showed gross ascites, but the rest of the study was normal. Ascetic fluid tapping showed an increase in protein 5 mg/dl with serum ascites albumin gradient 1.4 suggestive of transudative fluid. There was no malignant cell, and lymphocytic predominance. Cartridge-based nucleic acid amplification testing of ascetic fluid was negative, sputum was also negative but the Monteux test was strongly positive (3 cm) (Table 2). Based on the clinical findings, laboratory findings, imaging, and positive tuberculin skin test, the possibility of tuberculous peritonitis was considered and we started him on antitubercular therapy: isoniazid 300 mg, rifampicin 600 mg, pyrazinamide 1500 mg and ethambutol 750 mg given once daily, along with prednisolone, aldactone. His 2-D echocardiogram was done which was suggestive of constrictive pericarditis. These findings were confirmed by cardiac magnetic resonance imaging (MRI) (Figures 1–3) which showed diffuse enhancing pericardial thickening with maximum thickness along the lateral wall of left ventricle with small sized left and right ventricle and dilated right, left atrium SVC and IVC. Septal bounce was seen, as well as infective/inflammatory changes in the myocardium.\n\nBecause of constrictive pericarditis, a pediatric cardiothoracic surgeon's opinion was requested and pericardiectomy was advised and performed. Histopathological examination also confirmed the diagnosis of tubercular constrictive pericarditis after pericardiectomy. The child clinically and significantly improved and was discharged home in July 2022, on anti-tuberculous medication and prednisolone.\n\nWe tapered and stopped prednisolone after four weeks. The patient is reviewed in August 2022 in the pediatric outpatient department. Chest radiography was conducted after six months of anti-tuberculosis treatment in January 2023, and this showed that the lung and heart were normal; no pericardial effusion was seen on a 2D- echocardiogram.\n\n\nDiscussion\n\nA high index of suspicion is required to diagnose constrictive pericarditis. The incidence of constrictive pericarditis is low in the pediatrics age group because of underdiagnosed or delayed diagnosis. A rare, severe documented consequence of acute pericarditis is constrictive pericarditis.4 Constrictive pericarditis can present with a variety of symptoms, making diagnosis difficult. Consideration of it as a differential diagnosis, careful history taking, and a thorough physical examination are the most crucial components of the diagnosis.5 In India, there are few prospective studies that have assessed the particular risk in the context of various etiologies of constrictive pericarditis.4 This patient commonly presents with chest pain, breathlessness, pedal edema, narrow pulse pressure, pulse paradoxes, increased JVP, hepatomegaly, ascites, pericardial frictional rub and muffled heart sound. The long-lasting symptoms of this patient from refractory ascites led to pericardial involvement and constriction.\n\nInvestigations such as ECG show atypical ST-T wave changes and low voltage QRS complex. The chest radiograph showed an enlarged cardiac silhouette like an Erlenmeyer flask/water bottle appearance. A 2-dechocardiography is the choice of investigation as it identifies the distorted anatomical structure of heart like pericardial thickness of more than 4 mm, septal bounce, dynamic respiration variation, and enhanced ventricular interaction.6\n\nIt is particularly important to confirm the diagnosis of subacute constrictive pericarditis; however, sometimes this typical finding might not be present in some cases so cardiac magnetic resonance imaging is required. CT angiography is noninvasive, more tolerable and easier to perform. The pericardium may appear thickened and calcified, and the suprahepatic inferior vena cava may look dilated, both of these signs are indicative of constriction. Cardiac MRI is valuable for addressing the difficulties in confirming a diagnosis of constrictive pericarditis because it enables imaging of the thickened pericardium as well as the use of free breathing sequences to look for ventricular septal flattening on inspiration suggesting constrictive physiology.7 Cardiovascular catheterization is the gold standard, but it is an invasive procedure, thus it is only used in circumstances where other noninvasive tests have failed and there is uncertainty. The ratio of right ventricular to left ventricular systolic area during inspiration and expiration is known as the “systolic area index,” which has a 97% sensitivity prediction rate and a 100% positive predictive power when higher than 1.1.8 Tubercle bacilli in the pericardial fluid or a histopathological section of the pericardium are required for a confirmed diagnosis of tuberculous pericarditis.9 Accurately diagnosing and treating conditions like pericardial effusion or constriction is made simpler by integrating new imaging tools. Tissue doppler and colour M-mode echocardiography help with the clinical problem of distinguishing between constrictive pericarditis and restrictive cardiomyopathy.10\n\nPericarditis is most of the time self-limiting and responds to non-steroidal anti-inflammatory agents in uncomplicated cases. The majority of pericardial effusions may be safely managed using an echo-guided percutaneous approach. Pericardiectomy is still the most effective treatment for constrictive pericarditis and often reduces symptoms. The diseased pericardium is still best removed during surgery to treat constrictive pericarditis. While the exact timing of surgical operation is controversial, many doctors recommend pericardiectomy in non-responders following four to eight weeks of antituberculosis chemotherapy and a trial of medication for noncalcified pericardial constriction.9\n\nAfter the pericardiectomy in our case, ascites significantly decreased, and the patient was discharged. This case demonstrated chronic severe refractory ascites caused by prolonged undiagnosed constrictive pericarditis. The initial diagnostic test used to assess individuals with suspected constrictive pericarditis is echocardiography; even if the results of the test are nor- mal, constrictive pericarditis should be taken into consideration. For diagnostic certainty to confirm the diagnosis and begin the final course of therapy, the complementary roles of multidetector computed tomography (MDCT) and cardiac MRI are frequently useful.11\n\nThe patient’s symptoms were relived after pericardiectomy and treatment with antitubercular drugs and the parents of the patient were satisfied with treatment received.\n\n\nConclusions\n\nThis case demonstrated chronic constrictive pericarditis as the cause of chronic severe ascites. Pediatricians need to consider constrictive pericarditis when evaluating patients with unexplained ascites. Two-dimensional echocardiography is the first diagnostic test of choice in evaluating patients with suspected constrictive pericarditis, even if echocardiography is reported as being unremarkable, constrictive pericarditis may still be a possibility on the basis of clinical signs and symptoms and to rule out the possible common causes of ascites. The important role of multidetector computed tomography and cardiac magnetic resonance imaging can often provide diagnostic certainty to confirm the diagnosis and initiate treatment. Final or confirmatory diagnosis can be given by histopathology. After giving surgical or medical treatment such as antitubercular drugs the disease outcome can be changed.\n\n\nConsent\n\nWritten informed consent for publication of the patient’s clinical details and clinical images was obtained from the parents of the patient.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReferences\n\nYacoub M, Quintanilla Rodriguez BS, Mahajan K: StatPearls. Treasure Island (FL): StatPearls Publishing; Jul 25, 2022. Constrictive-Effusive Pericarditis.\n\nIqbal S, Sohail AA, Asif N, et al.: A rare case of constrictive pericarditis as initial manifestation of paediatric anaplastic large cell lymphoma requiring urgent pericardiectomy. Int. J. Surg. Case Rep. 2020; 73: 281–284. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMayosi BM, Burgess LJ, Doubell AF: Tuberculous pericarditis. Circulation. 2005; 112(23): 3608–3616. Publisher Full Text\n\nLaksono S, Aryadi A, Putra ICS, et al.: Pneumopericardium caused by tuberculous constrictive pericarditis and pericardiocentesis: A rare case. Crit. Care Shock. 2022; 25: 39–44.\n\nBarry M, Al-Muhaidb S, Fathala A: A case report of constrictive pericarditis: a forgotten cause of refractory ascites. Radiol. Case Rep. 2020 Oct 8; 15(12): 2565–2568. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTalreja DR, Edwards WD, Danielson GK, et al.: Constrictive pericarditis in 26 patients with histologically normal pericardial thickness. Circulation. 2003; 108(15): 1852–1857. PubMed Abstract | Publisher Full Text\n\nTse G, Ali A, Alpendurada F, et al.: Tuberculous Constrictive Pericarditis. Res. Cardiovasc. Med. 2015 Sep 7; 4(4): e29614. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFaustino M, Carmo Mendes I, Anjos R: Constrictive Pericarditis: A Challenging Diagnosis in Paediatrics. Case Rep. Cardiol. 2015; 2015: 402740–402744. Epub 2015 Sep 6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBongani M, Lesley JM, Doubell AF: Tuberculous Pericarditis. Circulation. 2005; 112: 3608–3616. Publisher Full Text\n\nTroughton RW, Asher CR, Klein AL: Pericarditis. Lancet. 2004; 363(9410): 717–727. Publisher Full Text\n\nBarry M, Al-Muhaidb S, Fathala A: A case report of constrictive pericarditis: a forgotten cause of refractory ascites. Radiol. Case Rep. 2020 Oct 8; 15(12): 2565–2568. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "322786",
"date": "23 Sep 2024",
"name": "Valentino Collini",
"expertise": [
"Reviewer Expertise Pericardial disease."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article is well written and presents an interesting case of tuberculous pericarditis in a child. The considerations are: - introduction: constrictive pericarditis can also be non-calcific - it is perhaps necessary to clarify that the tuberculin skin test and the IFN-γ release test (IGRA) are of limited value, especially in areas with a high prevalence of tuberculosis, as they cannot discriminate between previous exposure to mycobacterium and active disease - being constrictive pericarditis also for didactic purposes I would have well explained the ultrasound features of constrictive pericarditis in this case: for example the Mayo clinic criteria include septal rebound or ventricular septal shift with medial e' >8cm/s or hepatic vein expiratory diastolic inversion ratio >0.78 (sensitivity 87%, specificity 91%) - Prednisone therapy is the first-line therapy together with antibiotic therapy. However, I would specify caution in HIV-positive patients, as this therapy was associated with an increased risk of HIV-associated neoplasms in the prednisolone-treated group in the IMPI study. - With regard to therapy, if there are signs of inflammation on multimodal imaging, there is a good chance of cure with anti-inflammatory/antibiotic therapy. This includes steroid therapy (IMPI study) and also intrapericardial urokinase should be considered to reduce the risk of constriction in effusive TB pericarditis. However, I would like to stress that if there are no signs of inflammation, the probability of efficacy of anti-inflammatory therapy is very low and pericardiectomy should be considered. - As for pericardiectomy, radical pericardiectomy is recommended rather than phrenic to anterior phrenic pericardiectomy for best results (which option was chosen in our case?).\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
},
{
"id": "337495",
"date": "19 Nov 2024",
"name": "Monika Szturmowicz",
"expertise": [
"Reviewer Expertise pericardial diseases",
"tuberculosis",
"mycobacterial lung diseases",
"interstitial lung diseases"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAn interesting case report of constrictive pericarditis (presenting among others with ascites), that developed in 6-years old boy in the course of previously unrecognized tuberculous pericarditis.\nMy critical remarks concerning the article are:\nThe authors mentioned that pericardial histopathology was suggestive of tuberculous pericarditis. I would suggest to describe the results of histopathological examination in details and possibly include the microscopic view of the pericardium. Were acid-fast bacilli found in pericardial tissue? CEA and CA 125 are neoplastic markers ( not paraneoplastic). CA 125 cut off is 35 U/ml, thus an elevated level of this marker was found in the presented patient. The commentary should be added that increased CA 125 concentration may be found also in patients with non-neoplastic effusions, due to inflammatory reaction involving pleura or pericardium. Please include the initial prednisolone dose used in combination with anti-tuberculous drugs and the mode of its subsequent tapering. Were pericardial calcifications demonstrated on chest CT? The abbreviations used in the tables should be explained The discussion contains the data not included in the case description, such as the detailed results of physical examination, chest X-ray view. I would suggest to include those data also in the case report. I think that it is reasonable to include in the discussion a couple of data concerning the epidemiology of tuberculosis in India. The discussion should be more case –oriented. I would expect that the authors discuss the principles of the diagnosis of constrictive tuberculous pericarditis in the presented patient, the timing and indications for pericardiectomy as well as the differential diagnosis of ascites in pediatric patient born in India. The role of echocardiography in constrictive pericarditis is mostly to illustrate the disturbances in cardiac filling on the diastole, with increased respiratory variations, and septal bounce suggestive of the constriction. Echocardiography is not the best method of the assessment of pericardial thickness, in this respect – chest CT and MRI are much more precise.\n\nThe improvement of language mistakes (such as “ascetic fluid” – should be “ascetic fluid”, “antitubercular” should be “anti-tuberculous”) and style should be performed.\n\nIn summary: I think that the presented case report is interesting and deserves publication, but it needs the revision before indexing.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1220
|
https://f1000research.com/articles/12-1219/v1
|
26 Sep 23
|
{
"type": "Study Protocol",
"title": "A comparative study of corneal topographical and central corneal thickness changes in diabetics and non-diabetics before and after phacoemulsification: A study protocol",
"authors": [
"Dr Vijaya Mallareddy",
"Sachin Daigavane",
"Sachin Daigavane"
],
"abstract": "Diabetes is a chronic metabolic disorder and it has its effects in the eye causing various ocular complications. It is also found that diabetes causes changes in the corneal morphology. Corneal components such as epithelium, endothelium, nerves, and immune cells are affected by hyperglycemia. These changes cause a significant effect on vision in individuals with diabetes. Assessment of corneal parameters like central corneal thickness and corneal topography changes related to diabetes are essential in patients undergoing modern-day cataract surgery like phacoemulsification. Systemic condition like diabetes along with cataract surgery like phacoemulsification can influence corneal healing and fluid balance leading to changes in corneal thickness. Postoperative changes in the cornea are also important to assess the corneal health after the surgery. Comparison of preoperative and postoperative corneal measurements help in assessing the effect of phacoemulsification and health status of the cornea. Study of these changes help in preventing complications and effect on visual outcome and specialised management for individuals with diabetes undergoing cataract surgery. In diabetic patients the risk of intraoperative and postoperative complications in cataract surgery increases compared to non diabetic patients. The aim of the study is to compare corneal curvature and astigmatism by corneal topography and central corneal thickness in diabetic patients and controls before and after phacoemulsification. CTRI registration number: REF/2023/08/071341",
"keywords": [
"Diabetes",
"Corneal topography",
"Corneal curvature",
"Central corneal thickness",
"Phacoemulsification."
],
"content": "Introduction\n\nDiabetes mellitus is a metabolic disorder causing elevated blood glucose levels in the blood.1 Diabetes mellitus is a global concern and has several effects systemically.2\n\nOcular manifestations of diabetes include refractive changes, dry eye, extraocular muscle plasy, diplopia, diabetic macular edema, diabetic retinopathy and ischemic optic neuropathy.3 Corneal complications caused by diabetes include delay in wound healing, loss of sensitivity of cornea, recurrent erosions and changes in tear film.4 Diabetes mellitus affects metabolic, clinical, morphological, metabolic and physiological state of the cornea.5 Transient changes in the refraction can occur due to acute hyperglycemia.6 Several studies concluded that evidence of increased central corneal thickness, and decreased endothelial cell density,change in the size and shape of the endothelial cells is seen in diabetic cornea.3\n\nHyperglycemia causes overexpression of inflammatory mediators and proinflammatory proteins and plays a role in the development of diabetic keratopathy.7 Diabetic corneal neuropathy is caused due to damage to trigeminal nerve caused due to chronic hyperglycemia.8 Advanced glycation end products and Matrix metalloproteinases cause damage to the cornea by apoptosis of endothelial cells of cornea.9 Central corneal thickness changes in the cornea of the diabetic patients is caused due to metabolic stress affecting corneal hydration due to increase in the endothelial permeability.10 High glucose levels reduce the activity of Na-K+ ATPase which is the major component of endothelial cells causing morphological changes in the permeability of diabetic corneas. The development of changes also depends on the duration diabetes and the degree of metabolic dysregulation.11\n\nThe global diabetic population at present is 537 million. According to the international diabetes federation diabetes is expected to increase to 643 million by 2030.12\n\nSpecular microscopy is a diagnostic tool which is non-invasive and helps in the evaluation of corneal endothelium and central corneal thickness. This shows a distinctive pattern in different endothelial diseases.13\n\nCorneal topography is a non-invasive diagnostic tool used to assess corneal curvature and astigmatism. It works by projection of rings of light onto the cornea and capturing their image to generate a topographic image.14\n\nAs the prevalence of both diabetes and cataract are high it is important to know the changes that are caused due to diabetes and changes after cataract surgery on cornea. Corneal topography and central corneal thickness changes assessment helps in the understanding of ocular effects of diabetes and its influence on surgical outcomes. Accurate preoperative assessment of risk of the surgery and making decisions before the procedure and postoperative assessment help in identifying complications of the surgery and anticipate challenges related to healing, visual recovery and aid in management. With the advancements like corneal topography and central corneal thickness more precise data and valuable information for decision making can be obatined. This study helps in adding to the scientific knowledge to the existing studies and helps in improvement in the protocol of management of diabetic patients undergoing phacoemulsification.\n\nThe aim of this study is to compare corneal topography and central corneal thickness in diabetics and nondiabetics before and after phacoemulsification surgery.\n\n\n\n1. To assess and compare the baseline central corneal thickness and corneal topography in diabetics and nondiabetics.\n\n2. To identify any significant differences in corneal topography and central corneal thickness changes between two groups after phacoemulsification.\n\n3. To determine whether diabetes has an impact on corneal topography and central corneal thickness alterations following phacoemulsification.\n\n\nProtocol\n\nThis study is a non-randomised interventional study and will be conducted at Ophthalmology Department, AVBRH, Sawangi Meghe, Wardha. All the patients attending ophthalmology department for cataract surgery by phacoemulsification will be divided into diabetic and non-diabetic groups based on their diabetes status and after fulfilling inclusion and exclusion criteria. The study will take place from August 2022 to August 2024.\n\nThe sample size was calaculated using sample size formula with designed error of margin\n\nα = 1.96 (95 % Confidence interval)\n\nβ = 80% power = 0.84\n\nn = 69.02 rounding off to 70\n\n70 patients needed in each group\n\nTotal of 140 patients will be needed.\n\nStudy reference: Pateras Evangelos, Armenis J. Comparison of Corneal Topography in Eyes Before and One Month After the Phacoemulsification Procedure. Biomed J Sci & Tech Res 25(5)-2020. BJSTR. MS.ID.004275.15\n\nPreoperatively and one month after phacoemulsification surgery, topography was conducted on patients, corneal refractive forces were statistically analyzed, surgically produced astigmatism was researched, and comparisons between before and after the procedure were made.\n\nStatistical analysis will be done using chi-square test and Student’s unpaired t-test; values will be considered significant when p<0.005.\n\nSPSS version 27.0 will be used for analysis.\n\nA total of 69.02 rounding off to 70 patients will be required in each group hence a minimum 140 patients (70 eyes of 70 patients with cataract undergoing phacoemulsification having diabetes and 70 eyes of 70 patients with cataract undergoing phacoemulsification who are non-diabetic).\n\n\n\n1. Patients in the age group of 40 to 80 years.\n\n2. Patients undergoing cataract surgery by phacoemulsification.\n\n3. Patients diagnosed with diabetes are included in the diabetic group and without diabetes will be included in the non-diabetic group.\n\n4. Patients will be included in the study after giving written consent in local language.\n\n5. Patients willing to undergo postoperative follow up.\n\n1. Patients below 40 years and above 80 years.\n\n2. Patients with a history of corneal diseases such as corneal opacities, dystrophies.\n\n3. Patients with pterygium in the operating eye.\n\n4. Diagnosed cases of glaucoma.\n\n5. Patients with dry eye disease.\n\n6. Patients with a history of wearing contact lenses.\n\n7. Patients who have had traumatic cataract, post-uveitic cataract, subluxated lens and pseudoexfoliation syndrome.\n\n7. Patients unwilling to provide informed consent.\n\n8. Patients lost to follow up.\n\n\nMethods\n\nThis is a hospital based study where it is conducted in the Department of Ophthalmology at AVBRH, Sawangi after approval from the ethics committee of the institute. Patients admitted for the cataract extraction by phacoemulsification will be taken for the study where comprehensive ophthalmic examination, Visual acuity will be measured using Snellen chart where patient is made to sit at a distance of 6 meters from the chart. Then, one eye is covered with the hand and the patient is made to read the chart until they can no longer identify the majority of characters in that row. Then the result is recorded and the same is done for the other eye, and the results are interpreted. Slit lamp examination is done, where patient is made comfortably seated in the examination chair and the light of the slit lamp, light intensity and magnification are adjusted. The patient is positioned with their forehead and chin in place to keep the head steady, and the slit beam is adjusted. The examination of anterior segment is done. Fundus ophthalmoscopy is done by indirect ophthalmoscopy using 20D lens and fundus findings are noted. Intraocular pressure measurement by applanation tonometer will be carried out, where the patient is comfortably seated and topical anesthesia is applied to both eyes to minimize discomfort. The tonometer tip is placed on the cornea and gentle pressure applied, and the cornea is flattened while intraocular pressure measurements are taken. IOL power calculation using the SRK-T formula will be measured, where corneal curvature measurements are taken using corneal topography and axial length is measured using ultrasound biometry (A-scan), and anterior chamber depth is taken into account. The SRK/T formula is: IOL power (P)=A-constant(A) – (2.5×AL) + (0.9×K). Random blood sugar levels measured by glucometer will be taken into consideration, preoperative central corneal thickness by Topcon SP-IP specular microscope and corneal topography using Orbscan corneal topography system are recorded, detailed past history and history of systemic illness will be taken.\n\nStudy participants will be divided into two groups where people having Diabetes mellitus type 2 will be taken in group A and people having no history of diabetes will be taken in group B. All the patients are allotted in the groups after taking inclusion and exclusion criteria into consideration. Informed written consent will be taken from all the patients. Both study groups will undergo phacoemulsification surgery following standard surgical protocols. Corneal topographical and central corneal thickness changes will be recorded postoperatively after one week, one month and three months follow up. Statistical analysis will be conducted between the two groups to compare preoperative and postoperative central corneal thickness and corneal topography before and after phacoemulsification surgery.\n\nBoth the diabetic and non-diabetic groups will undergo phacoemulsification surgery.\n\nPhacoemulsification is a modern day cataract surgery. All the aseptic precautions like hand hygiene and use of sterile gloves and instruments to reduce risk of contamination will be taken and peribulbar anaesthesia is given to the operating eye and eye is draped and painted with betadine and globe exposure is done with eye speculum and sideport incision is taken with 15degree blade and continuous curvilinear capsulorrhexis of anterior capsule is performed with cystitome and clear corneal incision of 2.8mm wide is taken. Hydrodissection is performed using to separate the cortex from posterior capsule which helps in nucleus rotation and also facilitate to perform trenching as nucleus is prolapsed anteriorly and viscoelastic is introduced into anterior chamber before phacoemulsification which prevents corneal endothelial damage. Ultrasound energy is used to break the nucleus into fragments and then vacuum is used to catch the nuclear material and irrigation and aspiration for cortex removal and viscoelastic removal. Intraocular lens implantation is done under viscoelastic cover after extension of clear corneal incision in case of rigid intraocular lens implantation. Then the viscoelastic material is washed using Simcoe cannula and anterior chamber is formed and wound is closed.\n\nSelection bias can occur while conducting the study. To prevent selection bias, patients who have had diabetes for at least of 5 years will be taken into the study.\n\nConfidentiality of the study participants will be maintained by not revealing the identity of the patient like name and address and by using the admission code for identification. Raw data will be available only to the authorised individuals.\n\nTo publish in the academic journals and present the study outcomes in conferences once the study is completed.\n\nThe current status of the study is in the data collection stage.\n\n\nOutcomes\n\n\n\n1. This study analyses how systemic cause like diabetes influence ocular parameters like corneal topography and central corneal thickness and\n\n2. This study analyses how phacoemulsification impacts corneal parameters like corneal topography and corneal thickness.\n\nThese investigations conducted help in providing valuable insight in the potential difference in corneal responses to surgical procedure in both the groups helping improve understanding and clinical management in patients with diabetes undergoing phacoemulsification.\n\n\nDiscussion\n\nIn our study we are expecting differences in the corneal topography and central corneal thickness changes in diabetics preoperatively and postoperatively changes are seen in both the groups however we expect diabetic patients show prolonged corneal healing as compared to non-diabetics and diabetics are expected to show increased central corneal thickness following phacoemulsification.\n\nXiao-yang Luo et al., conducted a study which showed that diabetes and hyperglycemia are associated with greater central corneal thickness.16\n\nNagaraj et al., showed that endothelial cell density was decreased and central corneal thickness was increased in diabetics than non-diabetics.17\n\nSonmez et al., evaluated corneal topographic measurements in patients of acute severe hyperglycemia and concluded that eyes in diabetic patients displayed higher keratometric readings than eyes of nondiabetic ones.18\n\nBusted et al., no correlation was found between diabetes duration, blood sugar levels, and use of insulin and central corneal thickness.19\n\nArtur Jose Schmitt et al., showed that there is no significant change in the posterior corneal cuvature after phacoemulsification.20\n\nConsent will be taken from all the participants in the study and ethical committee approval from the institute was issued DMIMS (DU)/IEC/2022/195.",
"appendix": "Data availability\n\nNo data associated with this article.\n\n\nAcknowledgements\n\nI would like to acknowledge the Department of Ophthalmology, JNMC, AVBRH, Sawangi for their constant support.\n\n\nReferences\n\nDiabetes - StatPearls - NCBI Bookshelf: [cited 2023 Aug 4]. Reference Source\n\nHu FB: Globalization of Diabetes. Diabetes Care. 2011 Jun; 34(6): 1249–1257. Publisher Full Text\n\nMakkar B, Srivastav T, Mishra D, et al.: Changes in the Central Corneal Thickness in Diabetes Mellitus Patients with age and Gender Matched Healthy Controls in North Indian Population. AIMDR. 2018 Jun 24 [cited 2023 Aug 4]; 4(4). Publisher Full Text Reference Source\n\nDiabetic complications in the cornea - PMC: [cited 2023 Aug 4]. Reference Source\n\nSánchez-Thorin JC: The cornea in diabetes mellitus. Int. Ophthalmol. Clin. 1998; 38(2): 19–36. Publisher Full Text\n\nSonmez B, Bozkurt B, Atmaca A, et al.: Effect of Glycemic Control on Refractive Changes in Diabetic Patients With Hyperglycemia. Cornea. 2005 Jul; 24(5): 531–537. PubMed Abstract | Publisher Full Text\n\nMarkoulli M, Flanagan J, Tummanapalli SS, et al.: The impact of diabetes on corneal nerve morphology and ocular surface integrity. Ocul. Surf. 2018 Jan; 16(1): 45–57. PubMed Abstract | Publisher Full Text\n\nBikbova G, Oshitari T, Baba T, et al.: Diabetic corneal neuropathy: clinical perspectives. Clin. Ophthalmol. 2018; 12: 981–987. PubMed Abstract | Publisher Full Text\n\nAdvanced Glycation End Products Induce Apoptosis in Corneal Endothelium|IOVS|ARVO Journals: [cited 2023 Aug 4]. Reference Source\n\nUrban B, Raczyńska D, Bakunowicz-Łazarczyk A, et al.: Evaluation of corneal endothelium in children and adolescents with type 1 diabetes mellitus. Mediat. Inflamm. 2013; 2013: 913754.\n\nCorneal Endothelial Morphology in Children with Type 1 Diabetes.[cited 2023 Jul 17]. Reference Source\n\nFacts & figures - International Diabetes Federation: [cited 2023 Aug 3]. Reference Source\n\nChaurasia S, Vanathi M: Specular microscopy in clinical practice. Indian J. Ophthalmol. 2021 Mar; 69(3): 517–524. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCorneal Topography - EyeWiki: [cited 2023 Aug 4]. Reference Source\n\nEvangelos P: Comparison of Corneal Topography in Eyes Before and One Month After the Phacoemulsification Procedure. BJSTR. 2020 Feb 24 [cited 2023 Aug 29]; 25(5). Publisher Full Text Reference Source\n\nAssociation of Diabetes With Central Corneal Thickness Among a Multiethnic Asian Population - PMC: [cited 2023 Aug 3]. Reference Source\n\nNagaraj G, Desai AS, Jayaram N: Corneal thickness and endothelial cell density in diabetic and non- diabetic patients: a hospital based comparative study. International Journal of Advances in Medicine. 2018 May 22; 5(3): 694–699. Publisher Full Text\n\nSonmez B, Bozkurt B, Atmaca A, et al.: Effect of Glycemic Control on Refractive Changes in Diabetic Patients With Hyperglycemia. Cornea. 2005 Jul; 24(5): 531–537. PubMed Abstract | Publisher Full Text\n\nClinical observations on the corneal thickness and the corneal endothelium in diabetes mellitus - PubMed: [cited 2023 Aug 3]. Reference Source\n\nSchmitt AJ, Moreira ATR, Filho FAK, et al.: Corneal Posterior Curvature Changes After Phacoemulsification Cataract Surgery with 2.75 mm Corneal Incision. Med Hypothesis Discov Innov Ophthalmol. 2019; 8(2): 110–115. PubMed Abstract"
}
|
[
{
"id": "252769",
"date": "11 May 2024",
"name": "Aditya Verma",
"expertise": [
"Reviewer Expertise Diabetic Retinopathy",
"Age related macular degeneration",
"diabetic eye diseases",
"ophthalmic imaging"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n1. Grammatical errors 2. Introduction needs rephrasing. Diabetes is introduced in the first and 4th paragraph, and the rest is general introducing the effects of diabetes on corneal health. If the study is centered around topography and thickness, introduction can be concise and crisp rather than hitting the nail from all directions. 3. Introduction may also include the effects of phaco or cataract surgery in general on the topography and thickness values as these are the groups being compared. 4. In a study where the protocol is being submitted for approval, the intervention has already been done. Having said that, the study may be more aptly termed \"retro-prospective\", to indicate the retrospective and prospective nature of the study. 5. Patients with diabetes have been included with a bias. The diabetic status needs to be checked using prior glycosylated hemoglobin/ glucose levels (glycemic control), rather than restricting the patients with at least 5 years of diabetes. 6. Exclusion criteria need to be stricter. First, why are the patients outside of the 40-80 year age range were excluded? The authors also need to exclude any patients with previous ocular surgery/ long term use of any eye drops/ frequent blinking/ rubbing etc as the corneal topography may vary in all such instances. 7. Phaco surgery needs to be better explained. The location of the incision, the type of the IOL used, use of sutures (corneal/ scleral/ conjunctival, if any), needs to be mentioned. 8. The central corneal thickness may vary with systemic diseases, and with diurnal variation. That needs to be explained better. 9. Discussion can be limited to a general discussion of the subject rather than what is being expected. That induces observer bias which may alter the results. 10. I did not see the study parameters. These need to be defined clearly. Further, if vision is one of them, all patients with pre-existing retinal diseases/ intravitreal injections and post op cystoid edema need to be excluded\n\nIs the rationale for, and objectives of, the study clearly described? No\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1219
|
https://f1000research.com/articles/12-1218/v1
|
26 Sep 23
|
{
"type": "Study Protocol",
"title": "Changes in tear film function in patients after pterygium excision surgery done under topical anaesthesia with and without conjunctival autograft – A protocol for a randomized interventional study",
"authors": [
"Raina Jain",
"Pravin K. Tidake",
"Pravin K. Tidake"
],
"abstract": "Background: Pterygium is an extra-ocular disorder related to progressive subepithelial growth of degenerative conjunctival tissue over the cornea. There are multifactorial causes that lead to the growth of pterygium. The tear film becomes unstable due to the degenerative growth of the conjunctiva. The tear film is divided into three different layers. The lipid layer is secreted by the meibomian gland, which is the exterior layer exposed to the environment and prevents tears from drying out too rapidly. The lacrimal gland releases the middle layer, the aqueous layer, which provides oxygen to the corneal epithelial layer. The goblet cells secrete mucus, the innermost layer that makes the corneal epithelium hydrophilic. Due to uneven wettability brought on by the progression of pterygium, the tear film becomes unstable and may damage the ocular surface. It has been found that pterygium excision increases tear film stability. According to a study, the incidence of pterygium in central rural India is 12.9%. Incidence increases with age, gender, and occupation. Methods: The patients with pterygium will be divided into two groups for the pterygium excision surgery: Group 1 consists of patients in which conjunctival autograft will not be done after pterygium excision, and Group 2 consists of patients in which conjunctival autograft will be done after pterygium excision. Preoperatively and postoperatively, visual acuity was assessed in all the patients on day 1, 4 weeks, and 8 weeks on follow-up. Tear film evaluation was done through Tear film Break Up Time (T-BUT) and Schirmer’s Test in patients preoperatively and postoperatively on day 1, 4 weeks, and 8 weeks follow up. CTRI Registration: REF/2023/07/071130 (30/07/2023) Protocol version: v1 dated 7/08/2023",
"keywords": [
"Pterygium",
"Tear film",
"Schirmer’s Test",
"Tear film Break Up Time",
"Conjunctival autograft",
"Dry Eye",
"Meibomian gland."
],
"content": "Introduction\n\nThe subepithelial fibrovascular growth of the degenerative bulbar conjunctival tissue that extends to the cornea is known as pterygium. It may result in impaired cosmesis, diminished vision due to astigmatism caused by growth along the pupillary axis, disruption of the precorneal tear film, and persistent discomfort.1\n\nThe prevalence range of pterygium is 0.7% to 31% globally.2 It is roughly 13% prevalent in rural areas of central India. It is predominately observed in men in tropical and subtropical areas.2,3 The occurrence of pterygium is higher in equatorial countries because of higher exposure to ultraviolet (UV) light from the sun.4 Ultraviolet light causes hyperplasia and thickening in subconjunctival tissue due to damage to Bowmans’s membrane. The prevalence of pterygium in outdoor workers is comparatively more.4 Other potential contributing variables include age, sunlight, genetic factors, chronic inflammation, microtrauma, and dry eye.5 Low-grade pterygium may not cause symptoms but can lead to irritation, discomfort, impaired vision, induced astigmatism, and foreign body sensation.6 The epithelium of the cornea is considered hydrophobic as it is made of a lipophilic substance. So adequate surfactant is required in aqueous substance to wet the corneal surface. Proteins dissolved in tear film reduce surface tension and help it spread over the surface properly.7\n\nPrecorneal tear film can be divided into three parts. The lipid layer is produced by the meibomian glands. The lacrimal gland produces the aqueous layer, which provides the corneal epithelium with oxygen. The goblet cells secrete the inner mucous layer, which is responsible for the hydrophilic nature of corneal epithelium.8 Abnormal tear films are seen in patients with degenerative disease of the conjunctiva.9 Despite the significance of tear volume in pterygium patients, several studies have concluded with no change in tear volume and decreased tear output.10\n\nAccording to Wanzeler ACV et al., pterygium causes a significant effect on the surface of the eye because it directly alters meibomian gland patterns, which can cause discomfort and signs of dysfunction.11 Tear osmolarity increased in pterygium-affected eyes; the quantity and quality of tear film deteriorated while the number of goblet cells dropped.12 Several investigations are available for diagnosing dry eye, out of which Schirmer’s test and TBUT are commonly used due to their easy availability and cost-effectiveness. The TBUT test evaluates the tear film's quality.13,14 Rose Bengal staining detects damaged epithelial cells, which serves as an indirect indicator of decreased tear volume. The more the aqueous deficit, the more the degree of staining. Conjunctival impression cytology (CIC) tests the viability of the conjunctiva.15 Schirmer's and T-BUT levels are lower in pterygium-affected eyes, relating a link between abnormalities of ocular surface and tear film.16,17 Lower value TBUT is related to unstable tear films. Tear film stability can be measured rather quickly and simply with the TBUT. Keratograph 5M helps in the non-invasive evaluation of tear film with the help of the Placido concentric circles image. Images taken by Keratograph 5M allow us to measure tear meniscus height in millimetres. Meibomian gland function is assessed using a Keratograph 5M. The meiboscan infrared equipment was used to assess the gland. Infrared images of meibography of the meibomian glands were assessed by applying Meiboscore.11\n\nUsing Schirmer’s test and T-BUT, the evaluation is cheap, cost-effective, and reproducible. While the other methods will require the availability of instruments and are time-consuming.\n\nThe growth of pterygium is associated with the disruption of the integrity of the tear film. The disrupted tear film will cause ocular dryness, astigmatism, discomfort, and grittiness. Schirmer's test and tear film breakup time are two techniques for tear film evaluation. Tear film after pterygium excision surgery with and without conjunctival autograft will be evaluated postoperatively. This study will help to assess the postoperative complication and will enhance the already existing knowledge in the management of dry eye diseases in pterygium patients.\n\nThis protocol is reported inline with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.19\n\nChanges in tear film function in patients after pterygium excision surgery done under topical anaesthesia with and without conjunctival autograft.\n\n\n\n1) To assess the function of the tear film in patients with unilateral pterygium and unaffected other eye.\n\n2) To assess the change in tear film function in postoperative patients of pterygium excision under topical anaesthesia with and without conjunctival autograft using Schirmer’s test I and II.\n\n3) Tostudy the ocular surface through fluorescein staining and measuring tear film break up time.\n\n\nProtocol\n\nThis is a two-arm, open-labelled, non-randomized interventional study. It will take place over 2 years (August 2022 – August 2024). Study was conducted in Out-Patient Department of Ophthalmology, Acharya Vinobha Bhave Rural Hospital Sawangi (Meghe), Wardha, Maharashtra, after receiving approval from the Institutional Ethics Committee of Datta Meghe Institute of Higher Education and Research.\n\nAll the patients who will be coming the O.P.D from August 2022 to August 2024 with unilateral pterygium of all age groups will be included in the study with routine admissions and with proper information about benefits of surgery andafter considering inclusion and exclusion criteria and taking informed consent for surgery and follow-up.\n\nSample size calculation\n\nSample size formula for difference between two mean\n\nWhere Zα is the level of significance at 5%, i.e., 95% confidence interval = 1.96\n\nZ β is the power of test = 80% = 0.84\n\nΣ1 = S.D. of TBUT in diseased eye Pre-test = 3.4\n\nΣ2 = S.D. of TUBT in diseased eye Post-test = 2.7\n\nΔ = difference between two means. = 12.8 – 9.9 = 2.9\n\nK = 1\n\n\n\nAngli Manhan et al’s16 study is used for reference in our study.\n\nSoftware used: R-software version 4.3.2\n\n\n\n1) Patients who presented with a unilateral primary pterygium were observed.\n\n2) The comparison of tear film was made between the eye having pterygium and the other eye being considered as control.\n\n3) Patient who were willing for surgery.\n\n4) Patients willing for postoperative follow-up.\n\n\n\n1) Patients having a systemic disease that leads to dry eye example: Sjogren’s syndrome.\n\n2) Patients on medication like psychotropics and diuretics that cause ocular surface dryness.\n\n3) Patients using contact lenses.\n\n4) Patients with adnexal, anterior, or posterior segment diseases that affect the stability and secretion of the tear film.\n\n5) Patients who underwent ocular surgery recently.\n\n6) Patients using antiglaucoma drops, which cause ocular dryness.\n\n7) Patients having recurrent pterygium or bilateral pterygium.\n\n8) Patients who did not give consent for surgery.\n\n9) Patients who did not come for follow up regularly.\n\nAfter the enrolment of the subject in study, participants in the study will be split into two arms. Arm A (patients undergoing pterygium excision surgery combined with conjunctival autograft) and Arm B (patients with pterygium excision undergone without conjunctival autograft), randomly assigned for a 1:1 allocation with the intention for treatment. Subjects will be invited and screened as part of the study's inclusion process. For subject allocation, a randomization procedure using a computer-generated list will be used. Patients will undergo surgery. Participants will be assessed on day 1, 4 weeks, and 8 weeks postoperatively to assess primary and secondary parameters.\n\nFirstly, a thorough history of the symptoms will be taken, including their onset, duration, and any exacerbating factors. Secondly, a routine physical examination which will include blood investigations for complete blood count (CBC), random blood sugar, Electrocardiography (E.C.G) and Chest X-Ray will be performed on the patients. Thirdly, a comprehensive ocular examination will be performed on each patient, which includes the following procedures: a) Examination of the anterior segment of the eye involving the cornea, iris, pupil, lens, and eyelids. B) Evaluation of near vision and distant vision. The following examinations will be carried out in both eyes:\n\nSchirmer’s test:\n\n(a) Schirmer’s test- 1 (Without anaesthesia): This test helps in evaluation of aqueous deficiency in patients with dry eye by measuring reflex tear secretion after stimulation of conjunctiva. The reflex tear secretion is measured with the help of Whatman filter paper 41. It is placed at junction of middle and lateral one third of lower lid. The amount of wettability is measured in millimetre. If the reading is less than 10 mm, then aqueous tear deficiency is likely present.\n\n(b) Basal Secretion/SCH-2 (After anaesthesia).\n\nIn the dim light room, the patient will undergo examination under a slit lamp, followed by Schirmer's test and Tear Film Break Up Time evaluation which is described below. At the intersection of the lateral 1/3 and medial 2/3, the lower palpebral conjunctiva was gently covered by a Schirmer strip that was folded at the notch. Ask the patient to sustain an open eyelid and regular blink pattern. Five minutes later, the strip was removed and measured in mm for the amount of wettability. After five minutes, if the wetness length was less than 10 mm, the Schirmer's-1 test—which does not involve anesthesia—was considered positive. Schirmer's tear test filter strips, also known as Whatmann no. 41 filter paper strips, which are 35 x 5 mm and folded 5 mm from one end, were the commercially available material utilized.\n\nFollowing anesthesia, Schirmer's test (Basal secretion) was conducted similarly to the SCH-1 procedure but followed topical proparacaine 0.5%.\n\nTear film break up time (TBUT):\n\nThe cornea was first stained with fluorescein for this test, and then ophthalmic evaluation was under a red-free blue filter-lit slit lamp (Appasawamy LED Slit lamp AIA-11). The time between the first dry spots on the tear film and the lid blink is recorded. The average of the three recordings determined the TBUT. An average TBUT of less than 10 seconds indicated a positive result. Contact with the cornea was avoided to prevent excessive reflex tear production.\n\nOperative procedure:\n\nEvery patient was recommended to instil topical antibiotic eye drops four times a day before surgery. All patients granted their consent after being informed about the surgery. Every patient underwent laboratory testing, such as haemoglobin (Hb), blood sugar, and coagulation profile.\n\nA universal eye speculum was used to open the eye. Paracaine was used as a topical anaesthetic. Pterygium was dissected 4mm from the limbus to reveal the bare sclera. Using conjunctival scissors, fibrovascular tissue was dissected from the adjacent conjunctiva. The thickened conjunctiva and the tenon capsule below the conjunctiva were removed. The spontaneous process of haemostasis was achieved without the need for cautery. The further procedure would be different in both the groups. Group 1 was left with bare sclera and group 2 was proceeded with conjunctival autograft. The defect's size was measured using a calliper. A donor conjunctival graft, primarily obtained from the bulbar conjunctiva superiorly, was applied to the bare sclera. The original direction of the juxta-limbal boundary was carefully preserved. A lens spatula applied slight pressure to the free graft for eight to ten minutes to maintain its position. The bandage was left on for a whole day.\n\nPostoperative care:\n\nAfter a day, the bandage was removed, and topical application of a combination of antibiotic (Moxifloxacin 0.5%) and steroid (Dexamethasone 0.1%) eye drops combination formulation was prescribed. The drops were instilled four times a day for the first two weeks, tapered off to two times a day during the next 1 week and finally halted.\n\nFollowing surgery, patients were not advised artificial tear drops. Following surgery, all patients were monitored on day one, one month, and two months. Schirmer's test and TBUT were done two months after surgery and they were given refraction on follow up visit. On every follow up, complications will be noted, if any and will be managed accordingly. For follow up visit routine camps were organized in the same places and patients were given spectacles free of cost on follow up. The patients who did not show up for follow up were considered drop outs from the study.\n\nControl group\n\nTear film evaluation will be done in the control eye with the help of Schirmer’s Test I and II and Tear Film Break Up Time.\n\n\nOutcomes\n\n\n\n1) Evaluation of tear film function by using Schirmer’s test I and II.-\n\nThe evaluation of tear film by using a Schirmer’s strip in the control eye should be more than 10 mm.\n\nIf the reading is less than 10mm, then Schirmer's test is considered positive.\n\n2) Tear film evaluation using Tear Film Break Up Time-\n\nThree readings were observed. If the mean value was less than 10 seconds, then the TBUT is considered positive for the presence of dry eye.\n\n\n\n1) Evaluation of improvement in visual acuity after pterygium excision.\n\n2) Complications of pterygium surgery include lid oedema, haemorrhage, and displaced graft.\n\nAll the results for the outcome variables will be presented in tables and will be described over descriptive statistics. No blinding will be done in the study. Outcome variables (tear film evaluation by Schirmer’s test and Tear Film Break Up Time, visual acuity) will be firstly tested for normality for the quantitative measurement of mean and standard deviation (SD). Positional average (Median) statistics will be used to find out for skewed distributions and calculating the interquartile range (IQR). All the binary and catergorical variables will be described over the frequency and percentages for qualitative assessment. Results will be calculated using R-software free version 4.3.2 for all statistical analysis.\n\nThe inferential statistics for testing the significant difference over the outcome variables will be evaluated at 5% level of significance (p ≤ 0.05)\n\nOutcome Variable:- Baseline to endline visit assessment for pre operative procedure in comparison for two groups (pterygium excision done with conjunctival autograft and excision done without conjunctival autograft) over the measurement score for mean of primary variable (tear film evaluation by Schirmer’s test and Tear Film Break Up Time, visual acuity) will be evaluated for finding significance in mean using Anova or Kruskal wallis test for more than 2 assessment period. Post-hoc (Tuckey’s or Dunccan) test will be used to find the significance difference between two group for pair-wise comparison. Outcome variables will be tested for intra difference in measurement at pre & post visits using paired t-test for finding the significance in mean. While for inter group difference unpaired t- test for comparison of two group. Generalised models for repeated measures will be tested for different visit periods (within the group) & for comparison of two groups (between the group) to find fixed & random effects.\n\nFor non-normal distribution Mathematical algorithms will be used for conversion of the data to normal distribution. If Data over primary variable still follows the non normal distribution then we will use alternate non parametric test (Chi square, Mann Whitney, Wilcoxon test, Kruskal wallis, Friedmann test). If data for the outcome variable for testing normality results with non normal distribution for the quantitative assessment, it will be converted for normal distribution following mathematical algorithm, besides if data persists with non normal distribution we will use alternate non parametric test (Chi square, Mann Whitney, Wilcoxon test, Kruskal wallis, Friedmann test).\n\nFollowing Categorial distribution will be graded for scoring system (Binary):\n\nSchirmer’s test value of less than 10mm is considered positive.\n\nTBUT of less than 10 seconds is considered positive.\n\nAssessment of visual acuity will be done through Snellen’s Chart.\n\nChi square analysis will be performed for categorial evaluation between two groups pterygium excision done with conjunctival autograft and excision done without conjunctival autograft for statistical evidence of finding significance on Schirmer’s test less than 10mm considered as positive against normal& TBUT of less than 10 seconds considered as positive against normal at 5% l.o.s.(P = < 0.05).\n\nt-test unpaired or alternative non parametric test will be used for finding significance at 5% l.o.s. (P = < 0.05) between groups pterygium excision done with conjunctival autograft and excision done without conjunctival autograft\n\nThis study will help in assessment in the changes in tear film in the patients with pterygium and the change in tear film occurring after the excision of pterygium with and without conjunctival autograft. This study will also help to evaluate the better surgical method.\n\nTo publish the study outcome in an esteemed journal and present findings at a National Conference on completion of study.\n\nPatients are yet to be recruited.\n\n\nDiscussion\n\nManhas et al. in their study, found that tear film breakup time has a more diagnostic value than Schirmer's test II. They found that the TBUT test was abnormal in 21.11% of control eyes and 47.78% of pterygium patients. Their research concluded that the Schirmer's-2 test's statistical sensitivity was determined to be 24.4%, while its specificity was 90%. In eyes with pterygium, the TBUT test exhibited a sensitivity of 47.7% and a specificity of 78.8%, demonstrating that it was more sensitive than Schirmer's test performed under anaesthesia. Two months after surgery, the average TBUT was 12.8 + 2.7 seconds. This was a statistically significant improvement (p-value = 0.0001) from the preoperative readings.16\n\nIn a study by Shili Wang et al., the mean TBUT in the eyes with pterygium was determined to be 9.89 + 3.95 seconds before surgery. Four weeks after the operation, the TBUT value was 12.78 + 4.12 seconds; eight weeks later, it was 14.27 + 3.80 seconds. The two values were significantly different from those prior to surgery (p = 0.028 and p = 0.013). The final TBUT readings at the conclusion of the research period revealed a statistically significant improvement in the TBUT values, consistent with our investigation's anticipated outcomes.17\n\nIn the study conducted by Patkar P, Sune P on 100 patients, the preoperative Schirmer's value which was 13.00±2.47 mm was found to be increased to 14.39±2.34 mm, 14.78±2.11 mm and 14.78±2.11 mm, respectively on postoperative day 10th, 30th, and 60th. On preoperative day and postoperative day 10, the Schirmer's I value was significantly different (p-value 0.0001).18\n\nThe mean Schirmer's I measurement increased after the pterygium surgery in the study conducted by Neeraj Sharma et al., which found that following pterygium removal, the mean preoperative Tear Breakup Time (TBUT) increased from 7.212 seconds to 13.059 seconds, which is statistically significant.19 Statistically comparable postoperative improvement was seen in both groups. Postoperative outcomes were statistically superior in the conjunctival autograft group compared to those without graft. This is a similar outcome expected in our study8\n\nEthical committee approval from the DMIHER was issued DMIMS (DU)/IEC/2022/201on 28 August 2022. There was no involvement of animals Considering all the ethical values, informed consent was taken from all the subjects involved. The aim of the research will be explained to each participant. The lead investigator will obtain both written and verbal informed consent from each participant before the intervention. The Helsinki Declaration of 1975, mentioned in 2008, shall be followed for all procedures in this investigation.\n\nThe study documentation will be treated as confidential information and safely archived with only the principal investigator having access. Incase of any adverse effect, reporting will be done to the investigator and the subject will be treated accordingly and will be considered as drop out from the study.",
"appendix": "Data availability\n\nNo data is associated with this article.\n\nZenodo: SPIRIT checklist for ‘Changes in tear film function in patients after pterygium excision surgery done under topical anaesthesia with and without conjunctival autograft – A protocol for a randomized interventional study’. https://doi.org/10.5281/zenodo.8338924. 19\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgements\n\nI want to express gratitude to all personnel at the Department of Ophthalmology in JNMC, AVBRH, Sawangi, Wardha, Maharashtra, India for their assistance in the study and analysis of the data.\n\n\nReferences\n\nMutlu F: A comparative study of recurrent pterygium surgery Limbal conjunctival autograft transplantation versus mitomycin C with conjunctival flap. Ophthalmology. 1999 Apr 1; 106(4): 817–821. PubMed Abstract | Publisher Full Text\n\nDetels R, Dhir SP: Pterygium: A Geographical Study. Arch. Ophthalmol. 1967 Oct 1; 78(4): 485–491. Publisher Full Text\n\nHill JC, Maske R: Pathogenesis of pterygium. Eye. 1989 Mar; 3(2): 218–226. Publisher Full Text\n\nHilgers JHC: Pterygium: Its Incidence, Heredity and Etiology*. Am. J. Ophthalmol. 1960 Oct; 50(4): 635–644. Publisher Full Text\n\nTürkyılmaz K, Öner V, Sevim MŞ, et al.: Effect of Pterygium Surgery on Tear Osmolarity. J. Ophthalmol. 2013 Jan 20; 2013: 1–5. Publisher Full Text\n\nSaw SM, Tan D: Pterygium: prevalence, demography and risk factors. Ophthalmic Epidemiol. 1999 Jan; 6(3): 219–228. Publisher Full Text\n\nLemp MA: The Precorneal Tear Film: I. Factors in Spreading and Maintaining a Continuous Tear Film Over the Corneal Surface. Arch. Ophthalmol. 1970 Jan 1; 83(1): 89. Publisher Full Text\n\nSharma N, Sehrawat S, Sharma S: Comparative Analysis of Tear Film Parameters in Patients Undergoing Pterygium Excision by Conjunctival Autograft or Bare Sclera Technique Augmented by Intraoperative Mitomycin C Application. JCDR. 2022 [cited 2023 Jul 29]. Reference Source\n\nOguz H, Karadede S, Bitiren M, et al.: Tear functions in patients with pinguecula. Acta Ophthalmol. Scand. 2001 Jun; 79(3): 262–265. PubMed Abstract | Publisher Full Text\n\nChaidaroon W, Pongmoragot N: Basic tear secretion measurement in pterygium. J. Med. Assoc. Thail. 2003 Apr; 86(4): 348–352. PubMed Abstract\n\nWanzeler ACV, Barbosa IAF, Duarte B, et al.: Impact of pterygium on the ocular surface and meibomian glands. Shukla D, editor. PLoS One. 2019 Sep 12; 14(9): e0213956. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSafarzadeh M, Heidari S, Azizzadeh P, et al.: Comparative assessment of tear function tests, tear osmolarity, and conjunctival impression cytology between patients with pterygium and healthy eyes. J. Ophthalmic Vis. Res. 2019; 14(1): 11. Publisher Full Text\n\nSenchyna M, Wax MB: Quantitative assessment of tear production: A review of methods and utility in dry eye drug discovery. J. Ocul. Biol. Dis. inform. 2008 Mar; 1(1): 1–6. Publisher Full Text\n\nGaneshpuri AS, Kamble BS, Patil P, et al.: A Comparative Study of Tear Film Stability & Secretion in Pterygium Patients - Diabetic vs. Non-diabetic. Int. J. Health Sci. 2014; (4).\n\nSingh R: Impression cytology of the ocular surface. Br. J. Ophthalmol. 2005 Dec 1; 89(12): 1655–1659. PubMed Abstract | Publisher Full Text | Free Full Text\n\nManhas A, Gupta D, Manhas RS, et al.: Comparison of Tear Film Breakup Time with Schirmer's Test with Anesthesia to Detect Tear Film Abnormality in Patients with Pterygium - A Study from Jammu and Kashmir.2017; 5: 3.\n\nWang S, Jiang B, Gu Y: Changes of tear film function after pterygium operation. Ophthalmic Res. 2011; 45(4): 210–215. PubMed Abstract | Publisher Full Text\n\nPatkar P, Sune P: Evaluation of Tear Film Functions Preoperatively and Postoperatively in Cases with Pterygium: A Case Control Study. J. Clin. Diagn. Res. 2020 Jan 1; 14. Publisher Full Text\n\nDr Jain R , Dr Tidake P : Changes in tear film function in patients after pterygium excision surgery done under topical anesthesia with and without conjunctival autograft. (Version v1). Zenodo. 2023. Publisher Full Text"
}
|
[
{
"id": "219379",
"date": "27 Dec 2023",
"name": "Chizoba Udoka Uba-Obiano",
"expertise": [
"Reviewer Expertise General Ophthalmology."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n1. The title is long, although it summarizes the study (27 words). I would suggest this: CHANGES IN TEAR FILM FUNCTION AFTER PTERYGIUM EXCISION WITH AND WITHOUT CONJUNCTIVAL AUTOGRAFT: A PROTOCOL FOR A RANDOMISED INTERVENTIONAL STUDY.\n2. The abstract should provide an informative and balanced summary of what would be done. The background of the abstract should be summarized in one or two sentences. It is long and not well coordinated. The aim or objective of the study is not stated. The method should be explained briefly.\n3. The research needs to state the aim or objective of the study as the closing statement in the introduction.\n4. Methods: Since this is a study protocol, the method should be in future tenses and not past tense. It is important to state that randomization will be done and how the patients will be selected and assigned to each group.\n5. Key words should be reduced to three in number: Pterygium, tear film function. conjunctival autograft.\n6. The research should also state the reason for selecting conjunctival autograft, any effect on tear film, and back this up with studies.\n7. The researcher may lose some patients to follow. How will this be prevented? state.\n8. Recheck or rephrase: low-grade pterygium (which classification is this in paragraph 2?) kindly state or reference. Also, rephrase sentences on lines 9, 10, and 11.\n9. Rephrase the sentences in paragraph 4, lines 2–9; they are rather short sentences that can be merged, and they will follow sequentially.\n10. Aim: To determine the changes in tear film function before and after pterygium excision surgery done under topical anaesthesia with and without conjunctival autograft.\n11. Objectives should be clearly stated: i. to assess tear film function in eyes with unilateral pterygium and the eyes without pterygium using Schirmer's test and TBUT ii. to assess the change in tear film function after pterygium excision using Schirmer's test. iii. to assess the change in tear film function after pterygium excision using tear film break-up time. iv. to assess the ocular surface changes using fluorescein staining. (This fourth objective should be removed.)\n12. Protocol: why write non-randomized when the topic already bears a randomized study? Rephrase the sentences written in this section. Stick to future tenses. Suggestion: Patients of all age groups who will present to the outpatient clinic from August 2022 - August 2024 with unilateral pterygium will be included in the study. The eligibility criteria will be considered with proper information about the benefits of surgery explained to the patient. Written informed consent for the surgery and follow-up will also be obtained. The patients will be admitted accordingly.\n13. The sample size is small for the study: 20 in each group. Look for another study that can provide a larger sample size.\n14. The listed inclusion criteria should be present or future tenses. Also, remove No. 2 from the list.\n15. Exclusion criteria: No. 1: patient WITH NO. 9: patients who will be willing to come for follow-up regularly.\n16. Procedure: Arm B (patient UNDERGOING pterygium excision without conjunctival autograft) Paragraph 2: eyelids, cornea, iris, and pupils in this order. line 3: at the junction of the medial 2/3rd and lateral 1/3rd of the lower lid.\n17. Recheck this statement: if the reading is less than 10mm, then aqueous tear deficiency is LIKELY present\n18. Why Schirmer tests I and II? Choose one, preferably Schirmer test I.\n19. Correction: The patient will be asked to sustain open eyelids with a regular blink pattern. 5 minutes later, the strip will be removed.\n20. Correction: ARE the commercially available materials that will be utilized.\n21. Correction: the time between the lid blink and the appearance of the dry spot on the corneal surface.\n22. What type of fluorescein will be used? paper fluorescein strip? it should be moistened with sterile water to prevent irritation.\n23. Operative procedures should be described in the future tense.\n24. Post-op care: paragraph 2, line 2, sentence 2: Schirmer's test and TBUT will be done on each follow-up visit.\n25. Correction: Tear film evaluation will also be done in the control eyes using Schirmer tests and TBUT.\n26. Correction in Scope: This study will help to assess tear film changes ..........\n27. The Vancouver referencing style should be maintained.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
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https://f1000research.com/articles/12-1218
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https://f1000research.com/articles/11-398/v1
|
06 Apr 22
|
{
"type": "Research Article",
"title": "Pandemic Pedagogy: Perception of Nursing students’: A cross-sectional study",
"authors": [
"Prima Jenevive Jyothi D'Souza",
"Anil Raj Assariparambil",
"G Muthamilselvi",
"Veena M Joseph",
"Linu Sara George",
"Prima Jenevive Jyothi D'Souza",
"G Muthamilselvi",
"Veena M Joseph",
"Linu Sara George"
],
"abstract": "Coronavirus disease 2019 pandemic impacted across the globe disrupting all sectors including the higher education universities. Nursing institutions faced various challenges due to the pandemic restrictions, of which the abrupt shift of implementing the curriculum to online mode posed a major challenge to both the teachers and the students. To assess nursing students' perception of pandemic pedagogy and the challenges faced in online teaching-learning, this cross-sectional survey was conducted among 982 undergraduate nursing students from three Deemed to be University nursing institutions of Southern India. Institutional Ethics Committee approval (IEC 444/2020), permission from the heads of the institutions and study participant’s consent was obtained. Data was collected using an online survey questionnaire which had three domains, including student-related (19 items), teacher-related(5 items), and physical learning environment-related factors (11 items). The reliability was established using Cronbach’s Alpha (0.86). Explored the favouring, hindering factors and challenges faced during the emergency remote teaching with open-ended items. The overall mean score of perceptions on pandemic pedagogy was 89.03±10.03. Sixty-three percent of students had a total perception score above 87 which indicates that they preferred online learning during the pandemic whereas 45% preferred classroom learning. There was a significant difference in the total perception scores and the years of study( F (3, 978) = 4.96, p = 0.002). The factors favouring online learning were, an opportunity to view the recorded classes even after the live classes’ (n=165), and ‘more time to spend for learning activities’ (n=152). Factors that hindered the learning or the challenges faced were poor network connectivity (n=451), and lack of opportunity for group study (n=326). Students favoured online learning during the pandemic; however, there were several challenges. The educational institutions need to prepare themselves to overcome this and focus on a blended learning curriculum.",
"keywords": [
"Nursing",
"Perception",
"Pandemics",
"Students",
"Teaching"
],
"content": "What is already known about the topic?\n\n\n\n• COVID-19 pandemic has disrupted educational activities worldwide.\n\n• Higher education institutions, including nursing, have quickly moved to online education for uninterrupted education.\n\n• There is a gap in the knowledge of emergency remote teaching for the nursing curriculum during the COVID-19 pandemic.\n\n\nWhat this paper adds?\n\n\n\n• This study describes how nursing students perceived online learning and the challenges faced during the COVID-19 pandemic.\n\n• The findings of the study contribute to nursing education, emphasizing the need of online education for uninterrupted learning and prevent the spread of infection by staying safe at home.\n\n• The incorporation of blended learning post-pandemic helps nurse educators and the policymakers to take appropriate steps in escalating the nursing education in the country to greater heights.\n\n\nIntroduction\n\nThe outbreak of Coronavirus Disease 2019 (COVID-19) hampered educational activities worldwide. Educational institutions in most countries had to go online from face-to-face teaching during lockdown and after. When COVID-19 crisis would end in uncertain and colleges started functioning as before has led to continuing e-learning in many parts of the world indefinitely until the pandemic comes under control.\n\nWhat we experienced during the COVID-19 was unprecedented. Nursing institutions faced a unique challenge as they had a significant role in bringing up the next generation of care providers (Dewart et al., 2020). COVID-19 pandemic had pushed us towards e-learning from traditional classroom learning (Hodges et al., 2020). The abrupt interruption of the well-planned academic activities in the face-to-face classes and the shift to online teaching and learning was challenging for both teachers and students due to the technology and its accessibility.\n\nNursing education focuses on the development of knowledge and clinical competency for providing quality care to the patients. During the course of study, theory and practicum go hand-in-hand for students and thereby bridge the gap between theories and practice. Students acquire their clinical skills by practicing in both laboratory and hospital. Getting adequate clinical experiences would improves the skills in performing nursing procedure, rather than enhancing critical thinking and clinical decision-making abilities. As the government declared the closure of educational institutions due to the pandemic, students had to move to their homes without knowing about their return to the colleges. Both students and teachers assumed that they would return at the earliest, but the pandemic kept them in their homes for more than six months.\n\nAll the nursing schools in India quickly moved on to emergency remote teaching through online mode. The implementation of emergency remote teaching helped to continue learning outside educational institutions, keeping students and teachers safe in their homes. During this phase, students might have had varied experiences and faced various challenges due to the changes in learning environment. Before the pandemic, most of the teaching-learning activities occurred either in formal classrooms or laboratories under teacher’s constant mentoring, whereas in the mode of emergency remote teaching, the students had to take the responsibility for learning themselves.\n\nAn e-newsletter ‘education week’ reported the opinion of the high school students from France concerning online learning. A few views of students emphasized that learning from home might be more stressful. The students perceived that online learning was irritating, more difficult when the teachers pile up the assignments. A few students experienced that it was good as they could learn in a quiet place without rushing to the classes in the morning. In fact, during the regular classes students spend time with their friends interacting, which helps them manage their stress and academics (Larry Ferlazzo, n.d.).\n\nThe emergency remote teaching or pandemic pedagogy in nursing and other professions has not been much explored. The objective of the study is to assess the perceptions of the undergraduate students of nursing on the pandemic pedagogy and identify the challenges they faced in online learning.\n\n\nMethods\n\nThis cross-sectional survey was conducted among undergraduate nursing students studying in the deemed to be university nursing institutions, under the University Grants Commission of India, Southern India.\n\nInvestigators obtained the approval from the Institutional Ethics Committee (IEC 444/2020) for conducting the study and permission from the heads of the institutions. The study was registered under the clinical trial registry of India (CTRI/2020/08/027047).\n\nAll the deemed to be universities nursing institutions of Southern India were approached and included only those permitted to conduct the study. The students undergoing a four-year undergraduate nursing degree programme were included in the study. The students were sent home from the institutions under lockdown, and all three nursing institutions moved on to emergency remote teaching. Since the institutions did not have online teaching before the pandemic, it was a sudden change for both teachers and students. Initially, teachers themselves explored various platforms and later they were oriented to online teaching platforms by the institutions too. The nursing institutions offered around three to five hours of online instruction during the pandemic.\n\nAn online survey with written consent form was sent to all the participants via Google form to their contact details submitted to the institution and the students consented to participate in the study after reading the participant information sheet provided in the form.\n\nA complete enumeration of all the nursing institutions of the deemed to be universities of Southern India was the sampling technique considered in the study. However, out of 13 nursing institutions of the Deemed Universities in the selected geographical area, three nursing colleges accepted to participate in the study. The online survey questionnaire was sent to all the students of the three colleges and requested them to participate in the study if they were willing to. Figure 1 depicts the schematic flow chart representation of the sample selection.\n\nA demographic questionnaire was used for collecting the information on age, year of study, area of residence, mode of access to e-learning, and the device used.\n\nThe perception of students on the pandemic pedagogy was assessed using a four-point Likert scale. It consisted of 35 items with four open-ended questions. The questionnaire had three domains, including student-related (19 items), teacher-related(5 items), and physical learning environment-related factors (11 items). The response options for each item were: Strongly Agree (SA), Agree (A), Disagree (D), and Strongly Disagree (SD) with scores of 4, 3, 2, 1, respectively. The total score ranged from 35 to140, with a cut-off of > 87 as an indicator of favouring online learning. The scores less than 86 indicated that the students favoured the face-to-face classroom learning during the pandemic. The open-ended questions explored the favouring factors and the challenges students faced during the emergency remote teaching.\n\nThe investigators developed this survey questionnaire after reviewing the available literature and taking opinions from the students. It was validated by experts from the field of nursing and medical education. The reliability was established by administering the scale to 20 Post Basic BSc. nursing students and the Cronbach’s Alpha computed was 0.86.\n\nThe data analysis of the study was carried out using SPSS version 16 (SPSS, RRID:SCR_002865). The demographic variables and the perceptions of the students on online learning were expressed in frequency and percentage. The mean and the standard deviation of the perception score based on the year of study is described. To find the difference in the perception score between the years of study, ANOVA was used and post hoc comparisons was performed using the Hochberg’s GT2 test. Independent sample t-test was performed to find the difference between the areas of residence and the perception score. The factors facilitating the pandemic pedagogy and the challenges faced were described in frequency.\n\n\nResults\n\nThe characteristics of the nursing students who participated in the pandemic pedagogy perception survey are summarized in Table 1. The mean age of student nurses was 19.8 years (SD=1.4). The common platforms used by the institutions for the online pedagogy were Zoom (34.3%), MS Teams (34.3%), Webex (8.2%), Google meet (7.2%), Edmodo (7.1%), Impartus (5.8%), and Google classroom (2.7%).\n\nThe overall mean score of the perceptions of students on the pandemic pedagogy was 89.03±10.03. The year-wise mean scores are given in Table 3. 63% of students had a total perception score above 87 indicates that they preferred online learning during the pandemic, whereas 45% preferred face-to-face learning in the classroom. The response for the individual items on the perception scale is summarized in Table 2.\n\nThe three domains included in the perception tool were student-related, teacher-related, and physical learning environment-related factors. This section of the article discusses the comparison of domains wise analysis with the students as per their years of study. The comparison table depicted in Table 3 reveals no changes between the mean values of the domain scores across the different years of study. To make the comparison of nursing students’ perception on pandemic pedagogy with years of study, ANOVA was computed and it revealed that there was a significant difference (M=89.03, SD=10.03, F (3, 978)=4.96, p=0.002) in the total perception scores and the years of study. The post hoc comparisons using the Hochberg’s GT2 test indicated that the mean perception score of the first-year students (M=86.48, SD=10.95) was significantly different than the second-year students (M=90.97, M=9.83). However, the third (M=89.43, SD=9.11) and the fourth year (M=88.65, SD=10.26) students’ perception scores did not significantly differ from the first and the second-year students.\n\n* Significant at the level of p<0.05.\n\nA comparison of the perceptions of the students of nursing on the pandemic pedagogy with the area of residence has been described in Table 4. To make the comparison an independent sample ‘t’ test was used to compute. The findings reveal that there is no significant difference in the perception scores of the students residing in the rural (M=88.68, SD=9.86) and the urban (M=89.43, SD=10.23) areas; t (1.16), p=0.0243.\n\nThe participants were asked to express their views on the factors that favoured learning through the online mode during the COVID-19 pandemic. The responses are summarized descriptively, and the major aspects revealed were: ‘an opportunity to view the recorded classes even after the live classes’ (n=165), ‘more time to spend for learning activities’ (n=152), ‘ample opportunity to clarify doubts as same as a physical classroom’ (n=139) and ‘able to concentrate well as I felt that the teacher is directly interacting’ (n=110). Other opinions were, “flexible and convenient class timings motivated to do self-directed learning, study materials were made available immediately after each lecture helped in completing studies on time, in the current situation of a pandemic being along with parents were relaxing and stress-free and which helped in better learning, training sessions arranged by the college helped a lot in handling the online platform efficiently.”\n\nThe descriptive summarization of the responses towards the aspect of factors that hindered the learning or the challenges faced during the online mode of classes during the COVID-19 pandemic is discussed in this section. The majority of students of nursing responded that the internet issues, either due to poor network coverage, bad weather or monsoon, were a major concern as they could not understand the topics discussed (n=451). The participants also quoted a few other challenges: ‘could not have group study and discussion which was practiced in the college campus’ (n=326), ‘Clinical skills cannot be taught well through the online platforms’(n=315), ‘attending the classes through the mobile phone was difficult as often getting tired (headache, eye issues) due to the constant use’ (n=262), ‘less motivation to learn being away from the college’ (n=205), and ‘not able to concentrate being at home’ (n=135). Some of them also had mentioned the unavailability of library facilities and fewer opportunities to maintain the interpersonal relationship with the teachers and the friends as the challenges faced during this pandemic time.\n\nParticipants were asked to express their opinion on having a few hours of online classes along with the physical classes during the academic year post pandemic. The descriptive summary of the open-ended questions reveals that the future directions on the online classes were inconclusive. Most of them preferred to be at the safe places during the pandemic and continue with the online learning. Under the favouring factors and the challenges faced during the online classes, there is a mixture of opinions about the future direction of online learning. As the curriculum demands hands-on clinical experience through direct patient care, they opined that it was a major missing. A few of them even suggested that the theory hours in future could be a mixture of both the online and the offline classes, whereas a few felt that there were a lot of negative impacts of online learning since it had its pros and cons. To list a few physical ill effects, no opportunity for co-curricular activities, less opportunity to be together and interact with the friends and the teachers. Unanimously most of them expressed that though there were pros and cons for the online classes, the biggest challenges were the network issues, impact of weather over electricity, and data connectivity.\n\n\nDiscussion\n\nThis paper intended to study undergraduate nursing student’s perception towards the online learning adopted during the COVID-19 pandemic. The institutions of nursing education quickly moved on to the mode of online learning to have uninterrupted learning during the lockdown. This was an unprepared and sudden change in the education for which the students and the teachers were not ready. The institutions adopted synchronous and asynchronous technology based on convenience and availability. The synchronous technology included live interactions between teacher and students during online classes, whereas the asynchronous had a time gap between the instructor and its recipient (Finkelstein, 2006). Due to a lack of preparedness, the teachers and the students faced many challenges, especially during the transition period. The present study reveals that 81.4% of the participants (72.8% A and 8.6% SA) agreed that the online classes helped to accomplish the learning objectives. The most students (43.3% D, 15.3% SD) disagreed that they could concentrate better during the online classes compared to the classroom teaching and the online classes were more interactive than the classroom learning (47.4% D, 15.2% SD). Though there was an online learner engagement with the online learning, the majority worried (64.6%) about the depth of knowledge of the course content.\n\nBali and Liu (2018) explored higher education students’ perception and indicated that social presence, social interaction, and satisfaction were higher in the face-to-face learning than the online learning. However, a few students preferred the online learning as the technology led them to be innovative. The student engagement remains a challenge in the remote learning. Engaging the students and enhancing the student-learning may not be as effective in the online learning as in the classroom learning. The students may not be able to discuss and have their doubts that arise during the online classes cleared (Alturise, 2020). In the present study, the students perceived that they were kept active throughout the class (71.4% A, 10.3% SA) with the use of learner engagement applications (59.2% A, 12.7% SA). The online-only classes for instructions may affect the student performance, especially for those who are already academically struggling. The face-to-face instructions would enable the academic performance of students than the online courses (Xu & Jaggars, 2014). In the present study, there was a mixed response from the participants on the aspect of opportunity to communicate with classmates well during this pandemic time like that happened in the classroom (43.6% A, 36.9% D). The most of them (57.4 % A, 8.5% SA) agreed that they never got a sense of isolation while attending the online classes being away from the regular classroom and 63% agreed that the opportunities for extracurricular activities were more in the regular classroom learning. The majority of them (71%) perceived that the teachers kept the learners active throughout the class and 59% agreed that the use of learner engagement applications (Kahoot, Mentimeter, etc.) kept them active during the online class.\n\nThe online learning would hinder in acquiring clinical skills. A study conducted among the dental students and the staff reported that the closure of teaching clinics would affect the students’ clinical competence (Loch et al., 2020). In the present study, the most students felt that they were not confident to perform the clinical skills as they were away from the institution for a longer time (20.6% SA and 62.4% A). They also reported that the inability to incorporate the theory into the practice hindered their learning (15.7% SA, 68.6% A) and develop the clinical decision-making skills (15.2% SA, 68.6% A).\n\nDue to the abrupt shift from the face-to-face to the e-learning education, there were concerns about the availability of technology in terms of the devices used for attending the online instruction, internet access, and skills in the use of technology. Based on the socioeconomic status, the students used the devices for the online learning, and hence the quality of the device they used would vary. The researchers have found that when the students expected to use the electronic devices for the online instructions, classwork, online reading, and assignments, the problem with the technology caused stress and affected the academic performance of the students (Gonzales et al., 2020). The data from the present study revealed that 70% of the participants agreed that the software used for the online learning was user-friendly and 69% of them agreed that the teachers’ technical skills helped them a lot to have uninterrupted classes. However, contradicting that 53% of them perceived that unfamiliarity with the use of technology made the online learning difficult. Along with the technical issues, there were the major challenges such as network issues (52% A and 34.5% SA), electricity issues and bad weather during the online learning. One of the significant factors that favoured the online learning was the availability of teaching-learning material and the recordings of the classes on the same platform (72%).\n\nThe perceptions of online learning conducted among 804 medical students from Poland reported various advantages and disadvantages. The majority (73%) of students enjoyed the online learning. Learning at the students’ own pace (64%), ability to stay at home (69%), continuous access to online material (69%), and the comfortable environment were reported as the advantages of the online learning whereas, lack of patient interaction (70%) and technology-related problems (54%) were the disadvantages that the medical students faced. The online learning was considered less effective in honing the skills and the social competencies (p<0.001) than the face-to-face learning whereas there was no difference in knowledge gain (p=0.46). However, the students were less active during the online classes than the traditional classes (Bączek et al., 2020). In the present study, 71.5% of them expressed that the online class timings were convenient than the classroom learning. Mukhtar et al. (n.d.), reported that the online learning encouraged student-centred learning. They could learn asynchronously at any time of the day and become self-directed learners. In the present study, most of them (65%) agreed that their self-directed learning skills had improved.\n\nAs per the responses from the student nurses who participated in the present study, 61.5% agreed that the online classes provided enough opportunity to clarify the doubts with the teacher and they even agreed (70.7%) that the teachers did motivate them being away from the institution. The majority of the (56.2%) participants agreed that the teachers were able to give attention to the individual students as in the physical classroom. More than half of them (53%) perceived that being away from the institution for a longer duration and attending the classes online was a stressful situation for them. They perceive that being away from the regular classes affected the overall development (57.6%). Even though they perceived it as a stressful situation, the majority (61.9%) agreed that the instructions given during the online classes were clear as in the physical classroom. The most of the participants (66%) agreed that the online teaching mode gave an adequate opportunity for the instructor feedback for the students as in the physical classes.\n\nAccessibility is a major concern in the online education in most countries. The students from the remote areas faced connectivity problems. The English language education study programme in Indonesia identified that the availability and the sustainability of internet connection, accessibility of teaching media, and compatibility of the device used to access the media were the major obstacles for the online learning. Hence, to increase the student participation in the online learning there should be more friendly platforms (Agung & Surtikanti, 2020). A study conducted by Baloran (2020) reported that due to poor internet connectivity the college students refused to have a blended online learning approach during the COVID-19 pandemic. The majority students (61.78%) preferred learning inside the classroom than the online. This finding was also supported by Hassan Ja’ashan (2015). Subedi et al. (2020) reported that 63.2% of students were affected because of electricity and 63.6% internet problem, only 64.4% of the students had the internet access for their online classes. Khalil et al. (2020) reported that poor internet connectivity and utility of the online tools were the challenges of the online learning. In the present study, 86.2% of students reported that the connectivity issue (34.5% SA and 51.7% A) was a major concern during the classes, especially in the rural area.\n\nThe COVID-19 pandemic had a psychological and emotional impact and affected the students’ mental health (Lee, 2020). The students of the institutions of higher education, including nursing, experienced moderate to severe stress and anxiety in the virtual classrooms during the COVID-19 pandemic (AlAteeq et al., 2020; Gallego-Gómez et al., 2020; Sheroun et al., 2020). The findings of the present study also support this, where 52.9% agreed and 19% strongly agreed that they were stressed being away from the institution for a long time and attending the classes online. Providing a high-quality online education using a stable educational framework and encouraging the students may help in lowering their anxiety (Savitsky et al., 2020). The perceptions of the students from a university of higher education from India reported that the online learning helped them continue their learning and complete the syllabus. As the students were not accustomed to learning with cell phones or computers, it led to a lack of interest and attention during the online classes. The students were unable to attend a few classes when the data limit exceeded for the day (Mishra et al., 2020). In the present study, the majority of students agreed that they were able to accomplish the learning objectives (72.8% A, 8.6% DA).\n\nThe students found that if the recorded classes were available during the online classes, it helped in better understanding the information whereas if the concepts were difficult it was harder to follow (Khalil et al., 2020). Deepika (2020) reported that the quality and the timely interaction between the student and the teacher, availability of technical support, a structured module for the online classes, and facilities for conducting practical classes were essential for the student and the teacher satisfaction with the online classes. Most of the students (66.2%) agreed that they had an opportunity for the instructor feedback during the online teaching.\n\nThe present study findings revealed that among the student nurses who participated, 62% agreed and 29% of them strongly agreed that the online learning was safer amidst the COVID pandemic and 53% of them agreed that the online classes were interesting, and they enjoyed learning. The majority of them (65.0%) agreed that the new teaching environment improved self-directed learning skills. They perceived it as they needed to be more accountable (74.2%) and responsible (72.6%) to achieve the learning outcomes during the pandemic pedagogy. The half of the participants (51.0%) perceived no difference between the online and the regular classroom learning, as both helped them to understand the course concepts in the same manner. Nearly half of them (49%) agreed that a virtual demonstration of nursing procedures helped them to develop clinical skills as in the regular teaching. The students agreed that being away from the clinical setting for a long time affected the clinical skills (59%) and felt they were not confident in performing the procedures that they missed to practice (62.4%).\n\nA study conducted to explore the challenges to online medical education during the COVID-19 pandemic reported that pandemic related stress, issues related to the online experience, communication, and time management were the challenges faced (Rajab et al., 2020). The challenges faced by the teachers may influence the students’ online learning. A qualitative study conducted among the teachers in India reported that the home environment with family interruptions, external distractors, lack of basic facilities, lack of support from the institution on training and support for the use of technology, and lack of technical knowledge as the barriers faced by the teachers during the online teaching (Joshi et al., 2020). The present study also reported several challenges such as poor internet connectivity, inability to understand the concepts, lack of peer support, an opportunity for group study, and lack of opportunity for the clinical practice.\n\nThis study has several strengths. Firstly, the study tried to explore how nursing students perceived the online learning during the COVID-19 pandemic. This gives information to the institutions of nursing education to understand the views of the students. Secondly, the challenges identified allow the universities to overcome these factors and deliver quality nursing education. Thirdly, since the study is conducted in a multicentre with a large number, generalizability of the findings to all the nursing institutions in India is possible. Nonetheless, this study also has a few limitations. Firstly, since it was a cross-sectional study the detailed information on the challenges could not be explored. Secondly, since the study has not been focused on assessing the learning, it would help improving the assessment methods.\n\nThe implications of the study are as follows. Firstly, the emergency remote teaching-learning was the first experience for the students as well as the teachers and this study has explored the student’s perception towards this pandemic pedagogy. Secondly, various challenges that hindered the learning of students need to be deliberated by the institutions and the government so that we prepare well for such pandemics in the future.\n\n\nConclusions\n\nThe COVID-19 pandemic posed significant concerns among the students of higher education institutions. The results from the present study conclude that the students prefer the online as well as the physical classes. Though the online-only learning could be adopted during the pandemic, to achieve adequate clinical skills the students need to get clinical experience with adequate simulated learning and direct patient care. The nursing institutions must adopt blended learning to achieve competencies needed keeping in mind the control of the spreading COVID-19 infection. In addition, the challenges of the pandemic COVID-19 lead to prospects for the development of nursing education and provide quality education by adopting the technology.\n\n\nData availability\n\nThe undelying data set is available at: Assariparambil, Anil Raj (2022): Final_Pandemic_Study.xlsx. figshare. Dataset. https://doi.org/10.6084/m9.figshare.19170041.v1",
"appendix": "Acknowledgments\n\nThe authors are indebted to Dr Anice George, Professor & former Dean, Manipal College of Nursing, Manipal, for the constructive criticism and suggestions during the planning phase.\n\nThe authors are grateful to Dr Ravi Shankar, Statistician, Dept. of Data Science, PSPH, Manipal Academy of Higher Education, Manipal, for the statistical advice and the Validators of our tool Dr Binil V, Dr Sushmitha R Karkada, Dr. James Gonsalves, and Dr. Vinod Pallath.\n\n\nReferences\n\nAgung ASN, Surtikanti MW: Students’ Perception of Online Learning during COVID-19 Pandemic: A Case Study on the English Students of STKIP Pamane Talino. SOSHUM: Jurnal Sosial Dan Humaniora. 2020; 10(2): 225–235. Publisher Full Text\n\nAlAteeq DA, Aljhani S, AlEesa D: Perceived stress among students in virtual classrooms during the COVID-19 outbreak in KSA. Journal of Taibah University Medical Sciences. 2020; 15: 398–403. PubMed Abstract | Publisher Full Text\n\nAlturise F: Difficulties in teaching online with blackboard learn effects of the COVID-19 pandemic in the western branch colleges of Qassim University. International Journal of Advanced Computer Science and Applications. 2020; 11. Publisher Full Text\n\nBączek M, Zagańczyk-Bączek M, Szpringer M, et al.: Students’ perception of online learning during the COVID-19 pandemic: a survey study of Polish medical students. 2020: 1–14. Publisher Full Text\n\nBali S, Liu MC: Students’ perceptions toward online learning and face-to-face learning courses. Journal of Physics: Conference Series. 2018; 1108: 012094. Publisher Full Text\n\nBaloran ET: Knowledge, Attitudes, Anxiety, and Coping Strategies of Students during COVID-19 Pandemic. Journal of Loss and Trauma. 2020; 25: 635–642. Publisher Full Text\n\nDeepika N: The impact of online learning during COVID-19: students’ and teachers’ perspective. The International Journal of Indian Psychology. 2020.\n\nDewart G, Corcoran L, Thirsk L, et al.: Nursing education in a pandemic: Academic challenges in response to COVID-19. Nurse Education Today. 2020; 92: 104471. PubMed Abstract | Publisher Full Text\n\nFinkelstein J: Learning in real time: Synchronous teaching and learning online. Learning in real time: Synchronous teaching and learning online. 2006.\n\nGallego-Gómez JI, Campillo-Cano M, Carrión-Martínez A, et al.: The COVID-19 pandemic and its impact on homebound nursing students. International Journal of Environmental Research and Public Health. 2020; 17. Publisher Full Text\n\nGonzales AL, McCrory Calarco J, Lynch T: Technology Problems and Student Achievement Gaps: A Validation and Extension of the Technology Maintenance Construct. Communication Research. 2020; 47: 750–770. Publisher Full Text\n\nHassan Ja’ashan MMN: Perceptions and Attitudes towards Blended Learning for English Courses: A Case Study of Students at University of Bisha. English Language Teaching. 2015; 8. Publisher Full Text\n\nHodges C, Moore S, Lockee B, et al.: Remote Teaching and Online Learning. Educause Review. 2020.\n\nJoshi A, Vinay M, Bhaskar P: Impact of coronavirus pandemic on the Indian education sector: perspectives of teachers on online teaching and assessments. Interactive Technology and Smart Education. 2020; 18: 205–226. Publisher Full Text\n\nKhalil R, Mansour AE, Fadda WA, et al.: The sudden transition to synchronized online learning during the COVID-19 pandemic in Saudi Arabia: A qualitative study exploring medical students’ perspectives. BMC Medical Education. 2020; 20: 285. PubMed Abstract | Publisher Full Text\n\nFerlazzo L: Student: Online Learning Is’Stressful and Irritating. n.d.Reference Source\n\nLee J: Mental health effects of school closures during COVID-19. The Lancet Child and Adolescent Health. 2020; 4: 421. PubMed Abstract | Publisher Full Text\n\nLoch C, Kuan IBJ, Elsalem L, et al.: COVID-19 and dental clinical practice: Students and clinical staff perceptions of health risks and educational impact. Journal of Dental Education. 2020. Publisher Full Text\n\nMishra DL, Gupta DT, Shree DA: Online Teaching-Learning in Higher Education during Lockdown Period of COVID-19 Pandemic. International Journal of Educational Research Open. 2020; 1: 100012. PubMed Abstract | Publisher Full Text\n\nMukhtar K, Javed K, Arooj M, et al.: Advantages, Limitations and Recommendations for online learning during COVID-19 pandemic era How to cite this. n.d.; 36: S27–S31. PubMed Abstract | Publisher Full Text\n\nRajab MH, Gazal AM, Alkattan K: Challenges to Online Medical Education During the COVID-19 Pandemic. Cureus. 2020; 12: e8966. PubMed Abstract | Publisher Full Text\n\nSavitsky B, Findling Y, Ereli A, et al.: Anxiety and coping strategies among nursing students during the covid-19 pandemic. Nurse Education in Practice. 2020; 46: 102809. PubMed Abstract | Publisher Full Text\n\nSheroun D, Wankhar DD, Devrani A, et al.: A study to assess the perceived stress and coping strategies among B.Sc. nursing students of selected colleges in Pune during COVID-19 pandemic lockdown. International Journal of Science & Healthcare Research. 2020.\n\nSubedi S, Nayaju S, Subedi S, et al.: Impact of E-learning during COVID-19 Pandemic among Nursing Students and Teachers of Nepal. International Journal of Science and Healthcare Research. 2020. Reference Source\n\nXu D, Jaggars SS: Performance gaps between online and face-to-face courses: Differences across types of students and academic subject areas. Journal of Higher Education. 2014; 85: 633–659. Publisher Full Text"
}
|
[
{
"id": "135191",
"date": "13 Jun 2022",
"name": "Karen E. Alexander",
"expertise": [
"Reviewer Expertise Nursing education",
"vulnerable populations",
"and health disparities."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbstract: Regarding online learning, what was the students preferred online learning (synchronous/asynchronous)? This should be specified to provide clarity.\nSample: The sample characteristics would flow better under demographics instead of results.\nRemote versus Online instruction: Some parts of the article (i.e. the introduction) refer to “online” and other sections speak to “remote” teaching. Moreover, the authors speak to students sent home to learn online, it seems from the information provided, that they were learning remotely. Since there is a difference between remote versus online instruction this needs to be explicated. Remote instruction is most often a solution to facilitating a course curriculum in times of face-to-face class interruptions (e.g., a scheduled absence, an inclement weather day, or an emergency). In the case of this article, one would assume due to the pandemic. This form of instruction is typically designed in a responsive manner and often delivered through the instructor’s preferred technology at the time of delivery to best meet course outcomes under the given circumstance. On the other hand, Online instruction is the facilitation that occurs in a course that has been developed with the intention of fully online delivery. Instructional experiences are designed in a planned manner, over weeks and months, most often with the support of an instructional designer and a media services team. The learning experiences and instructional objects in an online course are typically fully-developed before the start of a semester. In other words, remote teaching occurs when the instructor, transitions the delivery of an on-campus course to online. An online course, however, has been purposely designed for online teaching using online learning design principles. Because the 2 terms are used interchangeably in this article it is difficult the understand what was actually the mode of delivery for the students.\nIntroduction: The reference “An e-newsletter ‘education week’ reported the opinion of the high school students from France concerning online learning.” Does not seem to reflect or compare to deemed university nursing students. Suggest a reference to students in another similar university setting as a freshman.\nTechnology Platform: Regarding the platform used “Initially, teachers themselves explored various platforms and later they were oriented to online teaching platforms by the institutions too.” This leaves the question. What was the platform used?\nResults/Discussion: The following information needed to be explicated earlier - “The institutions adopted synchronous and asynchronous technology based on convenience and availability. The synchronous technology included live interactions between teacher and students during online classes, whereas the asynchronous had a time gap between the instructor and its recipient.” Again, this needed to be explicated earlier in learner engagement application descriptions to understand the modality.\nReferences References were applicable and up-to-date to support the background and results. Summary, Overall good article. Interesting and timely.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8545",
"date": "26 Jul 2022",
"name": "Anil Raj Assariparambil",
"role": "Author Response",
"response": "We appreciate the reviewer’s effort in systematically cross-checking the manuscript and for your valuable suggestions. Abstract: Students favored synchronized online learning during the pandemic; however, there were several challenges. (We have modified it as per the reviewer’s comment) Sample: \"The sample characteristics would flow better under demographics instead of results.\" Respected reviewer, we are not very clear about this comment. However, is that before the results section, do we need to add a separate heading as sample demographics? We usually describe the sample demographics under the results section. Hence, we would like to retain the same format in the manuscript. Remote versus Online instruction: \"Some parts of the article (i.e. the introduction) refer to “online” and other sections speak to “remote” teaching.\" Thank you for notifying us with the detailed description. It was really an eye-opener! We have changed it to remote instruction instead of online. Introduction: Citation and reference were updated as per suggestion Technology Platform: Modified the sentence mentioning the platforms Results/Discussion: The following information needed to be explicated earlier - “The institutions adopted synchronous and asynchronous technology based on convenience and availability. We have incorporated this statement into the introduction Once again thank you so much for you generous inputs to modify the manuscript. Thanking you With Regards"
}
]
}
] | 1
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https://f1000research.com/articles/11-398
|
https://f1000research.com/articles/12-1213/v1
|
26 Sep 23
|
{
"type": "Research Article",
"title": "Impact of amyloidosis on the outcomes of percutaneous coronary intervention recipients: a nationwide analysis",
"authors": [
"Sukhnoor Singh",
"Yashvi Pethani",
"Arthur Alencar",
"Sravani Kommuru",
"Beegam Sulthana",
"Abhishek Chaudhary",
"Janani Prakash Babu",
"Iman Jasim Elttayef Elttayef",
"Kaushal Patel",
"Labdhi Sanghvi",
"Vidit Majmundar",
"Kanishka Uttam Chandani",
"Maharshi Raval",
"Sukhnoor Singh",
"Yashvi Pethani",
"Arthur Alencar",
"Sravani Kommuru",
"Beegam Sulthana",
"Abhishek Chaudhary",
"Janani Prakash Babu",
"Iman Jasim Elttayef Elttayef",
"Kaushal Patel",
"Labdhi Sanghvi",
"Vidit Majmundar",
"Kanishka Uttam Chandani"
],
"abstract": "Background: Interest in amyloidosis is increasing, primarily due to its high prevalence and recent advances in diagnostic and treatment modalities. The role of amyloidosis in aortic stenosis is established, and in coronary artery disease (CAD) outcomes are being reported. We aim to study the impact of amyloidosis on the outcomes of inpatient percutaneous coronary intervention (PCI) recipients. Methods: We conducted a cross-sectional cohort study using the nationwide inpatient sample (NIS) 2018-19. We included 457,730 adult inpatients with CAD managed with PCI and further divided by the presence of a co-diagnosis of amyloidosis. A logistic regression model was used to evaluate the odds ratio (OR) of the association between amyloidosis and various outcomes in PCI recipients. Results: Out of the total of 457,730 patients included, 30,905 (6.75%) had amyloidosis. Mean age (66.3 vs. 65.9), female sex (35.6% vs. 32.1%), and African American race (11.6% vs. 9.4%) were higher in the amyloidosis cohort (all P<0.001). The amyloidosis cohort also had a higher incidence of acute kidney injury (AKI) (29.9% vs. 15.5%), complications of surgical care (1.7% vs. 0.7%), complications of cardiovascular implant (9.5% vs. 8.5%), major loss of function (54.7% vs. 27.8%), length of stay (LOS) in days (6.3 vs. 3.8), total charges in $ (166,001 vs. 121,718), and in-hospital mortality (4.7% vs. 2.6%) compared to non-amyloidosis cohort (all P<0.001). Amyloidosis was associated with higher odds of in-hospital mortality (OR 1.3, 95CI 1.23-1.39, p<0.001), AKI (OR 1.89, 95CI 1.83-1.94, p<0.001), and complications of surgical care (OR 2.05, 95CI 1.87-2.26, p<0.001) but not with complications of cardiovascular implant (OR 1.01, 95CI 0.97-1.05, p=0.703). Conclusions: Amyloidosis is associated with worse outcomes in inpatient recipients of PCI. Further studies are needed to assess the implications, safety, and outcomes of elective PCI in patients with amyloidosis.",
"keywords": [
"Amyloidosis",
"coronary artery disease",
"percutaneous coronary intervention",
"in-hospital mortality",
"outcomes research"
],
"content": "Introduction\n\nAmyloidosis is a medical condition characterized by the irregular accumulation of amyloid protein in various organs, including the heart. Cardiac amyloidosis, which can be categorized into transthyretin (ATTR) and light chain (AL) amyloidosis, is the primary cause of restrictive cardiomyopathy. This condition can lead to myocardial ischemia and heart failure, similar to atherosclerotic disease. When combined with atherosclerosis and heart failure, cardiac amyloidosis can further exacerbate coronary artery disease and interstitial amyloidosis.1 Coronary artery disease is the most prevalent form of heart disease and a leading cause of mortality. In 2020, it was responsible for the death of 382,820 individuals, with 20% of these deaths occurring in people under the age of 65.2\n\nThe formation of amyloid fibrils in amyloidosis involves different precursor proteins. Protein misfolding and aggregation occur due to factors such as abnormal proteolysis, point mutations, and posttranslational modifications like phosphorylation, oxidation, and glycation.3,4 Research conducted in Germany examined trends in hospitalizations for heart failure and found that improved outcomes were partially attributed to the utilization of percutaneous coronary interventions.5 Another investigation focused on patients diagnosed with cardiac amyloidosis and revealed that individuals with ST-elevation myocardial infarction and cardiac amyloidosis had higher rates of signs and symptoms, including ventricular tachycardia/ventricular fibrillation, cardiogenic shock, acute kidney injury requiring dialysis, and admissions to the intensive care unit, compared to those without ST-elevation myocardial infarction.6\n\nThe present study aimed to investigate predictors of in-patient mortality after percutaneous coronary intervention (PCI), compare PCI recipients with and without amyloidosis and identify risk factors for post-PCI complications in amyloidosis patients. Notably, there is a lack of dedicated studies specifically addressing the immediate complications of PCI in patients with coronary amyloidosis, such as coronary artery perforation, coronary artery dissection, coronary artery aneurysm, failure of stent deployment, and patient-stent mismatch, when compared to patients without coronary amyloidosis.7 Evaluating the demographics and hospital outcomes of patients undergoing PCI is essential for enhancing patient care and outcomes. In our investigation, we analyzed variables such as age, gender, household income, and comorbidities, with a specific focus on assessing main risk factors, including acute kidney injury, complications of surgical care/injury, and complications of cardiovascular implant/graft.\n\n\nMethods\n\nWe conducted a cross-sectional study using the publicly available registry database nationwide inpatient sample (NIS, 2018 and 2019). The NIS dataset covers hospitalized patients from more than 4,400 non-federal community hospitals across 48 states and the District of Columbia in the United States. The clinical classifications software refined (CCSR) for international classification of diseases, tenth revision (ICD-10)-coded diagnoses classifies diagnoses into clinical categories. According to the agency for healthcare research and quality (AHRQ) and the Department of Health and Human Services (HHS), our study was based on the de-identified dataset of the NIS and does not require approval from an institutional review board. The data can be obtained from the website of the Healthcare Cost and Utilization Project, AHRQ.8\n\nWe included 457,730 adult inpatients (age ≥18 years, mean age 65.9) hospitalized with a primary discharge diagnosis of coronary atherosclerosis and other heart diseases (CCSR code: CIR011) and managed with the primary procedure of percutaneous coronary intervention (PCI). We used the term coronary artery disease (CAD) for “coronary atherosclerosis and other heart diseases” in this study. The study sample was further grouped by the co-diagnosis of amyloidosis (identified by CCSR code END016).\n\nThe variable of interest included demographic characteristics: age at admission, sex, race, and median household income. The following comorbidities were obtained from the data using CCSR codes in parenthesis: diabetes (END004, END005), hypertension (CIR007, CIR008), and obesity (END009). Acute complications during the hospitalization included acute kidney injury (AKI), complications of surgical care/injury, and complications of cardiovascular implant/graft. The hospitalization outcomes of interest include the severity of illness, which was measured using the all-patient refined DRG (APR-DRGs), length of stay (LOS), total charges, and disposition status, including all-cause in-hospital mortality.\n\nWe used descriptive statistics with Pearson’s chi-square test for categorical data and independent-sample T-test for continuous data (age, LOS, and total charges) to measure the differences between PCI recipients by co-diagnosis of amyloidosis. The binomial logistic regression model was used to evaluate the odds ratio (OR) of predictors associated with in-hospital mortality in PCI recipients. A P value <0.05 was used to detect the statistical significance, and all analyses were conducted using the Statistical Package for the social sciences (SPSS) version 27 (IBM Corp., Armonk, NY).\n\n\nResults\n\n426,825 patients admitted with a primary diagnosis of coronary artery disease received percutaneous coronary intervention. 30,905 (7.24%) of those had amyloidosis. Amyloidosis prevalence was significantly greater among males (64.4%) compared to females (35.6%). The mean age at admission was relatively higher in patients with concurrent amyloidosis. The prevalence of both CAD (52.5%) and CAD with concurrent amyloidosis (54.2%) was significantly greater among patients over 65 years. While studying ethnicities, the prevalence of CAD with coexisting amyloidosis was higher in Caucasian patients (72.4%), followed by African American patients (9.6%) and Hispanic patients (8.2%). The most significant comorbid conditions among patients with amyloidosis were complicated diabetes (40.8%), complicated hypertension (51.1%), and obesity (26.5%). It was also noted that patients with coexisting amyloidosis often had other statistically significant complications like acute kidney injury, seen in 29.9% of patients, post-surgical complications occurred in 1.7% of patients, and graft-related complications in 9.5%. Patients with amyloidosis were also reported to have a longer in-hospital admission duration, increasing the mean total expenditure. Patients with concurrent amyloidosis were also reported to have moderate (31.2%) to major (54.7%) loss of function post-procedure. Although most patients resumed routine life immediately following discharge, a considerable number of patients with amyloidosis were required to transfer to a skilled nursing care facility (13.2%) or home health care (13.9%). Our study also found that concurrent amyloidosis was much more prevalent among people with a median household income below the 50th percentile, as shown in Table 1.\n\nThe overall in-hospital mortality after PCI is 2.7%, of which 4.7% of patients had coexisting amyloidosis. Patients over 65 years were at 2.79 times higher mortality risk after PCI than other groups (OR 2.79 95% CI 1.88-4.12). Patients with AKI had a six-fold higher mortality (OR 6.49 95% CI 6.24-6.77). Post-procedure complications also led to a three-fold increase in mortality (OR 3.02 95% CI 2.70-3.37). The most important comorbid conditions that lead to in-hospital mortality after PCI include amyloidosis (OR 1.30 95% CI 1.23-1.39) and complicated hypertension (OR 1.13 95% CI 1.09-1.18) followed by complicated diabetes (OR 0.86 95% CI 0.82-0.89) and obesity (OR 0.69 95% CI 0.65-0.72). Other statistically significant risk factors for in-hospital mortality after PCI include female sex (OR 1.34 95% CI 1.28-1.39), African American ethnicity (OR 0.77 95% CI 0.72-0.83), and low socioeconomic status (OR 1.08 95% CI 1.04-1.12) as shown in Table 2. We also found that post-PCI complications such as AKI (OR 1.89 95% CI 1.83-1.94) and complications of surgical care/injury (OR 2.05 95% CI 1.87-2.26) are higher in patients with amyloidosis, but complications of cardiovascular implant/graft were similar in patients with or without amyloidosis (OR 1.01 95% CI 0.97-1.05) as shown in Table 3.\n\n\nDiscussion\n\nIn this study, we investigated the impact of amyloidosis on in-hospital mortality and outcomes among patients who underwent percutaneous coronary intervention (PCI). Our findings revealed that amyloidosis was an independent risk factor for in-hospital mortality. Patients with amyloidosis had a higher incidence of AKI, complications of surgical care, complications of cardiovascular implant, major loss of function, length of stay in days, and total charges.\n\nAmyloidosis is characterized by the deposition of misfolded protein subunits, forming insoluble amyloid fibrils in various tissues. This abnormal protein aggregation can disrupt normal tissue function and contribute to several diseases.9 Cardiac involvement is common in amyloidosis, which can be systemic or localized, primary or secondary, and varying in incidence rarity.10–12 Although cardiac amyloidosis is a recognized risk factor, its association with complications during PCI is often overlooked.13 Sometimes, the patient may not improve after revascularization.14 Therefore, it is clinically significant to identify amyloidosis as a risk factor and understand its association with other established risk factors, such as AKI.\n\nIn contrast to the general population in this study, patients with amyloidosis showed a higher association with the African American population and below 50th percentile household income. The prevalence of obesity, hypertension, and diabetes with chronic complications was significantly higher, as were complications such as major loss of function, acute kidney injury, complications of surgical care, and cardiovascular implant. Notably, acute kidney injury and complications of surgical care exhibited the strongest association with in-hospital mortality in this study.\n\nAlthough there are limited studies specifically addressing amyloidosis as an independent risk factor for PCI, cardiac amyloidosis (CA) has been identified as an independent risk factor for in-hospital mortality in patients with myocardial infarction (MI).15 However, CA was not found to be a risk factor for mortality during transcatheter aortic valve replacement.16 Many amyloidosis patients undergoing PCI may need intravascular ultrasound, which increases the cost of the hospitalization.17\n\nThis study determined that amyloidosis was an independent factor associated with in-hospital mortality, with an odds ratio of 1.3 (1.23-1.39). This increased mortality risk can be attributed to several factors, including the higher incidence of acute kidney injury in patients with amyloidosis (odds ratio 1.89, p<0.001). Acute kidney injury itself exhibited the strongest association with mortality, consistent with published data.18 Heart failure readmissions and the need for left ventricular assist devices may arise in these patients, which increase the length of stay, contributes to loss of function, and increases the total cost of hospitalization.19,20 In patients with cancer and amyloidosis, there could be racial differences in the cardiovascular outcomes as well.21 Amyloidosis was also associated with a higher incidence of complications of surgical care/injury (odds ratio 2.05, p<0.001). Considering the higher incidence of hypertension, diabetes, and obesity in this patient group, it is expected to observe a greater occurrence of surgical complications, in-hospital mortality, and major loss of function.\n\nFurthermore, this study observed a significant difference in intervention timing. Patients without amyloidosis had a routine PCI in 80.6% of cases, whereas only 65.3% of amyloidosis patients underwent a routine PCI. Emergency and urgent PCIs were significant risk factors for in-hospital mortality regardless of the presence of shock.22 Therefore, further studies are necessary to assess the significance of amyloidosis as an independent risk factor in both emergency and urgent scenarios.\n\nBased on our findings, we believe that clinicians should consider amyloidosis as a risk factor when performing PCI on patients. Although not currently included in existing risk calculation tools, amyloidosis increases the risk of procedure complications, either independently or possibly due to its association with other patient comorbidities. Moreover, it may be associated with a greater need for urgent procedures, leading to worse outcomes. This risk factor can be modified by implementing changes in clinical practice, such as closer follow-up or a lower threshold for elective PCI.\n\nThis study utilized a cross-sectional design with a large sample size obtained from a publicly available dataset. It is important to acknowledge that cross-sectional studies are prone to selection bias, information bias, and confounding. Furthermore, due to the nature of the dataset, we were unable to stratify cardiac amyloidosis and its specific types. As a result, we cannot draw any causal conclusions from this study. However, the study holds significant power due to the large sample size, and considering the limited available data on cardiac amyloidosis, our findings contribute to the existing literature in this field.\n\n\nConclusions\n\nAmyloidosis is associated with higher in-hospital mortality and worse outcomes in PCI recipients. This could be related to the increased incidence of complications of PCI in amyloidosis as a result of the low flow state. Further research is indicated to precisely define the etiologies behind the worse outcomes and mitigate the increased risk. This will also help address the unresolved question of the management of stable angina with stable CAD in patients with amyloidosis.",
"appendix": "Data availability\n\nThe HCUP NIS database used is a commercial database that requires the purchase of a license for use. Although publicly available, the data in this database cannot be freely shared with those who have not obtained the necessary permissions and licenses. As a researcher, I would need to follow the rules and regulations for accessing and using the HCUP NIS database, including obtaining the appropriate license and permissions. This involves signing a data use agreement and paying a fee to access the data. The authors have obtained the necessary permissions and licenses and are able to use the HCUP NIS data in my research, but making it publicly available at the time of publication is subject to any necessary privacy and confidentiality protections of the NIS data. Others would need to obtain their own licenses to access the data for their own research purposes. Anyone can access the data and replicate my findings given they have received necessary data usage agreements from HCUP NIS.\n\n\nReferences\n\nBeyene SS, Yacob O, Melaku GD, et al.: Comparison of Patterns of Coronary Artery Disease in Patients With Heart Failure by Cardiac Amyloidosis Status. Cardiovasc. Revasc. Med. 2021; 27: 31–35. PubMed Abstract | Publisher Full Text\n\nTsao CW, Aday AW, Almarzooq ZI, et al.: Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association. Circulation. 2022; 145(8): e153–e639. PubMed Abstract | Publisher Full Text\n\nGriffin JM, Rosenblum H, Maurer MS: Pathophysiology and Therapeutic Approaches to Cardiac Amyloidosis. Circ. Res. 2021; 128(10): 1554–1575. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRaval M, Siddiq S, Sharma K, et al.: A review of recent advances in the diagnosis of cardiac amyloidosis, treatment of its cardiac complications, and disease-modifying therapies. F1000Res. 2023; 12: 192. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKeller K, Hobohm L, Ostad MA, et al.: Temporal trends and predictors of inhospital death in patients hospitalised for heart failure in Germany. Eur. J. Prev. Cardiol. 2021; 28(9): 990–997. PubMed Abstract | Publisher Full Text\n\nUddin MM, Mir T, Kaur J, et al.: ST-elevation myocardial infarction among cardiac amyloidosis patients; a national readmission database study. Heart Fail. Rev. 2022; 27(5): 1579–1586. PubMed Abstract | Publisher Full Text\n\nWadhera RK, Joynt Maddox KE, Yeh RW, et al.: Public Reporting of Percutaneous Coronary Intervention Outcomes. JAMA Cardiol. 2018; 3(7): 635–640. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOverview of the National (Nationwide) Inpatient Sample (NIS): Reference Source\n\nKe PC, Zhou R, Serpell LC, et al.: Half a century of amyloids: past, present and future. Chem. Soc. Rev. 2020; 49(15): 5473–5509. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBenson MD, Buxbaum JN, Eisenberg DS, et al.: Amyloid nomenclature 2020: update and recommendations by the International Society of Amyloidosis (ISA) nomenclature committee. Amyloid. 2020; 27(4): 217–222. PubMed Abstract | Publisher Full Text\n\nRavichandran S, Lachmann HJ, Wechalekar AD: Epidemiologic and Survival Trends in Amyloidosis, 1987–2019. N. Engl. J. Med. 2020; 382(16): 1567–1568. PubMed Abstract | Publisher Full Text\n\nGöbel S, Hobohm L, Desuki A, et al.: Impact of cardiac amyloidosis on outcomes of patients hospitalized with heart failure. Eur. J. Intern. Med. 2022; 102: 88–96. PubMed Abstract | Publisher Full Text\n\nRaval M, Siddiq S: Clinical challenges in the management of cardiac amyloidosis complicating aortic stenosis and coronary artery disease. Front. Cardiovasc. Med. 2022; 9: 9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRaval M, Siddiq S: Extra-cardiac uptake of 99mTc-pyrophosphate scan leading to the diagnosis of stage IV metastatic prostatic adenocarcinoma. J. Nucl. Cardiol. February 2023. PubMed Abstract | Publisher Full Text\n\nUddin MM, Mir T, Pervez E, et al.: Trend in Incidence and Mortality of Cardiac Amyloidosis Among Patients With Acute Myocardial Infarction. Circulation. November 2021.\n\nElzeneini M, Gupta S, Assaf Y, et al.: Outcomes of Transcatheter Aortic Valve Replacement in Patients With Coexisiting Amyloidosis. JACC: Advances. 2023; 2(2): 100255. Publisher Full Text\n\nDesai R, Raval M, Adompreh-Fia KS, et al.: Role of Intravascular Ultrasound in Pulmonary Embolism Patients Undergoing Mechanical Thrombectomy: A Systematic Review. Tomography. 2023; 9(4): 1393–1407. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGriffin JM, Rosenblum H, Maurer MS: Pathophysiology and Therapeutic Approaches to Cardiac Amyloidosis. Circ. Res. 2021; 128(10): 1554–1575. PubMed Abstract | Publisher Full Text | Free Full Text\n\nModi K, Pannu AK, Modi RJ, et al.: Utilization of Left Ventricular Assist Device for Congestive Heart Failure: Inputs on Demographic and Hospital Characterization From Nationwide Inpatient Sample. Cureus. July 2021; 13: e16094. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJain A, Arora S, Patel V, et al.: Etiologies and Predictors of 30-Day Readmission in Heart Failure: An Updated Analysis. Int. J. Heart Fail. 2023; 5: 159–168. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJain A, Desai R, Ahmed I, et al.: Racial disparities in major cardiovascular and cerebrovascular adverse events in breast cancer survivors: A nationwide analysis. F1000Res. 2023; 12: 891. Publisher Full Text\n\nBrennan JM, Curtis JP, Dai D, et al.: Enhanced Mortality Risk Prediction With a Focus on High-Risk Percutaneous Coronary Intervention. JACC Cardiovasc. Interv. 2013; 6(8): 790–799. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "232304",
"date": "22 Jan 2024",
"name": "Wolfgang Rottbauer",
"expertise": [
"Reviewer Expertise clinical and experimental cardiological research in multiple areas."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a large nationwide analysis investigating the impact of amyloidosis on outcomes in patients with CAD undergoing percutaneous coronary intervention (PCI).\nBriefly, out of 457,730 patients included 30,905 (6,75%) had amyloidosis. Mean age, female sex, and African American race were higher in the amyloidosis cohort. Moreover, patients with amyloidosis were associated with worse clinical outcomes including higher incidence of acute kidney injury (AKI), complications of surgical care and cardiovascular implant, major loss of function, length of hospital stay as well as higher in-hospital mortality compared to the non-amyloidosis cohort. Diagnosis of amyloidosis was associated with an increased risk of in-hospital mortality (OR 1.3), AKI (OR 1.89) and complications of surgical care (OR 2.05).\nThe idea of investigating the impact of amyloidosis in CAD patients undergoing PCI as well as the study approach is very interesting. The identification of amyloidosis cases using the nationwide inpatient sample is appropriate. The strength of the present study is certainly the large data set and in particular the great number of patients with amyloidosis of almost 31,000.\nNevertheless, the quality of the available data is insufficient. Especially, the subtypes of amyloidosis are not further classified. Given the relatively low mean age (~ 66 years) and the high percentage of woman in the amyloidosis cohort (higher than in patients without amyloidosis!) a rather larger proportion of non-cardiac amyloidosis (not ATTR amyloidosis) can be assumed. Moreover, there will be also many cases without cardiac involvement in the other amyloidosis subtypes. On the other hand, there will be some cases in the non-amyloidosis group with previously unknown amyloidosis. Therefore, the exact impact of amyloidosis on the outcome of CAD patients undergoing PCI cannot be adequately assessed from the available data. The conclusion that can be drawn from the present data is simply that patients suffering from more diseases are associated with worse outcomes. In this regard, patients with amyloidosis had higher incidences of acute kidney injury and emergency PCIs, which, unsurprisingly, is associated with worse clinical outcome. Beside the subgroup of amyloidosis, it would be interesting to know among others more data of PCI like the specific indication. Moreover, the incidence of amyloidosis (6,75%) in the present patient population appears very high. What criteria were used to define amyloidosis.\nDue to the interesting patient population, we welcome the resubmission of the manuscript if relevant data can be supplemented and evaluated\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
},
{
"id": "232305",
"date": "22 Feb 2024",
"name": "Matteo Bianco",
"expertise": [
"Reviewer Expertise DAPT and cardiomyopathies"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSingh et al performed an epidemiological study on a national registry in US trying to describe the impact of amyloidosis on the prognosis of patients undergoing pci. Unfortunately the collected and analyzed data are insufficient to draw any conclusions due to the high risk of bias related to absence of informations on the number of acute coronary syndromes, type of amyloidosis ( AL vs TTR) treatment and complexity of CAD.\nMoreover, even if in the title only patients undergoing pci, then in the paper authors also describe the impact of surgical and medical treatment of cad.\nI have several comments\nIntroduction: amyloidosis are many, AL and TTR are only the commonest involving the heart. Please specify it in the introduction.\n\nMoreover, AL and TTR are different disease, describe the two disease briefly in the introduction. Talking about epidemiology, cite also this paper: doi: Bianco M, et. al. 2021 (Ref 1)\n\nResults: the results section shows multiple correlations between risk factors, complications and outcomes potentially associated with worse outcome in amyloidosis patients. Unfortunately those factors are also associated with age. The authors did not evaluated the association with heart failure, one of the main clinical manifestation of amyloidosis. Please, can the authors comment on this and add the analysis on heart failure incidence?\n\nMoreover can the authors add informations on the clinical presentation of cad? How many patients had acs? How mant underwent surgical repercussion.\nDiscussion: The discussion is not linear. There are many jump to different topic and sentences not appear to be well connected one to the other. Moreover, can the authors explain why the use of intravascular ultrasound is increased in patients with cardiac amyloidosis?\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1213
|
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