Monthly Archives: January 2025

Abstract

Objective: To conduct a systematic review of the experiences of patients with Sjögren’s syndrome.

Methods: We performed a computerized search across PubMed, Web of Science, Embase, Cochrane Library, CINAHL, PsychINFO, Proquest, CNKI, CBM, Wanfang Data, and VIP databases to identify qualitative studies on the illness experiences of Sjögren’s syndrome patients from the inception of the libraries to September 2023. The JBI Critical Appraisal Tool for qualitative research in Australia was utilized to assess the quality of the included studies, and synthesis methods were employed to integrate the findings.

Results: Nine studies were included, yielding 32 findings that were categorized into 10 themes, culminating in 4 overarching outcomes: (1) prolonged and challenging diagnostic and treatment journeys; (2) significant daily life disruptions; (3) diverse coping styles and illness attitudes; (4) a pronounced need for, yet scarcity of, social support.

Conclusions: Sjögren’s syndrome patients endure profound physical and mental disturbances, leading to a markedly diminished quality of life. It is imperative for healthcare professionals to enhance symptom management and intervention, focus on assessing patients’ psychological well-being and coping mechanisms, and develop a comprehensive medical and social support system to ameliorate patients’ quality of life.

Keywords

Sjögren’s syndrome, Illness experience, Qualitative research, Meta-synthesis

Introduction

Sjögren’s syndrome (SS) is a chronic autoimmune disease hallmarked by dry mouth and eyes due to lymphocytic infiltration of the salivary and lacrimal glands, with primary clinical manifestations including xerostomia, fatigue, and musculoskeletal pain [1]. Predominantly affecting middle-aged and elderly women, the global incidence rate ranges from 0.04% to 4.80% [2]. SS is a protracted and relapsing condition; as it advances, symptoms can impact multiple bodily systems, severely compromising patients’ physical and mental health [3,4]. Amid the evolution of the bio-psycho-social medical model, the psychological well-being of patients with SS has become a focal point for researchers. Existing studies, while exploring the experiences and sentiments of SS patients, exhibit variations in racial, contextual, and methodological aspects, preventing a comprehensive understanding from a single study. This investigation employs a meta-integration approach to compile a more exhaustive qualitative evidence base reflecting the experiences of SS patients, aiming to inform clinical healthcare professionals and bolster the development of targeted interventions and measures.

Methods

The protocol was registered a priori with the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42023472699.

Search Strategy

PubMed, Web of Science, Embase, Cochrane Library, CINAHL, PsychINFO, Proquest, CNKI, CBM, Wanfang Data and VIP was searched for qualitative studies on the experience of SS from its inception to 30 September 2024, and the references of the included studies were searched manually. Search terms such as ‘Sjogren’s Syndrome/primary Sjogren’s syndrome/Sjogren’s syndrome/ Sicca Syndrome/Sicca exocrinopathy/SS/pSS; illness experience/ experience/feel*; qualitative research/qualitative research/qualitative study/participant observation/phenomenology/action research’ etc. The search strategy is illustrated with a PubMed example, see Figure 1.

Figure 1: Pubmed search strategy

Literature Inclusion and Exclusion Criteria

The inclusion criteria referred to the PICoS model [5,6]. (1) Population (P): patients diagnosed with SS (including primary Sjögren’s syndrome and Sjögren’s syndrome), age≥18 years old, gender is not limited; (2)Interest phenomenon (I): patients with SS since the disease since the real experience of the disease and feelings; (3) Context (Co): the life experiences of patients with SS during or after the diagnosis and treatment process; (4)Study design (S): qualitative research, including phenomenology, Grounded theory, ethnography and action research. Exclusion criteria: (1)duplicated published literature; (3)non-Chinese and English literature; (2)literature with no access to full text.

Literature Screening and Data Extraction

Literature screening and data extraction were carried out independently by 2 researchers (1st and 2nd authors), with a 3rd researcher (4th author) assisting in judgement when differences of opinion were encountered. The retrieved literature was imported into Endnote21, duplicates were eliminated, titles and abstracts were read for initial screening, and the full text was further read for re-screening to make a final decision on whether to include the literature. The information extracted mainly included the author, year of publication, country, subject of study, research method, phenomenon of interest and findings.

Evaluation of Literature Quality

The included literature was evaluated by 2 researchers using the JBI qualitative research quality assessment tool [7]. The tool consists of 10 items designed to assess the quality of qualitative research literature with different methods, including research methodology and conceptual depth of information. 2 researchers were assessed with ‘yes’, ‘no’, ‘not clear’were used to assess the quality of the literature, which was classified into 3 grades, A, B, and C. All criteria were assessed as grade A if they were met, grade B if they were partially met, and grade C if none of them were met. Only studies with grades A and B were included in this study and studies with grade C were excluded. Disagreements, if any, were resolved through independent judgement by a 3rd researcher.

Meta Integration Methodology

The pooled integration method from the Australian JBI Centre for Evidence-Based Healthcare was employed to synthesize the qualitative research literature under review [7,8]. Researchers, well-versed in evidence-based nursing and experienced with qualitative methodologies, meticulously examined the included literature. This process aimed to comprehend and elucidate the significance of each finding, consolidate them into categories, and ultimately amalgamate these into novel insights by dissecting the interconnections between categories.

Results

Literature Search Results

The results of the initial literature search were 588 articles, and 9 articles were included after screening and quality evaluation. The time range was from 2001 to 2020, including 1 article in Chinese and 8 articles in English. Research methods phenomenology 6 articles, descriptive research 2 articles, grounded theory 1 article. The literature screening process is shown in Figure 2.

Figure 2: Flow chart of literature screening

Basic Characteristics and Quality Evaluation of the Included Literature

The basic characteristics of the literature are shown in Table 1 and the quality evaluation is shown in Table 2.

Table 1: The basic characteristics of the included literature(n=9).

Author	Year	Country	Participants	Study design	Location	Aim	Themes
Nancy et al. [9]	2001	America	10 patients	Descriptive Research	telephone interview	To explore the lived experiences of people with SS and to uncover the coping strategies and attitudes of actual patients with SS	Four themes: helping hindering hoping hurting
Rebecca J et al. [10]	2017	The United Kingdom	20 patients	Phenomenological Research	Hospital outpatient departments or research institutes	To investigate the experience of fatigue and related symptoms in patients with pSS	Three themes: the physical experience of fatigue; ocular fatigue and fatigue related to ocular complaints; cognitive aspects of fatigue
Jemma L et al. [11]	2023	The United Kingdom	not mentioned	Phenomenological Research	Online Sites	To qualitatively explore the conversations about sexual functioning that females with SS had on internet forums	Four themes: the symptoms of SS and their impact on the sexual environment; the emotional responses that are commonly evoked in response to sexual difficulties; the strategies that users have implemented to manage sexual problems; and the impact that a partner’s behavior may have on the sexual environment.
Di Ying J et al. [12]	2016	Singapore	10 patients	Phenomenological Research	Dental school conference room	To provide clinicians with insight into how dry mouth can impact on the daily lives of Sjögren’s Syndrome patients	Four themes: the journey to diagnosis; disease impact spectrum (of dry mouth amid other symptoms); interactions with healthcare professionals; and the positive coping process.
Angelika et al. [13]	2017	Austria	20 patients	Phenomenological Research	Outpatient quiet room	To explore perspectives and needs of patients with PSS that influence health related quality of life (HRQL)	Three themes: Physical dimension; psychological & emotional challenges; social life & daily living
Gonzalo et al. [14]	2016	Chile	12 patients	Grounded Theory	Hospital lighting and soundproofed private rooms	To give an encompassing in-depth account of the life experiences of women with pSS and health-related behaviours, and to summarize these experiences in an integrated model.	Three themes: illness experience, social interaction and psychological response
Peng et al. [15]	2023	Taiwan, Province of China	14 patients	Phenomenological Research	Patient’s neighborhood fast food restaurant or hospital	To explore the experiences of SS patients seeking care	Four themes: annoying symptoms; difficulty in confirming a diagnosis; fear of medication side effects; confronting the disease
Anne et al. [16]	2014	Norway	9 patients	Phenomenological Research	not mentioned	To examine how fatigue may differ from ordinary tiredness in patients with primary Sjögren’s syndrome (SS)	Two themes: a heavy, resistant body and ever- present lack of vitality; unpredictable and uncontrollable fluctuations in fatigue
Kerry et al. [17]	2020	The United Kingdom	48 patients	Descriptive Research	Online Forum	To explore the disease and treatment experiences of patients with pSS	Three themes: Symptoms; Symptom Impacts; Patient Experiences with pSS Management

Note: 1 Was there a clear statement of the aims of the research? 2 Is a qualitative methodology appropriate? 3 Was the research design appropriate to address the aims of the research? 4 Was the recruitment strategy appropriate to the aims of the research? 5 Was the data collected in a way that addressed the research issue? 6 Has the relationship between researcher and participants been adequately considered? 7 Have ethical issues been taken into consideration? 8 Was the data analysis sufficiently rigorous? 9Is there a clear statement of findings? 10 How valuable is the research?

Table 2: Methodological quality evaluation of the included literature (n=9).

Publication	1	2	3	4	5	6	7	8	9	10
Nancy et al. [9]	Yes	Yes	No	No	Yes	No	Yes	Yes	Yes	Yes
Rebecca J et al. [10]	Yes	Yes	Yes	Unclear	Yes	No	Yes	Yes	Yes	Yes
Jemma L et al. [11]	Yes	Yes	Yes	Unclear	Yes	No	No	Yes	Yes	Yes
Di Ying J et al. [12]	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes
Angelika et al. [13]	Yes	Yes	Yes	No	Yes	No	Yes	Yes	Yes	Yes
Gonzalo et al. [14]	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes
Peng et al. [15]	Yes	Yes	Yes	No	Yes	No	Yes	Yes	Yes	Yes
Anne et al. [16]	Yes	Yes	Yes	Unclear	Yes	No	No	Yes	Yes	Yes
Kerry et al. [17]	Unclear	Yes	Yes	Unclear	Yes	No	No	Yes	Yes	Yes

Results of Meta-integration

The researcher distilled a total of 32 findings by iteratively reading and analyzing the nine pieces of literature included, organizing and generalizing the similar findings into 10 new categories, and obtaining four integrative findings.

Integrating Outcome 1: A Long and Difficult Consultation Experience

Category 1: Long Time to Diagnosis of Disease

Patients often experience multiple visits to the doctor due to disease symptoms involving multiple systems throughout the body (‘These searches were complicated by the need for multiple diagnoses including fibromyalgia, Raynaud’s, RA, lupus, and chronic fatigue syndrome’[9] ‘Many respondents discussed their histories of multiple doctor visits both to general practitioners and to specialists’[9]), in which most patients received only specialist symptomatic management (‘the focus of the physician’s visit was on prescribing medication to bring symptomatic relief ’[15]), and the time to confirmation of the diagnosis was continually prolonged (‘after 5 years of symptoms and unsatisfying visits at different doctors, one doctor was on the right way’[13]) they questioned the professionalism of the doctors (‘the thing is do the general practitioners know about it ?’[12] ‘Every practitioner speaks differently, three speak three ways and no one can tell me what it really is’[15] ‘My doctor doesn’t believe I have SS’[9])

Category 2: Difficult Treatment Process

Due to a lack of knowledge about the disease, patients often felt overwhelmed (‘she didn’t always know what was enough importance to alert her doctor’[9], ‘I don’t know that I actually really need to know all just at this point in time’[12]), and showed concern about medications that bring about side effects and effectiveness (‘worried about the side effects from western medication’[15], ‘the various medications do not help much’[9]), and financial burdens that grew as the disease progressed (‘every year thousands of dollars to the dentist’[12], ‘my retirement and savings have been depleted’[16])

Integration Outcome 2: Severe Daily Life Distress

Category 3: Physical Symptoms Throughout the Body

The most common discomfort experienced by patients is dry mouth and eyes (‘my lips stick together and I can’t separate them’[14], ‘my eyes are dry it feels like sandpaper has been rubbed over them’[16] ‘a feeling of choking’[13]), limited dietary choices (‘I can’t eat dry food, I can’t swallow it’[13]) Some patients experience a gradual loss of their sense of taste (‘sometimes I can’t taste food, I also find myself losing my sense of taste and smell’[14]); pain accompanies the patient (‘limbs, everything hurts’[13]), and constant fatigue fills the daily routine (‘just peeling potatoes is exhausting!’[15], ‘I don’t even have the energy to talk’[16], ‘I can sleep for days at a time when the fatigue comes’[10]), and sleep is affected (‘When I sit up in bed, I can only sleep’[13], ‘When I turn around, I have a feeling of suffocation’[13])

Category 4: Intimate Relationships in Trouble

Disease manifestations of oral dryness and female vaginal dryness (‘I don’t realise that I’m only comfortable with kisses on the mouth’[11], ‘My vaginal dryness has gotten worse’[11]) affect the patient’s intimate relationship harmony(‘My husband and I have not had sex for over a year’[11] ‘My husband does not tolerate changes in our sex life’)[14]), patients’ libido declines, intimacy decreases, and they feel guilt and pain (‘It’s too painful’[11] ‘The guilt overwhelms me’[11])

Category 5: Negative Psychological Experiences

Patients often feel helpless and sad in the face of the disease (‘especially when you are tired, you feel low’ [9] ‘one time I broke down and burst into tears, which stressed me out a lot’ [9]) SS is a chronic disease for which there is no cure for it, and a variety of symptomatic medications such as immunological agents and other drugs are mostly used in the clinic. While taking medications, patients are concerned about their potential range of side effects (‘anti-inflammatories, paracetamol, codeine, you end up with more tablets’ [11] ‘too many side effects of western medication’ [15]), and some patients are annoyed with the status (‘a few people questioned what they were doing to deserve SS’ [11], ‘I’m getting very, very annoyed’ [10] ‘I’m getting very, very bad’ [10]). During the course of the disease, the functioning of multiple organ organs throughout the patient’s body is progressively affected, and the patient expresses his or her fears about the uncertainty of the future progression of the disease (‘The worst thing is not knowing what is going to happen’ [8] ‘Fear of organ failure and dialysis’ [8] ‘fear of incapacitation’ [8]) In understanding the incurable nature of the disease, coupled with the constant physical and mental distress, patients develop self-loathing (‘I hate myself, I hate this woman in pain’ [10]), they chose to reject the sympathy of others and tried to hide the condition (‘don’t want people to look at me differently or say ‘poor me’’ [8] ‘I don’t let anyone see it…I cover everything up’ [9])

Category 6: Social and Work Disorders

SS symptoms affect all systems throughout the body and cause many inconveniences to the patient during daily life and social interaction (‘I can’t read at night because my eyes are too sore and tired’ [9] ‘Driving is often limited due to fatigue and dry eyes’ [8] ‘My tongue gets stuck and I can’t express myself clearly’ [13] ‘I have a very limited life of shutting myself away and going to the hospital’ [13]), and was unable to perform previous work (‘I have noticed that I get tired faster in conversations’ [9] ‘Especially with computer work, patients find it challenging to have long conversations with clients’ [12] ‘My dryness is greatly affected my life, causing me to stop working and retire early’ [16])

Integrating Outcome 3: Very Different Coping Styles and Attitudes Towards Illness

Category 7: Positive Attitude and Coping

Patient maintains a positive outlook throughout the disease diagnosis and treatment process, believing that he or she will ultimately overcome the disease (‘I’ll be lucky if that’s all that’s knocked out of me’ [8] ‘I think in time I’ll get back to where I was before’ [13] ‘There are a lot of people who lie down and die, they sink because of health problems – not me!’ [13] ‘I’m trying to say come across it and accept it’ [15]) They actively use multiple resources around them to seek help to learn about the disease (‘learning how to understand and help themselves from multiple sources such as other patients, support groups, literature and computer searches’ [8]) while attempting to make lifestyle adjustments to accommodate the disease (‘Many respondents drank water more frequently and changed their eating patterns. Keeping their hands and feet as warm as possible and pacing themselves according to their activity and rest needs’[8] ‘Made a lateral move to work’ [8] ‘We tried all the backwash.’[10] ‘My water bottle is my best friend’ [10] ‘Making vaginal uterine trays, moisturisers or soaps to alleviate the dryness associated with dry syndrome’ [10]), and some patients try alternative medicine treatments (‘Started actively exploring complementary and alternative medicine and started seeing a nutritionist’ [11]) Some patients comfort their souls by being religious and helping each other (‘I also attend spiritual events and worship God, all we do is ask for human nature’ [13] ‘We would go to church, and when we were sick we would ask our brothers and sisters in the group to pray for me, and then there would be an outlet for our moods’[15] ‘Doing small feats of charity myself, exhorting people to be good, teaching while doing so, and contributing my skills during my lifetime’[15]), and in doing so, patients experienced positive physical and mental positive feedback (‘personal growth and development can be facilitated’ [8] ‘the research process itself is an altruistic act that positively affects their self-esteem’ [11])

Category 8: Negative Attitudes and Coping Styles

Conversely some patients maintained negative attitudes and chose to delay seeking treatment (‘She tried to deny her symptoms and sometimes let the bad signs and symptoms go on for too long before seeking help’ [8] ‘She tried not to think about anything and took it day by day. I didn’t cope with it properly and that was my way’ [8]).

Integration Outcome 4: Thirst for and Lack of Social Support

Category 9: Lack of Social Support

SS patients do not receive sufficient support from family (especially spouses) and friends (‘My husband is the worst problem because he doesn’t understand’ [8] ‘My husband is not supportive or helpful, and doesn’t tolerate changes in our sex life’ ‘There are no friends to talk to about dry syndrome’ [8]) and on the other hand, the help received by patients in peer support groups is not sufficiently represented (‘There is a marked negativity in the support group and a lack of shared responsibility for managing the group’ [8] ‘The support group did not support her as a leader and she found herself dragged down by the others’ [8])

Category 10: Desire for Social Support

Adequate support from close relationships brought great help to the patient (‘More than one person said that her best support came from her spouse’ [8] ‘My whole family knows about this and they all try to help me not to talk too much and to keep me calm’[13]) Meanwhile, during the visit, patients were eager to be able to communicate effectively with each other and with healthcare professionals to give them psychological support and comfort (‘It’s very important to be able to talk to the healthcare professionals, I know that at the moment they can’t do anything about it, it’s okay, but you’re listening to it, you’re not just folding it’ [11] ‘An understanding healthcare practitioner made a big impact’ [8])

Discussion

Focus on the Impact of SS Symptoms on Patients and Actively Take Appropriate Measures to Alleviate Them

Integration results reveal that Sjögren’s syndrome (SS) patients endure a spectrum of symptoms, including dry mouth and eyes, fatigue, and generalized pain, significantly impairing their quality of life. As dry eyes can progress to keratitis, patients may experience blurred vision, redness, and ocular discomfort. Reduced salivary gland secretion not only affects eating and swallowing but also speech and taste perception, potentially leading to halitosis, oral ulcers, and rampant caries, which disrupt daily eating and social interactions [17- 18]. Healthcare professionals should advise patients on maintaining oral and ocular hygiene, facilitate early screening and diagnosis, and intervene to enhance glandular secretion, thereby mitigating the symptoms’ impact on physical and mental well-being. Sleep quality is closely linked to quality of life; sleep disorders can affect daily life and may trigger immune and inflammatory responses, increasing the risk of autoimmune diseases [19]. Professionals should assess and address patients’ sleep issues promptly, employing personalized treatments. Cognitive-behavioral therapy has been shown to improve sleep quality in SS patients, and both exercise therapy and traditional Chinese medicine (TCM) offer safe and effective interventions for sleep disorders [20,21]. Sexual dysfunction, a significant aspect of physical and mental health, is prevalent among female SS patients, threatening intimacy and potentially inducing negative emotions such as embarrassment and helplessness. Studies indicate that the prevalence of sexual dysfunction in SS patients is twice that of the general population, with vaginal dryness, pain, and fatigue influencing sexual behavior [22]. Given the sensitive nature of this issue, few patients are willing to discuss it openly. Healthcare professionals should delve into patients’ experiences, bolster nurse-patient trust, and provide empathetic listening, respect, and support. Collaborating with gynecologists and psychologists can offer patients comprehensive professional and psychological assistance.

There is no cure for SS, hence treatment focuses on symptom relief, mitigating local and systemic damage, and enhancing quality of life [23]. The emphasis should be on early screening and diagnosis through collaborative efforts with multidisciplinary teams. In recent years, traditional Chinese medicine (TCM) and its techniques have gained traction in SS treatment, attributed to their efficacy in symptom improvement and lower incidence of toxic side effects [24,25]. Future clinical outcomes may be enhanced by integrating TCM with other therapeutic approaches. Additionally, patients can be empowered to adopt healthier lifestyles, thereby improving their quality of life, through comprehensive and personalized health education initiatives.

Focusing on Negative Emotions in SS Patients and Fostering Positive Coping Strategies

Integrative findings reveal that SS patients experience a spectrum of negative emotions, impacting their quality of life due to enduring clinical symptoms, daily life limitations, and compromised social functioning [27]. Research indicates that the prevalence of anxiety and depression among SS patients is markedly higher than in the general population, with rates of 33.8% and 36.9%, respectively [26]. Healthcare professionals must prioritize the emotional well-being of SS patients, delve into the origins of their negative emotions, and guide them towards effective emotional expression and coping mechanisms. Encouraging a realistic understanding of disease symptoms and bolstering confidence in treatment outcomes is crucial. Evidence supports the efficacy of positive thinking training therapy and narrative care in alleviating anxiety and depression, thereby enhancing life quality [28-30]. Tailored interventions for SS patients can strengthen nurse-patient rapport, mitigate negative emotional impacts, and promote a positive and stable mental state.

The study’s findings highlight the diverse coping strategies employed by SS patients, which are their cognitive and behavioral responses to the disease and its associated disruptions [31]. Effective coping strategies are crucial for alleviating symptoms, enhancing functional status, and improving quality of life [32,33]. Healthcare professionals should promptly assess these strategies and provide ongoing support to patients who utilize positive approaches. Additionally, professionals must delve into the challenges faced by patients with negative or avoidant coping mechanisms to foster better disease acceptance and develop constructive cognitive coping strategies. Family support is pivotal in bolstering patients’ confidence in treatment and in converting negative emotions and coping behaviors [34]. Engaging patients and their caregivers in treatment decisions is essential for increasing their investment in therapy. Continuity of care, including regular professional guidance, is vital for encouraging patients to actively engage in their disease management and to confront their condition with a positive attitude.

Constructing an Optimal Medical and Social Support System

The integration findings indicate that Sjögren’s syndrome (SS) can affect multiple bodily systems, prompting patients to seek treatment for their presenting symptoms. Without adequate disease knowledge and interdisciplinary collaboration in diagnosis and treatment, healthcare providers may fail to make accurate assessments, leading to delayed SS diagnoses. During consultations, patients often receive only symptomatic treatment, which falls short of addressing their comprehensive needs. Thus, medical staff must enhance their expertise and foster interdisciplinary collaboration to develop personalized diagnostic and treatment plans, as well as offer patients thorough, evidence-based education and guidance on SS [23]. Patient care continuity should also be a priority, leveraging ‘Internet + nursing services’, interdisciplinary nursing teams, and hospital-community- family collaborative frameworks to ensure precise and efficient patient management [35]. Additionally, family, peer, and social support are crucial for SS treatment. Patients require ample emotional support from families, and peer support groups should be professionalized and made more effective. Group composition should be carefully selected to foster constructive communication and sharing among patients, with ongoing monitoring to address their emotional and informational needs, and to implement timely adjustments and management strategies.

Conclusion

Using meta-integration methodology, this study thoroughly examined the illness experiences of patients with SS, revealing four key themes: the complexity and duration of diagnostic and treatment processes, substantial disruptions to daily life, a variety of coping styles and illness attitudes, and an evident gap in social support despite a high demand. Healthcare professionals are advised to implement personalized care strategies to mitigate patients’ distressing symptoms, address psychological well-being to foster positive outlooks, and engage in interdisciplinary collaboration to enhance diagnostic and therapeutic approaches.

Limitation

This study has certain limitations: it did not include studies that have not yet been published, introducing a degree of selective bias; and some of the included literature is relatively old, which may limit the applicability of the meta-integrated results and may not fully reflect the experiences of SS patients. This indirectly suggests that there is a current lack of attention to the psychological experiences of SS patients, which warrants further in-depth exploration in the future.

Acknowledgements

We would like to express our sincere gratitude to all those who contributed to this work. Your support and assistance have been invaluable throughout the research process.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

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

References

Seror R, Nocturne G, Mariette X (2021) Current and future therapies for primary Sjögren syndrome. Nature Reviews. Rheumatology. [crossref]
Cui Y, Li J, Li L, Zhao Q, Chen S, Xia L, Fu T, Ji J, Gu Z (2020) Prevalence, correlates, and impact of sleep disturbance in Chinese patients with primary Sjögren’s syndrome. International Journal of Rheumatic Diseases, 23(3): 367-373. [crossref]
Zhang W, Li X M, Xu D, Liu D Z, Dong Y (2020) Recommendations of diagnosis and treatment of primary sjgren’s syndrome in china. Zhonghua nei ke za zhi. [Chinese journal of internal medicine], 59(4): 269-276. [crossref]
Miyamoto, Samira T.Valim, ValeriaFisher, Benjamin A (2021) Health-related quality of life and costs in sjogren’s Rheumatology, 60(6) [crossref]
Westerlund A, Kejs A M T, Beydogan H, Gairy K (2021) Primary Sjögren’s Syndrome: A Retrospective Cohort Study of Burden of Illness in Sweden. Rheumatology and Therapy. [crossref]
Stern C, Jordan Z, McArthur A (2014) Developing the review question and inclusion The American Journal of Nursing. [crossref]
The Joanna Briggs Critical appraisal checklist for qualitative research[EB/ OL].[2022-02-05].
Lockwood C, Munn Z, Porritt K (2015) Qualitative research synthesis: methodological guidance for systematic reviewers utilizing meta-aggregation. International Journal of Evidence-based Healthcare. [crossref]
Schoofs N (2001) Seeing the glass half full: living with Sjogren’s Journal of Professional Nursing: Official Journal of the American Association of Colleges of Nursing. [crossref]
Stack R J, Southworth S, Fisher B A, Barone F, Buckley C D, Rauz S, Bowman S J (2017) A qualitative exploration of physical, mental and ocular fatigue in patients with primary Sjögren’s Syndrome. PloS One. [crossref]
McCready J L, McCarty K, Deary V, Collins T L, Hackett K L (2023) A qualitative exploration of internet forum discussions surrounding female sexual function for individuals with Sjögren’s PloS One 18(9): e0291422.
Ngo DYJ, Thomson WM, Nolan A, Ferguson S (2016) The lived experience of Sjögren’s BMC oral Health. [crossref]
Lackner A, Ficjan A, Stradner MH, Hermann J, Unger J, Stamm T, Stummvoll G, Dür M, Graninger WB, Dejaco C (2017) It’s more than dryness and fatigue The patient perspective on health-related quality of life in Primary Sjögren’s Syndrome – A qualitative study. PloS One 12(2) e0172056. [crossref]
Rojas-Alcayaga G, Herrera Ronda A, Espinoza Santander I, Bustos Reydet C, Ríos Erazo M, Wurmann P, Sabugo F, Geenen R (2016) Illness Experiences in Women with Oral Dryness as a Result of Sjögren’s Syndrome The Patient Point of View. Musculoskeletal Care 14(4): 233-242. [crossref]
Chih-Yu P, Mei-Ping L, Pin-Hsuan L, Cheng-I Y, Huai-Ti H, Meng-Chen H, Li- Hung L (2023) Experiences of patients with Sjögren’s Syndrome in seeking medical Nursing Magazine 70(5): 36-43.
Mengshoel AM, Norheim KB, Omdal R (2014) Primary Sjögren’s syndrome fatigue is an ever-present fluctuating and uncontrollable lack of energy. Arthritis Care & Research 66(8): 1227-1232. [crossref]
Gairy K, Ruark K, Sinclair SM, Brandwood H, Nelsen L (2020) An Innovative Online Qualitative Study to Explore the Symptom Experience of Patients with Primary Sjögren’s Rheumatology and Therapy 7(3): 601-615. [crossref]
Baer AN, Walitt B (2017) Sjögren Syndrome and Other Causes of Sicca in Older Clinics in Geriatric Medicine 33(1): 87-103. [crossref]
Chung SW, Hur J, Ha YJ, Kang EH, Hyon JY, Lee HJ, Song YW, Lee YJ (2019) Impact of sleep quality on clinical features of primary Sjögren’s syndrome. The Korean Journal of Internal Medicine 34(5): 1154-1164. [crossref]
Oláh C, Schwartz N, Denton C, Kardos Z, Putterman C, Szekanecz Z (2020) Cognitive dysfunction in autoimmune rheumatic diseases. Arthritis Research & Therapy 22(1) 78. [crossref]
Chen HH, Lai JN, Yu MC, Chen CY, Hsieh YT, Hsu YF, Wei JC (2021) Traditional Chinese Medicine in Patients With Primary Sjogren’s Syndrome A Randomized Double-Blind Placebo-Controlled Clinical Trial. Frontiers in Medicine 8 744194. [crossref]
Lp D, Aba G, Pa M et al. (2022) The effects of resistance training in patients with primary Sjögren’s Clinical Rheumatology 41(4) [crossref]
H I, M I, O A et (2017) Are the women with Sjögren’s syndrome satisfied with their sexual activity?. Revista Brasileira de Reumatologia 57(3) [crossref]
Liu H, Wang X, Liu W, He G, Liang X, Bian Y (2023) Effectiveness and Safety of Traditional Chinese Medicine in Treatment of Primary Sjögren’s Syndrome Patients A Meta-analysis. Combinatorial Chemistry & High Throughput Screening 26(14) 2554-2571. [crossref]
Yen CM, Lin HC, Chen WS, Hsu CC, Liaw CC, Kung YY, Ma CP, Chen HY, Su YT, Chang CM (2024) Evaluation of traditional Chinese medicine tea bag TBDESJS in patients with Sjögren’s syndrome and dry eye syndrome A phase II pilot study. International Journal of Rheumatic Diseases 27(11) [crossref]
Popescu A, Hickernell J, Paulson A, Aouhab Z (2024) Neurological and Psychiatric Clinical Manifestations of Sjögren Current Neurology and Neuroscience Reports 24(8): 293-301. [crossref]
Cui Y, Xia L, Li L et (2018) Anxiety and depression in primary Sjögren’s syndrome A cross-sectional study. BMC Psychiatry 18(1): 131. [crossref]
Liu Z, Dong Z, Liang X et (2017) Health-related quality of life and psychological status of women with primary Sjögren’s syndrome A cross-sectional study of 304 Chinese patients. Medicine 96(50) e9208. [crossref]
Mao WJ, Chen WD, Cai WD, Jiang MJ, Du J, Guo JY (2024) Effects of virtual reality- based positive thinking training on negative emotions and fatigue in ovarian cancer patients undergoing chemotherapy. China Nursing Management 24(1): 29-34
Lin Wan-Ting, Cai-Hong Lu, Zheng-Rong Wang, Huan Hong, Qiao-Rong Liu (2023) Effects of Focused Solution Brief Therapy Combined with Positive Thinking Training on Anxiety, Depression, and Quality of Life in Dry Eye Journal of Nursing 38(14): 72-76
Zhao Jiao, Li Aixian, Feng Yuanyuan, Zhu Ying, Yuan Jiu-Lian, Xu Meng (2022) Effects of narrative care on anxiety, depression and well-being in hematopoietic stem cell transplantation patients. China Nursing Management.
Folkman S (1984) Personal control and stress and coping processes A theoretical Journal of Personality and Social Psychology 46(4): 839-852.
Líška D (2022) Exercise in the treatment of ankylosing Vnitrni Lekarstvi 68(E-1): 16-21. [crossref]
Macfarlane TV, Abbood HM, Pathan E et al. (2018) Relationship between diet and ankylosing spondylitis A systematic European Journal of Rheumatology 5(1): 45-52. [crossref]
Yang HL, Wang P, Hou WX, Luan XR (2016) Design and application of a hospital- community-family ternary linkage continuity of care platform. Chinese Journal of Nursing.

Ending the Mpox Endemic: Beyond Declaring a Public Health Emergency

Leave a reply

DOI: 10.31038/IJVB.2025911

Abstract

The first recorded human case of the Monkeypox virus occurred in the Democratic Republic of the Congo in 1970. Over the past six decades, human Monkeypox has remained endemic in Western and Central Africa and emerged as a global public health threat since 2022 [1,2]. The Africa Centers for Disease Control and Prevention (Africa CDC) classified the escalating Mpox outbreak across 15 countries in the World Health Organization (WHO) African Region as a Public Health Emergency of Continental Security. In response, WHO Director-General Dr. Tedros Ghebreyesus declared a Public Health Emergency of International Concern (PHEIC) on 14 August 2024. This global outbreak has affected over 120 countries since 2022. Addressing this prolonged endemic requires global collaboration and concerted efforts. Given the similarities between smallpox and Mpox, valuable lessons can be drawn from the successful eradication of smallpox in 1980. The global vaccination model and eradication of smallpox in 1977 are compared with lessons from the ongoing Mpox endemic since 1970.

Keywords

Poxvirus vaccination, Monkeypox, Vaccine awareness, Vaccine inequity, Vaccine monopoly, Vaccine subsidy

The Global Vaccination Model and Eradication of Smallpox

The eradication of smallpox in 1980 was the result of a highly successful global vaccination campaign led by the World Health Organization (WHO). This effort demonstrated an unparalleled level of global collaboration among WHO, health agencies, epidemiologists, and international workers. The intensified smallpox eradication program successfully implemented six key components, which played a pivotal role in eradicating smallpox in Africa by 1977 [2]. As depicted in Figure 1, these components included international funding for the eradication program and collaboration efforts, vaccine production, technology transfer, vaccine donations, vaccine distribution, and vaccination mobilization.

Figure 1: Global Vaccination Model and Eradication of Smallpox in 1980.

International Funding for the Eradication Program and Collaboration

The intensified smallpox eradication program was funded by the WHO, the World Health Assembly, and endemic countries. The World Health Assembly mobilized member nations to commit resources, with two-thirds of the funding coming from donations. Maintaining the program over a decade depended on strong collaboration among eradication staff at WHO headquarters, supervisory personnel at national and provincial levels, and local health workers [2]. This multi-level global partnership and pooled resources were essential for the effective coordination of large-scale surveillance and containment initiatives [2,3].

Vaccine Production and Vaccine Technology Transfers

A key aspect of the vaccination efforts in the 1970s was the production of higher-quality freeze-dried vaccines and the large-scale manufacture of user-friendly bifurcated needles. Additionally, vaccine technology transfers enabled higher-risk countries to produce their freeze-dried vaccines and serve as suppliers [2].

Vaccine Donations

Many endemic countries, being developing nations, lacked sufficient health budgets to fund a smallpox eradication program. Vaccine donations played a crucial role, with the U.S. and Soviet Union leading as major contributors, providing over 450 million doses of vaccine. Other donor countries, including the U.K., France, Canada, and Cuba, also contributed vaccines, which were distributed by the WHO [2,4].

Vaccine Distribution and Vaccination Mobilization

Higher-quality freeze-dried vaccines, which were easier to store and administer, facilitated the mass distribution and mobilization of vaccines. This advancement supported universal childhood immunization programs and mass vaccination efforts, even in regions with underdeveloped health systems and significant logistical challenges. The global smallpox vaccination campaigns achieved remarkable success through targeted surveillance-containment strategies and robust collaboration among health personnel and surveillance officers [5].

Lessons from the Ongoing Mpox Endemic Since 1970

As discussed in the preceding section, the WHO played a pivotal role in the successful implementation of the global intensified smallpox eradication program by securing collaborative resources and driving mass vaccination efforts. Unfortunately, the strategies that proved effective in eradicating smallpox have not been adequately applied to combat Mpox. Since 1970, the Democratic Republic of Congo has experienced endemic Mpox cases. A WHO-sponsored global Mpox vaccination campaign remains largely absent due to significant barriers to vaccine access, despite the creation of the Mpox Strategic Preparedness, Readiness, and Response Plan (SPRP) [6,7]. As shown in Figure 2, six key components highlight the global disparities in Mpox vaccination efforts.

Figure 2: Lessons from the Ongoing Mpox Endemic Since 1970.

Lack of International Funds for the WHO and Africa CDC Plan

Although Mpox has persisted as an endemic issue in Western Africa for decades, international funding to combat this pandemic has been insufficient. As demonstrated by the global smallpox eradication campaign, international funding and collaborative efforts are critical for the success of the SPRP. The WHO should take a leading role in securing increased financial support from member nations to fund the WHO and Africa CDC Plan, complementing the U.S.’s pledge of at least $500 million [8].

Vaccine Monopoly and No Vaccine Technology Transfers

Compared to the AIDS and COVID-19 pandemic, Mpox endemic is experiencing more severe vaccine inequities due to the Mpox vaccine manufacturing monopoly [9]. The Danish Bavarian Nordic is the only Mpox vaccine manufacturer in the U.S. and the European Union. Deadweight loss occurs in a monopoly as its price is above the competitive price with an inefficient lower output. The significantly high price of the Mpox vaccine at $141 quoted by the WHO poses a high pricing barrier to low-income countries and poses challenges in securing millions of shots for Africa [10]. International agencies including UNICEF are trying to secure as many as 12 million doses for African countries by 2025 [10]. Africa’s vaccine manufacturing capacity remains limited, and the uncertainty surrounding future demand for vaccines in the region discourages vaccine technology transfers [10].

Pledged Vaccine Donations

High-income countries have secured the majority of available Mpox vaccine doses, leaving endemic African countries unable to afford vaccination for their populations due to high costs and limited supply. To effectively contain Mpox outbreaks in these regions, vaccine donations and subsidies for low-cost vaccines are crucial. More than 5.4 million vaccine doses have been pledged for the Mpox response, with 3 million doses committed by Japan and 2.34 million doses contributed by the U.S., Canada, EU Member States, the European Commission Health Emergency Preparedness and Response Authority, Gavi, the Vaccine Alliance, and Bavarian Nordic [11].

Limited Vaccine Distribution and Vaccination Mobilization

Significant barriers hinder Mpox vaccine distribution in African nations, including unaffordable pricing, limited supply, logistical challenges in storage and delivery, and the limited proximity of vaccination sites [12]. Socioeconomic and cultural factors further impede vaccination mobilization, such as mistrust of vaccines and cultural opposition [13,14]. At the community level, vaccine advocates and opinion leaders should work together to reduce stigma, raise awareness, and spread accurate vaccination information.

Conclusion

The successful eradication of smallpox was achieved through an unprecedented level of global collaboration, fully implementing the intensified smallpox eradication program. The WHO played a central role by mobilizing funding, coordinating targeted surveillance and containment efforts, and leading vaccination campaigns. Vaccine donations and technology transfers significantly expanded vaccine availability, while vaccines that were easy to store and administer facilitated mass immunization efforts. In contrast, the Mpox vaccine manufacturing monopoly is severely limiting access to vaccines in African countries hardest hit by the endemic. These nations also face infrastructural, logistical, economic, and cultural barriers. To address this, the WHO and Africa CDC must mobilize collaborative resources to bring the Mpox endemic under control. Bridging vaccine disparity gaps is critical, drawing lessons from past global health efforts [15]. Global coordinated actions are increasingly necessary to combat the rising threat of infectious disease outbreaks. High-income nations should support preventive measures in resource-poor countries by investing in healthcare infrastructure, water treatment, sanitation, waste management, and transportation systems.

References

Abbara A, Rao B, Titanji B, Boum Y, Zumla A (2022) The monkeypox outbreak must amplify hidden voices in the global discourse. The Lancet. [crossref]
Son BWK, Wambalaba OW, Wambalaba WF (2024) A Multi-pronged Approach to Addressing Global Poxviruses Vaccine Inequity: A Case of Monkeypox. In: Rezaei, N. (eds) Poxviruses. Advances in Experimental Medicine and Biology, vol 1451. Springer, Cham. [crossref]
Henderson, D, Klepac P (2013) Lessons from the eradication of smallpox: an interview with D. A. Henderson. Philosophical Transactions of the Royal Society of London. Series B, Biological sciences 368(1623): 20130113. [crossref]
Haynes J, Li C (2020) The US cooperated with the Soviets on smallpox – it should do the same with China on COVID-19 vaccine distribution.
Henderson DA, Moss B. (1999) Public Health. In: Plotkin SA, Orenstein WA, editors. Vaccines. 3rd edition. Philadelphia: Saunders.
WHO (2022) Monkeypox Strategic Preparedness, Readiness, and Response Plan (SPRP).
Yang Z, Gray M, Winter L (2021) Why do poxviruses still matter? Cell Biosci 11, 96. [crossref]
HHS (2024) Announces Mpox Vaccine Donations, Boosting Domestic and International Supply. [crossref]
Hart R (2024) Mpox Vaccine Maker Bavarian Nordic Shares Soar Amid Concern Over Virus Outbreak. Forbes.
Wass S, Kew J (2024) Higher price of mpox vaccine to pose key hurdle in Africa order talks. Business Standard.
WHO (2024) Donors making a difference: United against mpox, swift and effective response in action.
Molteni M, Branswell H, Joseph A, Mast J (2022) 10 key questions about monkeypox the world needs to answer.
Lancet Editorial Board (2022) Monkeypox: a global wake-up call. [Editorial]. The Lancet 400: 337. [crossref]
Son B, South-Winter C (2018) Human Behavior Impacts on Health Care. Journal of International & Interdisciplinary Business Research 5(8): 138-146.
Son BWK (2023) A Multipronged Approach to Combat COVID-19: Lessons from Previous Pandemics for the Future. In: Rezaei, N. (eds) Integrated Science of Global Epidemics. Integrated Science, vol 14. Springer, Cham.

Commentary: Implications of Critical Periods in the Development of Autism

1 Reply

DOI: 10.31038/PSYJ.2025711

Autism spectrum disorder (ASD, or autism) is a collection of developmental disorders with an increasing diagnosis rate. The most recent data compiled by the CDC (Centers for Disease Control and Prevention [1]) show a prevalence of 2.76% of 8 year olds in the US as diagnosed autistic in 2020, compared with 1.47% in 2010 and 0.67% in 2000. A new report [2] provides some guidance on factors that may contribute which, in combination with other recent studies, gives direction on what can be done to help mitigate this rise.

The report reviews determining factors of folate and of inflammation in the development of autism and observes that there are multiple critical periods in ASD where these factors play essential roles.

Critical Periods

The concept of critical periods was first demonstrated in the visual system, showing that the absence of light during a key period in visual cortex development determined the ultimate pathways made in the visual cortex, and that even normal exposure to light following this critical period was insufficient for the pathways to develop if they had not had light stimulation during the critical period. Wiesel and Hubel named this a critical period in the visual cortex, earning them the Nobel Prize in physiology or medicine in 1981 for this central understanding of the development of key brain functions [3]. The report [2] assesses that autism has multiple critical periods, and lists factors involved in at least two of these critical periods. In so doing, they point to a means to potentially reduce the diagnosis rate of ASD possibly other neurodevelopmental disorders (ADHD in particular comes to mind due to several overlapping symptoms in focus and attention).

Folate and Autism

Several clinical trials have shown that in the autistic population, about 70% make an autoantibody to the folate receptor [4,5]. Production of this folate receptor autoantibody (FRAA) seems to be triggered by dairy products in someone’s diet [6] and results in a cerebral folate deficiency (CFD, or folate deficiency in the brain). If CFD is not corrected by dosing with natural folate (the form used is folinic acid, trade name leucovorin), or by removing the FRAA antigen (presumably by eliminating all dairy products from the diet), the ASD symptom of poor social communication firms up during the critical period, and even if correction is made later, neurotypical behavior cannot be fully restored and the ASD behavior is not abbreviated.Thus, a critical period is the need for natural folate (folate in its reduced form), and an abundance of synthetic folate (folate in its oxidized form) cannot help those with FRAA. Indeed, excess oxidized folate (folic acid) may be detrimental, as there is increasing evidence that unmetabolized folic acid (UMFA) can outcompete natural folate at the folate receptor, creating a CFD despite measured high plasma folate [7].

Oxidative Stress

Similarly, there is now abundant evidence that oxidative stress can alter neurotypical development, as documented [8] and postulated in that oxidative stress during critical periods in development will result in a decrease in microglial cells in the brain [2]. Microglia serve as part of the brain’s immune system, since the lymphocytes (B cells and T cells) cannot cross the blood brain barrier. These microglia scavenge and clean out discarded or unused cell structures during development, most specifically for ASD, they remove unused synapses during the process of synaptic pruning. Synaptic pruning follows neurogenesis, when there is a proliferation of neuronal birth and synaptic contacts made, with only the active synapses retained later to create neurotypical brain pathways. If the excess synapses are not pruned, the report contends this gives rise to the ASD symptom of inability to focus on a task as well as explains a possible neural mechanism for the documented extraordinary memory for detail seen in ASD. Thus, this reduction in synaptic pruning can explain the excellent memory but also the inability to focus on a task that is seen in autism.

What are the causes of oxidative stress in neurodevelopment? Oxidative stress can be caused by inflammation from infection, emotional stress, under nutrition or exposure to foreign compounds [8,9]. The foreign chemicals include the usual litany of pesticides and persistent compounds from the environment (such as “forever chemicals”) [10] as well as heavy metal ions such as lead exposure [11] but also include a number of pharmacological drugs. While drug side effects are often well established, their impact on a developing fetus or infant can often be overlooked. Thus, even well-tolerated psychopharmacological medicines may need to be reconsidered during pregnancy, putting them in a category perhaps similar to alcohol or caffeine, which are not typically discontinued during pregnancy and nursing due to the potential lasting impact of such depressants and stimulants on neurodevelopment.

In addition to these known agents of oxidative stress, we may need to add micro- and nanoplastics to the list, as these are reported to be embedded in every human organ, with documented effect on cardiovascular system, development and the microbiome, according to a report from the December 2024 hearing on health impacts of plastics held in Korea [12]. Indeed, this report reminds us that the microbiome is the essential processing zone for all nutrients, and alterations to someone’s microbiome can have broad impacts.

Reducing Damage

While the report also reveals the mechanism of oxidative stress in the development of ASD, it also reveals the ways to minimize its effect. Oxidative stress depletes microglia nutrients, particularly N-acetyl cysteine and taurine. Increasing the intake of these nutrients should limit the damage to the microglia and support neurotypical development. Significantly, these small molecule nutrients are present in many foods (especially fish and seafood) and these are no reports of adverse effects of using supplements to restore these nutrients during periods of oxidative stress. Similarly with folate, many foods (including legumes, leafy greens, eggs and citrus) have high levels of this vitamin, and there is also a prescription source of natural folate available in leucovorin. Leucovorin has successfully been used in the ASD clinical trials mentioned above, and there are decades of its use in cancer treatment, where it is used to replenish the vitamin B-9 that is depleted by certain chemotherapies, so it is known to have no adverse effects.

Intriguingly, a new preprint [13] shows extra folate during pregnancy can reduce the impact of metabolism disrupting chemicals on a child. Thus, folate may be quite central to two mechanisms of neurotypical development.

Vaccine Impact

An intriguing aspect that comes out of the 2024 report [2] gives credence to the continued concern of vaccines and autism. In previous decades (until the 1980s), the pertussis vaccine was made from whole cells, which could be very inflammatory in up to one percent of children receiving the vaccine, causing brain fever. Now that we have an understanding about critical periods in autism development, we can see that if this inflammation occurred during such a critical neurodevelopmental period, there may be a lasting effect that could increase the risk of ASD. The most common pertussis vaccine used now no longer uses whole cells, and this acellular version does not cause such inflammation. Also, the timing of the vaccine is adjusted now to minimize developmental impact. However, the lingering concern among some parent groups about this vaccine is linked to a reality that is has passed. Originally, the vaccine used, DPT (for diphtheria-pertussis-tetanus) was problematic for neurodevelopment of an estimated 3 children per million vaccinations, while the newer version, the DTaP (for diphtheria-tetanus-acellular pertussis, or Tdap which is used for booster vaccinations) does not have this detrimental effect. This should be comforting news for parents, as they can continue to protect their children from these deadly diseases while no longer raising the risk for such children to have a neurological disorder.

Conclusion

Critical periods help us understand neurotypical as well as autistic development. The knowledge that those at higher risk due to inflammation and/or the presence of FRAA can help mitigate these risks with functional or lifestyle medical actions of modifying diet to include more foods with folate and with N-acetyl cysteine or taurine, along with getting regular exercise. Indeed, this may be an optimal treatment for someone at higher risk of ASD, further supporting use of a Mediterranean diet, which provides these nutrients, and also benefits the microbiome. Given the overabundance of ultra-processed foods (UPF) in many contemporary diets, we may have chosen a side of increased neurological disorders with the convenience of these fast foods. A comparison of neurodegenerative disorders in matched communities with UPF diets compared with blue zone diets may help provide confirmation that the increasing ASD diagnoses may be in part due to dietary changes made by families in the past half century.

References

https://www.cdc.gov/autism/data-research/index.html
Ayoub G (2024) Neurodevelopment of autism: critical periods, stress and Cells. 13: 1-11. [crossref]
Wiesel TN: Nobel NobelPrize.org.
Frye RE, Slattery J, Delhey L, et al. (2016) Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry. 23: 247-256. [crossref]
Renard E, Leheup B, Guéant-Rodriguez RM, Oussalah A, Quadros EV, et al. (2020) Folinic acid improves the score of Autism in the EFFET placebo-controlled randomized trial. Biochimie. 173: 57-61. [crossref]
Ramaekers VT, Sequeira JM, Blau N, Quadros EV (2008) A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency Dev Med Child Neurol. 50: 346-352. [crossref]
Akiyama T, Kuki I, Kim K, Yamamoto N, Yamada Y, et (2022) Folic acid inhibits 5-methyltetrahydrofolate transport across the blood–cerebrospinal fluid barrier: Clinical biochemical data from two cases. JIMD 63: 529-535. [crossref]
Usui n, Kobayashi H, Shimada S (2023) Neuroinflammation and oxidative stress in the pathogenesis of autism spectrum disorder. In J Mol Sci. 24: 5487. [crossref]
Ahmavaara K, Ayoub G (2024) Stress and folate impact neurodevelopmental J Health Care & Res 5: 1-6.
Parenti M, Slupsky CM (2024) Disrupted prenatal metabolism may explain the etiology of suboptimal neurodevelopment: a focus on phthalates and micronutrients and their relationship to autism spectrum disorder. Adv Nutri. 15: 3-19. [crossref]
McFarland 2024 https://doi.org/10.1111/jcpp.14072
Moulun AG (2024) Quel impact des micro- et nano-plastiques sur la santé humaine? Medscape.
India-Aldana S et al. (2024) Metabolism-Disrupting Chemical Mixtures during Pregnancy, Folic Acid Supplementation, and Liver Injury in Mother-Child Pairs. medRxiv. [crossref]

What is a Metallic Alloy in Reality?

Leave a reply

DOI: 10.31038/NAMS.2024733

Abstract

The article is a collection of ideas and experimental results that show that existing ideas about metallic alloys should go away to history of Metal Science. Here we present to the reader the results of experiments obtained as an example on four binary and two ternary alloys. Briefly, the main conclusions of the experiments are as follows: Interatomic chemical interactions exist in all metal alloys at temperature of both solid and liquid states. Chemical bonds in alloys have an amazing property to change their signs at a certain temperature (there is a phase transition “ordering – separation”). The reason for this transition is the electronic transition “ionic bond ↔ covalent bond”. The process of formation of new phases in binary alloys begins with the formation of solute clusters, in ternary alloys – with the formation of diffusion micro-pairs during the melting of the alloy. Such cardinal differences between the existing now notions about the nature of alloys and those revealed in this work should definitely lead to changes in the technology of heat treatment of alloys, to changes in the binary phase diagrams and to a change in the principles of creating new alloys.

Keywords

Introduction alloys, Chemical bonds, Transmission electron microscopy, Microstructure, Phase transition “ordering – separation”, Electron transition “ionic bond ↔ covalent bond”, Diffusion micro-pairs, Chemical bonds, Transmission electron microscopy, Microstructure; Phase transition “ordering – separation”, Electron transition “ionic bond ↔ covalent bond”

Introduction

Development of human civilization is inconceivable without progress in the advancement of its material base, in which metals and metal alloys play one of the leading roles. In recent years, we have observed significant changes for the better in the elaboration of new alloys. However, unfortunately, they achieved in a long, empirical way. This is because our ideas about the nature of alloys are still at the level of almost 100 years ago. This circumstance hinders progress in the development of new alloys and does not allow researching alloys in a necessary direction. The source of the existing now theory of alloys dates back to when researchers, studying the solubility of a salt in water with decreasing temperature, found that in time, salt crystals precipitate from the solution. They suggested whether the process of nucleation of particles of a new phase during the tempering of quenched metal alloys does not occur in the same way as during the isolation of salt crystals from a supersaturated aqueous solution. The idea turned out to be tempting, and since then, metal science has been living with the illusions of the past: a solid solution disordered after quenching becomes to supersaturated with a decrease in the heat treatment temperature, and particles of the excess phase precipitate. Only then, chemical bonds arise between the atoms of this phase. This means that not chemical interatomic bonds cause the formation of chemical compounds, but chemical compounds cause the occurrence of chemical interatomic bonds (!). Obviously, the comparison of the process of formation of a new phase during the tempering of a metal alloy and the process of precipitation of salt crystals with a decrease in the temperature of the water-salt solution is highly incorrect. However, this idea is so ingrained in our heads that even the discussion on this topic, held by the journal Acta Metallurgica in 1960-80 [1,2], ending in favor of existing ideas. This is not surprising, since in all universities of the world for many decades now, all professors have been presenting these ideas as an axiom that does not require proof.

The author of this article, starting his experimental work on the above topics, chose the direct method for studying the microstructure – TEM, and studied the microstructure of each alloy at all heat treatment temperatures (with an interval of about 200-300°C and, including in the liquid state). We hope that the reader already knows some of our papers or monography [3], where it is described what the “ordering-separation” phase transition is in binary alloys. This is a phase transition that occurs at a well-defined temperature, when, in the AxBy alloy, atoms A and atoms B, instead of mutual attraction experience mutual repulsing. This is not surprising if we consider alloys from the point of view of the structure of their electronic structure. As you know, in a pure metal between its atoms, takes place a 100% metallic bond. However, when atoms of another metal are added to one metal (i.e., when creating a binary alloy), a certain part of the metal bonds in the alloy are replaced by chemical ones, namely, ionic and/or covalent ones [4]. The ionic component of the chemical bond appears when, with a change in the alloy’s temperature, the B atoms become the nearest neighbors of the А atoms. Because of this instantaneous proximity, their valence orbitals localize the chemical compound AxBy form. The covalent component of a chemical bond forms when two atoms of the dissolved component B become the nearest neighbors. Because of this instant proximity, their valence orbitals hybridize, i.e. a cluster forms comprising these two atoms B. Thus, we understand how an ionic bond forms and how a covalent bond forms. However, it does not understand why, at the temperature characteristic of each alloy, these bonds pass one into the other, i.e., why an electronic transition “ionic bond ↔ covalent bond” occurs.

Materials and Methods

In this article, we will consider some binary alloys, for example, Ni75Mo25, Fe50Cr50 and Ni88Al12, as well as two ternary Ni65Mo20Cr15 and Ni53Mo35Al12 alloy, as examples. We smelted alloys from pure components in an induction furnace. We cut out specimens from them for research at different temperatures. After holding at any temperature, the specimens immediately cooled in water to fix the microstructure at this temperature. One of the specimens melted down and the contents of the crucible poured into water to study the microstructure of the liquid state. Foils cut out from all the blanks for study on a transmission electron microscope EM-125.

Results

Alloy Ni75Mo25. For those who had to deal with the problem of pouring liquid Ni-Mo alloys, it seemed surprising that its very low fluidity of that alloy even when it was overheated by 200°C above the solidus line. Now it becomes clear what we connect this with the phenomenon. The Figure 1a shows dark particles of molybdenum, which formed at the melting of the charge. This means that even at temperatures of the liquid state, the alloy under study has the tendency to phase separation. Indeed, we observe on the electron diffraction pattern a system of additional reflections {1 1½ 0} as four symmetrical pairs (Figure 1b). These reflections formed near each of the fundamental reflections {110} and {200}. Quenching of the same alloy from 1300̊°C, i.e. temperature, at which “a disordered solid solution” forms gives the same picture.

“a disordered solid solution” forms gives the same picture.

Figure 1a shows dark particles of molybdenum, which formed at the melting of the charge. This means that even at temperatures of the liquid state, the alloy under study has the tendency to phase separation. Indeed, we observe on the electron diffraction pattern a system of additional reflections {1 1½ 0} as four symmetrical pairs. These reflections formed near each of the fundamental reflections {110} and {200}. Quenching of the same alloy from 1300̊ C, i.e. temperature, at which “a disordered solid solution” forms gives the same picture. Exactly the same picture you can watch after quenching this alloy from 1300°C. This means that the type of microstructure of the alloy is determined not by its state of aggregation at such temperatures, but by completely different parameters. A further decrease in the alloy’s temperature by only 100°C dramatically changes the type of microstructure: instead of the structure formed because of a tendency to separation, a chemical compound Ni3Mo forms as long square-section laths (Figure 2a and 2b). This shows that in the temperature range of 1200-1300°C, the “ordering-separation” phase transition occurs in the alloy under study.

Comparing the microstructures shown in Figures 1 and 2, we see that there are two diametrically opposed types of interaction between dissimilar atoms: separation at high temperatures (liquid state), ordering at a temperature of 1000°C. It is even more interesting to observe the phase transition “Ordering – separation” in alloy Fe50Cr50, where it occurs twice with a change in the temperature of the alloy.

Figure 1: Alloy Ni₇₅Mo₂₅.Water quenching from liquid state: (a) microstructure (Mo-particles); (b) electron diffraction pattern.

Figure 2: Ni₇₅Mo₂₅ alloy. Quenching from 1000°С. Bright-field image of the microstructure (a); electron diffraction pattern (b).

Fe50Cr50 alloy (Figure 3). The author [3], investigating the microstructure of alloys of the iron-chromium system by TEM, discovered a surprising phenomenon, which consists in the fact that at a quite definite heating temperature of these alloys, the sign of the chemical interaction between iron and chromium atoms changes. At some temperatures (above 1150°C), repulsion is observed between these atoms (particles of atoms of pure chromium with the Al2 lattice are formed – Figure 3a), at other temperatures (600-830°C) – attraction (a ϭ-phase is formed – Figure 3b). At the boundary between these two regions, when the sign of the chemical interaction passes through zero, a solid solution was found in the alloys of the iron-chromium system, and electronic domains were found during two-stage heat treatment (Figure 3c). Such domains, arising during the “ordering-phase separation” transition, best observed when defocusing the electron microscopic image of the specimens. We consider electronic domains as some regions of the alloy, inside which the sign of the ordering energy has already changed, in comparison with the surrounding matrix, where it remains the same. Since the chemical interaction energies have opposite signs on both sides of the domain wall, the electron beam passing through the foil is deflected in opposite directions, which, upon defocusing, leads to a deficiency (light lines) or an excess (dark lines) of electrons. Thus, electronic domains, as well as magnetic and ferroelectric domains, are a reflection on a conventional photographic plate of a phase transition occurring at the level of changes in the electronic structure of the alloy.

In contrast to, where the formation of electronic domains was considered as a temporary, unstable state of the alloy (a state of transition from a tendency to phase separation to a tendency to ordering), it was shown in Ref. [3] at domains in Fe-Cr alloys under certain conditions can represent a stable state of the alloy. The existence in the alloy’s bulk of such a state (incomplete phase transition ordering-separation) prevents the formation of the σ-phase in the entire volume of the alloy; the σ-phase forms only in a thin surface layer, where, apparently, the surface plays the role of a catalyst for the “ordering-separation” transition process. A further decrease in temperature to 500°С again leads to the formation of particles (or, possibly, highly concentrated clusters) of chromium atoms, Figure 3e. At the boundary between the regions of the ϭ-phase and low-temperature separation, we again found electronic domains (Figure 3f). The formation of electronic domains on the line of the “ordering-phase separation” phase transition (Figure 3c and 3f) tells us it is the changes in the electronic structure that underlie the microstructural phase transition “ordering-phase separation”. Low-temperature domains occupy the entire volume of the alloy, and therefore it can expected that such a microstructure of the alloy will have certain specific properties, such as magnetic or ferroelectric.

Figure 3: Fe₅₀Cr₅₀alloy. Microstructure. Water quenching from 1400°C. Inset: electron diffraction pattern (a); σ-phase taken from subsurface layer (b). High-temperature (c) and low-temperature (d) electron domains. Microstructure of low-temperature phase separation (e).

Ni88Al12 Alloy

Figure 4a shows the electron diffraction pattern (a) and the dark-field image of the microstructure (b) got from a satellite near the (020) reflection [5,6]. Such formation of clusters usually shows the ordering of a binary alloy at 1300°C into particles comprising one component each, i.e. about the positive deviation of the investigated alloy from Raoult’s law. With a further decrease in temperature (1200, 1000 and 700°C), the sign of the ordering energy changes to the opposite and the chemical compound Ni3Mo (L12) forms in the alloy (Figure 4). Thus, we can conclude that in the Ni88Al12 alloy the “ordering-separation” phase transition occurs in the temperature range of 1200-1300°C.

Figure 4: Ni₈₈Al₁₂ alloy. Quenching from a liquid state (tendency to separation) (a). Quenching from 1000°С: chemical compound Ni₃Mo (L1₂). The electron diffraction pattern is in the Inset (b).

Alloys of Ni-Cr system

The phase transition “ordering-phase separation” in most of the binary systems studied by us occurs at a not quite definite heating temperature of the alloys (transition temperature). However, in alloys of the nickel-chromium system, a unique picture observed [7]. For example, in alloys with a chromium content of 32 wt.% and below at any heating temperature, there is only a tendency to phase separation since in the entire temperature range from 500 to 1500°C, clusters of chromium atoms are noticed in the microstructure of this alloy (Figure 5a and 5b). In alloys with a chromium content of 60 wt.% Cr and above at all temperatures is observed only a tendency toward ordering, since particles of the Cr2Ni compound are noticed in the microstructure (Figure 5c and 5d). In alloy Ni46Cr54, the composition of which is between concentrations from 32 to 60% Cr, with a change in the heating temperature of the alloy, the usual transition “ordering – phase separation” is observed at 1200°C (Figure 5e and 5f).

Figure 5: Alloys of the Ni-Cr system. (a) Ni₆₈Cr₃₂, water quenching from a liquid state. Absorption contrast. Cr-clusters; (b) Ni₆₈Cr₃₂, water quenching from 500°C; Absorption contrast. Cr-clusters; (c) Ni₄₀Cr₆₀ [9], water quenching from a liquid state. Ni₂Cr particles. (d) Ni₄₆Cr₅₄, water quenching from a liquid state. Absorption contrast. Cr-clusters; (e) Ni₄₆Cr₅₄, water quenching from 1000°C. Ni₂Cr particles [7].

As we see, we have investigated many other binary. It turned out that in almost every binary alloy there is a transition “ordering-phase separation”. In each alloy, this transition has its own characteristics, which manifested at the level of changes in the microstructure. In addition, in each alloy, we need to determine the temperature at which this transition occurs. The temperature can be any, but quite specific for each pair of atoms. For example, in the Co-30% Mo alloy, it is close to the solidus temperature. The regions of a so-called disordered solid solution located between the regions of phase separation and regions of ordering have not found in all systems where such a transition has occurred. In a number of alloys (for example, Ni-Co), the same image showed phase particles formed as a result of the appearance of a tendency to ordering in the alloy, and particles dissolving due to the disappearance of the tendency to phase separation in this alloy. We called such a transition the blurred “ordering -separation” one. As a result of this “mixing of phases”, a disordered solid solution was not found even on the line of the “ordering – separation” transition.

Ternary Alloys

Ternary Ni65Mo20Cr15 alloy [7]. Electron microscopic analysis shows that in different sites of the same foil quenched from the liquid state (1450°C) accumulations of only two types of precipitates of the second phase found. In the Ni/Mo diffusion pair, observed single-component particles of molybdenum atoms, in the Ni/Cr diffusion pair – two-component clusters chromium atoms. Since molybdenum is a refractory metal, the formation of particles of Mo atoms in the alloy under study occurs at the maximum temperature that reached in the melting zone of the furnace. Whereas formation of the Cr-clusters (Figures 5-7), observe a fully formed microstructure up to the temperature of 1300°C. In the Ni/Mo diffusion pair, below 1250°C, the tendency to phase separation is substituted for the tendency to ordering (the “ordering-separation” transition), and the particles of Mo atoms dissolve.

After quenching the alloy from 1550°C, clusters of chromium atoms observed in diffusion pairs Ni/Cr as concentration waves of absorption contrast, which emanate from a certain light-colored center in a thin foil, forming apparently, in the moment of contact of the liquid alloy with water (Figure 6).

Figure 6: Ni₆₅Mo₂₀Cr₁₅ alloy [8]. Nucleation of the Ni/Cr diffusion pair. Water quenching from 1550°C. Absorption contrast.

Comparing the microstructures in Figures 6-8, we can conclude that with a decrease in the temperature from which the alloy quenched the microstructure of the Cr-clusters forms over the entire volume of the alloy.

Figure 7: Ni₆₅Mo₂₀Cr₁₅ alloy [9]. Ni/Cr diffusion pair. Water quenching from 1450°C. Absorption contrast.

We investigated many other binary alloys. It turned out that in almost every binary alloy there is a transition “ordering-phase separation”. In each alloy, this transition has its own characteristics, which manifested at the level of changes in the microstructure. In addition, in each alloy, we need to determine the temperature at which this transition occurs. The temperature can be any, but quite specific for each pair of atoms. For example, in the Co-30% Mo alloy, it is close to the solidus temperature. The regions of a so-called disordered solid solution located between the regions of phase separation and regions of ordering have not found in all systems where such a transition has occurred. In a number of alloys (for example, Ni-Co), the same image showed phase particles formed as a result of the appearance of a tendency to ordering in the alloy, and particles dissolving due to the disappearance of the tendency to phase separation in this alloy. We called such a transition the blurred “ordering -separation” one. As a result of this “mixing of phases”, a disordered solid solution was not found even on the line of the “ordering – separation” transition.

We have investigated many alloys. It turned out that in almost every binary alloy there is a transition “ordering-phase separation”. In each alloy, this transition has its own characteristics, which manifested at the level of changes in the microstructure. In each alloy, we need to determine the temperature at which this transition occurs. The temperature can be any. For example, in the Co-30% Mo alloy, it is close to the solidus temperature. The regions of a disordered solid solution located between the regions of phase separation and regions of ordering have not found in all systems where such a transition has occurred. In a number of alloys (for example, Ni-Co), the same image showed phase particles formed as a result of the appearance of a tendency to ordering in the alloy, and particles dissolving due to the disappearance of the tendency to phase separation in this alloy. We called such a transition a blurred “ordering – separation” transition. As a result of this “mixing of phases”, a disordered solid solution was not found even on the line of the “ordering – phase separation” transition. Ternary Ni53Mo35Al12 alloy [8]. As is known from the electronic theory, in ternary alloys, as in binary ones, the chemical interatomic interaction is pair-wise [8]. Therefore, ternary Laves phases cannot form in a ternary alloy. We have shown that the ABC ternary alloy, while still in the liquid state divided into diffusion micro-pairs A/B, A/C, and B/C. Each diffusion micro-pair occupies its own microscopic area. All phases formed in ternary alloys comprised atoms of no more than two components [8].

In the Ni53Mo35Al12 alloy, this process has its own characteristics, since the aluminum and molybdenum atoms form the Mo3Al chemical compound, the melting point of which is about 2600°C. This means that the chemical bond between the Al and Mo atoms is very strong. Therefore, in Figure 8 we see the microstructure of solid Mo3Al particles in the investigated liquid alloy. This compound forms instantly in the process of melting the charge. The same microstructure as in Figure 1 retained in the alloy under study after its quenching from 1300°C. As was shown above, at a temperature of about 1200°С, the “ordering–separation” transition occurs in binary alloys of the Ni–Mo system [5]. This means that the chemical orientation of the Ni and Mo atoms relative to each other changes sharply at separation – ordering phase transition.

Figure 8: Ni₆₅Mo₂₀Cr₁₅ alloy. Ni/Cr diffusion micro-pair. Water quenching from 1300°C. Absorption contrast.

Figure 10 shows the internal microstructure of a large solid Mo3Al particle in the liquid alloy under study. When the charge melted, this compound form instantly. As long as it exists, the Mo/Ni and Al/Ni diffusion pairs cannot form in the alloy. The alloy under study has the same microstructure. However, at a temperature of about 1200°C, when the “ordering-separation” phase transition should have occurred in diffusion Ni/Mo pairs, the microstructure of the studied alloy completely changes (Figure 9).

Figure 9: Ni₅₃Mo₃₅Al₁₂ alloy [10]. Quenching from the liquid state. Light-field image. Accumulations of particles of the Mo₃Al phase. Inset: Electron diffraction pattern (the zone axis is close to the direction <001>).

Figure 10: Ni₅₃Mo₃₅Al₁₂ alloy. Quenching from the liquid state. Another bright-field image of the internal structure of a large Mo₃Al particle (a). Electron diffraction pattern (b).

Figure 11: Alloy Ni₅₃Mo₃₅Al₁₂. Quenching from 1000°С. Bright field images of the microstructure of diffusion micro-pairs Ni₃Mo (a) and Ni₃Al (L1₂).

The regions of a disordered solid solution located between the regions of phase separation and regions of ordering have not found in all systems where such a transition has occurred. In a number of alloys (for example, Ni-Co), the same image showed phase particles formed as a result of the appearance of a tendency to ordering in the alloy, and particles dissolving due to the disappearance of the tendency to phase separation in this alloy. We called such a transition a blurred “ordering – separation” transition. As a result of this “mixing of phases”, a disordered solid solution was not found even on the line of the “ordering – phase separation” transition.

When studying the Ni53Mo35Al12 alloy by TEM, we again encountered with the same fact that we discovered earlier in some other ternary alloys: in one region of the foil, we find one binary (or one-component) phase, in another region of the same foil, a completely different one. This immediately indicates that the alloy divided into certain sections that differ from each other in composition, i.e. into two different diffusion micro-pairs: Ni/Mo and Ni/Al.

In the Ni53Mo35Al12 alloy, this process has its own characteristics, since the aluminum and molybdenum atoms form the Mo3Al chemical compound, the melting point of which is about 2600°C. This means that the chemical bond between the Al and Mo atoms is very strong. Therefore, we see the microstructure of solid Mo3Al particles in the investigated liquid alloy. This compound forms instantly in the process of melting the charge. The same microstructure retained in the alloy under study after its quenching from 1300°C. As was shown above, at a temperature of about 1200°C, the “ordering–separation” transition occurs in binary alloys of the Ni–Mo system [5]. This means that the chemical orientation of the Ni and Mo atoms relative to each other changes sharply from separation to ordering.

Discussion

Our experimental detection of such transitions and their publication in the literature for during 20 years did not lead to any progress in the worldview of metallurgists, and, as a result, to the appearance of works by other authors on this topic. Although, thanks to our experiments, these changes simply suggested themselves, since their introduction would significantly improve the technological properties of all heat-treated parts and products made of metal alloys and more than halve the cost of their heat treatment [9]. It could happen in all the engineering plants in the world. Perhaps the complete lack of interest of metallurgists in these two transitions explained because, in this case, they would have to change their ideas about alloys and change your attitude towards binary phase diagrams [10]. However, it is difficult to make this step when the entire community of metallurgists thinks alternatively and university professors teach of students’ alternative.

Diffusion Micro-pairs

Usually, diffusion micro-pairs in multi-component alloys form during their smelting [11]. However, if a chemical compound’s melting point is higher than the alloy, we cannot fix these micro-pairs, and compounds will found first (for example, Mo3Al). If lower, then we will find the formation of chemical compounds takes place inside the diffusion micro-pairs.

Heat treatment of metal alloys “quenching + tempering (aging)” has known for a very long time and currently carried out at almost all machine-building plants in the world.

According to existing concepts, after quenching at high temperatures, a microstructure of a disordered solid solution forms in alloys. Subsequent tempering, carried out at a lower temperature, leads to the fact that the solid solution comprising quenching becomes “supersaturated” and “excess” phases are released from it (either by the spinodal mechanism or by the nucleation-growth mechanism).

In contrast to the existing theory of heat treatment, in alloys at all temperatures, there is a chemical interaction between similar (covalent bond) and dissimilar (ionic bond) atoms. Such an interaction exists both in the liquid and in the solid state of the alloy. This means that we can never get a disordered solid solution after quenching the alloy from high temperatures, even if we will quench from the liquid state. This also means that at each temperature forms own microstructure, which distinguished from any other microstructure by type or dispersity of precipitates. The final microstructure of an alloy is determined by the temperature of the final heat treatment, i.e. tempering. The heat treatment, such as quenching from region “disordered solid solutions”, does not affect the final microstructure of the alloy.

Because of this instantaneous proximity, their valence orbitals localized, i.e. the chemical compound AxBy forms. The covalent component of the chemical bond, which activated for the same reason, causes the two atoms of the dissolved component B to become the nearest neighbors. Because of this instantaneous proximity, their valence orbitals hybridize, i.e. a cluster forms comprising these two atoms B. However, our experimental detection of such transitions and their publication in the literature for over 20 years did not lead to any progress in the worldview of metallurgists, and, as a result, to the appearance of works by other authors on this topic. In addition, these changes simply suggested themselves, since their introduction would significantly improve the technological properties of all heat-treated parts and products made of metal alloys and more than halve the cost of their heat treatment. It could happen in all the engineering plants in the world. Perhaps the complete lack of interest of metallurgists in these two transitions explained because, in this case, they would have to change very many ideas about alloys. Moreover, it is difficult to take this step when the entire community of metallurgists thinks differently and university professors teach of students differently.

In the experimental part of the article, we presented the reader with the results of our studies of binary and ternary substitution alloys. The cardinal difference between our research (TEM) and those works (XRD) thanks to which the current theory of alloys built is immediately striking. Now that it has become clear to us that the X-ray method is not suitable for these purposes, and that those authors who used the TEM method in the discussion of 1960-80 were right, there is no doubt that our ideas about the existence of some disordered solid solution in alloys should go down in the history of alloy science. If this is really the case, then any quenching in water from any heating temperature of the alloy should lead to formation of the microstructure that formed in the alloy at this temperature. It has been known that almost every machine-building plant in the world uses “double” heat treatment of alloys – quenching from the region of a “disordered” solid solution + tempering at low temperatures. Select a few parts from the batch intended for quenching and simply do not make it.

Compare their microstructure and properties with those parts that have been as quenched. I should note that for the purity of the experiment, samples (or parts) that have quenched should cooled in water to fix the microstructure characteristic of your tempering temperature. Even if you are not strong in alloy theory, you will be able to deduce whether you need that quenching to get a “disordered solid solution” before tempering.

High-entropy Alloys

When a ternary alloy forms three diffusion micro-pairs at once, the uphill diffusion of atoms of each component will be on coming. As a result, the rate of formation of one or another diffusion pair will slow down significantly, and perhaps even drop to zero. Most likely, these streams separated either in time or in temperature. However, when many number of streams of different directions, they completely suppressed to each other. Therefore, the more components an alloy contains, the slower one or other diffusion micro-pairs will form in it. That is why in high-entropy alloys (HEA), which contain five or more components, diffusion micro-pairs do not form. By performing a straightforward calculation, it becomes apparent that formation 10 diffusion micro-pairs in 5-component alloy is possible only on paper. In reality, it is impossible. This is why long-distance diffusion is completely absent in HEA and diffusion micro-pairs do not form. This meant that chemical bonds between the atoms of the components cannot manifest themselves in these alloys and no chemical compounds can form in them. The question arises: whom needs such alloys that do not have the properties of alloys and microstructure of which represents randomly arranged different atoms (only sometimes -small solid solution regions).

In their properties and structure, they are more similar to metal ore. It turns out interesting with HEA. A person has invested considerable effort to receive pure metals from natural metal ore, only to produce a new synthetic metal ore from these metals later. Typically, diffusion micro-pairs in multicomponent alloys form during their smelting, when the crystal lattice of the alloy has not yet formed. In the solid state of the alloy, uphill diffusion of atoms of the dissolved component also occurs, but much more slowly. I am not maintaining, but it is hardly possible to expect that in the solid state in a ternary alloy, uphill diffusion of atoms of two components at once is possible. Most likely, either on time or on temperature separate these flows. However, with a large number of flows in different directions, they are completely suppress each other. Consequently, the more components an alloy contains, the lower the likelihood of the formation of certain diffusion micro-pairs and, consequently, particles of new phases of one or other type.

It should be noted that to obtain true alloys, one should avoid not only adding a large number of alloying components (usually more than two), but also adding a small amount of any component (usually 3% or less). With such alloying, one must proceed from the principle that the amount of the alloying component would been enough to form diffusion micro-pairs in the alloy, i.e. so that particles containing this component formed. Otherwise, such doping can considered as simple clogging of the crystal lattice with foreign atoms. Our understanding of this or that physical phenomenon always changes with time and usually corresponds to the level of experimental technique in the period under consideration. Let us recall the once fashionable classical theory of the “nucleation and growth” of a new phase, the theory of the “in situ” nucleation of special carbides in alloyed steels, and so on. Where are they now? They forgotten because their description of processes occurring in nature differs from reality. At the same time, there are theories and ideas with a different fate, which came to us from the past century, but are so deeply rooted in our minds that even now, when the experiment does not confirm them, we believe that they are an indisputable truth. For example, we cannot imagine equilibrium phase diagrams without solid solution regions at high temperatures, although a solid solution, from the point of view of thermodynamics, is not an equilibrium phase at any temperature. We cannot imagine the probability of decomposition of a quenched solid solution without its “supersaturation” in solutes, which occurs at a decrease of heat treatment temperature. We cannot imagine the heat treatment carried out to obtain a highly dispersed two-phase structure, which would not include the preliminary high-temperature quenching from the solid solution region, and so on.

The discovery of the ‘ordering-phase separation’ transition in alloys puts an end to these ideas. It becomes clear that the ideas about the nature of alloys that we acquired in our universities turn out to be largely outdated, as they based on experimental data obtained as far back as the mid-twentieth century and without the use of the method of TEM. From the above discussion, it follows that introduction of such a concept as the ‘ordering-phase separation’ transition into common use changes our previous understanding of the driving forces of the process of new phase formation. In addition, it becomes apparent that in order to change this situation a great number of experimental studies is to upgrade existing phase diagrams. The ‘ordering-phase separation’ transition, regarded as changes in the chemical interaction sign, is such a transition, in the process of which the ionic component of the chemical bond between the atoms, due to the electron-phonon interaction, replaced by the covalent component, or vice versa. All processes occurring in alloys during heat treatment and leading to a change in their properties considered from the point of view that the disordered solid solution is the initial phase in these processes, and the elastic forces arising between dissimilar atoms are the driving force. The experimental results presented in this monograph debunk this point of view and show that it is necessary to take the liquid state of the alloy as the initial phase, and interatomic chemical interactions as the driving force of all diffusion processes occurring in the condensed state of an alloy.

Cardinal Changes in Heat Treatment of Alloys

The detection of the ‘ordering-phase separation’ transition allowed for the conclusion that, at a certain temperature, the sign of the chemical interaction between dissimilar atoms can change. This means that it is only at the temperature of such a transition, when the energy of the interatomic chemical interaction is close to zero, which a disordered solid solution can form in the alloys. However, such a clearly pronounced change in the microstructure not observed in the alloys of all systems. In the alloys of some other systems, at a transition temperature one can see a mixture of microstructures of phase separation and ordering. It should also note that the microstructure of the solid solution could observed in alloys in which the energy of the interatomic chemical interaction is low at all temperatures. When any composition of the alloy is in a molten state, it subdivided into microscopic areas, each of which enriched with one alloying component or another (in other words, one or several types of diffusion pairs formed in it). Binary chemical compounds (tendency to ordering) or clusters (tendency to phase separation) can form inside these diffusion pairs. When the heat treatment temperature decreases, the average chemical composition of such diffusion pairs is always preserved, and at the same time the distribution of components inside the diffusion pairs themselves becomes more heterogeneous: chemical compounds (if their melting point is higher than the melting temperature of the alloy itself) or clusters similar to the corresponding binary alloys are formed. The driving force of such a partitioning process is the tendency of the similar atoms to form clusters in the solvent lattice or the tendency of dissimilar atoms to form a chemical compound.

The ‘ordering-phase separation’ transition, which at the microstructure level manifests itself as changing of the sign of energy of the chemical interaction between the atoms A and B, at the electronic level manifests itself in exactly the same way. It is a transition from the state when all pairs of valence electrons localized on atoms A and B and forming ionic bonds between atoms come out from this state. At the same time, some pairs of valence electrons, due to the electron-phonon interaction, are involved in the formation of hybridized orbitals between two B atoms (which leads to the formation of B clusters, i.e. phase separation). This means that the ‘ordering-phase separation’ transition in an alloy is a consequence of the electronic ‘covalent bond ↔ ionic bond’ transition. This article shows metallurgists should come to terms with the existence in nature of such a type of microstructure as diffusion micro-pairs and say goodbye to such a type of microstructure as a disordered solid solution. And the sooner they do this, the less effort and money will be spent all over the world on heat treatment of alloys (water-quenching “to get a disordered solid solution” will disappear), on the design of new and improvement of existing alloys. The phase diagrams of binary alloys will become more informative and truthful (because of the regions of non-existent disordered solid solutions will disappear). We will understand many of the mysteries of nature regarding metallic alloys that nature has hidden from us for many years. In the case, all of us, metallurgical scientists, will need to contribute to this work.

Conclusion

This article shows metallurgists should come to terms with the existence in nature of such a type of microstructure as diffusion micro-pairs and say goodbye to such a type of microstructure as a disordered solid solution. And the sooner they do this, the less effort and money will be spent all over the world on heat treatment of alloys (water-quenching “to get a disordered solid solution” will disappear), on the design of new and improvement of existing alloys. The phase diagrams of binary alloys will become more informative and truthful (because of the regions of non-existent disordered solid solutions will disappear). We will understand many of the mysteries of nature regarding metallic alloys that nature has hidden from us for many years. However, for this, all of us, alloy specialists, will need to contribute to this work.

References

Nesbit LA (1981) Laughlin DE. Solid-state morphological instability of Ni4Mo precipitates. J Crystal Growth 51: 273-278.
Van Tendeloo G, Amelinkx S (1985) De Fontaine D. On the nature of the “short-range order” in 1 ½ 0 alloys. Acta Crystallography.B41: 281-292.
Ustinovshikov Yuri (2019) The ‘Ordering-Phase Separation’ Transition in Alloys. Cambridge Scholars Publishing.
Ustinovshikov Y (2017) Changes in electronic structure of metallic alloys at the transition ‘ordering-phase separation’. J Alloys & Compounds 714: 476-483.
Ustinovshikov Y, Shabanova I (2011) Phase transitions in alloys of the Ni-Mo system. Mat Chemic Phys 129: 975-980.
Ustinovshikov Y (2012) Phase transition ‘ordering-phase separation’ in the Ni-12 at. % Al alloy. J Alloys & Compounds 528: 141-145.
Ustinovshikov Y (2018) Multi-component alloys: Regularities in the formation of microstructures. J Alloys & Compounds. 735: 2298-2302.
Ustinovshikov Y (2016) Formation of microstructures responsible for remarkable properties of the Ni- and Co-based super-alloys. Acta Mater 111: 66-74.
Ustinovshikov Y (2014) A new paradigm for heat treatment of alloys. J Alloys & Compounds 614: 258-263
Ustinovshikov Y (2017) Mapping of the transition ‘ordering-phase separation’ into phase diagrams. J Alloys & Compounds. 691: 713-720.
Ustinovshikov Y (2014) Phase and structural transformation in the Ni65Mo20Cr15 alloy at changing the temperature of heat treatment. Journal of Alloys and Compounds 588: 470-473.

Changing Lives by Changing Minds: Reducing Cognitive Biases to Enhance Psychological Health

Leave a reply

DOI: 10.31038/PSYJ.2024654

Abstract

Our central thesis is that integrating multiple evidence-based techniques will offer the best results for optimizing psychological health. We believe that effectively addressing the escalating mental health crisis will require a comprehensive, multi-pronged, approach. Decades of research across the psychological and cognitive sciences have shown that errors in the way people think, called cognitive biases, have a profound impact on many aspects of psychological health. In this manuscript we review several research-based approaches for changing the way people think to improve psychological health. We review evidence on how different cognitive biases—negativity bias, framing bias, confirmation bias, and essentialism bias—impact various aspects of psychological health, and the benefits of mitigating those biases. We also review the important role of social perspective taking in psychological health and how cognitive biases, such as the curse of knowledge bias, the false consensus effect, the spotlight effect, and the fundamental attribution error, interfere with social perspective taking, further highlighting the merits of strategies to minimize these biases. In conclusion, we propose that an integrated, multi-pronged approach is the best way to address the unique and diverse challenges individuals face to maximize the benefits for individuals, and society as a whole.

Keywords

Psychological health, Cognitive bias, Social emotional health, Intervention, Education, Social perspective-taking, Mindset, Theory of mind, Anxiety, Depression, Coping

Introduction

The world is experiencing a mental health crisis! 1 in 8 people worldwide are struggling with their psychological health [1]. In the US, 1 in 5 adults currently have psychological health issues, placing a tremendous $300 billion burden on the economy in lost productivity and healthcare costs [2,3]. Frighteningly, the situation is getting worse. As just one example, the number of Canadians diagnosed with anxiety and depression has more than doubled in the last 2 decades and ERs have seen a 75% rise in psychological health-related visits, especially among younger individuals [3,4]. To prevent this crisis from escalating, there is an urgent need for more effective approaches to improve psychological health, not only for those currently struggling but also for the general public. Everyone can benefit from learning research-based strategies to enhance their psychological well-being. In this manuscript we review research showing that changing the way you think can profoundly improve your psychological health and well-being. Psychological health refers to a person’s social, emotional, and mental well-being. It encompasses many facets including emotional regulation, communication, decision-making, relationship satisfaction, as well as the ability to cope with stress and work productively. Psychologically healthy individuals typically manage their emotions effectively, have a positive sense of self, make sound decisions, and maintain healthy relationships with others. Decades of research have shown that errors in the way we think, called cognitive biases, have a profound impact on our psychological health. Fortunately, the ability to minimize many cognitive biases has been well-documented. Yet, individual research projects tend to focus on one specific bias, one specific debiasing approach, or one aspect of psychological health, with limited communication and integration across disciplines. For example, research on how cognitive biases can be reduced to improve decision-making has primarily been the purview of cognitive and social psychologists or behavioral economists (e.g., [5-8]); whereas, essentialism bias and mindset modification have roots in developmental psychology (e.g., [9,10]) and research on modifying negativity bias is most often studied by clinical psychologists treating depression and anxiety (e.g. [11-15]). In a similar vein, most manuscripts also focus on discussing one type of bias, and its implications for one area of research.

In this manuscript we bring together research from various disciplines to provide a more complete account of how changing the way we think can improve psychological health. First, we review evidence on how different cognitive biases—negativity bias, framing bias, confirmation bias, and essentialism bias—can impact several aspects of psychological health. Next, we review the cognitive biases that interfere with social perspective taking to impact well-being. Throughout our review we highlight the tremendous benefits of mitigating cognitive biases for several facets of psychological health. Our overarching aim is to make the case for integrating multiple evidence-based strategies from different disciplines because we believe that combining these strategies is the best way to maximize social-emotional health.

Minimizing Cognitive Biases to Maximize Social-Emotional Health

Cognitive biases are normal by-products of how the mind works, yet vast individual differences in the magnitude of these biases predict myriad aspects of psychological health and quality of life including, but not limited to, decision-making abilities, interpersonal skills, relationship satisfaction, stress management, workplace productivity, academic achievement, self-esteem, and mental illness [10,16- 18]. One prominent example of the link between cognitive biases and psychological health comes from clinical research showing evidence that depression, stress, and anxiety are all associated with negativity bias. Negativity bias is the tendency for negative events, information, or emotions to weigh more heavily in our minds than positive ones. For example, if you have ten good experiences and one bad one, you’re likely to remember the bad one more vividly and let it affect you more deeply (e.g., [19,20]). The lion’s share of research in this area has been conducted by clinical psychologists focusing on two categories of negativity bias; attentional bias and interpretation bias. Attentional bias is characterized by the preferential allocation of cognitive resources (e.g., attention) to negative stimuli. Numerous studies have demonstrated that individuals with depression show a heightened attentional bias toward negative information. For instance, research has shown that depressed individuals are faster to detect and respond to negative stimuli compared to neutral or positive stimuli [15]. This bias is thought to perpetuate and intensify negative mood states by reinforcing the focus on distressing information.

Interpretation bias involves the tendency to interpret ambiguous or neutral information in a negative manner. This type of bias has also been linked to depression. Experimental evidence reveals that individuals with depression are more likely to interpret ambiguous situations negatively compared to non-depressed individuals (e.g., [21]). This bias is also associated with higher levels of stress and anxiety. Research indicates that negativity bias exacerbates anxiety symptoms by skewing the perception of everyday stressors as more threatening than they really are [22]. For instance, a study by MacLeod and Mathews [23] found that individuals with a strong negativity bias are more likely to experience heightened anxiety and stress, as they tend to focus on potential dangers and threats. Importantly, research suggests these biases are not merely associated with mood disorders but actively contribute to their development and maintenance (e.g., [13,14,24]). For example, one study found that individuals with a negative attentional bias were more likely to experience longer- lasting depressive symptoms over time [13]. These findings are further supported by prospective studies indicating that even among nonclinical samples, such as university undergraduate students, greater biases predict elevated depressive symptoms months later [25-28]. Critically, training aimed at reducing these biases has been shown to lessen the severity of depressive symptoms from pre- to post-training in individuals with a history of depression [29,30].

Notably, negativity bias does not operate in isolation to affect psychological health. Research shows that other cognitive biases can reinforce or amplify negativity bias and exacerbate pessimistic thinking, stress, and dissatisfaction [31]. Although dozens of cognitive biases can impact psychological health (e.g., [32-34]), we highlight three more in this section with clear health consequences, namely confirmation bias, framing bias, and essentialism bias. Confirmation bias is the tendency to search for, interpret, and remember information that confirms one’s preconceptions [35]. Confirmation bias can work in tandem with negativity bias to exacerbate pessimistic thinking, stress, and dissatisfaction and reinforce negative beliefs. As an example, a study found that individuals who hold negative biases about their partners are more likely to interpret their partners’ actions in a negative light, which can erode relationship satisfaction [31]. Similarly, another study found that children with higher levels of worry tended to seek information confirming danger and avoid information disconfirming it, showing how confirmation bias can amplify anxiety by promoting a skewed perception of threats [36].

As a different example of how confirmation bias can impact health, consider how it impacts the diagnostic accuracy of healthcare providers. Research showed that approximately one in eight physicians and one in four medical students exhibited confirmation bias when gathering new information after forming initial diagnoses [37]. This tendency to seek confirmatory evidence not only increased the likelihood of incorrect diagnoses, but also impacted future therapeutic decisions. This example reiterates the point that everyone can benefit from learning strategies to minimize cognitive biases. Fortunately, researchers have identified promising interventions to mitigate the effects of many cognitive biases, including confirmation bias. For instance, Morewedge et al. [38] found that a single session of training, involving education about cognitive biases via videos or interactive computer games, significantly reduced confirmation bias (among other biases). These reductions were observed immediately and were still present at least two months later (see also [39,40]).

Another cognitive bias with psychological health implications is framing bias. Framing bias refers to the cognitive tendency to respond differently to the same information depending on how it is presented or “framed”. This bias significantly impacts decision-making, risk perception, health behaviours, and consumer choices. Framing bias has been extensively studied in the context of financial decision-making and marketing (e.g., [41,42]). In health contexts, framing bias affects how individuals perceive risks and make health-related decisions. For instance, studies have shown that people are more likely to accept treatment options when the benefits are framed positively (e.g., “90% survival rate”) rather than negatively (e.g., “10% mortality rate”) [43]. Similarly, framing bias also impacts adherence to medical treatments and health regimens. Research indicates that patients are more likely to comply with medical advice when the benefits of adherence are framed positively. For example, presenting a medication’s benefits in terms of enhanced quality of life, rather than in terms of avoiding negative outcomes, has been shown to increase adherence rates [44]. Framing bias also influences decisions related to vaccinations, health screenings, dietary choices, and lifestyle options, as just some examples (e.g., [45,46]. Clearly, the way information is communicated can either hinder or enhance efforts to improve public health.

The effects of framing bias are not limited to decision-making—it also profoundly affects our emotional responses. Individuals are more likely to experience positive emotions when information is framed positively, and negative emotions when it is framed negatively. This dynamic has significant implications for therapeutic practices as well as preventative approaches. Cognitive Behavioral Therapy (CBT), for example, employs cognitive reframing techniques to help individuals identify and challenge negative thought patterns, replacing them with more constructive perspectives. CBT has been shown to be highly effective in clinical settings (see [Hofmann et al (2012) for a meta- analysis). Similarly, other research indicates that reframing stressful events in a more positive or controllable light can reduce perceived stress and enhance coping mechanisms (e.g., [47]). The concept of learned optimism [48] also capitalizes on reframing techniques. Learned optimism approaches teach individuals to adopt a more optimistic explanatory style by reframing adversities as opportunities for growth and challenging and reframing pessimistic beliefs. These approaches reduce depression and anxiety while improving emotional regulation and overall well-being (e.g., [49]), underscoring the importance of addressing framing bias to enhance resilience.

Essentialism bias is yet another cognitive bias that impacts well-being in several ways. Essentialism bias refers to the cognitive tendency to view certain categories or groups as having an underlying, unchanging essence that defines their characteristics [9]. This bias can lead individuals to believe that one’s attributes are inherent and immutable rather than subject to change [9] and can lead to stereotyping and prejudice towards social groups [50,51]. People also show essentialism bias regarding their own characteristics. In this sense, this bias is closely linked to the concept of a fixed mindset— the belief that human traits, such as intelligence, are innate and unchangeable [10]. A fixed mindset can hinder personal development and resilience because individuals who hold this mindset perceive their traits and abilities as largely unchangeable, reducing their motivation to seek improvement. A growth mindset it the opposite of a fixed mindset and is best described as the belief that one’s traits, attributes, or abilities can be shaped through effort [10].

Our mindset permeates nearly every facet of our personal and interpersonal experiences (e.g. [10,52]). For example, studies have shown that possessing a growth mindset enables psychological resilience in the face of negative life events [53]; see also [54,55]. This mindset is also positively correlated with perceived control and self-efficacy in health behavior [56]. In contrast, people with a fixed mindset are more likely to experience anxiety and depression in response to failure [57]. The key to this association may be in the improved coping strategies that individuals with growth mindsets demonstrate [52,58]. Research has shown that individuals who hold a growth mindset are more willing to learn and more likely to seek and adopt coping strategies than those who hold a fixed mindset [52]. In other words, individuals who hold a growth mindset believe that they can adapt to a difficult situation, whereas someone who views their abilities as fixed tends to avoid challenges. Furthermore, individuals who hold a fixed mindset report greater shame and stress in the face of failure and are more likely to blame themselves [52-59]. In contrast, individuals with a growth mindset are shown to be more optimistic, believing that people can change and improve [10]. A 2024 study with middle-school adolescents revealed that higher growth mindset predicted greater psychological resilience and mediated the relationship between mindset and mental health [60].

Fortunately, a wealth of research has shown that people can be readily taught to be more ‘growth-minded’. Recent research on growth mindset interventions highlights the effectiveness of even brief online programs. One such intervention, ‘Learning Mindsets’ (delivered in 2 online sessions in under an hour) showed significant positive effects on students’ mindsets [59]. Similar short interventions were also effective at promoting a growth mindset, even more than some longer in-person approaches, suggesting that concise and accessible formats may be particularly impactful [61]. Importantly, neurocognitive research reveals that adopting a growth mindset can mitigate the negative effects of depression on cognitive abilities [62] and encourage individuals to accept, and utilize, critical feedback [63]. The willingness to adopt positive coping strategies such as acceptance, as opposed to rumination or self-blame, has a strong impact on the social and emotional well-being of individuals facing negative life events. For example, a study examining cancer patients and individual coping strategies found that those practicing adaptive strategies such as modifying uncomfortable situations showed greater resilience and psychological adjustment [64]. Another study showed that breast- cancer patients who used adaptive coping styles reported fewer depressive symptoms [65]. Consistently, cultivating a growth mindset and teaching adolescents to adopt positive coping strategies has also been shown to improve adolescents’ mental health [58]. Notably, addressing these biases early in development has the greatest potential to prevent social-emotional problems and yield the most long-term benefits.

Improving Perspective Taking to Maximize Social- Emotional Competence

Social perspective taking, the ability to infer and reason about others’ mental states (e.g., their knowledge, beliefs, intentions, desires, thoughts, and emotions; sometimes called ‘theory of mind’ or mentalizing) is a core component of psychological competence. Perspective taking enables individuals to appreciate diverse viewpoints, empathize with others, and understand the impact of their actions on others (e.g., [66,67]). Research has consistently shown that perspective taking abilities are involved in virtually every social interaction and are critical for effective communication, social decision-making, and maintaining social relationships (e.g., [68-70]). For example, perspective taking is associated with higher levels of empathy, prosocial behavior, and social understanding, which can lead to reduced interpersonal conflicts and increased relationship satisfaction [71]. For instance, studies by Peterson et al. [72] found that perspective taking is associated with increased self-esteem and higher quality friendships. More advanced social perspective taking also appears to act as a protective factor against trauma and adversity (e.g., [73-75]). Conversely, poor perspective taking skills are associated with greater psychological distress [76], more emotional symptoms, and increased loneliness [77]. This latter result is especially noteworthy given longitudinal studies linking loneliness to a variety of negative health outcomes, including poorer sleep quality [78], and increased depressive symptoms [79]. For instance, a meta-analysis of 18 studies examining the relationship between social perspective taking and Major Depressive Disorder in adults revealed that deficits in perspective taking can be a risk factor for depression and psychosocial impairment, with the level of perspective taking problems predicting symptom severity [80].

Not surprisingly, the way we think about others and their mental states (i.e., perspective taking) is also vulnerable to cognitive biases. Of particular interest in this manuscript is the category of cognitive biases called perspective-taking biases (sometimes called ‘egocentric biases or social cognitive biases). Perspective-taking biases, systematic tendencies or errors in the way we think about others’ mental states (or perspectives), can be particularly damaging to interpersonal relationships, impair communication, and lead to poor social decision-making (e.g., [6,81,82]). One perspective taking bias, the curse of knowledge bias, refers to the tendency to be swayed by one’s knowledge when reasoning about a more naive perspective (e.g., [7- 8,83-87]). A classic example of the curse of knowledge bias (sometimes called ‘hindsight bias’) is when adults who know the outcome of an event (e.g., a sports game, an election, or a battle) overestimate how likely others are to predict that outcome. In contrast, adults who are unaware of the event’s outcome tend to make more accurate estimates of what others will predict (e.g., [88-91]). This bias has been shown to affect judgements and decision making across a wide range of contexts including medicine, education, politics, law, business, and economics (e.g., [6,92-94]; see [91,94] for reviews). In education, for example, teachers with knowledge of the subject matter they are teaching often overestimate how clear their lessons are for students (e.g., [92]). This bias affects communication and social judgments in various ways because it causes individuals to overestimate the likelihood that others share their knowledge. Given the regularity with which we must gauge what others know, this bias frequently leads to miscommunication and misunderstandings in everyday conversations as well as formal communications (e.g., [68,83,95-96]). These communication breakdowns can create conflict and stress and may impact an individual’s self-esteem if repeated miscommunications make them question their ability to relate to others. A related perspective taking bias, the false consensus effect, is the tendency for people to overestimate the extent to which others share their beliefs, opinions, and behaviors [97]. In other words, individuals often assume that most people think or behave the same way they do, negatively influencing decision-making, social interactions, and group dynamics. For example, when individuals assume that others share their views, it can lead to disagreements and conflict when they realize their opinions differ. This effect can similarly lead to distorted perceptions of social norms and contribute to problems in group decision-making and impair group cohesion [97-101].

Another perspective taking bias, the spotlight effect, occurs when individuals overestimate the extent to which others notice and evaluate their actions and appearance. This can lead to heightened self- consciousness and increased social anxiety, as individuals mistakenly gauge the level of social scrutiny they will receive. Gilovich et al. [102] demonstrated this in a study where participants consistently overestimated the attention they received—believing that twice as many people would remember the embarrassing T-shirt they wore, compared to the actual number who remembered. In a follow-up study, participants also overestimated the likelihood their classmates would notice even minor fluctuations in their physical appearance [103]. This effect occurs across many different contexts from volleyball games to video games. Consistently, participants overestimate how much their teammates will notice their performance flaws and expect more critical feedback than they receive [102,103]. This tendency for individuals to feel that they are the center of attention is linked to increased self-consciousness and social anxiety, directly affecting their psychological health. For instance, researchers found that socially anxious individuals were more likely to exhibit the spotlight effect, reporting heightened anxiety and evaluating their performance more harshly when they felt observed by others [32].

Another bias related to perspective taking is the fundamental attribution error (FAE). FAE is a cognitive bias that leads individuals to overestimate how much another person’s behavior or circumstance is due to their personal character (i.e., their ‘fundamental nature’), rather than considering the influence of external (situational) factors on their actions [104]. In a classic example of FAE, participants listening to a speech believed that the speaker’s personal beliefs aligned with their presentation even when they were explicitly told the speaker’s position was “decided by a coin toss” [105]. Participants disregarded the situational constraints and tended to assume that the speech was based on personal beliefs and traits [105]. Some researchers suggest that this tendency arises because people find it simpler to attribute a person’s actions to their personal characteristics [106,107]. For example, researchers have argued that in the context of people’s misfortunes, it is easier to blame an individual for their circumstances, by attributing their misfortunes to their personal characteristics, actions, and choices rather than considering more complex contextual factors [106,107]. This process appears to emphasize personal responsibility and foster victim blaming [108]. Consequently, FAE can contribute to increased judgments of others and reduced compassion [97].

Perhaps not surprisingly, perspective taking offers a powerful countermeasure to the FAE. Perspective taking encourages people to adopt the viewpoint of the other person to consider the situational factors contributing to their actions before blaming the individual. That is, by reasoning about another person’s mental states, individuals can better understand their point of view and acknowledge the situational constraints that affect their actions and decisions. Thus, perspective taking may lead to a reduced sense that the other person is accountable, especially towards victims of circumstance, such as those trapped in a systemic cycle of poverty. For example, Hooper et al. [104] demonstrated that a brief perspective-taking exercise focusing on shifting perspectives significantly reduced the FAE. Participants who completed the exercise were better able to attribute behaviors to situational factors rather than dispositional traits (see also [109]). In other words, perspective taking seems to shift the blame from individuals to broader situational factors, fostering a more empathetic view of behavior. Following a similar logic, researchers should be able to reduce the FAE, and other perspective taking biases, through a range of activities that enhance perspective- taking (e.g., [110-112]).

To date there are several promising methods for enhancing perspective-taking. Research in this area has taken one of two general approaches. One general approach involves highlighting the different kinds of thoughts, emotions, and opinions people have in different contexts, depending on their unique experiences, backgrounds, and predispositions. There are several different types of techniques used in this area of research; collectively we call this type of approach the ‘Alternate Views’ approach. This general approach can be conducted passively (e.g., by exposing individuals to scenarios, real or hypothetical, with a range of different viewpoints) or actively (e.g., asking individuals to engage in real or imagined role-taking exercises, or reflect on their own thoughts and actions in different contexts and how those actions might be perceived by others (e.g., [113-115]). For example, Rezaei et al. [109] found that medical students who engaged in these reflective practices (e.g., via journaling), improved their empathy and ability to adopt patients’ perspectives. Other work has examined the efficacy of using acting lessons to foster perspective taking [116]. A wealth of other research has highlighted how increasing mental state discourse (i.e., simply talking more about mental states and differing points of view) can improve perspective taking abilities (for a review see [117]).

A second general approach that has been used to improve perspective taking is the Cognitive Debiasing approach which directly targets the biases that can impede perspective-taking. This approach involves educating individuals about common cognitive biases and strategies for minimizing them (e.g., [82]). Notably, cognitive debiasing methods are not specific to enhancing perspective taking but are commonly used to reduce cognitive biases to improve decision- making across a range of contexts (e.g., [38-39,102,118,119]). Given the many benefits of enhancing perspective-taking, we believe that approaches for enhancing psychological health should incorporate strategies for improving perspective taking as often as possible. In our opinion, the most effective interventions to foster psychological health will capitalize on the benefits of the Alternate Views approach and the Cognitive Debiasing approach. That is, we believe optimal results can be achieved by integrating the alternate views approach with education about cognitive biases and strategies for minimizing them.

Closing Remarks

Effectively addressing the mental health crisis will require a comprehensive, multi-pronged, approach. While piecemeal approaches provide valuable insights into the individual factors that influence well-being, overcoming the mental health crisis will require multiple evidence-based strategies. Individuals experience psychological health problems for a myriad of reasons (e.g., [120]). The kind of treatment or strategy that works for one person may not work for everyone. Combining strategies is the best way to address the unique and diverse challenges individuals face to maximize the benefits for individuals and society.

References

World Health Organization (2022) Mental disorders.
Centers for Disease Control and Prevention (CDC) (2022) Mental Health: The Economic Burden.
Moroz N, Moroz I, D’Angelo MS (2020) Mental health services in canada: Barriers and cost-effective solutions to increase access Healthcare Management Forum. [crossref]
Vankar, P (2024) Number of Canadians who reported being diagnosed with a mood disorder from 2003 to 2022
Tversky A, Kahneman D (1986) Rational choices and the framing of decisions Journal of Business.
Keysar B (1994) The illusory transparency of intention: Linguistic perspective taking in text. Cognitive Psychology
Camerer C, Loewenstein G, Weber M (1989) The curse of knowledge in economic settings: An experimental analysis Journal of Political Economy
Fischhoff B (1977) Perceived informativeness of facts. Journal of Experimental Psychology: Human Perception and Performance
Gelman SA (2003) The essential child: Origins of essentialism in everyday USA: Oxford University Press.
Dweck CS (2006) Mindset: The new psychology of Random House
Beck AT (1979) Cognitive Therapy of New York, NY: Guilford Press.
LeMoult J, Colich N, Joormann J, Singh MK, et (2018) Interpretation bias training in depressed adolescents: Near- and far-transfer effects. Journal of Abnormal Child Psychology. [crossref]
Gotlib IH, Joormann J (2010) Cognition and depression: Current status and future Annual Review of Clinical Psychology. [crossref]
Mathews A, Mackintosh B (2000) Induced emotional interpretation bias and Journal of Abnormal Psychology. [crossref]
Williams JMG, Mathews A, MacLeod C (1996) The role of abnormal cognitive biases in depression: A Cognitive Therapy and Research.
Müller-Pinzler L, Czekalla N, Mayer AV, Stolz DS, et (2019) Negativity-bias in forming beliefs about own abilities. Scientific Reports.
Neta M, Norris CJ, Whalen PJ (2009) Corrugator muscle responses are associated with individual differences in positivity-negativity bias. Emotion. [crossref]
Neta M, Brock RL (2021) Social connectedness and negative affect uniquely explain individual differences in response to emotional ambiguity. Scientific Reports. [crossref]
Rozin P, Royzman EB (2001) Negativity bias, negativity dominance, and Personality and Social Psychology Review.
Larsen R (2009) The contributions of positive and negative affect to emotional well- Psychological Topics.
Mathews A, MacLeod C (2005) Cognitive vulnerability to emotional Annual Review of Clinical Psychology. [crossref]
Murray SL, Johnson MK (2013) The role of negativity bias in social and emotional Journal of Social and Clinical Psychology.
MacLeod C, Mathews A (1988) Cognitive biases in anxiety and Behaviour Research and Therapy.
Mathews A, MacLeod C (2002) Induced processing biases have causal effects on Cognition and Emotion.
Beevers CG, Carver CS (2003) Attentional bias and mood persistence as prospective predictors of Cognitive Therapy and Research.
Sanchez-Lopez A, Koster EH, Van Put J, De Raedt R (2019) Attentional disengagement from emotional information predicts future depression via changes in ruminative brooding: A five-month longitudinal eye-tracking study. Behaviour Research and Therapy. 118: 30-42 [crossref]
Everaert J, Duyck W, Koster EHW (2015) Emotionally biased cognitive processes: The weakest link predicts prospective changes in depressive symptom severity. PLOS ONE.
Joormann J, Gotlib IH (2007) Selective attention to emotional faces following recovery from Journal of Abnormal Psychology. 116: 80-5 [crossref]
Browning M, Holmes EA, Charles M, Cowen PJ, et (2012) Using attentional bias modification as a cognitive vaccine against depression. Biological Psychiatry. 72: 572- 579 [crossref]
Hofmann SG, Asnaani A, Vonk IJJ, Sawyer AT, et (2012) The efficacy of cognitive behavioural therapy: A review of meta-analyses. Cognitive Therapy and Research. 36: 427-440 [crossref]
Murray SL, Holmes JG, Griffin DW (2000) Self-esteem and the quest for felt security: How perceived regard regulates attachment processes. Journal of Personality and Social Psychology. [crossref]
Brown MA, Stopa L (2007) The spotlight effect and the illusion of transparency in social Journal of Anxiety Disorders. 21: 804-19. [crossref]
Weinstein ND, Klein WM (1995) Resistance of personal risk perceptions to debiasing Health Psychology. [crossref]
Claus N, Takano K, Wittekind CE (2023) The interplay between cognitive biases, attention control, and social anxiety symptoms: A network and cluster approach. PLOS ONE. 18: e0282259 [crossref]
American Psychological Association (2018) Confirmation bias. APA Dictionary of Psychology
Muris P, Debipersad S, Mayer B (2014) Searching for danger: On the link between worry and threat-related confirmation bias in Journal of Child and Family Studies.
Mendel R, Traut-Mattausch E, Jonas E, Leucht S, et al. (2011) Confirmation bias: Why psychiatrists stick to wrong preliminary diagnoses. Psychological Medicine. 41: 2651-9. [crossref]
Morewedge CK, Yoon H, Scopelliti I, Symborski CW, et al. (2015) Debiasing decisions: Improved decision making with a single training intervention. Policy Insights from the Behavioral and Brain Sciences.
van Brussel S, Timmermans M, Verkoeijen P, Paas F (2021) Teaching on video as an instructional strategy to reduce confirmation bias—A pre-registered study. Instructional Science.
Schwind C, Buder J (2012) Reducing confirmation bias and evaluation bias: When are preference-inconsistent recommendations effective – and when not?. Computers in Human Behavior.
Tversky A, Kahneman D (1981) The framing of decisions and the psychology of Science.
Tversky A, Kahneman D (1986) Rational choices and the framing of Journal of Business
Minton AR, Young NA, Nievera MA, Mikels JA (2021) Positivity helps the medicine go down: Leveraging framing and affective contexts to enhance the likelihood to take Emotion. 21: 1062-1073 [crossref]
Peng J, Li H, Miao D, Feng X, et (2013) Five different types of framing effects in medical situations: A preliminary exploration. Iranian Red Crescent Medical Journal.
Wang K, Wong EL, Cheung AW, Chung VC, et al. (2022) Impact of information framing and vaccination characteristics on parental COVID-19 vaccine acceptance for children: A discrete choice experiment. European Journal of Pediatrics. 181(: 3839-3849. [crossref]
Shan L, Jiao X, Wu L, Shao Y, et (2022) Influence of framing effect on consumers’ purchase intention of artificial meat—Based on empirical analysis of consumers in seven cities. Frontiers in Psychology. [crossref]
Robbins ML, Wright RC, María López A, Weihs K (2019) Interpersonal positive reframing in the daily lives of couples coping with breast cancer. Journal of Psychosocial Oncology.
Seligman MEP (1990) Learned optimism: How to change your mind and your London: Nicholas Brealey Publishing.
Buchanan GM, Gardenswartz CAR, Seligman MEP (1999) Physical health following a cognitive-behavioural intervention. Prevention & Treatment.
Gelman SA, Taylor MG, Nguyen SP, Leaper C, Bigler RS (2004) Mother-child conversations about gender: Understanding the acquisition of essentialist beliefs. Monographs of the Society for Research in Child Development.
Gelman SA, Heyman GD, Legare CH (2007) Developmental changes in the coherence of essentialist beliefs about psychological characteristics. Child Development. [crossref]
Tao W, Zhao D, Yue H, Horton I, et (2022) The influence of growth mindset on the mental health and life events of college students. Frontiers in Psychology. [crossref]
Calvete E, Orue I, Echezarraga A, Cortazar N, et al. (2022) A growth mindset intervention to promote resilience against online peer victimization: A randomized controlled trial. Computers in Human Behavior.
Lurie LA, Hangen EJ, Rosen ML, Crosnoe R, et (2023) Reduced growth mindset as a mechanism linking childhood trauma with academic performance and internalizing psychopathology. Child Abuse & Neglect. [crossref]
Schroder HS, Yalch MM, Dawood S, Callahan CP, et (2017) Growth mindset of anxiety buffers the link between stressful life events and psychological distress and coping strategies. Personality and Individual Differences.
Orvidas K, Burnette JL, Russell VM (2018) Mindsets applied to fitness: Growth beliefs predict exercise efficacy, value, and Psychology of Sport and Exercise.
Dweck CS, Leggett EL (1988) A social-cognitive approach to motivation and Psychological Review.
Zhang L, Qi H, Wang C, Wang T, et (2022) How does growth mindset affect mental health of high school students during the COVID-19 epidemic? The role of grit and coping strategies. Frontiers in Psychiatry.
Yeager DS, Walton GM, Brady ST, Akcinar EN, et (2016) Teaching a lay theory before college narrows achievement gaps at scale. Proceedings of the National Academy of Sciences.
Lei W, Hu W, Guo H, Dai DY (2024) Does growth mindset benefit negative mental health among middle school students: The role of psychological resilience and Psychology in the Schools. 2024. DOI: 10.1002/pits.23227
Paunesku D, Walton GM, Romero C, Smith EN, et (2015) Mind-set interventions are a scalable treatment for academic underachievement. Psychological Science.26(6). [crossref ]
Hu X, Sidhu GK, Lu X (2022) Relationship between growth mindset and English language performance among Chinese EFL university students: The mediating roles of grit and foreign language Frontiers in Psychology.
Puusepp I, Linnavalli T, Huuskonen M, Kukkonen K, et al. (2021) Mindsets and neural mechanisms of automatic reactions to negative feedback in mathematics in elementary school students. Frontiers in Psychology. [crossref]
Macía P, Barranco M, Gorbeña S, Álvarez-Fuentes E, et al. (2021) Resilience and coping strategies in relation to mental health outcomes in people with PLOS ONE. [crossref]
Lai HL, Hung CM, Chen CI, Shih ML et (2020) Resilience and coping styles as predictors of health outcomes in breast cancer patients: A structural equation modelling analysis. European Journal of Cancer Care. 29(1). [crossref]
Eisenberg N, Miller PA (1987) The relation of empathy to prosocial and related Psychological Bulletin.101(1): 91-97
Repacholi BM, Slaughter V (2003) Individual differences in theory of mind: Implications for typical and atypical Hove: Psychology Press.
Birch SAJ, Li V, Haddock T, Ghrear S, Brosseau-Liard P, et (2017) Perspectives on perspective taking: How children think about the minds of others., Advances in Child Development and Behavior. Elsevier Academic Press.
Damon W (2008) The path to purpose: Helping our children find their calling in New York, NY: Free Press
Haddock TB, Birch SAJ (2024) The relationship between children’s theory of mind and social-emotional Psychology Journal Research Open. 6(1) .
Davis MH (1983) Measuring individual differences in empathy: Evidence for a multidimensional Journal of Personality and Social Psychology. 44(1) .
Peterson JL, Bellows A, Peterson S (2015) Promoting connection: Perspective- taking improves relationship closeness and perceived regard in participants with low implicit self-esteem. Journal of Experimental Social Psychology.
Cadamuro A, Versari A, Vezzali L, Trifiletti E (2016) Preventing the detrimental effect of posttraumatic stress in young children: The role of theory of mind in the aftermath of a natural European Journal of Developmental Psychology. 13(1) .
Hughes C, Ensor R (2006) Behavioural problems in 2‐year‐olds: Links with individual differences in theory of mind, executive function and harsh parenting. Journal of Child Psychology and Psychiatry. 47(5). [crossref]
Hughes C, Ensor R (2007) Positive and protective: Effects of early theory of mind on problem behaviours in at‐risk preschoolers. Journal of Child Psychology and Psychiatry.48(10). [crossref]
Wolgast A, Tandler N, Harrison L, Umlauft S (2020) Adults’ dispositional and situational perspective-taking: A systematic review. Educational Psychology Review.32(2) .
Caputi M, Schoenborn H (2018) Theory of mind and internalizing symptoms during middle childhood and early adolescence: The mediating role of coping strategies. Cogent Psychology. 5(1) .
Cacioppo JT, Hawkley LC, Berntson GG, Ernst JM, et (2002) Lonely days invade the night: Social modulation of sleep efficiency. Psychological Science.13(4). [crossref]
Cacioppo JT, Hawkley LC, Thisted RA (2010) Perceived social isolation makes me sad: Five-year cross-lagged analyses of loneliness and depressive symptomatology in the Chicago Health, Aging, and Social Relations Study. Psychology and Aging.25(2) .
Bora E, Berk M (2016) Theory of mind in major depressive disorder: A meta-analysis. Journal of Affective Disorders. [crossref]
Birch SAJ, Bernstein DM (2007) What can children tell us about hindsight bias: A fundamental constraint on perspective-taking?. Social Cognition.25(1)
Nickerson RS (1999) How we know—and sometimes misjudge—what others know: Imputing one’s own knowledge to Psychological Bulletin.125(6)
Birch SAJ, Bloom P (2003) Children are cursed: An asymmetric bias in mental-state Psychological Science. 14(3). [crossref]
Bernstein DM, Atance C, Loftus GR, Meltzoff A (2004) We saw it all along: Visual hindsight bias in children and Psychological Science.15(4). [crossref]
Taylor M, Esbensen BM, Bennett RT (1994) Children’s understanding of knowledge acquisition: The tendency for children to report that they have always known what they have just learned. Child Development. 65(6). [crossref]
Sutherland SL, Cimpian A (2015) Children show heightened knew-it-all-along errors when learning new facts about kinds: Evidence for the power of kind representations in children’s Developmental Psychology51(8). [crossref]
Christensen-Szalanski JJ, Willham CF (1991) The hindsight bias: A meta-Organizational Behavior and Human Decision Processes. 48(1) .
Blank H, Fischer V, Erdfelder E (2003) Hindsight bias in political elections. Memory. 11(4-5). [crossref]
Fischhoff B, Beyth R (1975) “I knew it would happen”: Remembered probabilities of once-future things. Organizational Behavior and Human Performance.13(1) .
Ghrear S, Birch SAJ, Bernstein D (2016) Outcome knowledge and false Frontiers in Psychology.V(7) .
Guilbault RL, Bryant FB, Brockway JH, Posavac EJ (2004) A meta-analysis of research on hindsight Basic and Applied Social Psychology.26(2-3) .
Hinds PJ (1999) The curse of expertise: The effects of expertise and debiasing methods on predictions of novice performance. Journal of Experimental Psychology: Applied. 5(2) .
Keysar B, Bly B (1995) Intuitions of the transparency of idioms: Can one keep a secret by spilling the beans?. Journal of Memory and Language. 34(1)
Hawkins SA, Hastie R (1990) Hindsight: Biased judgments of past events after the outcomes are Psychological Bulletin.107(3) .
Keysar B, Lin S, Barr DJ (2003) Limits on theory of mind use in Cognition. 89(1). [crossref]
Pinker S (2015) The sense of style: The thinking person’s guide to writing in the 21st New York, NY: Penguin Books.
Ross L, Greene D, House P (1977) The false consensus effect: An egocentric bias in social perception and attribution processes. Journal of Experimental Social Psychology. 13(3) .
Strube MJ, Rahimi AM (2006) “Everybody knows it’s true”: Social dominance orientation and right-wing authoritarianism moderate false consensus for stereotypic Journal of Research in Personality. 40(6) .
Bauman KP, Geher G (2002) We think you agree: The detrimental impact of the false consensus effect on Current Psychology. 21(4) .
Janis IL (1972) Victims of groupthink: A psychological study of foreign-policy decisions and fiascoes. Houghton Mifflin.
Schanck RL (1932) A study of community and its group institutions conceived of as behaviour of Psychological Monographs. 43(2) .
Gilovich T, Medvec VH, Savitsky K (2000) The spotlight effect in social judgment: An egocentric bias in estimates of the salience of one’s own actions and Journal of Personality and Social Psychology. 78(2). [crossref]
Gilovich T, Kruger J, Medvec VH (2002) The spotlight effect revisited: Overestimating the manifest variability of our actions and appearance. Journal of Experimental Social Psychology.38(1) .
Hooper N, Erdogan A, Keen G, Lawton K, et al. (2015) Perspective taking reduces the fundamental attribution Journal of Contextual Behavioral Science. 4(2) .
Jones EE, Harris VA (1967) The attribution of attitudes. Journal of Experimental Social Psychology. 3(1) .
Delgado J (2021) Fundamental attribution error: Blaming people by forgetting the Pcsyhology Spot.
Miller JG (1984) Culture and the development of everyday social Journal of Personality and Social Psychology 46(5) [crossref].
Flick C, Schweitzer K (2021) Influence of the Fundamental Attribution Error on perceptions of blame and Experimental Psychology. 68(4). [crossref]
Gomide CP, Perez WF, Pessôa CVBB (2024) Perspective taking reduces the correspondence bias: A systematic replication of Hooper et al Journal of Contextual Behavioral Science. 32(4) .
Debnath SK, Khatri P, Nanda S (2024) Study of mediating effect of emotional coping ability in the relationship between emotional intelligence and wellness of nursing professionals. International Journal of System Assurance Engineering and Management.
Schröder-Abé M, Schütz A (2011) Walking in each other’s shoes: Perspective taking mediates effects of emotional intelligence on relationship European Journal of Personality. 25(2) .
Alan S, Baysan C, Gumren M, Kubilay E (2021) Building social cohesion in ethnically mixed schools: An intervention on perspective taking. The Quarterly Journal of Economics. 136(4) .
Caldwell MP, Cheung H, Cheung SK (2022) Visuospatial perspective-taking in social-emotional development: Enhancing young children’s mind and emotion understanding via block building training. BMC Psychology. 10(1). [crossref]
Rezende JF, Shigaeff N (2023) The effects of reading and watching fiction on the development of social cognition: A systematic Dementia & Neuropsychologia [crossref]
Rezaei S, Childress A, Kaul B, Rosales KM, Newell A, al ( 2023) Rose S. Using visual arts education and reflective practice to increase empathy and perspective taking in medical students. MedEdPORTAL. [crossref]
McDonald B, Goldstein TR, Kanske P (2020) Could acting training improve social cognition and emotional control?. Frontiers in Human Neuroscience.
Haddock T, Lau P, Ghrear S, Birch S (2017) What happens at home: How family discourse fosters social perspective-taking in children with autism spectrum disorder and typically-developing Acta Psychopathologica.
Hershberger PJ, Part HM, Markert RJ, et (1995) Teaching awareness of cognitive bias in medical decision making. Academic Medicine.70(8). [crossref]
Clegg BA, Martey RM, Stromer-Galley J, Kenski K, et (2014) Game-based training to mitigate three forms of cognitive bias. In Proceedings of Interservice/Industry Training, Simulation and Education Conference (I/ITSEC) 2014.
Remes O, Mendes JF, Templeton P (2021) Biological, psychological, and social determinants of depression: A review of recent literature. Brain Sciences. 11(12). [crossref]

Pheromonicin: A Novel Antimicrobial Inhibited Fatal Multidrug-Resistant M. tuberculosis Infection in Animal Models

1 Reply

DOI: 10.31038/MIP.2024521

Abstract

There is an urgent need for effective new drugs to combat multidrug-resistant M. tuberculosis (MDR-TB). We found the outer membrane porin A of MDR-TB (OmpATb), a member of the OmpA family which shares epitopes with a variety of microbes, could be targeted by a 28-residue antibody mimetic by fusing two antibody Fab complementarity-determining regions (VHCDR1 and VLCDR3) through a cognate framework region (VHFR2) of a monoclonal antibody which recognizes OmpA of N. meningitidis. We constructed a fusion protein, pheromonicin-NM (PMC-NM), by linking colicin Ia, a bactericidal molecule produced by E. coli which kills target cells by forming a voltage-dependent channel in target cell membrane, to that antibody mimetic. The OmpATb/antibody mimetic interaction initiated the formation of irreversible PMC-NM channel in MDR-TB cell membrane resulting in leakage of cellular contents. PMC-NM demonstrates high efficacy, 103-5 times greater than that of current anti-TB agents, against 506 isolates of MDR-It can reduce pulmonary TB CFU 2-3 logs compared to controls in murine TB models. With a 22-wk PMC-NM treatment, 75% macaques survived MDR-TB infection that was lethal to untreated and INH/RIF-treated controls. No relapse occurred in the subsequent 26-wk observation period for 60% of the macaques. PMC-NM significantly altered outcomes of in vivo fatal MDR-TB infection without evident toxicity, making it an appropriate candidate for further clinical evaluation.

Keywords

OmpATb, Guidance of antibody mimetic, Cellular leakage, Intracellular clearance, Pulmonary TB burdens, Clinical outcomes

Introduction

Tuberculosis (TB) is the biggest infectious killer of adults, causing approximately 1.8 million deaths and 10.4 million new cases each year [1-4]. Multidrug-resistant tuberculosis (MDR-TB), caused by strains of Mycobacterium tuberculosis resistant to at least isoniazid (INH) and rifampicin (RIF), the backbone of the current empirical first-line anti-tuberculosis regimen, affects an estimated 600,000 people every year. Cases of extensively drug- resistant tuberculosis (XDR-TB), resistant to INH/RIF, fluoroquinolone, and amikacin, capreomycin or kanamycin, have been observed worldwide, most notably in high burden countries such as China, India, throughout Africa, and Eastern Europe [1-4]. Current therapies for drug-resistant tuberculosis offer a very low cure rate – roughly 50 percent – and therapy ranges from 9 months to two years, therefore, new drugs are urgently needed to combat MDR/XDR-TB infections [4].

Outer membrane porin A of M. tuberculosis (OmpATb), located on the outer membrane of Mtb cells [5-8], could serve as a potential target for new drugs. We postulated that OmpATb might appear on the surface of infected host cells [9,10] If that was the case, the new drug would be able to kill both Mtb cells and infected host cells.

As an example of channel-forming bacteriocins, colicin Ia, a typical E1 family colicin, is bactericidal to E. coli and might be able to be developed as a novel candidate against MDR-TB infection, if the native targeting ability of wild-type colicin Ia could be altered. Colicin Ia kills target cells by forming a voltage-activated channel in the target cell membrane via its 175-residue C-terminal channel- forming domain [11-16]. It acts on the lipid bilayer of cell membranes, therefore, colicin Ia could be engineered for insertion into the cell membrane of bacteria that are not its natural targets [18]. In target cell membrane, the active form of colicin Ia is a monomer [12-16].

To target the channel-forming domain of colicin Ia to the cell membrane of other bacteria, we initially constructed fusion proteins consisting of either an 8-residue staphylococcal AgrD1 pheromone, or a 7-residue enterococcal cCF-10 pheromone, or a 13-residue Candida a-factor pheromone fused to the channel-forming domain of colicin Ia. The fusion proteins demonstrated effective bactericidal activities against methicillin- resistant Staphylococcus aureus, or vancomycin- resistant Enterococcus faecalis, or Candida albicans in vitro and in vivo, respectively [17-19]. We then selected certain antibody complementarity- determining regions (CDRs) and framework region sequences to create a single-chain antibody mimetic comprising two interacting V_H– and V_L– derived CDRs. The mimetic retains the basic antigen-recognition ability of the whole parent antibody and acts as a smaller, proper-affinity binder [20]. We previously found that the most promising structure comprises V_HCDR1 and V_LCDR3 connected by a corresponding V_HFR2 sequence, forming a 28-residue antibody mimetic [20].

Materials and Methods

Construction and Purification of Pheromonicin-NM

The antibody mimetic amino acid sequence was constructed to followpositionI626 ofcolicin Iabydouble-strandedmutagenesis(Quick Change kit, Strategene) using a pET-11 plasmid containing the colicin Ia gene to form pheromonicin-NM (PMC-NM). The oligonucleotide used, containing the desired SYWLHWIKQRPGQGLEWIGSQS

THVPRT mutation, was 5’-GCG AAT AAG TTC TGG GGT ATT TCT TAT TGG CTG CAT TGG ATT AAA CAG TAA ATA AAA TAT AAG ACA GGC-3’, 5’-TGG CTG CAT TGG ATT AAA CAG AGA CCT GGT CAG GGA CTG GAA TGG ATA TAA ATA AAA TAT AAG ACA GGC-3’ and 5’- GGT CAG GGA CTG GAA TGG ATA GGA TCT CAG TCC ACG CAT GTG CCG AGA ACC TAA ATA AAA TAT AAG ACA GGC-3’. The harvested plasmid was transfected into pET BL-21 (DE3) E. coli cells to produce PMC-NM as previously described10-13. As determined from 12% SDS-polyacrylamide gel assays, PMC-NM eluted by 0.3 M NaCl comprised about 90% of total eluted protein (Figure 1d).

Amino acid Sequences of Mimetics of Other Tested Pheromonicins

The sequences of the V_HCDR1-V_HFR2-V_LCDR3 of the following parent molecules are:

HB8627 IgM recognized non-small cell lung cancer: DYYLHWVKQRTEQGLEWIGQHIRELTRS

IgG recognized B. dendrobatidis: GYTMEWVKQSHGKN- LEWIGQNGNTLPYT

AF468835 recombinant single chain Fv Ab recognized N. gonor- rhoeae:

TYAMNWVRQAPGKGLEWVAQQGQSYPLT

IgG recognized Cyanobacteria: SYWMQWVKQRPGQGLEWIGQ- QYWSTPPWT

MDR-TB Isolates Used for In vitro and In vivo Rodent and Primate Infection

506 clinical isolates of MDR-TB were collected by China CDC from southern and western China with 10% XDR-TB isolates for in vitro study. Mtb Erdman, H37Rv, MDR-06005 and PUMC-94789 were used for rodent and primate infection models in the present study. MDR-06005 is a Beijing genotype strain that is katG 315 and gyrA 281 genetic mutations (isolated by Institute of Tuberculosis Research, 309 Hospital, Beijing). PUMC-94789 is a Beijing genotype strain that is with katG 315, rpoB 531, 526 and gyrA 94 genetic mutations, and presented a 7-d median death time in mice test (isolated by Institute of Experimental Animal Sciences, Peking Union Medical College).

Minimum Inhibition Concentration

100 μl of double-diluted preparations of either PMC-NM, INH, or other routine anti-TB agents was added into respective wells of 96- well plate while only 100 μl 7H9-S broth was added into the control well, then 100 μl of inoculum (TB cells, 10⁶CFU/ml in 7H9-S broth) was added into each well. The plates were sealed in plastic bags and incubated 10 days (37°C) after inoculation. The lowest concentration of each agent which prevented the visual growth of Mtb cells was interpreted as MIC. MIC measurement of PMC-NM against isolates of Gram-positive and -negative Omp A bacterium were performed at Antibiotic Division, National Inst. for Food and Drug Control. China FDA with a paid service contract. Incubation time was 12-24 hrs (37°C) after inoculation.

In vitro Inhibition Test

100 μl of preparations of PMC-NM, or INH, or wild-type colicin Ia, or Rev-PMC-NM was added into respective wells of 96-well plate while only 100 μl 7H9-S broth was added into the control well, then 100 μl of inoculum (H37Rv cells, 10⁶CFU/ml in 7H9-S broth) was added into each well. The plates were sealed in plastic bags and incubated 2, 3, 7, 8 days (37°C) after inoculation. Turbidometric absorbance of each well was measured.

Phase I incubation test, 3 ml 7H9 solution inoculated with H37Rv (0.1 ml, 10^4-5 CFU), treated with (1) 50 mM borate buffer (colicin Ia and PMC-NM stock solution), (2) 1 ug/ml wild-type colicin Ia, (3) 1 ug/ml PMC-NM, incubated at 37°C for 6 weeks.

Phase II incubation test, 3 ml 7H9 solution inoculated with H37Rv, treated with (1) nothing, (2) 50 mM borate buffer, (3) 2 ug/ml wild-type colicin Ia, (4) no inoculation but remains of phase I PMC- NM treatment culture (3,000 rpm centrifuged 10 min), incubated at 37°C for 10 weeks.

Bifidobacterium longum (1.2186) and Lactococcus lactis (1.2472) (Inst. Microbiology, China Academy of Science) (50 μl, 10^3-4 CFU/ml) was smeared on the surface of respective solid medium with PMC- NM and ampicillin treatments, incubated 18 hrs (37°C).

Rodent In vivo Bactericidal Activity

Female BALB/C mice (six per group) were infected intranasally with 6.8 x 10² CFU of Mtb Erdman (ATCC35801). Twenty-one days post-infection mice were treated with either intraperitoneal injection (i.p.) of saline, or PMC-NM 20 or 40 mg/kg/d, or oral delivery of INH 25 mg/kg/d for 4 weeks. Right lungs were collected for Mtb CFU determination.

Female BALB/C mice were injected with 0.2 ml 105-6 CFU/ ml of MDR06005 MDR-TB strain through the tail vein. Three days after infection, mice were randomly assigned into four treatment groups (twenty per group) and i.p. with 0.9% saline alone, INH 6, or 12, or 27 mg/kg/d, PMC-NM 5, 10, or 20 mg/kg/d daily for 4-weeks. The number of surviving animals at various time points was determined. Kaplan-Meier analysis was used to determine the significance of differences between the PMC-NM and control groups. All in vivo protocols were approved by the Institutional Animal Care and Use Committee of Sichuan University and Project of Sichuan Animal Experimental Committee, License 045, Institutional Animal Care and Use Committee of China CDC and Project of Beijing Animal Experiment Committee, license CNAS BL0047, China, and Subcommittee for Animal Safety, VAMC, Syracuse, NY.

Immunolabeling Assay

Pheromonicin-NM was injected i.p. into mice, or macaques that had been infected with MDR-TB cells 4-6 weeks (mice), or 17 weeks (macaque) prior. The animals were killed 12-24 hrs after injection, and the lungs were fixed for formalin and paraffin-embedded prior to sectioning. Sections were sealed with 5% BSA, and then incubated with anti-OmpA (rabbit IgG, MyBioSource, San Diego, USA), or anti- pheromonicin (mouse, AbMax, Beijing) antibodies for 30 min. at 37°C, washed and incubated with FITC- anti-rabbit and rhodamine- anti-mouse goat antibodies (Bioss, Beijing) for 15 min. at 37°C, and washed. The sections were examined under an optical/fluorescent microscope (Nikon 90i) with DM400, DM505 and DM565 filters.

MDR-TB infected macaque lung tissues were fixed with 2.5% paraformaldehyde, dehydrated with gradient concentrations of ethyl alcohol, embedded in gelatin, and sectioned with Leica EM UC6 ultramicrotome, ultra-thin sections were probed with above rabbit anti-OmpA Ab and mouse anti-pheromonicin Ab as first Ab, 2nd Ab were goat anti-rabbit 5 nm colloidal gold and goat anti-mouse 10 nm colloidal gold IgGs, (Sigma), stained with uranyl acetate and observed under a transmission electron microscope (Hitachi HT7700, Japan).

Immunoblotting Assay

Pellets of H37Rv Mtb strain (2 gm) and macaque lung tissues (2 gm, extracted from autopsy as CFU counting collection) were homogenized, suspended with extract solution A (9 ml with 1: 250 extract sol. C), sonicated for 1hr at 2-8°C, centrifuged 10,000g, 5 min at 2-8°C, supernate suspended with 1: 30 extract solution B, 37°C bathing for 10 min, centrifuged 1,000g, 3 min at 37°C, the thick liquid (bottom layer of layered centrifugation) blended with 1: 1 extract sol. B (membrane protein extraction kit, BestBio, Shanghai). 60 ug preps per well, SDS-10% PAGE electrophoretic transferred to nitrocellulose membrane, incubated with, or without 10 ug/ml PMC-NM, or other tested pheromonicins for 1 hr, 20°C, then 4°C over night, the resulting material were probed with anti-pheromonicin Ab and appropriate secondary antibodies (AbMax, Beijing).

Ethics Statement

The work described in this study was carried out at Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago and Institute of Experimental Sciences, Peking Union Medical College via paid service contracts, and the Veterans Affairs medical center, Syracuse, NY). All animals were housed in the Animal Bio-Safety Level III (ABSL-III) facility located at Biologic Resources Laboratory, University of Illinois at Chicago and Institute of Laboratory Animal Science, Peking Union Medical College. The housing and animal care procedures were in compliance with the Chinese guidelines for animal experiments (Laboratory animal Requirements of environment and housing facilities GB 14925–2010, China; Regulations on administration of laboratory animals, Ministry of Science and Technology, 1988, China) and with the 8th Guide for the Care and Use of Laboratory Animals of Association (National Research Council, 2011). The animal housing and care procedures were in compliance with the United States Department of Agriculture (USDA) through the Animal and Plant Health Inspection Service under the Animal Welfare Act (AWA). The ABSL-III facility was certified by USDA and Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) prior to initiation of this project. Office of Animal Care and Institutional Biosafety (OACIB) of University of Illinois at Chicago approved all the study protocols and procedures before this project begins. The approval numbers were: IBC#12-089; ACC#12-210. The ABSL-III Laboratory is certified by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International). Institutional Animal Care and Use Committee of Peking Union Medical College approved study protocols and procedures prior to starting this project (ILAS-PC-2014-009). Animal protocols were approved by the Subcommittee for Animal Studies (SAS), Veterans Affairs Medical Center, Syracuse, NY. Animals were individually housed in stainless steel wire-bottomed cages (80×80×80 cm3) with sufficient space supplied with a commercial monkey diet and water and twice daily with fresh fruit in an air-conditioned room and monitored by a computer-based system. After infection, animals were also monitored twice daily by experienced staff. Animal health was monitored daily by the animal care and veterinary personnel. Pre-defined humane endpoints including depressed or withdrawn behavior, abnormal respiration rates, serious loss of appetite, severe body weight loss and severe abnormal radiographic changes were applied to reduce discomfort in this study. Serious loss of appetite was defined as no food intake during at least two meals. Severe body weight loss was defined as a 20% weight loss in three consecutive weeks compared to the body weight before TB infection. Animals were euthanized by anesthesia with ketamine (i.m. 3～5 mg/kg).

Study Plans

Cynomolgus macaques (Macacca fasicularis) were infected with MDR-TB PUMC-94789 via bronchoscope and monitored clinically, as previous described. Upon development of active TB, animals were randomly assigned to one of three groups: untreated, combind INH/ RIF, or PMN-NM. Animals were followed for 22-wk treatment and subsequent 26-wk observation period. Gross pathology, overall bacterial burden scores, and lung CFU were calculated as described for treatment response. CT scans were performed (a) before infection as the baseline background, (b) day 22 after infection to confirm infection, (c) at time points of 22-wk treatment and subsequent 26-wk observation period and (d) at the end of treatment or termination of animal. Cynomolgus macaques were infected with M. tuberculosis H37Rv via bronchoscope and underwent clinical observation, necropsy and histology.

Clinical Observation, Necropsy and Histopathology

Clinical assessments included body weight, respiratory distress, general alertness/activities and food uptake. Clinical lab tests included CBC, differentials, calculation of total lymphocyte population and serum biochemical examination. Extensive quantification of gross TB lesions in each lung lobe, hilar lymph nodes, pleural and extra thoracic organs was undertaken. Histopathology of TB lesions from right caudal lobe (infection site) and other lobes, chest lymph nodes, and extra thoracic organ/tissues was evaluated.

Tissue Bacterial Burden Measurement

Lung samples (4-5 gm) were collected at necropsy from upper, middle and caudal lobes of left and right lungs. Samples were homogenized with a grinder, and digested in N-acetyl-L-cysteine- NaOH-Na citrate (1.5% final concentration) for 15 min at room temperature, neutralized with phosphate-buffered saline (PBS, 67 mM, pH=7.4) and centrifuged at 4,000 g for 15 min. Sediments were re-suspended with 2 ml PBS buffer. 100 μl of each 10-fold serial dilution was inoculated on 7H11 agar plate, and then incubated at 37°C for 4 weeks. The bacteria burden was calculated according to the number of CFUs on the agar plate.

CFU of organ (lung) was calculated as, [CFU number of agar plate x 10 (10-fold serial dilution)/[weight of sample (mg)/1,000 (gm) ]] x weight of lung (gm) CFU/lung

CT Scanning and Abnormal Volume Measurement

Image acquisition. All scans were acquired with a 16-section CT scanner (μCT S-160 scanner, United Imaging, Shanghai) by using a spiral mode with 16 × 0.9375-mm collimation. Exposure settings were 140 kVp and 200 mA. Transverse images were reconstructed at a thickness of 1.0 mm and a 1.0-mm increment by using a moderately soft reconstruction kernel, the smallest field of view that included the outer rib margins at the widest dimension of the thorax, and a 1024 × 1024 matrix. All images were interpreted by radiologists who were blind to the identity of the subject. Semi automated measurements of Pulmonary Abnormal Volume (PAV). Data were transferred from the CT scanner to a digital workstation (United Imaging, Shanghai) with commercially available software for semi-automated PAV measurements (Lung lesions; Tissue Management). Lesions were identified by using transverse thin-slab Maximum Intensity Projections (MIP) that were displayed with window width and level settings of 1500 and −500 HU, respectively. With the candidate lesion was marked, the program automatically looked for adjacent structures which matched conditions around the lesion, started volume measurement by using volume-rendered with the structure and the volume of segmented lesion was calculated. The CT scan which taken before TB infection was used as the baseline.

Statistical Analysis

Comparison of data among experimental groups were performed by t test. Comparison of cumulative survival among experimental groups were performed by Kaplan-Meier analysis. P values of <0.05 were considered to be statistically significant. The following inclusion criteria were used to select macaques: no infectious or chronic diseases, good appetite and behavior, age 2-4 yrs, bodyweight 4-6 kg. The macaques were individually housed in cages for five weeks before pulmonary MDR-TB infection. Three weeks after infection with confirmation of eyelid tuberculin test and pulmonary CT scan, animals were randomly allocated into three treatment groups according to a Blocked Randomization Method.

The sample size was estimated according to following assumption: Group I (placebo control) and Group II (traditional medications control) would have an effect of survivor rate equal to 0%, respectively. Group III (PMC-NM) would be a 50% of survivor rate after a 22- wk treatment intervention (25-wk pulmonary infection). When we combined Group I and Group II into a control group to conduct difference comparing of two survivor rates (0% and 50%) between control group (8 animals) and experiment group (8 animals), and defining alpha=0.05, beta=0.2, a Fisher exact test P value=0.038 under selecting n1=8 and n2=8.

Data from our study showed that the survivor rate of PMN- NM treated group was 75% (6/8,) and the survivor rate of control and traditional medications group was 0% (0/4, 0/4), a Fisher exact test P value=0.030 (one-side), it indicated significant statistical difference. The numbers of surviving animals at various time points were determined, and Kaplan-Meier analysis showed a significant difference between the control and PMC-NM treated group (p=0.003). Therefore, we assume that the sample sizes of our study are sufficient.

Results

PMC-NM demonstrated high efficacy against pan-susceptible and MDR-TB strains under the guidance of 28-residue antibody mimetic.

We fused the antibody mimetic at the C-terminus of colicin Ia to construct colicin Ia-antibody mimetic fusion proteins (Figure 1A-E). The targeting domain in one of them is a mimetic of a mAb (NCBI 2MPA) that recognizes the OmpA of N. meningitides, a member of the OmpA family which shares epitopes with over 600 other microbes, including Gram negatives (E. coli, K. peumoniae, E. cloacae, Y. pestis, V. cholerae) and Gram positives including M. tuberculosis (Mtb) [5- 8,21]. This porin A-specific antimicrobial fusion protein was named pheromonicin-NM (PMC-NM). Interestingly, PMC-NM does not inhibit the growth of certain probiotics, e.g., Bifidobacterium longum and Lactococcus lactis, presumably due to their lack of similar OmpA analogs on their surface (Figure S3A).

Among several tested pheromonicins with relevant antibody mimetics derived from antibodies targeting different epitopes, only the PMC-NM interacted with OmpATb of Mtb (Figure 1F). PMC- NM inhibited the growth of OmpA pathogens as a bactericidal agent (Figure 1G) [17,18]. In contrast, significant differences regarding in vitro activity indicated that neither wild-type colicin Ia, nor reversed PMC-NM with a scramble mimetic, is be able to target Mtb cells (Figure 1G).

The results of two-phases Mtb growth inhibition showed that phase I (6-wk), PMC-NM (1 ug/ml) inhibited the growth of H37Rv cells while wild-type colicin Ia (1 ug/ml) failed; phase II (10-wk), wild- type colicin Ia (2 ug/ml) still did not inhibit the growth of H37Rv cells. Interestingly, in the phase II tube which was inoculated with remains of phase I PMC-NM-treatment culture, no H37Rv cells re-grew, suggesting that PMC-NM was bactericidal (Figure 1H).

A Minimum Inhibitory Concentration (MIC) assay of 39 isolates of MDR-TB (collected by China CDC) showed there were significant differences regarding MIC50 and MIC90 among PMC-NM, wild-type colicin Ia and reversed PMC-NM (Table 1).

Table 1: MIC (ug/ml) of PM-NM and colicin Ia against 39 isolates of MDR-TB.

Above results indicated that only the PMC-NM with constructed NM antibody mimetic with accurate N- to C-terminal sequence could target the Mtb cells.

A MIC assay of several pan-susceptible Mtb strains (Mtb Erdman, Mtb HN878 etc) and 506 clinical isolates of MDR-TB (collected by China CDC from southern/western China with 10% XDR-TB) indicated that the PMC-NM MIC of pan-susceptible Mtb strains were 0.027-0.11 nmol (1.875-3.75 x 10^-3 μg/ml) and the MIC₅₀/MIC₉₀ of MDR-TB isolates was 1.14/143 nmol (0.08/10 μg/ml), which were significantly lower than the MIC₅₀/MIC₉₀ of 11 standard anti-TB drugs (Figure1I and Table 2). Considering the differences in molecular weight between PMC-NM (70 kDa) and standard anti-TB agents (≤1 kDa), the inhibitory activity of PMC-NM against pan-susceptible Mtb strains and MDR-TB isolates was approximately 10^3-5 times greater, on a molar basis, than that of standard anti-TB agents. The inclusion of 10% XDR isolates likely expanded the MIC range of PMC-NM.

Table 2: Killing rate against Mtb cell/human pulmonary cell culture

PMC-NM suppressed the pulmonary TB burdens and altered the clinical outcomes in murine pan-susceptible/MDR-TB infection.

Figure 1: Structure and in vitro bioactivity of PMC-NM.
(A) Structure of the antibody mimetic comprising the V CDR1, V FR2, V CDR3 domains of Fab of 2MPA mAb. (B) 8.3 kbp colicin Ia plasmid used for site-directed mutagenesis of colicin Ia gene to insert the gene encoding the antibody mim^H etic. (C)^HA dom^Lain diagram of the PMC-NM. (D) The Rev-PMC-NM constructed with scramble mimetic. (E) PMC-NM (70 kDa) comprised about 90% of total SDS eluted protein. Lanes, (1) marker, (2) PMC-NM.

To evaluate whether PMC-NM suppressed the pulmonary TB burdens and altered the clinical outcomes of murine TB infection, we first tested the PMC-NM efficacy against drug-sensitive Mtb Erdman infection model. We subsequently studied PMC-NM efficacy with a mildly drug-resistant Mtb strain infection model using a short- term (30 days) treatment. Female BALB/C mice (six per group) were infected intranasally with 6.8×10² CFU of Mtb Erdman. Twenty-one days post-infection mice were treated with either intraperitoneal injection (i.p.) of saline, PMC-NM (20 or 40 mg/kg/d), or oral delivery of INH (25 mg/kg/d) for 4 weeks. Right lungs were collected for TB CFU determination. Both INH and PMC-NM treatment significantly reduced TB CFU about 10^2-3 logs compared to that of controls (Figure 2A).

We tested several doses (5, 10 and 20 mg/kg/d, i.p.) of PMC-NM in female BALB/C mice infected with a fatal inoculum of MDR-TB [MDR-06005, PMC-NM (_MIC=0.08 μg/ml), INH (_MIC > 0.2 μg/ml), levofloxacin (_MIC=4 μg/ml), and moxifloxacin (_MIC=2 μg/ml), 0.2 ml, 10^5-6 CFU/ml] given through the tail vein. We found that 10 mg/kg/d of PMC-NM yielded a 75-80% survival rate but 5 mg/kg/d of PMC- NM failed (Figure 2B). Subsequently, we selected 10 mg/kg/d as an in vivo protective dose against MDR-TB infection for further studies.

The PMC-NM molecules were able to selectively accumulate in the pulmonary TB lesions 1 to 12 hrs after a one-time i.p. application (10 mg/kg) (Figure 2C).

PMC-NM treatments significantly reduced TB burdens and infection levels in macaque pan-susceptible Mtb infection [22-26]. Since primate models are most similar clinically and pathologically to human TB infection, cynomolgus macaques were selected to determine in vivo efficacy of PMC-NM. Healthy cynomolgus macaques could tolerate 2-wk PMC-NM treatment with daily intravenous injection (i.v.) as the dose increased from 0.8 to 2 mg/kg/d with no apparent abnormalities.

Sixteen macaques were studied using several regimens to compare 5-wk PMC-NM treatment (i.v. 2 mg/kg/d, n=6) with a saline-treated control group (n=6) and orally dosed INH groups (0.1 mg/kg/d, n=2), or (1.0 mg/kg/d, n=2). Five hundred CFU pan-susceptible H37Rv cells was inoculated into the right caudal lung lobe of each macaque through a bronchoscope. Treatment started at day 24 post -infection. Comparative measurements of TB CFU and pathology scores suggested that PMC-NM treatments significantly reduced TB burdens and pathology score in lung tissues (Figure 2D-E and Figure S1A).

Figure 2: (A) Immunoblotting assay showed that only the PMC-NM, not other PMCs, interacted with extracted OmpATb of Mtb H37Rv (about 114 kDa). Lanes, (1) PMC-NM, (2) PMC- cyanobacteria, (3) PMC-B.dendrobatidis, (4) PMC-HB8627, (5) PMC-N.gonorrhoeae. (B) PMC-NM inhibited the growth of OmpATb pathogens (Mtb H37Rv) as a bactericidal agent. (C) Wild-type colicin Ia could not inhibit but PMC-NM inhibited the growth of H37Rv in the test tube. Phase I (6-wk), all tubes inoculated with H37Rv cells, (a) control, (b) wild-type colicin Ia 1 ug/ml, (c) PMC-NM 1 ug/ml, phase II (17-wk), all tubes inoculated with H37Rv cells, but tube g inoculated with remains of phase I PMC-NM-treated culture. (d) control, (e) spare borate buffer, (f) wild-type colicin Ia 2 ug/ml. (D) The MIC frequency distribution of PMC-NM against measured several drug-sensitive Mtb strains and 506 isolates of MDR-TB/XDR-TB. (E) After 2 hrs incubation with (Ea) INH 1 μg/ml, or (Eb) PMC-NM 2 μg/ml, INH did not show any efficacy on MDR-TB cells but PMC-NM killed all MDR-TB cells. Bar, 10 or 20 μm. (F) Comparing with normal MDR-TB cells (Fa), (Fb) Destroyed MDR-TB cells were either ruptured, or shrinkage as empty cell-ghosts with leakage of cellular contents with PMC-NM treatment (2 μg/ml).

PMC-NM Altered the Clinical Outcomes in Macaque MDR- TB Infection

Pharmacokinetic assays indicated that i.p. application provided a longer circulatory retention contour than that of i.v. application (Figure 3A), therefore, we selected i.p. delivery to yield a longer PMC- NM exposure in pulmonary lesions.

A high virulence MDR-TB isolate [PUMC-94789], PMC-NM (_MIC=0.08 μg/ml), INH (_MIC=4 μg/ml), RIF (_MIC=64 μg/ml), ethambutol (_MIC=4 μg/ml) was selected to infect macaques (Table 3). Four-wks of PMC-NM treatment (i.p. 3 mg/kg/d, n=4) was compared to untreated controls (n=4)( Figure S1B). Results indicated that (a) 300 CFU of PUMC-94789 cells created a successful infection model, (b) i.p. PMC- NM was efficacious in this model.

Table 3: Killing rate against Mtb cell/human pulmonary cell culture

Note: Conc.2 : Seed 0.5ml-A549/well at 2×10⁵/ml in 24 well flat-plate. Conc.1 : Seed 0.5ml-A549/well at 1×10⁵/ml in 24 well flat-plate.
Comments:
1. The killing rate as control group, Isoniazid (1ug/ml), reaches 78% on day 3.
2. The killing rate as exp. group, pheromonicin (1ug/ml & 10ug/ml), reaches 33% & 61% respectively on day 3.
3. A549 cells will be apoptotic from on day 3 as critical point under the exp. concentrations.
4. Mtb bacteria die on day 7 with loss of cell host.

Sixteen macaques were infected with 300 CFU of PUMC-94789 cells in the right caudal lung lobe. Infection was confirmed by eyelid tuberculin testing and CT scans 3-wks after inoculation. The animals were randomly allocated into three 22-wk treatment groups: untreated controls (n=4), combined INH/RIF-treated (i.p. 21.8/3.65 μmol/kg/d (3/3 mg/kg/d), n=4, doses adjusted from reported MDR-TB rodent studies) [27,28], and PMC-NM-treated (i.p. 43 nmol/kg/d (3 mg/ kg/d), dose adjusted from previous rodent/macaque doses, n=8). Treatment was initiated day 24 post-infection. Seventy-five per cent of PMC-NM-treated group survived. All untreated and INH/RIF- treated controls and two PMC-NM-treated macaques reached the humane endpoint within 10-17 weeks post-infection. All macaques that reached the humane endpoint suffered from clinical symptoms related to MDR-TB infection confirmed at necropsy (Figure 3B, C and Figure S2A-C). Serial CT scans were performed before the infection, and during the entire test period [29,30]. The whole pulmonary TB lesion volume in each CT scan was the summation of lesions in every 1-mm thick digitally dissected CT image (Figure S2A and S2D). The clinical outcome of each macaque was quantitatively extrapolated as the function of serial variation of TB lesion volumes during the entire test period (Figure 3D-F).

The MDR-TB infection in the macaques underwent different clinical courses with respective treatments (Figure 3B-G and Figure S2A-C), (a) all untreated and INH/RIF-treated macaques were euthanized around 10～17-wk post-infection while TB lesion volumes continuously enlarged with pulmonary TB CFU growth (Figure 3Da, Fa ); (b) two macaques with low bodyweight (≤ 4 kg) were randomly allocated in the PMC-NM group, we assume that poor physiological conditions might be the reason for the apparent failure of PMC-NM. The lung cultures yielded no growth and decreased TB lesion volumes suggesting control of the TB infection (Figure 3Db, Fb); (c) two PMC-NM-treated macaques were euthanized at 47-wk post-infection with relapsed infection which suppressed by a second 18-wk PMC-NM treatment, presumably their doubled lesion volumes compared to the other PMC-NM treated animals at the end of first treatment, facilitated their relapse (Figure 3Ea, Fc); (d) sixty per cent of surviving PMC-treated macaques completed the 52-wk study with no measurable lesion volumes or TB CFU growth but increased their body weight (Figure 3Eb, Fd).

The TB strain which grew in the infected macaque lungs displayed the same resistance profile as the original PUMC-94789 strain (Table 4). The main lesion in untreated primates was acute tuberculosis pneumonia while in INH/RIF-treated primates was granulomas. In contrast, the lesions in PMC-NM-treated primates was significantly less than above groups (Figure 3G,H and Figure S2E).

Figure 3: Probably PMC-NM targeting/killing mechanism.
(A) Antibody mimetic (green) interacted with OmpATb to drag the channel-forming domain (orange) to bind the cell membrane, (B) hydrophobic interaction drove the channel-forming domain to form channel, (C) transmembrane potential opened the channel resulting in the leakage of cellular contents.

Table 4:

The serum biochemical data of untreated and PMC-treated monkeys were compared in reference to normal values (Table 5), The BUN/CRE of PMC-treated were in normal range but that of untreated were upper limit of normal or above ; the GLU and TG values of untreated were low, the CK and LDH of untreated were almost 10 times higher than upper limit of normal indicated there might be some muscle/bone and multi-organ TB lesions. Above significant differences between untreated and PMC-treated serum biochemical data indicated that untreated monkeys had serious multi-organ and metabolic abnormalities due to MDR-TB infection, however, PMC protected monkeys with no apparent toxicity.

Table 5:

Discussion

Our results indicate that daily PMC-NM treatment (i.p. 43 nM/ kg/d for 22-wks), initiated 24 days after fatal MDR-TB infection can significantly reduce MDR-TB lesions in lungs and clinically cure certain cases. To our knowledge, this is the first report of a channel- forming toxin-antibody mimetic fusion protein altering the clinical course in fatal MDR-TB infected rodent and primate models.

Several findings suggested the antibody mimetic domain of PMC-NM molecules targeted the OmpATb appearing on the surface of either Mtb cells, or infected host cells with internalized Mtb cells [5-10,31-35]; (a) immunoblotting data showed only PMC-NM with 28-residue antibody mimetic of 2MPA mAb, not other tested pheromonicins, interacted with OmpATb (Figure 1f), (b) Growth inhibition data demonstrated that without fused 28-residue VHCDR1- VHFR2-VLCDR3 mimetic with accurate N- to C-terminal sequence, wild-type colicin Ia would not be able to recognize OmpATb (Figure 1G), (c)immunofluorescent dyes showed that OmpATb appeared in the infected lung tissues, even traced the outlines of infected cell membrane and organelles (Figure 4B), (d) PMC-NM molecules selectively interacted with OmpATb, then accumulated in the lesion tissues from circulation (Figure 4B), (e) with immuno-labeling electron microscopic assay, paired 5/10 nm colloid gold molecule images revealed the interaction between OmpATb and PMC-NM molecules at infected host cell membrane (Figure 4D,E), and (f) immunoblotting assay showed PMC-NM recognized the membrane precipitates of the infected lungs, as well as OmpATb of Mtb cells, but did not recognize the precipitates of uninfected and PMC-NM-treated lungs (Figure 1F and 4F).

Early OmpATb studies suggested that OmpATb might act on the outer membrane as a monomer pore (38 kDa)(5, 8). In our immunoblotting assay, the OmpATb precipitations of H37Rv were around 114 kDa, if the interaction with the PMC-NM occurred less than 24 hrs after OmpATb preparation was made, however, they were degraded as 38 kDa precipitations, if the interaction with the PMC- NM occurred beyond 48 hrs. These findings suggest that in vivo, at least some part of OmpATb might be in trimmeric form (Figure S3).

Two main domains of PMC-NM are involved in killing Mtb cells, (a) antibody mimetic interacted with OmpATb to drag the channel-forming domain to bind the cell membrane, (b) hydrophobic interaction drove the channel-forming domain to form channel in the cell membrane irreversibly, (c) transmembrane potential opened the channel to induce the leakage of cellular contents resulting in cell death (Figure 4G). Cellular content leakage through the large ion-conductive lumen (9-11 Å) of the colicin channel is a novel mechanism of action against TB cells, as well as infected host cells (9-12,16-19). Either rupture, or shrinkage as empty cell-ghosts occurred in all cells treated with PMC-NM (Figure 4H,I). PMC-NM could therefore target/kill any cell, either prokaryocytes, or eukaryocytes, with lipid bilayer cell membranes, if OmpATb appeared on their surface. Future studies will help to further define the specific mechanism of action of PMC-NM.

Figure 4: In vivo activity of PMC-NM in murine and macaque TB.
(A) Mtb CFU of Mtb Erdman infected mice lung after 4-wk treatment with either saline, INH, or PMC-NM. t test was used to determine significant differences between the PMC-NM and saline groups (p<0.05), INH and saline groups (p<0.05). (B) Cumulative survival of MDR-TB (MDR-06005) infected mice with 4-wk injected intraperitonealy (i.p.) with saline, INH 6, 12 mg/kg/d, or PMC-NM 10, 20 mg/kg/d; or with saline, or PMC-NM 5, 10, 20 mg/kg/d. The numbers of surviving mice at various time points were determined, and Kaplan-Meier analysis was used to determine significant differences between the PMC-NM 10, or 20 mg/ml treatment with other treatments (p<0.05). (C) Immunolabeled PMC-NM molecules (green) selectively accumulated in mice pulmonary MDR-TB lesions at 1 to 12 hrs after one- t ime i.p. application (40x, inlet, optical images). (D) 5-wk i.v. 2 mg/kg/d PMC-NM significantly reduced Mtb H37Rv burdens in macaque lungs. (E) PMC-NM significantly controlled macaque gross TB pathology and lesions.

Figure 5: In vivo activity of PMC-NM against MDR-TB infection in macaque.
(A) Pharmacokinetic assays indicate that i.p. application provided a longer circulatory retention contour. (B, C) Cumulative survival of PMC-NM-treated macaques and controls. The numbers of surviving animals at various time points were determined, and Kaplan-Meier analysis was used to determine the significance of difference between the PMC-NM and control groups (p=0.003) and the non relapsed and relapsed cases (p<0.05). (D) Variations of pulmonary TB lesion volumes with different treatments, (a)Untreated and INH / RIF, n=8, (b) euthanized of PMC-NM, n=2. (E) Variations of pulmonary TB lesion volumes with PMC-NM treatment, (a) relapsed, n=2, (b) non relapsed, n=4. (F) The clinical outcomes of respective treatments were extrapolated as the function of D and E variations, (a) untreated and INH/RIF treatments; (b) euthanized, (c) relapsed and (d) non relapsed cases of PMC-NM treatment. (G) MDR- TB burdens of the whole lung. Each symbol is one macaque. Macroscopic view of lungs of control (Ha,b), INH/RIF-treated (Hc,d, granulomas, yellow circles) and PMC-NM- treated macaques (He,f). Microscopic view of lungs, (Ia) Miliary TB dissemination with necrotic mineralization in the lung of untreated controls. (Ib) Aggravated granulomas in the lung of INH/RIF-treated controls. Conversely, the lung appearance of PMC-NM treated animals was almost normal at the end of 22-wk treatment (Ic), or at the end of 52-wk test (Id). (40x, HE staining)

Figure 6: Probably PMC-NM targeting/killing mechanism.
(A) Untreated control. (200x) (B) OmpATb appeared on cell membranes and organelles of infected host cells (insets).(200x) (C) PMC-NM molecules accumulated on the surface of infected host cells through circulation. (200x) (D,E) Mtb and Infected host cells were probed with anti-OmpA and anti-PMC-NM Abs with 5 and 10 nm colloid gold molecules (grey and black arrows, respectively). Paired gold molecules revealed the OmpATb/PMC-NM interaction around the cell membranes (blue arrows). Bar, 0.2–1 μm. (inset, the location of higher resolution images). (F) Immunoblotting assay showed that PMC-NM interacted with the membrane precipitates of infected macaque lung, as well as OmpATb of Mtb cells, but interacted nothing with the precipitates of uninfected and PMC-NM-treated lungs. Lanes, (1) Mtb H37Rv, (2) infected lung, (3) uninfected lung, (4) PMC-NM-treated infected lung.

Comparing with activities of tested standard anti-TB agents, MIC of pan-susceptible Mtb strains/MDR-TB isolates and in vivo efficacy indicated that PMC-NM presents a new mechanism of action. Cellular content leakage induced by PMC-NM channels is much more robust, as compared to biochemical activity of standard anti-TB agents which is more easily interrupted through mutagenesis. Present resistance mechanisms of MDR-TB, such as interfering with the binding of drug to target protein, or reducing drug-activating enzymes, presumably were unable to block the activation of PMC-NM channels in the TB cell membrane.

Notably, the MICs of PMC-NM against MDR and XDR Mtb strains were commonly higher than that of against drug-sensitive Mbt strains. The following factors might explain the variance of PMC- NM inhibition concentrations across various clinical and lab strains of Mtb, (a) mutant or other structural alterations of Mtb surface, (b) differential expression of OmpATb by these Mtb strains, or the differential presentation of OmpATb on the surface of infected host cells and (c) functional alteration of antibody mimetic domain of PMC-NM. We will continue related investigation in future studies.

Normal blood biochemical parameters, and lack of weight loss or abnormal behavior indicated that treatment with PMC-NM for 22-wks did not induce evident toxicity (Table 5). PMC-NM in vivo bactericidal efficacy against MDR-TB infection indicated that PMC- NM appears to act in the host circulation with full bioactivity.

Table 6:

Additional studies will be necessary to better understand the potential therapeutic efficacy of PMC-NM in multi-drug regimens in combination with anti-TB chemotherapy.

Our data supports the further development of this biological agent and future use with an optimized background regimen against MDR- TB infection in human trials.

Acknowledgment

This work was supported by National Science and Technology Major Projects of New Drugs 2012ZX09103301-024 and 2015ZX09102007-014, National High Technology Research and Development Program of China 2011AA10A214 of Ministry of Science and Technology; Beijing Municipal Science & Technology Commission Z131100002713010 and Z161100000116016 to X-Q.Q.

We would like to acknowledge the help and scientific critique of H. Li, G. Zeng and CY. Jiang during the preparation of this manuscript. We would also like to acknowledge the help of HL Ma, SB Liang, TF Liu, WC Wang, JY Tang, F Meng, XC Li and BG Yuan in PMC-NM preparation and animal care.

Author Distribution

X-Q.Q., K-F.C., Z-H.X., X-F.Z., Y. P., C-Y.T., C.S., R-Q.L, and

M.C. prepared antibody mimetics and pheromonicin-NM molecules, measured in vitro and in vivo activity; X-D.H., and G-K.O. did CT assays and analysis; X-Q.Q., M.C., S.K., Y-L. Z., and Y.W. designed and organized the study and manuscript.

Competing Interests

All authors declare that they have no conflicts of interest.

Summary

Antibody mimetic interaction with OmpATb initiated the channel formation in target cell membrane, then formed channel led cellular content leakage is a novel mechanism of action against MDR-Tb cells. PMC-NM demonstrated high efficacy against pan-susceptible and MDR-TB strains, suppressed the pulmonary TB burdens in murine/ macaque TB models and altered the clinical outcomes in macaque MDR-TB infection. Above in vivo efficacy indicated that PMC-NM appears to act in the host circulation with full bioactivity and no evident toxicity. Our data supports the further development of this biological agent and future use against MDR-TB infection in human trials.

Materials & Correspondence Data and material availability: All isolates of MDR-TB are available from China Centers for Disease Control, Beijing (pangyu@chinatb.org). The PMC-NM source and methods are available from Lab. of Biomembrane & Membrane Proteins, West China Hospital, Sichuan University (491607484@ qq.com). All CT data are available from Dept. of Radiology, 309 Hospital, Beijing (hxd83405107@163.com).

References

S Keshavjee, PE Farmer (2012) Tuberculosis, drug resistance, and the history of modern medicine. N Engl J Med 367: 931-936. [crossref]
M Zignol, AS Dean, D Falzon, W van Gemert, A Wright, et (2016) Twenty years of global surveillance of antituberculosis-drug resistance. N Engl J Med 375: 1081- 1089. [crossref]
J Hoffmann, C Chedid, O Ocheretina, C Masetti, P Joseph, et al. (2021) Drug- resistant TB prevalence study in 5 health institutions in PLos One 16: e0248707. [crossref]
DT Hoagland, J Liu, RB Lee, RE Lee (2016) New agents for the treatment of drug- resistant tuberculosis. Adv Drug Deliv Rev 102: 55-72.
RH Senaratne, H Mobasheri, KG Papavinasasundaram, P Jenner, EJ Lea, et al. (1998) Expression of a Gene for a Porin-Like Protein of the OmpA Family from Mycobacterium tuberculosis J Bacteriol 180: 3541-3547.
B Kartmann, S Stenger, M Niederweis (1999) Porins in the wall of Mycobacterium J Bacteriol 181: 6543-6546. [crossref]
C Raynaude, KG Papavinasasundaram, RA Speight, B Springer, P Sander, et (2002) The functions of OmpATb, a pore-forming protein of Mycobacterium tuberculosis. Mol Microbiol 46: 191-201. [crossref]
M Niederweis (2003) Mycobacterial porings-new channel proteins in unique outer Molecular Microbiol 49: 1167-1177. [crossref]
WL Beatty, DG Russell (2000) Identification of mycobaterial surface proteins released into subcellular compartments of infected macrophages. Infect Immun 68: 6997-7002. [crossref]
JJ Athman, Y Wang, DJ McDonald, WH Boom, CV Harding, PA Wearsch (2015) Bacterial membrane vesicles mediate the release of Mycobacterium tuberculosis lipoglycans and lipoproteins from infected macrophages. J Immunol 195: 1044-1053. [crossref]
NG Heatley, HW Florey (1946) An antibiotic from Bacterium Br J Exp Pathol 27: 378-390.
E Cascales, SK Buchanan, D Duché, C Kleanthous, R Lloubès, et (2007) Colicin Biology. Microbiol Mol Biol Rev 71: 158-229. [crossref]
WA Cramer, JB Heymann, SL Schendel, BN Deriy, FS Cohen, et (1995) Structure- function of the channel-forming colicins. Annu Rev Biophys Biomol Struct 24: 611- 641. [crossref]
XQ Qiu, KS Jakes, PK Kienker, A Finkelstein, SL Slatin (1996) Major transmembrane movement associated with colicin Ia channel gating. JGen Physiol 107: 313-328. [crossref]
PK Kienker, XQ Qiu, SL Slatin, A Finkelstein, KS Jakes (1997) Transmembrane insertion of the colicin Ia hydrophobic hairpin. J Membr Biol 157: 27-37.
XQ Qiu, MA Riley, in The Bacteriocins: current knowledge and future prospects, R Dorit, SM Roy, MA Riley (Caister Academic Press, Norfolk, 2016), Chap. 4. Capturing the Power of Van der Waals Zone in the Creation of a Novel Family of Bacteriocin-based Antibiotics 65-80.
XQ Qiu, H Wang, XF Lu, J Zhang, SF Li, et (2003) An engineered multidomain bactericidal peptide as a model for targeted antibiotics against specific bacteria. Nat Biotechnol 21: 1480-1485. [crossref]
XQ Qiu, J Zhang, H Wang, GY Wu (2005) A novel engineered peptide, a narrow- spectrum antibiotic, is effective against vancomycin-resistant Enterococcus Antimicrob Agents Chemother 49: 184-1189. [crossref]
XQ Qiu, CY Tong, ZQ Zhong, WQ Wang, YW Zuo, et al. (2013) An engineered multidomain fungicidal peptide against plant fungal pathogens. Acta Physiologica Sinica 65: 417-432. [crossref]
XQ Qiu, H Wang, B Cai, LL Wang, ST Yue (2007) Small antibody mimetics comprising two complementarity -determining regions and a framework region for tumor targeting. Nat Biotechnol 25: 921-929.
J van den Elsen, L Vandeputte-Rutten, J Kroon, P Gros (1999) Bactericidal antibody recognition of meningococcal PorA by induced fit. Comparison of liganded and unliganded Fab structures. J Biol Chem 274: 1495-1501. [crossref]
GP Walsh, EV Tan, EC dela Cruz, RM Abalos, LG Villahermosa, et (1996) The Philippine cynomolgues monkey (Macaca fascicularis) provide a new non-human primate model of tuberculosis that resembles human disease. Nat Med 2: 430-436. [crossref]
D Kaushal, S Mehra, PJ Didier, AA Lackner (2012) The non-human primate model of J Med Primatol 41: 191-201. [crossref]
J Zhang, YQ Ye, Y Wang, PZ Mo, QY Xian Y, et (2011) M tuberculosis H37Rv infection of chinese Rhesus Macaques. J Neuroimmune Pharmacol 6: 362-370. [crossref]
Macaque H37Rv-infection studies were performed at Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago (2012-2016) and macaque MDR-TB-infection studies were performed at Institute of Experimental Animal Sciences, Peking Union Medical College (2014-2016) with paid service contracts.
DM Lewinsohn, IS Tydeman, M Frieder, JE Grotzke, RA Lines, et al. (2006) High resolution radiographic and fine immunologic definition of TB disease progression in the rhesus macaque. Microbes Infect 8: 2587-2598. [crossref]
T Zhang, SY Li, KN Williams, K Andries, EL Nuermberger (2011) Short-course chemotherapy with TMC207 and rifapentine in a murine model of latent tuberculosis Am J Respir Crit Care Med. 184: 732-737. [crossref]
JP Lanoix, F Betoudji, E Nuermberger (2014) Novel regimens identified in mice for treatment of latent tuberculosis infection in contacts of patients with multidrug- resistant tuberculosis. Antimicrob Agents Chemother 58: 2316-2321. [crossref]
MT Coleman, RY Chen, M Lee, PL Lin, LE Dodd, et al. (2014) PET/CT imagine reveals a therapeutic response to oxazolodinones in macaques and humans with Sci Transl Med 6: 265-274. [crossref]
PL Lin, T Coleman, JP Carney, BJ Lopresti, J Tomko, et al. (2013) Radiologic responses in cynomolgus macaques for assessing tuberculosis chemotherapy Antimicrob Agents Chemother 57: 4237-4244. [crossref]
J Trias, V Jarlier, R Benz (1992) Porins in the cell wall of Science 258: 1479-1481. [crossref]
M Faller, M Niederweis, GE Schulz (2004) The structure of a mycobacterial outer- membrane channel. Science 303: 1189-1192.
M Niederweis, O Danilchanka, J Huff, C Hoffmann, H Engelhardt (2010) Mycobacterial membranes: in search of proteins. Trends Microbiol 18: 109-116. [crossref]
M Pavlenok, M Niederweis (2016) Hetero-oligomeric MspA pores in mycobacterium FEMS Microbiol Lett 363: fnw046. [crossref]
SC Chow, H Wang, J Shao (2007) Sample Size Calculation in Clinical Research (Chapman & Hall/CRC, New York, 2, 2007) 5: 121-123.

Treatment of Genital Warts in Pregnant Women

Leave a reply

DOI: 10.31038/AWHC.2024752

Abstract

There are various treatments available for managing genital warts in pregnant women, but this does not mean that there is a definitive treatment protocol. We conducted a review to gain a better understanding of the available treatments for genital warts during pregnancy. We used Google Scholar, PubMed, and Web of Science databases to search for articles on this topic. To date, the most effective treatment is still unknown. Many indicators, including patient satisfaction and physiological conditions, are effective in determining treatment. Cryotherapy, laser therapy, and Trichloracetic acid 80–90% solution are among the safe treatments with the least side effects. Given that the likelihood of genital warts recurring increases due to changes in the body’s immune system during pregnancy especially in younger pregnant women, more research is needed on this subject. We used the keywords pregnancy, genital warts, HPV, cryotherapy, laser therapy, electrocautery, surgery, topical treatments, and safe treatments in pregnancy in the article search process.

Keywords

Pregnancy, genital warts, HPV, Cryotherapy, Laser therapy, Topical treatments, Common and safe treatments

Introduction

Human papillomavirus (HPV) poses a significant public health challenge, particularly due to its role in various anogenital conditions, including condyloma acuminata. This virus consists of over 100 different types, which are categorized into low-risk and high-risk groups based on their potential to cause cancer. Low-risk types, especially HPV 6 and 11, are primarily responsible for benign lesions such as genital warts, while high-risk types, including HPV 16 and 18, are associated with cervical cancer and other anogenital malignancie.

The global prevalence of HPV infection is estimated to be between 9% and 13%, with a notably higher incidence observed among sexually active individuals aged 20 to 39 years. Genital warts, largely caused by HPV, are a considerable public health issue due to their widespread occurrence and related complications. The often asymptomatic nature of HPV infections can lead to underdiagnosis, particularly among partners of infected individuals. Research assessing the prevalence of HPV in spouses of men with genital warts revealed that many of these women were infected despite appearing healthy during clinical evaluations, highlighting the inadequacies of conventional diagnostic techniques [1-3].

Pregnancy creates a distinct environment for HPV infections, as physiological changes and a mildly immunocompromised state can affect the virus’s behaviour. Evidence suggests that the rate of HPV infections increases during pregnancy, particularly in the third trimester [2,4]. Effective treatment options for genital warts are crucial, especially for vulnerable populations such as pregnant women. Among the most commonly employed treatments are cryotherapy and trichloroacetic acid (TCA), each having distinct efficacy and safety profiles. A randomized controlled trial comparing these two treatment modalities indicated that while TCA had a higher cure rate, both treatments were effective and well-tolerated by patients. This emphasizes the necessity for tailored treatment strategies that take into account patient preferences and the specific clinical situation, especially when managing genital warts related to HPV infection [5].

Managing genital warts in pregnant women presents several challenges due to the potential risks associated with various treatment options. Traditional approaches, such as surgical excision, may pose risks to both the mother and the fetus. As a result, less invasive alternatives like cryotherapy have become preferred first-line treatments because of their safety and effectiveness [2,6]. Additionally, the possibility of vertical transmission of HPV during childbirth raises concerns about neonatal health outcomes, including the risk of juvenile laryngeal papillomatosis [2]. Given the complexities involved in treating HPV-related genital warts during pregnancy, it is essential to investigate optimal management strategies for this demographic. This study aims to assess the efficacy and safety of various treatment modalities for genital warts associated with HPV in pregnant women, with a focus on minimizing risks to both maternal and neonatal health. Through this research, we aspire to improve clinical practices and contribute to the broader understanding of managing HPV-related conditions in pregnant patients.

Methods

A review of the keywords of scientific journal articles on the management of genital warts in pregnant women showed that the important issue in the management of this disease in pregnancy is the presence of the least side effects of the selected treatment on the mother and fetus, and common but teratogenic treatments are completely excluded from the treatment strategies. We tried to extracted and summarize the studies related to the title in order to provide useful information to the readers. In writing this review, the scientific databases PubMed, Scopus, Google Scholar and Web of Science were used.

HPV in Pregnancy

Human papillomavirus (HPV) infection is among the most prevalent sexually transmitted infections in both young individuals and adults. It often presents without symptoms, can remain dormant for months, and may not be detectable through routine clinical examinations. Despite its asymptomatic nature, HPV infection can progress to cancer, contributing significantly to morbidity and mortality worldwide [3]. Although HPV infections are generally transient and self-limiting, they can persist in immunocompromised individuals, and pregnancy is considered a state of immunosuppression Pregnant women are at a higher risk of HPV infection due to their altered immunological and endocrinological status [7]. In a review study with 13,640 pregnant women, the rate of HPV infection was higher than that of age-matched non-pregnant women, especially in those under 25 years of age. HPV-16 was the most common observed type [2]. This prevalence is two times higher in pregnant women compared to non-pregnant women. Furthermore, there is a potential risk of vertical transmission of HPV from the mother to the fetus during pregnancy or delivery. HPV cervical infections are also detected more frequently during pregnancy (15.53%) than in the non-pregnant population (12.6%). A systematics review that analyzed 14 articles involving a total of 7008 women demonstrated the significant association was identified between HPV infection and preterm delivery A comparative study showed a higher rate of HPV infection in women with abnormal course of the first trimester of pregnancy Compared to women with a normal pregnancy period. Intrauterine HPV infections are also possible, as HPV DNA has been detected in the placenta, amniotic fluid, and fetal membranes. Transmission to the fetus can occur through ascending infection from the vagina and cervix or via hematogenous spread. Studies further indicate that HPV can infect trophoblastic cells, potentially impacting the intrauterine environment and influencing pregnancy outcomes [7-9].

The Prevalence of HPV Infection in Pregnant Women

Pregnancy-related hormonal changes, including mild immunosuppression and elevated steroid levels, may further promote HPV replication. These physiological changes often lead to the proliferation of condyloma acuminata, resulting in larger lesions [10-12]. While some studies suggest pregnancy as a risk factor for HPV infection, findings remain inconsistent [2,13-15].

A meta-analysis by Liu et al reported a higher prevalence of HPV in pregnant women (16.82%) compared to non-pregnant women (12.2%) [2]. More recently, Ardekani and collogues, found that nearly one-third of pregnant women globally test positive for HPV based on cervico-vaginal samples. HPV infection during pregnancy has been associated with significant maternal and fetal morbidity and mortality [16,17]. Studies link HPV to placental abnormalities and adverse outcomes, including spontaneous abortion, preterm birth, premature rupture of membranes, intrauterine growth restriction, fetal death, and low birth weight [11,18]. Regarding HPV prevalence across pregnancy trimesters, results have varied. While Ardekani et al, reported the highest prevalence in the second trimester [16]. Liu et al, found the lowest prevalence during this period [2]. Ambühl et al, observed a declining trend from the first to the third trimester [14]. Globally, HPV types 16 and 18 are the most prevalent across all sampling sites [16]. Due to their oncogenic potential, these types are linked to pregnancy complications and future cancer risks, emphasizing the need for further research and preventive measures [19,20].

Treatment Strategy in Pregnant Women

Pregnancy creates a situation in which genital warts may recur and grow more rapidly in pregnant women than in non-pregnant women. Growth is most rapid between weeks 12 and 14 of pregnancy, and the lesions are larger in size. The severity of these processes is greater in new warts that develop during pregnancy. Changes such as decreased cellular immunity and increased blood vessel number, which consequently leads to increased blood flow in the genital area, increase human papillomavirus activity. Among the features of warts that develop during pregnancy, could mention their fragility of their structure, which leads to itching and bleeding [21,22]. Warts that become exceptionally large can cause labor dystonia or heavy bleeding by blocking the birth canal, and in such cases, a cesarean section is recommended for patients. There is a risk of human papillomavirus transmission from mother to fetus during childbirth. Infants infected with the virus may develop lesions on the conjunctiva, mouth, and/or genitals. [22-24]. Prenatal transmission of HPV types 6 and 11 from mother to fetus can rarely cause juvenile laryngeal papillomatosis (JLP). These clinical observations make effective management of genital warts during pregnancy essential. Our goal in this review is to provide a summary of approved and unapproved treatments for genital warts during pregnancy.

Cryotherapy

Cryotherapy is a therapeutic process in which liquid nitrogen causes tissue freezing and ultimately necrosis. Cryotherapy is one of the main treatments for genital warts, which, in addition to causing tissue necrosis, can stimulate specific immune responses against the remaining lesion tissue, resulting in the immunomodulatory function of T lymphocytes [25,26]. One of the unique features of cryotherapy is that it is safe during pregnancy. In addition, it is a simple and inexpensive treatment that rarely causes scarring or pigmentation in patients’ skin [6]. The liquid nitrogen used in cryotherapy causes inflammation as it destroys the wart tissue, which subsides after a short period of time [27]. In cryotherapy, the base of the lesions and 1 to 2 millimeters of surrounding normal tissue are frozen. This treatment is continued every 2 weeks until the lesions are completely gone [27-29]. Although there have been reports of swelling, discharge, erythema, and pain in patients, all patients were able to complete the treatment. In the study by Bergman et al., cryotherapy resulted in two preterm deliveries in 28 pregnant women (7.1%) [30,31] and in the study by Matsunaga et al., in 51 pregnant women, it resulted in five preterm deliveries (9.8%). Cryotherapy is a suitable treatment modality in non-pregnant patients, and results in satisfactory results, but it should be used with caution in pregnant women. Despite the weak evidence of the side effects mentioned, cryotherapy is considered a safe treatment for genital warts during pregnancy [28,32].

Laser Therapy

The advantages of using laser therapy include high precision of operation, reduced bleeding through vessel sealing and reduced scar surface. In addition, this treatment method has the ability to cause necrosis in a specific area. This ability leads to reduced inflammation, edema and infection . In a study conducted by Kryger and Baggesen, 15 pregnant women underwent laser therapy for genital warts. Except for one pregnant woman who experienced “symptoms of preterm labor for a few days,” the rest responded to the treatment without any side effects [33,34]. The use of CO2 lasers and Nd-YAG lasers is known as effective treatment methods for removing genital warts. This treatment method reduces the risk of recurrence and complications during childbirth and prevents infection of the fetus [30,35,36]. Overall, various studies showed that the use of lasers for the removal of vascular lesions of the skin, pigmented lesions and treatment of genital warts is a safe and effective method [37].

Electrocautery and Surgery

Surgery is a mechanical procedure using a scalpel or scissors that allows for direct removal of the genital wart. The use of electrical energy during surgery is called electrosurgery, which is a more advanced method of lesion removal [28]. In a study conducted by Duus et al., it was shown that the clearance, recurrence, and postoperative side effects including pain, healing time, and scar formation of surgical treatments were similar to laser therapy [38]. One advantage of these methods is the possibility of removing all lesions in one session and creating the opportunity for pathological evaluation [30]. In addition, they are considered a suitable treatment option during pregnancy [39].

Photodynamic Therapy

Photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) method clears a very large volume of lesions and is well tolerated by the patient. This method is a unique treatment in pregnant women with genital warts with minimal adverse effects on the mother and fetus [40]. Other studies have shown that photodynamic therapy, in addition to helping to better clear the lesion, reduces the recurrence rate more than other treatment methods. However, further studies are recommended to ensure fewer side effects and the safety of this treatment in pregnant women [30].

5-Fluorouracil

In addition to inhibiting DNA synthesis, 5-fluorouracil can block thymidylate synthase, thereby inducing apoptosis [41]. It is available commercially as a 5% cream. Pain, burning, inflammation, and ulceration are known side effects of 5-fluorouracil therapy [42]. Studies have shown that 5-fluorouracil therapy should not be used during pregnancy [30,41].

Interferon

Interferon heals virus-infected cells by strengthening the immune system. Interferon can reduce the risk of relapse by treating virus-infected cells. In addition, it is also used to treat lesions that are visible to the naked eye [43,44]. Interferon is contraindicated during pregnancy [30]. Because interferon therapy is expensive, and because it is controversial in the treatment of genital warts, it is preferred for treatment-resistant cases [45]. In refractory non-pregnant patients, interferon may be used as an adjunct to other treatment strategies, such as surgical and ablative therapies. Overall, the evaluations suggest that interferon is contraindicated in pregnancy [41].

Podophyllotoxin

Topical podophyllotoxin, which is prescribed as one of the first-line medications for the treatment of genital warts, is contraindicated during pregnancy, All medications that use this compound in their structure are contraindicated during pregnancy due to its antimitotic properties, which are considered a toxic compound for the fetus [46-48]. No teratogenic effects have been observed following topical administration in animal studies, but the use of this drug during pregnancy is limited due to the limitations in extrapolating animal data to humans. The lack of teratogenic effects has also been demonstrated at doses up to 5 times the maximum recommended human dose [49-51]. Studies have shown that doses much higher than the maximum recommended human dose, approximately 19 times, administered intraperitoneally to pregnant rats resulted in fetal toxicity. However, topical application of podophyllotoxin has shown negligible systemic absorption. Avoiding topical treatments for genital warts with Topical podophyllotoxin is recommended during pregnancy [52-54].

Sinecathecins

Treatment of genital warts with syncatechin resulted in the occurrence of the side effects of urethral stricture, urinary tract irritation, genital herpes simplex, vulvitis, hypersensitivity, skin pruritus, pyelonephritis, application site reactions, phimosis, and inguinal lymphadenitis in 5% of patients, which led to discontinuation of further treatment. Sinecatechins is FDA Pregnancy Category C According to the FDA, Sinecatechins is a Category C drug and is contraindicated during pregnancy [55].

Retinoids

Retinoids are contraindicated in pregnant women and women attempting to conceive because of their teratogenic effects. Retinoid therapy during pregnancy has been associated with skeletal abnormalities that result from long-term chronic toxicity. In most cases, these symptoms correspond to the symptoms of diffuse idiopathic hyperostosis syndrome [56].

Imiquimod 5% Cream

Imiquimod was first approved by the U.S. Food and Drug Administration (FDA) in 1997 as a treatment option for genital warts. Randomized, double-blind, placebo-controlled trials have confirmed the effectiveness of imiquimod. It is a member of a class of immune response modifiers that is well tolerated. The U.S. Food and Drug Administration does not recommend the use of imiquimod during pregnancy and has classified it as a category B drug. It should only be used as a last resort when the benefits outweigh the risks [57-59].

Trichloracetic acid 80–90% Solution

The therapeutic effect of trichloroacetic acid on genital warts is by chemical coagulation of the proteins of the wart cells, which leads to corrosion of the skin and mucous membranes. These processes ultimately lead to tissue necrosis. Because trichloroacetic acid is not absorbed through the skin and mucous membranes, it is considered a safe treatment for pregnant women. However, the effectiveness of this compound in different populations requires further study [27,30]. Studies have shown the positive effect of administering trichloroacetic acid in combination with laser therapy in pregnant women. In another study, treatment with trichloroacetic acid resulted in complete clearance of the wart lesions in 97% of women, but premature rupture of membranes in one patient at 35 weeks of gestation and acute pyelonephritis in another pregnant patient were side effects of this type of treatment. However, it is not definitively determined whether these adverse effects were side effects of the drug [60]. Despite the widespread use of trichloroacetic acid in clinical practice, this drug should be prescribed with caution [47].

Topical and Intralesional Immunotherapy

The use of immunotherapy in the treatment of genital warts has been associated with good efficacy. The advantages of this method include high safety, low recurrence rate, and clearance of untreated long-term warts. Bayoumy et al., showed showed that the use of immunotherapy in 40 pregnant women resulted in improvement in 85% of patients. Among them, 47.5% showed complete clearance with minimal side effects. This treatment leads to increased serum interleukin-12 (IL-12) and the production of Th1 cytokines such as interleukin-4 (IL-4), interleukin-5 (IL-5), IL-8 through recruitment of antigen-presenting cells. It also helps to clear warts through a general response that includes the secretion of interferon (IFN)-gamma and TNF-alpha. This treatment method is considered safe for use in children and pregnant women [61-63].

Conclusion

Given that genital warts are among one of the common sexually transmitted diseases, and that pregnant mothers are at risk of contracting this disease, it seems appropriate to pay attention to these patients and choose the appropriate treatment for them. During pregnancy, the exacerbation of genital warts and the risk of transmitting the disease to the fetus must be considered. Another important point to keep in mind is the limitations of available treatments that can be chosen for mothers during pregnancy. Cryotherapy, TCA application, Topical and intralesional immunotherapy, as well as laser and surgical treatments, are among the treatments that can be usable and safe in during pregnancy.

References

Chang, K.C, Yen-Chang MD; Ding Dah-Ching MD (2022) Condyloma acuminatum mimicking cervical cancer in a pregnant woman and treatment with cryotherapy: A case report. Medicine. 101(49). [crossref]
Liu P, et al. (2014) The prevalence and risk of human papillomavirus infection in pregnant women. Epidemiology & Infection. 142(8). [crossref]
Maleki M, et al. (2020) Prevalence of HPV Infection in Spouses of Men with Genital Warts. Archives of Pharmacy Practice. 11(1-2020)
Robert F. Rando P, Steven Lindheim, MD, Lisa Hasty, MD, Thomas V. Sedlacek, MD, Mark Woodland, MD, Catherine Eder, BA (1989) Increased frequency of detection of human papillomavirus deoxyribonucleic acid in exfoliated cervical cells during pregnancy. American Journal of Obstetrics and Gynecology. 161(1). [crossref]
Pegah Lotfabadi M, Farzaneh Maleki, MD, Ali Gholami, MSc, Mohammad Javad Yazdanpanah, MD (2015) Liquid nitrogen cryotherapy versus 70% trichloroacetic acid in the treatment of anogenital warts: A randomized controlled trial. Iranian Journal of Dermatology. 18(4).
Yang, L.J, et al. (2016) Treatment of condyloma acuminata in pregnant women with cryotherapy combined with proanthocyanidins: Outcome and safety. Experimental and Therapeutic Medicine. 11(6). [crossref]
Popescu, S.D, et al. (2022) Maternal HPV infection and the estimated risks for adverse pregnancy outcomes—a systematic review. Diagnostics 12(6). [crossref]
Kovács D, et al. (2024) Association between human papillomavirus and preterm delivery: A systematic review and meta‐analysis. Acta obstetricia et gynecologica Scandinavica. 103(10). [crossref]
Bober L, et al. (2019) Influence of human Papilloma Virus (hPV) infection on early pregnancy. Ginekologia polska. 90(2). [crossref]
Robinson, D.P, S.L. Klein (2012) Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Hormones and Behavior. 62(3). [crossref]
Schumacher A, S.-D. Costa, A.C. Zenclussen (2014) Endocrine factors modulating immune responses in pregnancy. Frontiers in Immunology. 5: 196. [crossref]
Suzuki S, et al. (2016) Current status of condylomata acuminata in pregnant Japanese women. Japanese Journal of Infectious Diseases. 69(4). [crossref]
Schmeink, C.E, et al. (2012) Human papillomavirus detection in pregnant women: a prospective matched cohort study. Journal of women’s health.21(12). [crossref]
Ambühl, L.M.M, et al. (2016) Human papillomavirus infection as a possible cause of spontaneous abortion and spontaneous preterm delivery. Infectious diseases in obstetrics and gynecology. 2016(1). [crossref]
Mittal R, A. Pater, M.M. Pater (1993) Multiple human papillomavirus type 16 glucocorticoid response elements functional for transformation, transient expression, and DNA-protein interactions. Journal of virology.67(9). [crossref]
Ardekani A, et al. (2023) Worldwide prevalence of human papillomavirus among pregnant women: A systematic review and meta‐analysis. Reviews in medical virology. 33(1). [crossref]
Wiik J, et al. (2021) Associations of treated and untreated human papillomavirus infection with preterm delivery and neonatal mortality: A Swedish population-based study. PLoS medicine. 18(5). [crossref]
Niyibizi J, et al. (2020) Association between maternal human papillomavirus infection and adverse pregnancy outcomes: systematic review and meta-analysis. The Journal of infectious diseases. 221(12). [crossref]
Faridi R, et al. (2011) Oncogenic potential of Human Papillomavirus (HPV) and its relation with cervical cancer. Virology Journal. 8: 1-8. [crossref]
Boon, S.S, et al. (2019) Human papillomavirus type 18 oncoproteins exert their oncogenicity in esophageal and tongue squamous cell carcinoma cell lines distinctly. BMC cancer. 19: 1-12. [crossref]
Osborne, N.G, M.D. Adelson (1990) Herpes simplex and human papillomavirus genital infections: controversy over obstetric management. Clinical obstetrics and gynecology. 33(4). [crossref]
Workowski, K.A, et al. (2000) Sexually transmitted diseases treatment guidelines, 2015.
Mant C, et al. (2000) Non-sexual transmission of cervical cancer-associated papillomaviruses: an update. Papillomavirus Report. 11(1). [crossref]
Ferenczy A, (1989) HPV-associated lesions in pregnancy and their clinical implications. Clinical obstetrics and gynecology. 32(1). [crossref]
Gilson R, et al. (2009) A multicentre, randomised, double-blind, placebo controlled study of cryotherapy versus cryotherapy and podophyllotoxin cream as treatment for external anogenital warts. Sexually transmitted infections. 85(7). [crossref]
Mi X, et al. (2011) A randomized clinical comparative study of cryotherapy plus photodynamic therapy vs. cryotherapy in the treatment of multiple condylomata acuminata. Photodermatology, Photoimmunology & Photomedicine. 27(4). [crossref]
Wiley D, et al. (2002) External genital warts: diagnosis, treatment, and prevention. Clinical Infectious Diseases. 35(Supplement_2). [crossref]
J, A. Bergman, N.N. Bhatia, (1987) Genital condylomata acuminata in pregnancy: effectiveness, safety and pregnancy outcome following cryotherapy. BJOG: An International Journal of Obstetrics & Gynaecology. 94(2). [crossref]
Bergman A, N. Bhatia, E. Broen (1984) Cryotherapy for treatment of genital condylomata during pregnancy. The Journal of Reproductive Medicine. 29(7). [crossref]
Sugai S, K. Nishijima, T. Enomoto, (2021) Management of condyloma acuminata in pregnancy: a review. Sexually transmitted diseases. 48(6). [crossref]
Bergman A,J. Matsunaga, N.N. Bhatia (1987) Cervical cryotherapy for condylomata acuminata during pregnancy. Obstetrics & Gynecology. 69(1). [crossref]
Javame Ghazvini F, et al. (2024) Comparison of topical potassium hydroxide 5% solution with cryotherapy in the treatment of patients with genital warts: A randomized controlled clinical trial. International Journal of STD & AIDS. p. 09564624241300776. [crossref]
Hankins, G.D, et al. (1989) Use of laser vaporization for management of extensive genital tract condyloma acuminata during pregnancy. Journal of Infectious Diseases. 159(5). [crossref]
Kryger-Baggesen N, J.F. Larsen, P.H. Pedersen, (1984) CO2-laser treatment of condylomata acuminata. Acta obstetricia et gynecologica Scandinavica. 63(4). [crossref]
ADELSON, M.D, et al. (1990) Laser vaporization of genital condylomata in pregnancy. Journal of gynecologic surgery. 6(4). [crossref]
Ferenczy A, (1984) Treating genital condyloma during pregnancy with the carbon dioxide laser. American journal of obstetrics and gynecology. 148(1). [crossref]
Allameh F, et al. (2021) A systematic review of elective laser therapy during pregnancy. Journal of Lasers in Medical Sciences. 12. [crossref]
Duus B, et al. (1985) Refractory condylomata acuminata: a controlled clinical trial of carbon dioxide laser versus conventional surgical treatment. Genitourin Med. 61(1). [crossref]
Kodner, C.M, S. Nasraty (2004) Management of genital warts. American family physician. 70(12): 2335-2342.
Yang, Y.G, et al. Photodynamic therapy of condyloma acuminata in pregnant women. Chinese medical journal. 125(16). [crossref]
Kilic A, U.M. Ural, (2019) Anogenital warts: an update on human papilloma virus, clinical manifestations and treatment strategies. Mucosa. 2(2): 30-40.
Atista, C.S, et al. (2010) 5‐FU for genital warts in non‐immunocompromised individuals. Cochrane Database of Systematic Reviews, 2010(4). [crossref]
Westfechtel L, et al. (2018) Adjuvant treatment of anogenital warts with systemic interferon: a systematic review and meta-analysis. Sexually Transmitted Infections. 94(1). [crossref]
Yang J, et al. (2009) Interferon for the treatment of genital warts: a systematic review. BMC Infectious Diseases.9: 156. [crossref]
Özkaya, D.B, G. Erfan, B. Çıtamak (2023) The Effectiveness of Genital Wart Treatments.
Lacey C, et al. ( 2013) European guideline for the management of anogenital wart Journal of the European Academy of Dermatology and Venereology.27(3). [crossref]
Workowski, K.A, S.M. Berman, (2011) Centers for Disease Control and Prevention sexually transmitted disease treatment guidelines. Clinical infectious diseases. 53(suppl_3): S59-S63.
Patel V, R. Schwartz, W. Lambert (2017) Topical antiviral and antifungal medications in pregnancy: a review of safety profiles. Journal of the European Academy of Dermatology and Venereology.31(9). [crossref]
Briggs, G.G, R.K. Freeman, S.J. Yaffe (2011) Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk.Lippincott Williams & Wilkins.
Didcock K, C. Picard, J. Robson (1952) The action of podophyllotoxin on pregnancy. The Journal of physiology. 117(4)
Bargman, H (1988) Is podophyllin a safe drug to use and can it be used during pregnancy? Archives of Dermatology. 124(11): 1718-1720. [crossref]
Thiersch, J (1963) Effect of podophyllin (P) and podophyllotoxine (PT) on the rat litter in utero. Proceedings of the Society for Experimental Biology and Medicine, 113(1): 124-127.
Von Krogh G, E. Longstaff (2001) Podophyllin office therapy against condyloma should be abandoned. Sexually transmitted infections. 77(6). [crossref]
G, (1982) Podophyllotoxin in serum: Absorption subsequent to three-day repeated applications of a 0.5% ethanolic preparation on condylomata acuminata. Sexually Transmitted Diseases. 9(1). [crossref]
Masters, K.P, (2009) Sinecatechins (Veregen) for external genital and perianal warts. American Family Physician. 80(12): 1447-1454.
Zasada M, E. Budzisz (2019) Retinoids: active molecules influencing skin structure formation in cosmetic and dermatological treatments. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii. 36(4). [crossref]
Edwards L, et al. (1998) Self-administered topical 5% imiquimod cream for external anogenital warts. Archives of dermatology. 134(1). [crossref]
O’mahony C, et al. (2001) New patient-applied therapy for anogenital warts is rated favourably by patients. International journal of STD & AIDS. 12(9). [crossref]
Ciavattini A, et al. (2012) Topical Imiquimod 5% cream therapy for external anogenital warts in pregnant women: Report of four cases and review of the literature. The Journal of Maternal-Fetal & Neonatal Medicine.25(7). [crossref]
chwartz, D.B, et al. (1988) Genital condylomas in pregnancy: use of trichloroacetic acid and laser therapy. American journal of obstetrics and gynecology. 158(6). [crossref]
Othman, N.E, F.A. Safan (2023) Immunotherapy for the treatment of female anogenital wart with purified protein derivative and measles mumps rubella vaccine: a comparative clinical and immunological study. Journal of Pharmaceutical Negative Results, 2023: 640-649.
Eassa, B.I, A.A. Abou‐Bakr, M.A. El‐Khalawany, (2011) Intradermal injection of PPD as a novel approach of immunotherapy in anogenital warts in pregnant women. Dermatologic therapy. 24(1). [crossref]
Jain S, Y.S. Marfatia (2021) A comparative study of intralesional vitamin D3, measles mumps rubella vaccine, and tuberculin purified protein derivative in the treatment of recalcitrant warts: an approach to solve a therapeutic conundrum. The Journal of Clinical and Aesthetic Dermatology. 14(11). [crossref]

Determination of Awareness and Knowledge Levels of Men Between the Ages of 18-45 About HPV and HPV Vaccine

Leave a reply

DOI: 10.31038/AWHC.2024751

Abstract

This study was designed to determine the awareness and knowledge levels of male patients about HPV and the HPV vaccine. This study was planned as a single-center, descriptive and cross-sectional study. This cross-sectional study included 255 patients who presented to the Family Medicine Polyclinic at Tekirdağ Namık Kemal University Hospital. Data were collected between 01.07.2023 and 01.12.2023 with a face-to-face survey form. The content of the survey form included questions about the participants, a survey assessing awareness and knowledge regarding HPV and the HPV vaccine, which we prepared by scanning the literature and whose content validity index was 0.98. The data obtained were evaluated in the 152 (59.6%) of the men stated that they did not have information about HPV, 250 (98.0%) stated that they had not received the HPV vaccine, 102 (40.0%) stated that they did not consider getting the HPV vaccine, and 144 (56,5%) stated they thought it was difficult to access the HPV vaccine. The median (min-max) score of the men in the study group from the survey was 24.0 (6.0-32.0) and the mean (SD) was 23.20. The findings of this study showed that more than half of the men had not heard of the HPV vaccine, almost all of the men had not received the HPV vaccine, and the majority thought it was difficult to access the vaccine. However, men’s general HPV knowledge was average and their knowledge of the current HPV vaccination program was low. In addition, men’s awareness and knowledge survey scores about HPV and the HPV vaccine were at an average level, and HPV knowledge affected men’s attitudes and behaviors. It may be recommended to take initiatives to increase men’s knowledge about general HPV and the HPV vaccine.

Keywords

Man, HPV, HPV vaccine, Knowledge level, Awareness

Introduction

Human Papilloma Virus (HPV) is a DNA virus belonging to the Papillomavirinae family. HPV infects the basal epithelial layer cells of human skin and mucosal surfaces. This virus is a non-enveloped, double-stranded circular DNA virus. The genome of HPV is approximately 8 kilobase pairs long. The replication cycle of HPV is a very slow process. There can be a long period between the onset of HPV infection and the appearance of symptoms, and this period can vary from person to person. It can take weeks or even months from the moment the infection begins to appear for symptoms to appear. HPV can be transmitted directly from cracks in the skin and mucosa, as well as during sexual intercourse. In addition, HPV can be transmitted indirectly from contaminated surfaces (fomites) of shared bathroom floors, towels, clothing or personal belongings, and from the mother to the newborn during birth through the infected birth canal [1-3]. HPV is a common sexually transmitted infection worldwide. There are many different types of HPV, and most types of the virus do not cause any symptoms or health problems in the infected person; however, a small percentage of infections caused by certain types of HPV can persist and cause clinically significant disease. HPV types are classified according to their epidemiological association with cancer. Low-risk HPV types can also cause genital warts and a rare condition called recurrent respiratory papillomatosis. High-risk HPV types are associated with a variety of cancers, including cervical, anal, penile, vaginal, vulvar, and head and neck. Different vaccines have been developed for HPV vaccination, and there are currently three vaccines: bivalent (HPV types 16 and 18), quadrivalent (HPV types 6, 11, 16, and 18), and nonavalent (HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58). Each HPV vaccine has been shown to be safe and effective against the HPV strains involved [3-6]. HPV vaccines are used as part of national vaccination programs in the United States, Australia, and many European countries. The fact that HPV vaccines are not included in national vaccination programs and are not covered by health insurance affects access to the vaccine and vaccination rates. Parental knowledge, mentality, and income levels affect whether HPV vaccines are widely used. Increasing resistance to vaccination can make it difficult for vaccines to be accepted and implemented in society [5-7]. HPV research generally focuses on understanding the development of cervical cancer and precancerous lesions, as well as how to prevent and control these conditions. This research focuses particularly on women’s health and the prevention of cervical cancer. The administration of HPV vaccines to women has been seen as an effective strategy for preventing cervical cancer. Recent studies have shown that HPV-related cancers pose a significant burden not only to women but also to men. In addition to HPV being linked to cervical cancer in women, HPV infections in areas such as the anus, oral cavity, and oropharynx pose a serious cancer risk in men [8-10]. HPV infections have now become preventable thanks to HPV vaccines. Countries can increase cancer prevention by expanding such vaccines through vaccination programs [1-4]. The aim of this study was to assess the knowledge and behaviors of men aged 18-45 about HPV and the HPV vaccine.

Material and Methods

This study is a cross-sectional descriptive survey. In order to evaluate the level of knowledge and behavior about HPV and HPV vaccine among male patients aged 18-45 who applied to Tekirdağ Namık Kemal University Hospital Family Medicine Outpatient Clinic between July 1, 2023 and December 1, 2023, the Adult Vaccination Knowledge Level Survey consisting of 16 questions was applied on a voluntary basis. Data from a total of 255 participants were analyzed. Before starting the study, approval was obtained from the Namık Kemal University Faculty of Medicine Ethics Committee (protocol no: 223.129.06.15).

Criteria for Including Participants in the Study

Being between the ages of 18-45
Having applied to Tekirdağ Namık Kemal University Hospital Family Medicine Polyclinic center
Being male
Having mental competence
Being a volunteer

Criteria for Exclusion of Volunteers from the Study

Being under the age of 18 and over the age of 45,
Not having mental competence
Being a woman

A questionnaire form prepared by the researcher based on literature review at the time of application, which questioned the sociodemographic data of the patients, their knowledge level and behaviors about HPV and HPV vaccine, was filled out by the volunteers.

Validity and Reliability of the Awareness and Knowledge Questionnaire on HPV and HPV Vaccine

A total of 16 items were created to measure awareness and knowledge levels on HPV and HPV vaccine in line with the literature. The suitability and comprehensibility of each scale item was assessed by 10 experts (1 internal medicine, 4 family physicians, 1 emergency, 1 public health, 1 infection, 1 dermatology and 1 gynecology and obstetrics). The experts were asked to evaluate the items in three groups as “important”, “useful but insufficient”, and “unnecessary”. The scope validity rates of the scale ranged from 0.8 to 1.0 and the scope validity index was 0.98.

The Adult Vaccination Knowledge Level Questionnaire, which was created to assess the knowledge level, consists of 16 questions. Factor analysis was used for structural validity. It was performed using Principal Component Analysis (PCA) with Varimax rotation. PCA generally tests the psychometric qualities of structured questionnaires and is a frequently used multivariate statistical technique and is used to determine the structure . The reliability levels expressed by the Cronbach alpha coefficient range were taken into account in the study. For the reliability analyses of the scale, it was calculated again according to the Cronbach alpha coefficient and item total correlation. In the factor analysis, Kaiser-Meyer-Olkin: 0.875, Barlett’s test result was p<0.001. Factor loadings below 0.30 varied between 0.302-0.812, and it was determined that the items collected in a single sub-domain explained 31.63% of the total variance. Cronbach alpha value was determined as 0.814. The item total correlation values for the items in the questionnaire varied between 0.201-0.714. For confirmatory factor analysis, goodness of fit statistic (GFI), adjusted goodness of fit statistic (AGFI), CFI (Comparative fit index), Normed fit index (NFI), Incremental Fit Index (IFI), Relative Fit Index (RFI), Parsimony Fit Index (PNFI), Root Mean Square Error of Approximation (RMSEA) and Standardized Root Mean Square Residual (SRMR) indices were calculated. For the acceptability levels of fit indices, CFI, NFI, IFI and AGFI ≥0.90, RMSEA <0.08 and SRMR ≤0.10 were taken as criteria. As a result of confirmatory factor analysis, no incompatible values were detected for each item for CFI (0.89), NFI (0.81), IFI (0.89), RFI (0.76) and SRMR (0.06). The values were in appropriate ranges. When the fit indices of the model obtained with CFA were examined, it was seen that the X2/df (2.08) value was less than 3, but the CFI (0.89), RFI (0.76), GFI (0.90), AGFI (0.87) and SRMR (0.06) values were at an acceptable level. As a result of the confirmatory factor analysis, these fit indices showed that the model had a good fit [11-14].

The correct answer given to the awareness and knowledge survey items regarding HPV and HPV vaccine was calculated as “2”, the “I don’t know” answer as “1” and the wrong answer as “0”. It was accepted that the awareness and knowledge level increased as the score obtained from the survey increased.

Statistical Analysis

The obtained data were evaluated in the Statistical Package for Social Sciences (SPSS) 25.0 statistical package program. Descriptive statistics were given as mean, standard deviation, median for numerical variables, and number and percentage for categorical variables. In the evaluation of validity and reliability, Exploratory Factor Analysis was applied and factor loadings, item total correlation values, and Cronbach alpha values were calculated for the items. Confirmatory factor analysis was performed using the R studio package program. The conformity of the data to normal distribution was assessed using the Kolmogorov-Smirnov test. Differences between two groups in terms of continuous variables that were not normally distributed were analyzed using the Mann Whitney U test, and differences between multiple groups were analyzed using the Kruskal Wallis test. The results were evaluated at a 95% confidence interval and p<0.05 values were considered significant.

Results

The mean age of the participants was 29.04 ± 6.62 years. 156 (61.2%) of the participants were in the 21-30 age group and 174 (68.2%) were university graduates. 148 (58.0%) of the participants were single, 158 (62.0%) were employed, 73 (28.6) were healthcare workers, and 181 (71.0%) lived in the city center or a metropolitan city. 225 (88.2%) of the participants had no chronic disease and (98.8%) stated that they were heterosexual (Table 1). Of the men, 152 (59.6%) reported that they had not received any information about HPV, 250 (98.0%) had not received the HPV vaccine, 102 (40.0%) did not consider receiving the HPV vaccine, and 144 (56.5%) thought that it was difficult to obtain the HPV vaccine.

Table 1: Distribution of participants according to sociodemographic characteristics and some variables related to HPV.

	n	%
n	255	100
Age group (year)
18-20	11	4.3
21-25	82	32.2
25-30	74	29
31-35	51	20
36-40	16	6.3
41-45	21	8.2
Marital status
Single	148	58
Married	102	40
Widow	5	2
Eğitim düzeyi
Primary – secondary school	13	5.1
High school	23	9
College	174	68.2
Masters	45	17.7
Occupation
Working	158	62
Not working	21	8.2
Student	76	29.8
Health worker	73	28.6
Place where lived during most of life
City center	181	71
District	58	22.7
Village	16	6.3
Income level
Income is less than expenses	84	32.9
Income is equal to expenses	102	40
Income is more than expenses	69	27.1
Has children	78	30.6
Smoking	96	37.6
Comorbidity	30	11.8
Sexual orientation
Heterosexual	252	98.8
Homosexual	3	1.2
Given information about HPV vaccine	103	40.4
HPV vaccination status
Not vaccined	250	98
Gardasil 4/2 dose	3	1.2
Gardasil 9/2 dose	2	0.8
Considering to be vaccined for HPV
Yes	55	21.6
No	102	40
Undecided	98	38.4
Considers hard to reach HPV vaccine	111	43.5

184 (72.2%) of the men in the study group thought that HPV was a very common disease in humans. The item with the highest number of correct answers among men (82.7%) was “Having more than one sexual partner increases the risk of HPV transmission.”, while the item with the lowest number of correct answers (8.6%) was “How many types of HPV vaccines are there?” (Table 2).

Table 2: Distribution of responses to the participants’ awareness and knowledge survey regarding HPV and HPV vaccine.

	n	%
1. HPV is a virus that is quite common in humans.
Yes (C)	184	72.2
No	71	27.8
2. How many types of HPV are there?
2	2	0.7
4	10	3.9
9	17	6.7
More than 200 (C)	93	36.5
I don’t know	133	52.2
3. HPV can often be found in a person without any symptoms or signs.
Yes (C)	153	60
No	19	7.5
I don’t know	83	32.5
4. HPV does not cause disease anywhere on the body except the genital areas.
Yes	21	8.2
No (C)	145	56.9
I don’t know	89	34.9
5. HPV only causes disease in women.
Yes	5	2
No (C)	178	69.8
I don’t know	72	28.2
6. HPV can cause mouth, pharynx, anus and penis cancer and genital warts in men.
Yes (C)	172	67.5
No	5	2
I don’t know	78	30.5
7. HPV is transmitted only through genital contact.
Yes	59	23.1
No (C)	119	46.7
I don’t know	77	30.2
8. Using a condom reduces the risk of HPV infection.
Yes (C)	193	75.7
No	13	5.1
I don’t know	49	19.2
9. Having more than one sexual partner increases the risk of contracting HPV.
Yes (C)	211	82.7
No	3	1.2
I don’t know	41	16.1
10. Are there any medications that can be used against HPV?
Yes (C)	125	49
No	36	14.1
I don’t know	94	36.9
11. How many types of HPV vaccines are there?
1	8	3.1
2	48	18.8
3 (C)	22	8.6
4	18	7.1
I don’t know	159	62.4
12. What is the best age for the first HPV vaccine?
9 (C)	83	32.5
11	22	8.7
13	28	11
18	114	44.7
45	8	3.1
13. How many doses of HPV vaccine given after the age of 18 provide immunity?
1	9	3.5
2	35	13.8
3 (C)	51	20
I don’t know	160	62.7
14. HPV vaccine has side effects that can cause health problems.
Yes	48	18.8
No (C)	61	23.9
I don’t know	146	57.3
15. HPV vaccine is only administered to women
Yes	10	3.9
No (C)	159	62.4
I don’t know	86	33.7
16. Do you think that HPV vaccination should be given to men?
Yes (C)	201	78.8
No	54	21.2
17. HPV vaccine can be administered to men between the ages of 18-45
Yes (C)	146	57.2
No	15	5.9
I don’t know	94	36.9
18. HPV vaccination in men can contribute to the elimination of HPV (having no patients in the community).
Yes (C)	146	57.3
No	12	4.7
I don’t know	97	38

(C): Correct answer.

In the factor analysis for the awareness and knowledge survey about HPV and HPV vaccine, Kaiser-Meyer-Olkin: 0.875, Barlett’s test result was p<0.001. Two items in the survey (Item 13: 0.021 and Item 14: 0.038) were removed from the survey because their factor loadings were below 0.30. The factor loadings ranged between 0.302 and 0.812, and it was determined that the items collected in a single sub-domain explained 31.63% of the total variance. Cronbach’s alpha value was determined as 0.814. The item-total correlation values for the items in the survey ranged between 0.201 and 0.714 . In addition, according to the confirmatory factor analysis results of the awareness and knowledge scale regarding HPV and HPV vaccine, the x2/dF value was determined as 2.08, AGFI as 0.87, RMSEA as 0.07, SRMR as 0.06, and GFI as 0.90. The path diagram showing the model structure and standard regression coefficients is shown in Figure 1. The median (min-max) score of the men in the study group from the survey was 24.0 (6.0-32.0) and the mean (SD) was found to be 23.20. In the study group, those in the 26-30 age group were found to have higher knowledge and awareness scores than those in the 31-35 age group (p=0.032). Singles had higher scores than married individuals (p=0.014). In terms of educational status, those with primary school education had lower scores than those with university and master’s degrees, those with high school education had lower scores than those with university and master’s degrees, and those with university level education had lower scores than those with master’s degrees (p<0.001). Those who were health workers had higher scores than those who were not (p<0.001). Those whose income was equal to expenses had lower scores than those whose income was greater than expenses (p=0.012). Those who did not have children were found to have higher scores than those who did (p=0.002). Those who had information about HPV vaccination had higher scores than those who had not (p<0.001). Those who considered getting HPV vaccination were found to have higher levels of awareness and knowledge about HPV and HPV vaccination than those who did not consider it and were undecided (p<0.001). Those who thought it was difficult to access HPV vaccination were found to have higher scores than those who did not consider it (p<0.001) (Figure 1 and Tables 3-5).

Figure 1: Path diagram showing the model structure and standard regression coefficients.

Table 3: Factor loadings for the questionnaire, correlation between items and Cronbach alpha values when items are removed.

Items	Factor loading	Correlation between items	Cronbach alpha value when item is removed
Item 1	0.493	0.409	0.814
Item 2	0.504	0.420	0.811
Item 3	0.657	0.561	0.803
Item 4	0.615	0.523	0.805
Item 5	0.749	0.645	0.801
Item 6	0.812	0.714	0.797
Item 7	0.416	0.351	0.817
Item 8	0.483	0.361	0.815
Item 9	0.684	0.575	0.807
Item 10	0.302	0.201	0.827
Item 11	0.305	0.203	0.823
Item 12	0.373	0.316	0.823
Item 15	0.641	0.542	0.805
Item 16	0.594	0.500	0.806
Item 17	0.550	0.432	0.811
Item 18	0.473	0.476	0.808

Scale Cronbach alpha value: 0.821.

Table 4: Katılımcıların sosyodemografik özelliklerine göre anketten aldıkları puanın karşılaştırılması.

	Median (min-max)	p
Age group (year)		0.032*
18-20	26.0 (18.0-30.0)
21-25	25.0 (6.0-32.0)
26-30	26.0 (13.0-32.0)
31-35	21.0 (13.0-32.0)
36-40	23.5 (13.0-32.0)
41-45	20.0 (13.0-32.0)
Marital status		0.014*
Single	25.0 (6.0-32.0)
Married	22.0 (13.0-32.0)
Widow	20.0 (15.0-28.0)
Eğitim düzeyi		<0.001*
Primary – secondary school	16.0 (13.0-22.0)
High school	18.0 (13.0-32.0)
College	24.0 (6.0-32.0)
Masters	28.0 (13.0-32.0)
Occupation		0.075*
Working	23.0 (13.0-32.0)
Not working	22.0 (13.0-30.0)
Student	25.0 (6.0-31.0)
Health worker		<0.001**
No	22.0 (6.0-32.0)
Yes	27.0 (13.0-32.0)
Place where lived during most of life		0.407*
City center	24.0 (6.0-32.0)
District	23.0 (12.0-31.0)
Village	22.5 (13.0-30.0)
Income level		0.012*
Income is less than expenses	23.0 (6.0-32.0)
Income is equal to expenses	23.0 (12.0-32.0)
Income is more than expenses	26.0 (13.0-32.0)
Has children		0.002**
No	25.0 (6.0-32.0)
Yes	20.5 (13.0-32.0)
Smoking		0.149**
No	24.0 (6.0-32.0)
Yes	23.0 (13.0-32.0)
Comorbidity		0.837**
No	24.0 (6.0-32.0)
Present	22.5 (13.0-32.0)
Sexual orientation		0.699**
Heterosexual	24.0 (6.0-32.0)
Homosexual	19,0 (18,0-29,0)

*Kruskal-Wallis test, **Mann-Whitney U test

Table 5: Comparison of the participants’ scores on the survey according to factors that may be related to them.

	Median (min-max)	p
Given information about HPV vaccine		<0.001*
Yes	28.0 (6.0-32.0)
No	21.0 (12.0-32.0)
HPV vaccination status		0.320*
Yes	26.0 (6.0-32.0)
No	24.0 (12.0-32.0)
HPV vaccination status according to vaccine type		0.336**
Not vaccined	24.0 (12.0-32.0)
Gardasil 4/2 doz	25.0 (6.0-32.0)
Gardasil 9/2 doz	29.0 (26.0-32.0)
Considering to be vaccined for HPV		<0.001**
Yes	28.0 (15.0-32.0)
No	23.0 (6.0-32.0)
Undecided	23.0 (12.0-32.0)
Considers hard to reach HPV vaccine		<0.001*
Yes	27.0 (13.0-32.0)
No	22.0 (6.0-32.0)

Discussion

Among sexually transmitted diseases, HPV infection is considered the most common worldwide. Persistent HPV infection is associated with more than 5% of all cancers worldwide. One of the main problems with HPV as an oncovirus is the significant difference between the time of diagnosis and the early stages of chronic infection. Early detection of HPV infection and HPV-induced lesions is critical for cancer prevention [1,3,15]. Genital HPV infection is very common among males, with an estimated prevalence of 65.2% in asymptomatic males aged 18–70 [16]. In our survey, most participants correctly answered a similar question: “HPV is a highly prevalent virus in humans.” Regarding risks to daughters, single fathers were significantly more likely to believe that their daughters were at risk for both HPV and cervical cancer. Concerns specific to single fathers included explaining the sexual nature of HPV and taking their daughters to the gynecologist for vaccination. In this respect, the results obtained for single men in our study are similar [17].

In the awareness and knowledge scale regarding HPV and HPV vaccine in this study, it was determined that those with primary school education had lower scores than those with university and master’s degrees, those with high school education had lower scores than those with university and master’s degrees, and those with university education had lower scores than those with master’s degrees. It is known that risky sexual behaviors are directly related to low education levels. Insufficient education levels negatively affect the tendency to this problem. This situation makes it difficult to prevent and treat these diseases. Similar to our findings, a cross-sectional study of 22,974 men in Denmark found that higher education was strongly associated with having heard of HPV. One study reported that men with less than a high school education were approximately 40% more likely to develop HPV infection. A cohort study of men in the United States found that having a college degree or other higher education was significantly associated with a lower risk of new infection with any type of HPV. The effectiveness of medical education has been demonstrated in an experimental study that demonstrated a statistically significant difference between pretest and posttest scores after the implementation of the education. These results support our findings. This suggests that level of education is a factor associated with HPV infection and that educated individuals have easier access to information sources and can use information more effectively. Our study found that those who were healthcare workers had higher scores than those who were not. Aslan and Bakan found that in a descriptive study conducted among health education students, including men, students who had knowledge about sexually transmitted infections had significantly higher levels of HPV knowledge. Lack of knowledge is a significant barrier to the prevention, diagnosis, and treatment of HPV infections and related diseases. The reason for the high level of knowledge among those who were knowledgeable about HPV and HPV vaccines may be attributed to the education men received as students or employees in the health field. In our study, 98% of the participants reported that they had not received HPV vaccination. In a similar study, Loke et al. reported that the HPV vaccination rate among men in the United States and Canada was very low, with rates ranging from 1.1% to 31.7% . This systematic review and meta-analysis showed that compliance with HPV vaccination was low (11% in total) among young men of working age (18-30 years). In addition, in our study, those whose income was equal to their expenses had lower scores than those whose income was greater than their expenses (0: 0.012). When the HPV and HPV vaccine awareness and knowledge level score is low, the rate of HPV vaccination is also low. From this, it is inferred that the lower the socioeconomic level, the lower the rate of HPV vaccination. The results in another study were similar. In this study, the fact that the vaccine is not covered by many health insurance companies makes it difficult for men to access the vaccine [18-24].

In this study, those who considered getting HPV vaccine were found to have higher levels of awareness and knowledge about HPV and HPV vaccine compared to those who were not considering or were undecided (p<0.001). One study found that they were more willing to get vaccinated and had higher awareness about HPV infection and malignancy [25]. Another study found that students who were more willing to get vaccinated had higher HPV knowledge scores [26]. Our findings are supported by similar studies. This situation can be explained by the fact that knowledge about the risk of exposure to HPV, especially in men, increases vaccine acceptance. In fact, when the HPV and HPV vaccine awareness and knowledge score is low, the rate of HPV vaccine application may be low. When the HPV and HPV vaccine awareness and knowledge score is high, the rate of HPV vaccine application is also high [27]. Our results were comparable to a previous study that showed that knowledge and awareness about HPV and HPV vaccine predicted it. The median score (min-max) of the men in this study group from the survey was 24.0 (6.0-32.0) and the mean (SD) was determined as 23.20. In the study group, those in the 26-30 age group were found to have higher knowledge and awareness scores than those in the 31-35 age group. In addition, men who obtained information about the HPV vaccine had higher scores than those who did not. The reason for the high mean score may be that the study was conducted in a university hospital polyclinic and most of the participants who applied were students or workers in the health field. Contrary to our findings, a study reported that 930 Singaporean men had insufficient knowledge and awareness about HPV [28]. In a descriptive study conducted by Aslan and Bakan [22] on health education students, it was found that male students had lower mean scores on the HPV knowledge level. These different results may be due to the recent increase in information about HPV and the HPV vaccine. In this study, more than half of the participants stated that HPV does not only cause diseases in women (69.8%) and that it can also cause mouth, pharynx, anus and penis cancer and genital warts in men (67.5). In a study conducted in Syria, 8.7% stated that HPV can be transmitted to both women and men [29]. According to these studies, it is thought that introducing Human papillomavirus as a cause of cervical cancer in particular may lead to the wrong perception that it is a disease specific to women only. The reason for the different results in our study is thought to be that the majority of the participants in the study are healthcare workers working at a university hospital and that there have been intensive information activities on HPV recently. It is known that HPV is a virus with more than 200 types that can be transmitted directly to the genital area, mouth and throat through sexual contact. In this study, less than half of the participants (47%) answered the question ‘HPV is transmitted only through contact with the genital area.’ correctly. According to literature data, participants stated that HPV can be transmitted sexually with a percentage ranging from 7.4% to 74.1% [30]. As can be seen, the awareness rate regarding the sexual transmission of HPV is generally low, although it varies between countries. Conservative family structures, education levels, and socioeconomic conditions can restrict society’s attitudes toward sexuality and the freedom to conduct research and discuss sexuality. In our study, more than half of the participants had a bachelor’s degree or higher, and the study was conducted in a large city, suggesting that the participants may be more aware of sexuality.

As of 2018, more than 80 countries and regions have implemented HPV vaccination programs. Although international organizations have made significant efforts to expand HPV vaccination programs, HPV vaccination rates remain below 50% in many countries worldwide. In our study, almost all participants (98%) did not receive HPV vaccination. In terms of considering HPV vaccination, the majority (78.4%) said ‘no’ or ‘undecided’. In terms of accessing HPV vaccination, more than half of the participants (56.5%) thought it was difficult. A study from sixteen European countries reported that the rate of participants considering HPV vaccination ranged from 45.6% to 79.5%. Among the Scandinavian countries, Sweden and Iceland have the highest acceptance rates of HPV vaccination. In studies, 7.7% to 37% of participants believed that the HPV vaccine could lead to early sexual orientation, while 7.9% to 68.1% stated that they avoided vaccinating themselves or their children due to safety concerns [6-8,31]. One study revealed that 62.3% of participants had heard of the HPV vaccine and 50.7% agreed to have themselves or their children vaccinated [32]. One study determined that 39.6% of participants did not get vaccinated because they did not have sufficient information and 30.8% did not get vaccinated because they thought it was unnecessary . Concerns about the potential side effects of the vaccine are an effective factor in not reaching the desired level of vaccination rates [6-9]. Research findings also reveal the need for HPV education interventions aimed at men. The level of knowledge about the HPV vaccine can affect an individual’s intention to get vaccinated. In male-specific HPV training, when the incidence of oropharyngeal and penile cancer was emphasized, it was found that men wanted to be vaccinated [33]. In a study conducted in Turkey, it was revealed that 1.1% of the participants had received the HPV vaccine. The reason for this was 94.4% of the participants stated that they were not informed, 18.7% thought it was harmful, and 4% avoided the vaccine because they were afraid of possible side effects [34]. In our study, only five (2%) of the male participants had received the HPV vaccine. In studies conducted in Turkey, the rates of receiving the HPV vaccine ranged from 1.0% to 4.3% [35]. Lack of information about HPV and the HPV vaccine prevents the desired level of interest in the vaccine both in our country and worldwide. In our country, the HPV vaccine has not yet been included in the vaccination calendar of the Ministry of Health. Although the level of knowledge about the HPV vaccine varies by country, it is generally low. Governments should make the Human Papillomavirus vaccine freely available, make it an important part of their national agenda and actively fight against it. There is generally less awareness among men that the HPV vaccine can also protect against various HPV-related cancers in men. HPV-related cancers can be largely prevented through vaccination. Vaccination protects men from developing anogenital condylomas, other malignancies related to the infection, including the penis, anus and base of the tongue. If both sexes are vaccinated, the spread of the virus decreases. Thus, it can be more effective in successfully achieving herd immunity against the virus [5-9]. In our study, most participants answered a similar question correctly. ‘HPV vaccination in men can contribute to the elimination of HPV (no cases in the community)’. HPV vaccination also helps to control the spread of HPV and reduce the overall burden of the virus on health systems. In addition, HPV-related cancer treatments are often costly and require significant resources from health systems, so vaccination against HPV may also provide cost savings in the long term. Primary and school-based HPV vaccination programs at this stage allow for higher vaccination rates and contribute to sociodemographic equality. A good solution to increase vaccination worldwide is to provide catch-up vaccination, preferably in school health systems [7-10]. The biggest problem is the lack of knowledge about preventing HPV-related pathologies. More education on this issue will increase compliance with vaccination campaigns. People who are not recommended for vaccination by their primary care physicians are less likely to receive HPV vaccination than young people who are. Vaccination of men, as well as women, is being integrated into national school-based and primary care vaccination programs worldwide, but vaccination coverage is still patchy, information is insufficient, and misconceptions persist [8-13]. Our study had some limitations. Since the data were collected cross-sectionally at a single university clinic over a specific time period, the results may not be generalizable to the entire population.

When we look at the content of our study, it is seen that healthcare workers, participants with higher income than expenses and undergraduate/graduate degrees scored higher in terms of knowledge and awareness levels about HPV and HPV vaccine. Considering the general structure of the society, male compliance with HPV vaccine is not considered sufficient. This study investigates a population of men aged 18-45, where there is evidence that compliance with vaccines is extremely poor. In order to achieve a higher level of compliance, it is important to give importance to vaccination campaigns and dissemination of information about the benefits of the vaccine as well as the risks of HPV infection.

To date, vaccination is the only way to break the chain of infection, but HPV vaccination programs, especially gender-neutral programs, are still inadequate. This makes it difficult to achieve herd immunity, especially in men who are invited to get vaccinated years after their first vaccination. There is increasing evidence that gender-neutral vaccination alone can significantly control HPV-related diseases in both women and men and can maximize the prevention of cervical cancer, especially if vaccine coverage is not high among girls in a given region. Given the current situation, it is reasonable to assume that secondary prevention will continue to be the basis for cervical cancer prevention. Another global public health goal should also be to provide scientific evidence to determine the most appropriate timing of vaccination to maximize cancer recurrence and improve outcomes of recommended treatments. Finally, health communication should also play an important role. Indeed, standardizing both the quality and quantity of information can lead to increased adherence to various vaccine awareness campaigns, which must already overcome the biases and psychological factors that complicate promotion and prevention interventions. Of course, investing in promotion campaigns, as in the case of polio, will both improve the cost-benefit balance (making this balance even more favorable than that achieved by primary prevention alone) and equalize vaccination coverage between the two sexes.

References

Zayats R, Murooka TT, McKinnon LR (2022) HPV and the Risk of HIV Acquisition in Women. Front Cell Infect Microbiol 12: 814948. [crossref]
Muñoz-Bello JO, Carrillo-García A, Lizano M (2022) Epidemiology and Molecular Biology of HPV Variants in Cervical Cancer: The State of the Art in Mexico. Int J Mol Sci 23(15). [crossref]
Lin G, Li J (2023) Circulating HPV DNA in HPV-associated cancers. Clin Chim Acta 542: 117269. [crossref]
Võrno T, Lutsar K, Uusküla A, Padrik L, Raud T, et al. (2017) Cost-effectiveness of HPV vaccination in the context of high cervical cancer incidence and low screening coverage. Vaccine 35(46). [crossref]
de Oliveira CM, Fregnani JHTG, Villa LL (2019) HPV Vaccine: Updates and Highlights. Acta Cytol 63(2). [crossref]
Conageski C (2023) Human Papillomavirus Vaccines. Clin Obstet Gynecol 66(3). [crossref]
Marshall S, Fleming A, Sahm LJ, Moore AC (2023) Identifying intervention strategies to improve HPV vaccine decision-making using behaviour change theory. Vaccine 41(7). [crossref]
Garolla A, Graziani A, Grande G, Ortolani C, Ferlin A (2024) HPV-related diseases in male patients: an underestimated conundrum. J Endocrinol Invest 47(2). [crossref]
Williamson AL (2023) Recent Developments in Human Papillomavirus (HPV) Vaccinology. Viruses 15(7)[crossref]
Gamboa-Hoil SI (2023) Human papillomavirus in men. Rev Int Androl 21(1). [crossref]
Erkorkmaz U, Ozdamar K, Sanisoglu Y (2013) Confirmatory Factor Analysis and Fit Indices: Review. Article in Turkiye Klinikleri Journal of Medical Sciences. Turkiye Klinikleri J Med Sci 33(1)
Abdi H, Williams LJ (2010) Principal component analysis. Wiley Interdiscip Rev Comput Stat 2: 433–59.
Kılıç S (2016) Cronbachs alpha reliability coefficient. Psychiatry and Behavioral Sciences 6(1)
Cakmur H (2012) Measurement-Reliability-Validity in Research. TAF Preventive Medicine Bulletin 11(3)
Yarbrough ML, Burnham CAD (2016) The ABCs of STIs: An Update on Sexually Transmitted Infections. Clin Chem 62(6). [crossref]
Spencer JC, Brewer NT, Trogdon JG, Weinberger M, Coyne-Beasley T, Wheeler SB (2020) Cost- effectiveness of Interventions to Increase HPV Vaccine Uptake. Pediatrics 146(6). [crossref]
Lelliott M, Sahker E, Poudyal H (2023) A Review of Parental Vaccine Hesitancy for Human Papillomavirus in Japan. J Clin Med 12(5). [crossref]
Nielsen A, Munk C, Liaw KL, Kjær SK .(2009) Awareness of human papillomavirus in 23 000 Danish men from the general male population. European Journal of Cancer Prevention 18(3). [crossref]
Han JJ, Beltran TH, Song JW, Klaric J, Choi YS (2017) Prevalence of Genital Human Papillomavirus Infection and Human Papillomavirus Vaccination Rates Among US Adult Men: National Health and Nutrition Examination Survey (NHANES) 2013-2014. JAMA Oncol 3(6). [crossref]
Lu B, Wu Y, Nielson CM, Flores R, Abrahamsen M, et al. (2009) Factors Associated with Acquisition and Clearance of Human Papillomavirus Infection in a Cohort of US Men: A Prospective Study. J Infect Dis 199(3). [crossref]
Ford ME, Cannady K, Nahhas GJ, Knight KD, Chavis C, et al. (2020) Assessing an intervention to increase knowledge related to cervical cancer and the HPV vaccine. Adv Cancer Res 146: 115–37. [crossref]
Aslan G, Bakan AB (2021) Identification of the Knowledge Level of Students Receiving Health Education About the Human Papilloma Virus, Screening Tests, and Human Papilloma Virus Vaccination. J Community Health 46(2). [crossref]
Loke AY, Kwan ML, Wong YT, Wong AKY (2017) The uptake of human papillomavirus vaccination and its associated factors among adolescents: A systematic review. J Prim Care Community Health 8(4). [crossref]
Chow EPF, Tabrizi SN, Fairley CK, Wigan R, Machalek DA, et al. (2021) Prevalence of human papillomavirus in young men who have sex with men after the implementation of gender-neutral HPV vaccination: a repeated cross-sectional study. Lancet Infect Dis 21(10). [crossref]
Baloch Z, Yasmeen N, Li Y, Zhang W, Lu H, et al. (2017) Knowledge and awareness of cervical cancer, human papillomavirus (HPV), and HPV vaccine among HPV-infected chinese women. Medical Science Monitor 23: 4269–77. [crossref]
Varer Akpinar C, Alanya Tosun S (2023) Knowledge and perceptions regarding Human Papillomavirus (HPV) and willingness to receive HPV vaccination among university students in a north-eastern city in Turkey. BMC Womens Health 23(1). [crossref]
Dönmez S, Öztürk R, Kısa S, Karaoz Weller B, Zeyneloğlu S (2019) Knowledge and perception of female nursing students about human papillomavirus (HPV), cervical cancer, and attitudes toward HPV vaccination. J Am Coll Health 67(5). [crossref]
Pitts M, Smith A, Croy S, Lyons A, Ryall R, et al. (2009) Singaporean men’s knowledge of cervical cancer and human papillomavirus (HPV) and their attitudes towards HPV vaccination. Vaccine 27(22). [crossref]
Alsaad MA, Shamsuddin K, Fadzil F (2012) Knowledge towards HPV infection and HPV vaccines among Syrian mothers. Asian Pac J Cancer Prev 13(3). [crossref]
Koç Z (2015) University students’ knowledge and attitudes regarding cervical cancer, human papillomavirus, and human papillomavirus vaccines in Turkey. J Am Coll Health 63(1). [crossref]
López N, Garcés-Sánchez M, Panizo MB, De La Cueva IS, Artés MT, et al. (2020) HPV knowledge and vaccine acceptance among European adolescents and their parents: a systematic literature review. Public Health Rev 41. [crossref]
Ortiz RR, Smith A, Coyne-Beasley T (2019) A systematic literature review to examine the potential for social media to impact HPV vaccine uptake and awareness, knowledge, and attitudes about HPV and HPV vaccination. Hum Vaccin Immunother; 15(7-8). [crossref]
Bonafide KE, Vanable PA (2015) Male human papillomavirus vaccine acceptance is enhanced by a brief intervention that emphasizes both male-specific vaccine benefits and altruistic motives. Sex Transm Dis 42(2). [crossref]
Keten HS, Ucer H, Dalgaci AF, Isik O, Ercan Ö, Guvenc N (2021) Knowledge, Attitude, and Behavior of Teachers Regarding HPV (Human Papillomavirus) and Vaccination. J Cancer Educ 36(3). [crossref]
Karasu AFG, Adanir I, Aydin S, Ilhan GK, Ofli T (2019) Nurses’ Knowledge and Opinions on HPV Vaccination: a Cross-Sectional Study from Istanbul. J Cancer Educ 34(1). [crossref]

Putting A Human Face on ‘Burnout’ in the World of Medicine: Using AI and Mind Genomics Thinking about Mind-Sets to Create a Sense of what is Going on, and What to Do

1 Reply

DOI: 10.31038/ALE.2024124

Abstract

This paper explores the emerging problem of burnout among medical professionals. The approach is a combination of simulations using artificial intelligence structured by Mind Genomics thinking about mind-sets. The paper begins with using the simulations to explore the way professionals talk when in a staff meeting at a local hospital when the hospital was independent versus when it was acquired by a private equity firm. The paper continues with the exploration of mind-sets about the way medical professionals burn out, showing five different patterns or types of people. The paper continues with the use of AI to suggest messaging for the five burnout mind-sets to encourage preventive actions, and then finishes with the use of AI as a co-development coach or even partner. Through the paper the stress is on simplicity, speed, iterations to gradually improve, and the opportunity for the democratization of solving problems and advancing medicine.

Introduction

The topic of burnout and the immediate stimulus for writing this paper comes from a web posting in the news section (Table 1). Service in the medical profession at all levels and in all functions seems to be hitting the ‘respected brick wall’, of frustration. Medical professional burnout is causing higher healthcare costs, higher turnover rates, and decreased patient care. This is detrimental to the healthcare system and patients. Non-medical professionals should address mental health and well-being, empathizing with healthcare workers experiencing burnout. They should advocate for better support systems and resources for medical professionals. Concern should also arise for non-medical professionals, as a healthcare system struggling to meet patient needs due to burnout could lead to dangerous situations and subpar care [1-4].

Table 1: The Story about burnout the world of burnouts in the world of medicine.

Phase 1 – Simulations of Interviews with People

Taking a simulation approach to understanding burnout in the medical profession (Table 2) allows for a more in-depth exploration of the personal thoughts and feelings of those experiencing it. By bringing together a variety of relevant individuals, such as doctors, nurses, and administrators, and simulating discussions using advanced AI like GPT 3.5, this method delves into the underlying issues driving burnout. It personalizes the experience by allowing participants to express their true feelings, creating a more intimate and detailed understanding of the challenges they face.

Table 2: Three simulations about the causes of burnout, two from medical professionals, one from employees who are not medical professionals.

The benefits of this approach include gaining insights that may not be uncovered through traditional methods like surveys or interviews. First, simulations allow the investigator to do more deeply into inner thoughts and motivations, leading to a deeper understanding of the root causes of burnout. Second, simulation of interviews allows for a more nuanced exploration of complex relationships and dynamics within the healthcare system, providing a holistic view of the issues at hand.

When people question the validity of using simulations and AI like GPT 3.5 for understanding burnout, it can be argued that this method allows for a unique glimpse into the minds of individuals in the medical profession. By focusing on personal experiences and emotions, rather than just facts and figures, simulations provide a rich tapestry of insights that can inform future interventions and solutions. The simulated interview offers a novel way to explore the complexities of burnout and relationships within the healthcare system, paving the way for more effective strategies to address these challenges [5-8].

Phase 2 – The Value of Mind-sets and How AI Uncovers These Mind-sets Through Simulation

Carol Dweck’s seminal work on mindsets developed the concept of fixed vs growth mindsets, emphasizing the value of trusting in one’s ability to learn and evolve. This concept has been used to many fields, including medicine. Mind Genomics, as well as Moskowitz and colleagues’ research, have expanded on the concept of mindsets in healthcare, utilizing experimental design to blend multiple messages about the medical experience and analyze how people respond to them [9-11].

Researchers were able to identify fundamentally diverse attitudes among individuals by employing well established approaches such as regression analysis, grouping, and permutation. These mindsets are not necessarily innate characteristics, but rather modes of thinking that can influence behavior and decision-making.

In Phase 2 we simulate mind-sets, first using mind-sets typically discussed in the popular press because it involves the world of the everyday. We then move to simulating mind-sets focusing strictly on patterns of burnout among medical processionals (Table 3).

Table 3: Simulation of burnout mind-sets.

Simulating Solutions to Problem by the Targeted Messages Appropriate for a Mind-set

One way to begin dealing with burnout is the ‘soft’ approach of messaging. The development of Mind Genomic starting almost 40 years ago in the mid 1980’s recognized that there were different mind-sets for items as simple as toothpaste. The continuing use of Mind Genomics, and the emerge of speed, the lowering of cost, and the ease of application ended with revealing that much could be gained by working with mind-sets to craft effective messages.

Table 4 shows how generative AI can be ‘fed’ a group of mind-sets, and emerge with appropriate messages that might be used. In conventional use, these messages might either be developed with empirical-based Mind Genomics using people, or at least checked and validated later before use. Right now, however, Table 4 shows a richness of messaging to jump start the solution and can probably outperform many suggestions emerging from brainstorming. The process can be looked at as a cost-effective AI-brainstorm.

Table 4: Five AI-suggested mind-sets of doctors based on burnout patterns, and AI-suggested appropriate messaging to them to reduce burnout.

Using AI as an Invention Machine, or at least as an Invention Colleague

Generative AI, along with Mind Genomics thinking, can transform the way we address burnout by proposing new ideas that provide general guidance and explain what the innovation achieves/ The strength of generative AI in conjunction with Mind Genomics thinking stems from its potential to handle complicated human nature concerns, such as burnout, which are currently baffling and difficult to address.

Using the Mind Genomics platform such as BimLeap.com, those in the medical world may run the AI numerous times in minutes and quickly modify components of their request to adapt the suggestions to their exact needs. This ability to swiftly produce and customize burnout solutions can be extremely beneficial when made publicly available, low-cost, and user-friendly.

Table 5 shows nine innovations from one run. The objective of showing the ideas in Table 5 is to demonstrate the ease with which AI can become an integral part, even perhaps a ‘member’ in the effort to solve human-experience problems, where the issue no long is ‘factual correctness’ but rather ‘it is useful?’.

Table 5: Nine suggested innovations suggested by AI and returned to the user automatically after the ‘study’ is closed and AI has had a chance to further analyze the information it provided. The material comes from the ‘Idea Book’, and Idea Coach, attached to the project.

Discussion and Conclusions

Generative AI coupled with Mind Genomics thinking has the potential to revolutionize the way we approach burnout by suggesting innovative solutions that give general direction and outline what the innovation accomplishes. By utilizing a Mind Genomics platform like Bimieap.com, users can run the AI multiple times in minutes and easily change aspects of their request to tailor the suggestions to their specific needs. This ability to quickly generate and customize solutions for burnout can be incredibly valuable when made widely available, inexpensive, and user-friendly.

The power of generative AI in conjunction with Mind Genomics thinking lies in its ability to tackle complex human nature issues, such as burnout, that are currently perplexing and challenging to address. With the AI’s capacity to generate a multitude of suggestions and ideas, users can explore a range of innovative solutions that may not have been considered before. This opens up new possibilities for individuals to find effective ways to combat burnout and improve their overall well-being.

The democratization of expertise through generative AI and Mind Genomics platforms like Bimieap.com means that everyone can become an expert when it comes to addressing personal challenges like burnout. By empowering individuals to take control of their own solutions and decisions, this technology promotes a sense of agency and ownership over one’s well-being. This shift towards self-directed problem-solving can lead to more effective and sustainable strategies for managing burnout.

As generative AI becomes more widely accessible and user-friendly, the potential for addressing a range of human nature issues beyond burnout increases exponentially. From stress management to mental health support, the applications of AI and Mind Genomics thinking are limitless. By encouraging widespread discussion and exploration of innovative solutions, this technology has the power to catalyze positive changes in how we approach and overcome challenges in our daily lives.

Overall, the combination of generative AI and Mind Genomics thinking represents a new frontier in problem-solving and innovation, offering individuals the tools and resources they need to address complex issues like burnout in a creative and effective manner. Through this technology, we can tap into our collective expertise and wisdom, empowering everyone to become a master of their own well-being. The future looks bright with these powerful tools at our disposal, ready to shape a more resilient and thriving society.

Acknowledgments

The authors thank Vanessa M Arcenas and Isabelle Porat of the Tactical Data Group for help in preparing this and companion manuscripts in this set.

References

Bridgeman PJ, Bridgeman MB, Barone J (2018) Burnout syndrome among healthcare professionals. The Bulletin of the American Society of Hospital Pharmacists 75: 147-152. [crossref]
Chou LP, Li CY, Hu SC (2014) Job stress and burnout in hospital employees: comparisons of different medical professions in a regional hospital in Taiwan. BMJ open 4: e004185. [crossref]
Erschens R, Keifenheim KE, Herrmann-Werner A, Loda T, Schwille-Kiuntke J, et al. (2019) Professional burnout among medical students: systematic literature review and meta-analysis. Medical teacher 41: 172-183. [crossref]
Schrijver I (2016) Pathology in the medical profession?: taking the pulse of physician wellness and burnout. Archives of pathology & laboratory medicine 140: 976-982. [crossref]
Fuse Brown EC, Hall MA (2024) Private equity and the corporatization of health care. Stanford Law Review 76.
Gerard RA (2024) Lead With Purpose: Reignite Passion and Engagement for Professionals in Crisis. Friesen Press.
Howell TG, Mylod DE, Lee TH, Shanafelt T, Prissel P (2020) Physician Burnout, Resilience, and Patient Experience in a Community Practice: Correlations and the Central Role of Activation. J Patient Exp 7: 1491-1500. [crossref]
Peterson MD (2024) Another View on Workforce Projections: A Bright Future, but the Details Can Be Cloudy. ASA Monitor 88: 29.
Jahja E, Papajorgji P, Moskowitz H, Margioukla I, Nasto F, et al. (2024) Measuring the perceived wellbeing of hemodialysis patients: A Mind Genomics cartography. Plos one 19: e0302526. [crossref]
Moskowitz Howard R, Stephen D Rappaport, Sunaina Saharan, Sharon Wingert, Tonya Anderson, et al. (2024) “Mind-Sets for Prescription Weight Loss Products That Are Advertised Directly to Consumers: Using Mind Genomics Thinking with AI for Synthesis and Exploration.” Acta Scientific Pharmaceutical Sciences (ISSN: 2581-5423)
Moskowitz H, Rappaport SD, Wingert S, DiLorenzo A, Sunaina Saharan, et al. (2024) Learning from Ai Synthesis of Mind-Sets: Dealing with Patients Injured by Violence in The New York City Subway System. J Clin Nur Rep 3: 01-06.

Putting a Human Face on Legal Disputes: Eviction for Non-Payment of Rent Simulated by AI and Mind Genomics Thinking

Leave a reply

DOI: 10.31038/ALE.2024123

Abstract

Using generative AI (Chat GPT3.5), the paper shows how a legal case such as eviction for non-payment of rent can be ‘brought to life’. The first simulation shows how AI can be used as a preparatory device for the Mind Genomics experiment, thus making the lawyer’s job easier when using Mind Genomics for a legal case. This first simulation focuses on AI-created questions and answers, and the ‘guesstimate’ by AI as to the likelihood that a jury will find ‘for the plaintiff’ vs ‘for the defendant’. The second simulation focuses on different reasons for the eviction, and AI-based analyses of legal aspects vs ethical aspects. This second stimulation demonstrates the ability of AI to consider the nuances of a case. In both simulations the focus is on types of issues that are best described by phrase ‘subjective, and open to interpretation.’

Introduction

As legal education evolves, law schools are placing greater emphasis on equipping students with the skills to critically analyze intricate legal cases. Traditional methods for teaching law methods frequently rely on rote memorization of statutes and procedures. However, a growing number of educators are now embracing experiential learning opportunities, allowing students to hone their analytical skills in practical contexts. In this new era of legal education, innovative technologies such as generative AI are increasingly being utilized to simulate legal cases, enabling students to navigate real-world scenarios effectively. When combined with the emerging science of Mind Genomics the new mix enables students, or indeed anyone, to gain a human perspective on the law, viz., put a human face on the facts through simulation. The simulation allows learning by asking ‘what-if’ questions, not about the case law itself, but about the softer, human aspects [1-5].

This paper shows two simulations of the same case, where a landlord seeks to evict tenants who have fallen behind on rent for two months due to job loss. The case itself is rich with legal versus emotional and moral complexities. In the classroom, students might end up relishing the back-and-forth analysis, as they engage in a spirited discussion, exploring the pertinent legal principles, the rights of both landlords and tenants, and possible solutions to the issue at hand. This exchange of ideas enables students to examine various viewpoints, sharpen their arguments, and gain a richer insight into the intricacies of legal decision-making.Can we make this back and forth into an AI application, using currently available LLM’s, large language models? As this paper shows, we can do so in ways which are staggeringly fast, inexpensive, scalable, and adaptable to many situations [6-8].

Simulation in the legal field breathes life into cases, offering a vivid experience which textbooks and lectures often fail to convey. Generative AI lets law students explore the intricate complexities and subtleties of real-world legal dilemmas through simulated cases. In this scenario, the AI offers clarity on landlord-tenant laws, the eviction process, and the delicate balance of interests between property owners and tenants.Students can delve into various viewpoints and possible results of the case through simulation. The legal rights and responsibilities of both landlords and tenants can be examined, alongside an evaluation of the ethical implications stemming from the decisions made by each party. This practical method sharpens critical thinking and fosters a richer comprehension of legal principles at work.

This paper explores the two simulations, based on the same ‘facts of the case’. Simulation 1 deals with what to present to a jury to get the jury to vote for the client. Simulation 2 moves more deeply into the role of the lawyer as an advocate for their client.

Simulation 1: Mr. Owner vs Mr. & Mrs. Tenant – Rent Dispute and the Search for Discovering Powerful Messages Resonating with the Jury

We begin with the facts in the case, shown in Table 1. The stimulation is set up to provide messages that can be tested by the emerging science of Mind Genomics, to identify those specific messages which will resonate with a jury [9-12].

Table 1: Facts of the case and instructions to AI (Simulation 1)

The actual Mind Genomics experiment with real people (not shown) follows a straightforward process. The steps are as follows:

Select a topic
Develop four different questions about that topic which give a human face to the topic
For each question develop four different answers to the question, phrased as stand-alone phrases which paint a word picture
Combine the 16 elements into small, easy-to-read vignettes comprising a minimum of two and a maximum of four elements. The composition of the 24 vignettes to be evaluated by a single respondent follows an underlying experimental design. Each question contributes only one element to the vignette. Across the set of 24 vignettes each of the 16 elements appears 5x and is absent 19x. Mathematically the structure of each respondent’s set of 24 vignettes is identical, but the permutation ensures that the vignettes are different across all respondents.
Each respondent evaluates a permuted set of 24 vignettes, using a simple rating scale. The vignette is a stand-alone composition, easy to read. The respondent requires about 3-4 seconds to scan the combination of messages and assign a rating.
The data are put into a simple data base to prepare them for statistical analysis. Ordinary least-squares, dummy variable regression analysis shows the driving power of each element, first for each respondent, and then for groups of respondents defined by methods such as cluster analysis.

Up to now the creation of raw material, questions especially, has emerged as a stumbling block. For whatever reason, people are intimidated. Over a 24-year period, 1998 to 2022, the same plaint was heard, always by the researcher using the tool. It was simply daunting, although children had fewer problems than did adults, and especially far fewer problems than did professionals. Professionals wanted perfection in the vignette, ending up enamored with overly polished, wordy paragraphs, hard to read, hard to test more than a few.

The introduction of AI in 2022 revolutionized this emerging science of Mind Genomics. As Table 1 showed it is straightforward to come up with the statement of the ‘facts of the case’. It is the creation of the questions and elements (answer) which are difficult.

Table 2 shows what emerged after one iteration requiring 10-15 seconds. These four answers are statements about the case, and the AI’s ‘guesstimate’ about the jury’s decision based on each answer. The key benefit to critical thinking is the ability of AI to jump-start the thought process. To ‘have fun’ one could iterate, with each iteration requiring the 15 seconds. An encyclopedia of questions and elements (answers) would emerge in about 10 minutes or shorter. The enterprising user could change the facts in the case as well and explore different ‘what if’ aspects, using the Idea Coach features.

Table 2: Simulation of four questions and four elements (answers to each question), prepared for a Mind Genomics experiment with actual people (Simulation 1).

The effort is finished, whether one iteration or 100 iterations, the results of each iteration are stored on an Excel spreadsheet, with one tab dedicated to each iteration. Thus, it is possible to run many iterations, acquire the data, but leave the subsequent analysis to an off-line effort, that effort taking about 5-6 hours. The results are returned to the user by email. The remainder of this simulation is generated after the study preparation is closed. AI then goes over its own questions and answers and provides a summarization and deeper analysis shown in Table 3, and beyond. Table 3 presents the first set of information,

Key Ideas: AI can provide valuable insights into key ideas by analyzing large amounts of data and identifying patterns and trends. It can summarize complex concepts and present them in a clear and concise manner. This can help individuals better understand key concepts and make informed decisions.
Themes: AI can also identify common themes across different sources of information, allowing for a deeper understanding of the subject matter. This can help in identifying trends and patterns that may not be apparent at first glance.
Perspectives: AI can provide different perspectives on a topic by analyzing a wide range of sources and presenting diverse viewpoints. This can help individuals gain a more comprehensive understanding of the subject matter and consider different angles.
What is missing: AI can also highlight what is missing in a particular discussion or research study by pointing out gaps in information or potential areas for further exploration. This can guide researchers in identifying areas that need further investigation.
Alternative viewpoints: Additionally, AI can present alternative viewpoints on a topic by analyzing conflicting information and presenting different sides of the argument. This can help individuals consider different perspectives and make well-informed decisions.

Table 3: AI summarization of simulation 1 in terms of key ideas, themes, perspectives, what is missing and alternative viewpoints.

Table 4 compares interested audiences versus opposing audiences regarding the material presented in Table 3. AI can expand the topic by questions and answers tailored to specific interested audiences, allowing for a more personalized and engaging experience for learners. AI can create content that is relevant and meaningful content. increasing their motivation and interest in the material. Going a step further, AI can also identify prospective opposing audiences by presenting diverse perspectives and challenging viewpoints. By generating questions and answers that provoke critical thinking and debate, AI can stimulate discussions and encourage individuals to consider alternative viewpoints. This can lead to a more well-rounded understanding of the topic and foster a culture of open-mindedness and tolerance.

Table 4: AI synthesis of interested versus opposing audiences, based on material in Table 3.

The final analysis as of this writing (November 2024) is the suggestion of innovations. The initial suggestion of innovations produced a list of AI-generated innovations. During the summer of 2024, the Mind Genomics system was modified so that the post-creation of the study (not-yet-run with people) would offer a far more complete analysis of each innovation that was being created and offered to the user. These nine aspects appear below and are shown in Table 5 for each of the four innovations.

Specific suggestion: AI can provide specific and targeted suggestions based on data analysis and patterns
Explanation why the suggestion is relevant:
Importance and uniqueness of the suggestion:
Social Good resulting from the suggestion.
Slogan which emblemizes the suggestion:
Investment pitch:
Potential investor pushback:
Answer to the potential investor pushback:
Compromise, go forward positioning:

Table 5: The four innovations suggested by AI and an AI ‘work-up’ of each innovation

Simulation 2 – Dealing with the Same Issue, but From the Point of View as the Lawyers Helping Both Sides as ‘Trusted Parties’

In this simulation we move backwards, away from the situation of a lawyer trying to anticipate what to say to the jury (Mind Genomics approach), to understanding the ‘facts in the case’ from the point of view of the client. Here the lawyer becomes a trusted friend. The process becomes more personal and empathic.

Table 6 shows the ‘facts of the case’ and the instructions to AI to generate the relevant questions and answers. Table 7 shows nine different questions and the structured answers to those questions.

Table 6: Facts of the case and instructions to AI (Simulation 2)

It is worth noting here that generative AI such as Chat GPT3.5 used here, can be instructed to simulate different people talking to each other, e.g., listening in as a ‘fly on the wall’ to the lawyer’s conference.

Table 7: Nine relevant questions generated by AI regarding the case, with answers simulated by AI with respect to from the legal standpoint and the moral standpoint.

Discussion and Conclusion

Simulations are crucial for students to understand the intricacies of legal decision-making, enabling active engagement with complex scenarios and practicing their knowledge in real-world contexts. These simulations enhance students’ understanding of the law and its real-world uses, as well as their critical thinking and problem-solving abilities. The future of law schools will likely employ diverse techniques and technologies, guiding students to think critically about complex issues. Mind Genomics, enhanced by AI, presents a groundbreaking solution for the legal system, offering students an engaging and interactive approach to grasp the intricacies of legal cases. This technology has the potential to reshape the legal landscape, fostering quicker case resolutions, enhancing transparency, and expanding access to justice for everyone. Mind Genomics and generative AI can craft realistic legal scenarios by examining the many factors which shape legal decision-making, including case law, evidence, and ethical considerations. These scenarios can provide students with practical experience to enhance their legal reasoning skills in a simulated environment.

Mind Genomics, powered by AI, has the potential to revolutionize the legal profession by improving decision-making, streamlining case resolutions, and ensuring justice is served efficiently and transparently. This technology would benefit students by providing interactive learning tools, real-world case studies, and hands-on experience, while professors would have access to cutting-edge research tools and real-time data. The implementation of Mind Genomics could transform the legal practice, leading to more efficient case resolutions, improved transparency, and greater access to justice for all individuals.

Reflection and debriefing sessions on simulated legal cases can help students improve their legal reasoning abilities, bridge the gap between theoretical legal knowledge and practical application in real-world scenarios, and develop a deeper understanding of human factors involved in legal decision-making. At the same, it might well be productive is during the application of AI to legal issues the user requests both legal and ethical/moral considerations as separable steps in the process.In conclusion, using technology-driven simulations in legal education can promote active learning, enhance critical thinking skills, and provide practical experience in legal decision-making, equipping students for successful careers in law.

Acknowledgments

Author Moskowitz wishes to acknowledge the help of the audience at his lecture at the law school in of the University of Kragujevac, November, 2024. Many of the points of view regarding ethics and morality and the law were challenged by the students and professors, leading to refinements in the authors’ thinking.

The authors would like to thank Vanessa M. Arcenas and Isabelle Porat for help in preparing this manuscript for publication.

References

Curcio AA (2009) Assessing differently and using empirical studies to see if it makes a difference: Can law schools do it better. Quinnipiac L Rev 27: 899.
Horwitz P (2012) What Ails the Law Schools. Mich L Rev 111: 955.
Katz HN (2006) Evaluating the skills curriculum: Challenges and opportunities for law schools. Mercer L Rev 59: 909.
Mertz E (2007) The language of law school: learning to” think like a lawyer”. Oxford University Press, USA.
Shah M (2010) The legal education bubble: how law schools should respond to changes in the legal market. Geo J Legal Ethics, 23: 843.
Alarie B, Niblett A, Yoon AH (2018) How artificial intelligence will affect the practice of law. University of Toronto Law Journal, 68: 106-124.
Jinzhe Tan, Hannes Westermann, Karim Benyekhlef (2023)ChatGPT as an Artificial Lawyer? Canad Workshop on Artificial Intelligence for Access to Justice (AI4AJ 2023)
Susskind R, Susskind RE (2023) Tomorrow’s lawyers: An introduction to your future. Oxford University Press.
Moskowitz H, Kover A, Papajorgji P (2022) Applying mind genomics to social sciences. IGI Global.
Moskowitz HR, Wren J,Papajorgji P (2020) Mind genomics and the law. Mauritius: LAP Lambert Academic Publishing.
Papajorgji P (2023) Knowledge as a service: The case of Mind Genomics. EuroMediterranean, 19: 34-47.
Porretta S, Gere A, Radványi D,Moskowitz H (2019) Mind Genomics (Conjoint Analysis): The new concept research in the analysis of consumer behaviour and choice. Trends in food science & technology, 84: 29-33.