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An Extensive Research on Immune-modulating MOFbased Nanodrug for Enhanced Photothermal Therapy of Melanoma

DOI: 10.31038/NAMS.2023642

Abstract

Original research on the application of MOF-based nanodrugs for photothermal and immune therapy of melanoma has been developed. This study, aimed at addressing the limitations of melanoma treatment, constructed indocyanine green (ICG) loaded GSH-responsive PD-1 inhibitory polypeptide AUNP12-modified MOF nanodrugs for photothermal and immune therapy of melanoma. The AUNP12 could be released to bind PDL-1, effectively blocking the PD-1/PD-L1 pathway at high concentrations of glutathione (GSH). This MOF-based nanodrugs could promote the maturation of DC cells, while the ICG exhibits strong photothermal effects, achieving synergistic photothermal and immunotherapy for melanoma.

MOF-based Nanodrugs for Melanoma Treatment General Achievements

Melanoma is a cutaneous neoplasm arising from the malignant transformation of melanocytes, exhibiting a high degree of malignancy and a propensity for metastasis, thereby resulting in a poor clinical prognosis and a heightened fatality rate [1]. The chief limitations of traditional clinical interventions (surgery, radiation therapy, and chemotherapy) primarily lie in their limited efficacy in suppressing metastatic lesions and their substantial toxic and side effect [2]. Hence, the focal point in the clinical management of malignant melanoma is how to efficaciously inhibit its growth and metastasis with reduced toxicity, constituting a pivotal juncture in clinical practice and a current scientific research challenge.

Immunotherapy has recently emerged as an advanced therapeutic strategy with attracted widespread attention in clinical and foundational research. Immune checkpoint blockade holds promise in the treatment of melanoma, particularly through the inhibition of programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) [3]. Nevertheless, the currently available immunotherapeutic antibodies targeting melanoma exhibit expensive, considerable toxicity, robust immune reactions, and substantial interindividual variability. In contrast, PD-1 inhibitory peptide AUNP12 (AUR-12/Aurigene-012), developed by Aurigene and Pierre Fabre, is characterized by its affordability and minimal adverse effects and is presently in the preclinical research phase [4].

Nevertheless, research has illuminated the limited efficacy of singular immune checkpoint blockade in restraining tumor growth and metastasis [5]. A synergistic approach, with methodologies such as chemotherapy, photodynamic, or photothermal therapy, can amplify therapeutic potency [6,7]. Photothermal therapy, an exceedingly promising novel method for tumor treatment, relies on the conversion of external light sources into localized thermal energy to kill neoplastic cells, particularly suitable for cutaneous malignancies. Remarkably, studies have also reported the capability of photothermal therapy to stimulate an immune response within the host organism, by generating endogenous antigens during the thermal ablation of tumor tissue, subsequently activating cytotoxic T cells [8,9]. Therefore, the synergistic treatment of immune checkpoint blockade and photothermal therapy holds extensive promise in the management of melanoma.

This work “The GSH responsive indocyanine green loaded PD-1 inhibitory polypeptide AUNP12 modified MOF nanoparticles for photothermal and immunotherapy of melanoma” has designed and constructed a nanomedicine that combines the photothermal and immunotherapy [10]. Through click chemistry, AUNP12, linked by disulfide bonds, was modified onto the surface of a metal-organic framework (MOF) and loaded with the photothermal converter indocyanine green (ICG) which has strong photothermal effect. The PD-1 inhibitory peptide AUNP12 could be responsive release from MOF-based nanodrug and promote the maturation of DC cells, which combine with the ICG to achieve synergistic photothermal and immunotherapy for melanoma (Figure 1).

Figure 1: The schematic diagram of ICG-MOF-SS-AUNP12 nanoparticles for synergistic photothermal and immunotherapy.

Conclusion

The MOF-based nanodrugs exhibits potent photothermal effects for tumor cell ablation while intelligently releasing PD-1 inhibitory peptides to enhance DC cell maturation. The study primarily furnishes a concept of substantial value, albeit at a relatively preliminary stage. With a clinical translation objective in mind, the exploration of a secure and efficacious delivery modality for nanomedicines is essential in the future. Taking into account the unique biological characteristics of melanoma, a comprehensive research effort is currently underway to explore alternative drug delivery methods, such as microneedle-based transdermal delivery, with the ultimate goal of developing innovative treatment strategies for this deadly cancer.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (32101134, 32101161), Program of Science and Technology Department of Sichuan Province (23NSFSC0884, 2022YFS0203), the Technology Innovation Project of Science and Technology Bureau of Chengdu (2022-YF05-01468-SN, 2022-YF05-01724-SN).

References

Garbe C, et al. (2022) European consensus-based interdisciplinary guideline for melanoma. European Journal of Cancer 236-255. [crossref]
Long GV, et al. (2023) Cutaneous melanoma. Lancet 485-502.
Kubli SP, et al. (2021) Beyond immune checkpoint blockade: emerging immunological strategies. Nature Reviews Drug Discovery 899-919. [crossref]
Zhan MM, et al. (2016) From monoclonal antibodies to small molecules: the development of inhibitors targeting the PD-1/PD-L1 pathway. Drug Discovery Today 1027-1036.
Chen W, et al. (2018) Combining photothermal therapy and immunotherapy against melanoma by polydopamine-coated Al₂O₃ nanoparticles. Theranostics 2229-2241. [crossref]
Lu J, et al. (2018) Breast Cancer Chemo-immunotherapy through Liposomal Delivery of an Immunogenic Cell Death Stimulus Plus Interference in the IDO-1 Pathway. ACS Nano 11041-11061. [crossref]
Li Y, et al. (2019) Nanotechnology-based photoimmunological therapies for cancer. Cancer Letters 429-438. [crossref]
Huang L, et al. (2019) Mild photothermal therapy potentiates anti-PD-L1 treatment for immunologically cold tumors via an all-in-one and all-in-control strategy. Nature Communications 4871.
Balakrishnan PB, et al. (2020) Photothermal therapies to improve immune checkpoint blockade for cancer. International Journal of Hyperthermia 34-49. [crossref]
Hao Y, et al. (2023) The GSH responsive indocyanine green loaded PD-1 inhibitory polypeptide AUNP12 modified MOF nanoparticles for photothermal and immunotherapy of melanoma. Frontiers in Bioengineering and Biotechnology. [crossref]

The Process of Being Hospitalized for Bowel Preparation before Colonoscopy

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DOI: 10.31038/IJNM.2023441

Abstract

Background: Inadequate bowel preparation before a colonoscopy is troublesome for patients and costly for healthcare. Therefore, some patients are hospitalized for bowel preparation, but the number of patients and criteria involved in decision-making vary.

Aim: To investigate the variables included in decision-making concerning whether patients should be hospitalized for bowel preparation before colonoscopy.

Methods: Qualitative dynamic system modeling, including interviews with patients, nurses, and physicians and examining guidelines

Findings: The decision to offer hospitalization for bowel preparation was discussed only in a few cases with patients, and there was no dialogue with primary care. The decision was based on guidelines, rules of thumb, and healthcare professionals’ subjective judgment and did not follow evidence-based criteria.

Conclusion: Several factors, such as dialogue across healthcare sectors, involving patients in decision-making and adjusting clinical guidelines, were identified in the model that can be used to improve clinical practice and the experiences of patients.

Keywords

Clinical decision making, Colonoscopy, Qualitative

Introduction

Worldwide, colonoscopy is the most common method for diagnosing diseases of the intestinal mucosa, such as cancer or inflammatory conditions [1]. The number of colonoscopies is steadily increasing in most countries [2]. Likewise, in Denmark, where the implementation of a screening program for colorectal cancer for the population between the ages of 50 and 74 years has significantly increased the number of colonoscopies [3]. To ensure adequate visualization of the intestinal mucosa and thereby optimize the possibility of successful diagnosis and treatment during the colonoscopy, bowel preparation is crucial [4]. Bowel preparation implies that the patient must follow specific diet restrictions and consume laxatives to achieve successful bowel cleansing [5]. Most patients manage bowel preparation at home, while some patients are hospitalized, but overall patients experience bowel preparation as unpleasant and challenging due to uncontrolled diarrhoea, nausea, and sleep deprivation [6,7]. A guideline from the European Society of Gastrointestinal Endoscopy highlights that 18–35% of bowel preparation is inadequate in patients undergoing colonoscopy [8]. Notably, a study found that outpatients had more adequate bowel preparations than inpatients [9]. In the context of three major gastroenterology centres in the Capital Region of Denmark, the complex challenges of daily decision-making concerning the management of the growing number of colonoscopies and the shortage of available hospital beds have been identified. An overview of the number of colonoscopies at each of the three hospitals and the number of patients hospitalized for bowel preparation are illustrated in Table 1.

This study aimed to investigate the variables included in the decision and to determine whether patients were offered hospitalization for bowel preparation.

Table 1: Overview of colonoscopies and hospitalizations for bowel preparation at three hospitals in Denmark

Site	Colonoscopies per year (2020)	Colonoscopies per month ^#			Hospitalization for bowel preparation n (%) ^#
HGH	5689	475	477	490	15 (3.2)	12 (2.5)	12 (2.4)
AHH	7500	361	422	459	34 (9.4)	29 (6.9)	40 (8.7)
BFH	5581	430	521	535	29 (6.7)	22 (4.2)	26 (4.9)

HGH: Herlev and Gentofte Hospital, AHH Amager and Hvidovre Hospital, BFH Bispebjerg and Frederiksberg hospital.
#Numbers from HGH and AHH are from April, May, and June 2021, and numbers from BFH are from January, February, and March 2022.

Methods

Design

We developed a descriptive model based on participatory system modelling (SDM) to explore the interactions between variables included in the process of deciding if a patient is offered hospitalization for bowel cleansing [10]. The intended outcome was to help stakeholders illustrate the process of decision-making, and thereby also highlight potential areas for improvement of the process. SDM is a method used to explore and understand complex decision-making involving multiple actors [10]. In the data collection phase, this entails identifying the current and potential decision-makers, understanding their influence and rationale behind the decision-making. Relevant policies and guidelines are also considered as part of the data. The data was analyzed and discussed using a qualitative approach. This study was conducted in the Capital Region in Denmark at the Departments of Gastroenterology at three university hospitals: Herlev and Gentofte Hospital (HGH), Amager and Hvidovre Hospital (AHH), and Frederiksberg and Bispebjerg Hospital (FBH).

Data Collection

Data were collected from March to June 2021 and included patients admitted for bowel preparation before colonoscopy, above 18 years of age, capable of giving informed consent, and able to speak and understand Danish. Patients were contacted after admittance and before bowel preparation. After obtaining informed consent, the time for a telephone interview was agreed upon with the patient one or two days after discharge. The interviews included questions on experiences of hospital admission and bowel preparation, as well as data on patients’ living conditions, support from primary care, and functional status (using the Barthel Index for Activities of Daily Living (ADL)) [11]. Data regarding patients’ age, gender, diagnosis, and cause for colonoscopy were obtained from the patients’ medical records. Physicians’ and nurses’ written documentation regarding their considerations and reasoning on whether this patient should be hospitalized for bowel preparation and, their knowledge of clinical guidelines. Ward managers’ experiences and general views on hospital admission for bowel preparation were investigated at each hospital through individual interviews. In the cases where the patients received help from home care, primary care nurses in the municipality were interviewed by telephone regarding their views on the possibility of the patients carrying out bowel preparation at home. Clinical guidelines at the three hospitals were collected to identify formal criteria for admission for bowel preparation.

Data Analysis

The analytic process developed continuously alongside the data collection. First, we identified key variables that potentially influenced the decision for hospitalization. The basic structure of a model was first agreed upon by the group of authors. A template was developed from which data were collected. In an iterative process, the data were discussed and analyzed at each group meeting. The analysis focused on the development of a descriptive model; therefore, data were grouped into categories and re-grouped until the model was clear. The process continued until a consensus was reached on the final model.

Ethics

All patients were informed orally and in writing about the project, after which they provided informed consent and agreed to have their anonymized responses published. Healthcare professionals were informed orally and agreed to have their anonymized responses published. Permission to store data confidentially was obtained from the Danish Data Protection Agency (ID no: P-2020-1172). According to Danish law, no formal ethical approval was needed for this study.

Results

A model of the decision process and related variables in the decision on hospitalization before colonoscopy was developed (Figure 1). The study included 17 patients (5 from HGH, 3 from FBH, and 9 from AHH). The median age of the patients was 74 years (ranging from 50 to 86), of whom 10 were male. The demographics of the participating patients are shown in Table 2. Of those involved in the decision-making process, 10 physicians and 12 nurses were also included. Two of the physicians were the patient’s family physician, and 10 were hospital-employed physicians from the Departments of Gastroenterology. The 12 nurses were employed in outpatient clinics and had between 1 and 15 years of experience in the specialty of gastroenterology. Furthermore, nine nurses from the municipalities were contacted. Management at the departments was interviewed at the hospitals.

Figure 1: A flow chart model of the decision process for patients to either stay at home or be hospitalized for bowel preparation before a colonoscopy

Table 2: Demographics of the participating patients

Number	Age (years)	Gender	Cohabitating	Housing type	Home care services	Bartell score	Cause of referral for colonoscopy
1	80	male	no	sheltered housing	medication	18	suspected colorectal cancer
2	85	female	no	apartment	none	20	suspected colorectal cancer
3	74	female	no	apartment	cleaning, shopping, food preparation, laundry, medication, treatment of ulcer, personal hygiene, and mobilization	10	diarrhea, reduced appetite, weight loss
4	64	female	no	apartment	cleaning	20	suspected colorectal cancer
5	74	female	no	house	tube feeding 4 times a day	20	bleeding from the rectum
6	70	female	yes	house	none	20	abdominal pain and bleeding from the rectum
7	81	male	no	apartment	cleaning, shopping, and laundry	18	diarrhea for several weeks
8	74	female	no	house	help for anti-embolism stockings twice a day and wound care twice a week	19	suspected colorectal cancer
9	69	male	no	apartment	personal hygiene daily, bath two times a week, cleaning every 14 days	18	suspected colorectal cancer
10	76	male	yes	house	change of bladder catheter every ten week	16	abdominal pain, weight loss, suspected colorectal cancer
11	63	male	no	house	every morning for medicine, cleaning every 14 days.	18	removal of polyps
12	83	female	yes	house	shower once a week, medicine and food delivery twice a week, and incontinence treatment daily	15	alternating bowel movements
13	82	male	no	nursing home	medication, help with personal hygiene, and mobilization every day	5	suspected colorectal cancer
14	50	male	no	apartment	cleaning every other week	20	suspected colorectal cancer
15	81	male	no	house	cleaning every other week	20	diarrhea for six months
16	73	male	yes	house	none	20	suspected colorectal cancer
17	86	male	no	house	none	19	bleeding from the rectum

Referral for Colonoscopy

Overall, there were different ways in which patients could be referred for colonoscopy. However, the decision on whether the patient should be admitted to the hospital for bowel preparation was formally decided by a physician employed at the hospital, and no signs of nurses being involved in this decision were found. Sometimes the decision was made concerning the patient visiting the outpatient department and sometimes as an administrative decision, without seeing or talking to the patient.

Decision

The three hospitals had very different administrative guidelines for identifying patients who needed hospitalization for bowel preparation. One hospital’s guidelines stated that patients with severe renal insufficiency (creatinine clearance > 30 ml/min), congestive heart failure (NYHA III or IV), or needing help from healthcare professionals to go to the toilet must be admitted during bowel preparation. The second hospital only used general guidelines for being hospitalized, such as diabetes, heart disease, kidney disease, or disability. The third hospital had no guidelines and relied on an individual assessment by the admitting physician. In some cases, the possibility of hospital admission for bowel preparation was discussed with the patient and/or relatives, i.e., when the referral for colonoscopy was decided after a visit to the outpatient clinic or if a clear decision was stated in the referral from a family physician. The arguments for admitting patients included being nervous about undergoing bowel preparation at home, faecal incontinence, dizziness, difficulty walking, and insufficient help at home. In the guidelines for the two hospitals, only difficulty walking was mentioned as a recommendation for admission, but despite that, in all cases, the recommendations from the family physician were followed without question by both the nurse and admitting physician. Most often, when the hospital physician decided that a patient should be hospitalized for bowel preparation; the decision was primarily based on the physician’s subjective judgment, without talking to the patient or primary care or following guidelines (if there were any). Reasons such as suffering from a cognitive disability or a previously cancelled colonoscopy due to inadequate bowel preparation were not mentioned in the guidelines. Still, both nurses and physicians agreed that these patients should be admitted for bowel preparation without further dialogue with the patient. At one hospital, there was an administrative rule of thumb stating that there could be no more than two patients admitted for bowel cleansing at a time. This rule of thumb would therefore determine when a colonoscopy could take place.

Collaboration with Primary Care

The care offered by the six municipalities included in this study was very similar. However, there was considerable variation between municipalities’ rules for visitation for help with bowel preparation at home. Significantly, the notification deadline for the preparations varied. One municipality needed to be advised 24 hours before, while another municipality needed three days. At the administrative level, there was broad agreement from the nurses in primary care to follow their service catalogue, in which it was specified, which services they could offer a citizen who had to go through bowel preparation before a colonoscopy. The services the primary sector could offer included help to read and understand the instructions for bowel preparation, medication administration, help with toilet visits, change of diapers, change of bed linen, follow-up visits, phone calls to make sure the person was okay, and visitation based on an emergency call from the person. However, in practice, there were several challenges, such as planning the visits, which could make it difficult to help with toilet visits because it was unpredictable when the person needed to go to the toilet. Even if a person had an emergency call, some healthcare professionals expressed concerns since it could take a long time from the call until someone came for help. Optimally, the person should, to a certain extent, be able to control bowel movements and manage toilet visits relatively independently. Similarly, if the person needed help during the night, there would be a long waiting time, and the primary care nurse would need a key to the home. They also required that the person be cognitively well-preserved and follow the bowel preparation instructions.

Patients’ Experiences

Some patients were thankful that they were admitted to a hospital ward instead of undergoing bowel preparation at home. In addition, receiving the medication from the nurses at the precise hours contributed to a feeling of being taken care of and safe. The loss of control over bodily responses meant that they had to run to the toilet, and not knowing whether they would be able to hold back the faeces was highly stressful. Some patients felt embarrassed due to the lack of privacy in the hospital ward as they shared the toilet with another patient. They needed unrestricted access to the toilet, and the lack of privacy made them uncomfortable. Patients mentioned the importance of being well-informed. Some felt a lack of information but, even so, found it safer to be admitted than to undergo bowel preparation at home. On a few occasions, the patients went through bowel preparation, but their colonoscopy was cancelled due to miscommunication regarding their medication. For example, if the patient had not paused an anticoagulant drug or iron, the coloscopy could not be completed, and it had to be scheduled for weeks later. Consequently, the patients had to undergo bowel preparation once again. A situation that made the patients frustrated and angry. Generally, the patients feared managing the bowel preparation procedure at home because of their fear of making a mess.

Discussion

Our results indicate that nurses and primary care was not involved in the decision-making process whether a citizen could undergo bowel preparation at home with assistance from home care nurses or if hospital admission would be necessary. These results may contrast with the Danish healthcare systems’ vision of coherent care pathways across regions, municipalities, and the primary healthcare sector, intending to improve and coordinate tasks in close collaboration [12]. It also contrasts with the highly experienced nurses’ ability to include their assessment of the patient in clinical decision making. Our results also indicate that the services primary care could offer align with the care needs of most patients during hospitalization for bowel cleansing. This suggests that more patients might conduct bowel cleansing at home with the support of primary care. However, primary care faced challenges related to the time sensitivity of assisting patients. Considering the substantial number of patients hospitalized for bowel cleansing, it may be worthwhile to further explore involving primary healthcare professionals in the decision-making process, potentially leading to the development of new workflows. This approach may not only help patients feel confident about undergoing bowel cleansing at home but also avoid the costs associated with hospitalization. Moreover, it is worth noting that one of the patients in our study resided in a nursing home, which raises questions about the necessity of hospitalizing the patient for bowel cleansing. It may be reasonable to involve healthcare professionals from nursing homes in the decision-making to identify potential barriers in assisting patients during bowel cleansing. This collaborative effort could lead to development of workflow that eliminates the need for hospitalization in such cases.

Overall, we found no national guidelines describing which criteria should determine which patients should be hospitalized for bowel preparation before a colonoscopy. Furthermore, the practices at the three hospitals varied. Studies indicate that factors such as high age, male sex, low level of physical activity, lower educational level, several comorbidities, diabetes, chronic constipation, and polypharmacy are associated with inadequate bowel preparation [13-16]. However, none of these factors was reflected in the hospitals’ local guidelines. Although comprehensive European guidelines underline the importance of sufficient bowel preparation for a successful colonoscopy [8], it has not been possible to clarify recommendations identifying factors that determine whether a patient should be hospitalized for bowel preparation or undergo bowel preparation at home. Another study also found that several patients were referred directly to colonoscopy without being in contact with the hospital. These patients participated in screening programs, follow-up on colon cancer screening tests, and surveillance colonoscopy. This may be problematic, as many patients undergo colonoscopy unnecessarily because no physician has engaged in a conversation with the patients regarding the indications and risks of the procedure or the reason why some patients decide not to show up for the colonoscopy [17]. A recent study found that patients’ decision on whether to undergo a colonoscopy was characterized by uncertainty about what to expect [18]. Shared decision-making has been found to improve patients’ feelings of being well-informed [19] and to improve patients’ attentiveness and adherence to recommendations [20]. Thereby, whether shared decision-making is a tool to reduce the number of inadequate bowel preparations should be discussed. We found no studies investigating shared decision-making concerning patients referred to colonoscopy, but shared decision-making is recommended in other gastroenterological settings such as general screening for colon cancer [21,22]. Several factors have been related to the adequacy of bowel preparation, and inpatient status represents one of the strongest independent predictors of inadequate colon cleansing. Inadequate inpatient bowel preparation may increase the length of hospital stay by about 25% and costs by 30% compared to adequate preparation [14]. Ideally, patients understand and are well prepared for the procedure, which requires dialogue between patients and healthcare professionals [17]. However, some patients miss pieces of information [18]. The completion of bowel preparation is incredibly challenging for older patients, and a low score of ADL has been found to be a significant predictor of inadequate bowel preparation [23]. However, in our study, the patients had a high Barthel score, indicating a high level of physical functional performance. This indicate that no formal assessment of patients’ physical status are included in the decision of whether a patient should be hospitalized. Furthermore, undergoing bowel cleansing is a stressful procedure, unfamiliar to most patients. Therefore, relying solely on scores such Barthel may not provide an accurate assessment of patients’ ability to independently manage bowel cleansing at home. In our study, other factors, such as psychological aspects or previous experiences of inadequate bowel cleansing, influenced the decision for hospitalization.

Hospitalization for bowel preparation is associated with an almost two-fold higher risk of inadequate bowel preparation before colonoscopy. This may be associated with the fact that inpatients have more comorbidities than patients undergoing bowel preparation at home. Likewise, it may be associated with nurses’ and physicians’ need for specific education in bowel preparation [24-26]. Interventions, such as videos or phone calls the day before the colonoscopy, have been explored, but the optimal solution has still not been found [27].

The findings in this study might not be transferrable to settings outside Denmark, even though the high number of patients not sufficiently prepared for colonoscopy is well known in many countries. In addition, there are factors influencing the decision for hospitalization that have not been considered in this study, including the economic constraints of the healthcare system, the lack of nurses influencing the number of beds available, the need for further improvement of the medication used for bowel preparation, and screening the level of patients’ constipation before a decision on admission. This will probably also affect the future administrative procedures of patient care. Moreover, we did not explore the perspectives of the relatives, which could have provided insight into the feasibility and appropriateness of asking close relatives to support their family member during bowel cleansing. Such insight could have shed light on the role of the relatives in this context.

Conclusion

Different variables included in the decision to hospitalize patients for bowel preparation were identified. The lack of evidence-informed decision-making, the involvement of patients in decision-making, and the missing collaboration across healthcare sectors are possible essential factors to include in developing better care trajectories.

Acknowledgment

We wish to thank the patients, nurses, and physicians participating in this study for taking the time to talk to us.

Funding

This research did not receive any specific grant from funding agencies

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What Ordinary People Want from Their ‘Regular’ Visits to the Doctor: A Mind Genomics Cartography

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DOI: 10.31038/IMROJ.2023824

Abstract

Respondents evaluated systematically created vignettes, viz., combinations of elements (messages) about benefits to going to their doctor for a yearly check-up. The vignettes comprised 2-4 elements selected from the set of 16 elements, with the vignettes created by experimental design which ensured both that the elements did not mutually contradict each other, and that the elements were statistically independent of each other. Each of 101 US respondents evaluated a unique set of 24 vignettes, following the standard test protocol used in the emerging science of Mind Genomics. Respondents rated these vignettes on a two-sided scale of motivation and believability. Based upon the pattern of coefficients for equations relating elements to the rating of ‘motivates me’, three clearly different mind-sets emerged; respectively, those focusing on the visit to assess the growth of children, those focusing on obtaining their vital measures and advice about eating, and those focus on advice from the doctor about what to do to maintain an active lifestyle. In contrast, self-profiling classification of attitudes could not uncover these three clearly different and intuitively meaningful mind-sets. The paper finishes by introducing the PVI, personal viewpoint identifier, comprising six elements from the study, a two-point scale, the pattern of answers to which assigned a new person to one of the three mind-sets.

Background

The objective of this paper is the continuing effort of an emerging science, Mind Genomics, to understand how people perceive the world of the ordinary, how people make decisions, and perhaps most important, the existence of and nature of different ways that ordinary people look at topics of their everyday world. Rather than focusing on unusual situations to increase our understanding, Mind Genomics focuses on the daily, quotidian world, in which most people live.

The particular topic dealt with here is the understanding of what ordinary people look for when they think about what is important to the when they make their regular appointments to see their doctor. The notion of regular appointments may seem obvious, but if we were to probe more deeply into the topic, might we end up seeing deep differences which make sense, differences that we intuitively know, but differences which when recognized allow the visit to the doctor to be much more effective for both patient and doctor A simple Google Scholar® query about ‘attitudes regarding ‘attitudes about yearly check up visits to the doctor’ generated 90,400 hits as of October 16, 2023. Many more hits 384,000, emerged when the query was ‘what patients want from doctors during their annual visit’. For Google itself, there were upwards of 400,00 hits. Clearly this is an important topic to people.

The approach present here, Mind Genomics, provides the researcher with the opportunity to structure a situation of the ordinary life, so that situation can be explored with ordinary people, an exploration that can be done in a matter of hours and days, at an affordable price, in a structured, templated fashion anywhere in the world, and with powerful knowledge and tools emerging from the exercise [1,2]. The objective is to see whether or now the Mind Genomics science can produce new-to-the-world information in hours and days, teaching the profession new things, providing new tools for the world of health.

Doing the Study

The Mind Genomics approach works by creating vignettes, combinations of ideas pertaining to the topic, instructing the respondents to rate these vignettes on a scale, and then deconstructing the rating to estimate the contribution of each of the ideas or elements to the overall rating. The rationale for this ‘indirect’ approach is that the test stimuli more naturally approximate what the person might experience in everyday life. Rather than having the respondent evaluate ideas one by one, as is done in typical questionnaires, Mind Genomics reduces the intellectual burden by simply having the respondent respond with an immediate feeling to what is read.

The nature of the stimuli, these vignettes, deserves explication because of the power of the approach:

The vignettes evaluated by the respondents are created by so-called experimental design. The experimental design prescribes the precise combination of elements to appear in each vignette. The use of experimental design to create the combinations means that each respondent’s data can be analyzed totally separately, for that respondent, OR incorporated into an analysis for a defined group of respondents. This is called a ‘within-subjects design,’ and constitutes a powerful features for analysis.
Each respondent evaluates a totally different set of vignettes, the totally different sets created by a systematic permutation of the elements, with the statistical properties of the underlying experimental design maintained [3]. Thus, the researcher can do studies on topics without having had to plan for a long time in order to make sure that the testing is done on the ‘right’ vignettes. Mind Genomics encourages the researcher to ‘do the experiment’ rather than be subject to paralysis, to the overthinking captured by the popular adage ‘measure nine times and cut once.’ Mind Genomics encourages experimentation, not over-thinking, and as we will see below, prevents ’analysis paralysis.’
The respondent is given 24 vignettes to evaluate, one vignette after the other. The underlying experimental design prescribes the combinations. The respondent need only read and react to the vignette. The vignette is created to be simple, comprising a set of phrases, the elements, one phrase on each line, without connecting words which end up cluttering. The structure enables the respondent to ‘graze’ through the information and assign a rating. The structure also ends up being less ‘taxing’ on the respondent because the physical format of the vignette, one line (approximately) per element, requires less effort. Figure 1 shows the distribution of responses times with response times of 9 seconds or longer truncated to 9 seconds. It is clear from Figure 1 that the respondents appeared to be able to assess and rate the vignette very easily. Most of the responses times are three seconds or shorter. Whether or not the data are ‘valid’, make sense, and teach us will be discussed below.
The use of compound vignettes comprising different elements ensures that it is impossible to ‘game the system.’ In study after study, the desire to game the system emerges among academics and professionals, who feel stymied, complaining that they could not ascertain the ‘correct answer.’ It is the combinations of elements of different kinds which creates seeming a ‘blooming, buzzing confusion, ‘ in the words of Harvard’s eminent, late 19^th Century psychologist, William James..

Figure 1: Distribution of response times across all vignettes evaluated in positions 2-24

The Mechanics of Creating the elqements and the Test Vignettes

The actual construction of the study by the researcher is straightforward. The researcher follows a set of templated steps, the first being a request for four questions which explore the topic, and the second being the request for four answers to each question. When first confronted with the task of choosing a topic and then asking four questions which ‘tell a story’ or at least ‘flesh out the topic’, the unpracticed researcher in Mind Genomics finds it easy to choose a topic but becomes flustered when requested to ask four questions which ‘tell a story.’ Simply put, the education that people receive all too often focuses on choosing the right answer, or even coming up with an answer to a question. The ‘thinking’ is structured, and not necessarily good. Memory and perhaps judgment are rewarded, but not the ability to create a new edifice to house knowledge. It is at this point, the request for the four questions, that many would-be researchers ‘freeze’, often abandoning the effort in anticipated frustration.

Figure 2 shows an example of the templated format for a typical study. Panel A at the top shows the screen shots for the four questions. This is the point at which the excitement may turn to dismay. Panel B shows the Idea Coach, with a box encouraging the researcher to write a short paragraph, a ‘squib’ in Mind Genomics language. The squib provides a chance for the researcher to describe the problem in detail, and specify the nature of the answers, both in terms of tonality (explanation vs list), and in terms of style (approximate number of words, reading level, etc.). Panel C shows the types of answers returned by the Idea Coach. The actual results, viz., questions, answers (elements), and results, will constitute the remaining topics of this paper.

Figure 2: A typical set-up template for questions showing where Idea Coach enters and can be invoked. The actual text for the Idea Coach query and the four questions returned by AI are specific to the study.

The AI-enhanced feature of the Mind Genomics platform in BimiLeap.com.com is called Idea Coach. With Idea Coach, the researcher simply types in a paragraph about the topic(called here ‘squib’) , requesting questions to be asked. The Idea Coach returns with 15 questions, and later with an AI-summarization of the themes and other features of those 15 questions. The researcher selects the questions which are of interest or can request a ‘re-run’ of the Idea Coach for another 15 questions. Furthermore, the researcher can modify the paragraph to change the direction of the underlying AI as that AI attempts to create the questions.

Table 1 present the first set of 15 questions, along with the subsequent AI based summarization of patterns in these 15 questions The 15 questions appear immediately, but the AI summarized appears later, after the researcher has completed the selection of questions and answers. When looking at Table 1, one can focus on the original paragraph, the questions, and then the different types of AI summarization. These questions, or more specifically the answer book of ‘logical pages,’ one page for each request for questions (and later for answers to the questions), provides an education in and of itself.

Table 1: Results from the first effort to create 15 questions

The ingoing questions posed by the researcher are the following: Topic: We’re having a problem. We don’t know how to get patients to come back for yearly visits. How can we communicate with our patients to convince them that’s it’s important to come back? Make the questions more of explanations than just a list. Make the questions understandable to a 10-year-old. Make the questions 20 words or fewer.

When looking at the ‘top’, viz. query, it is important to keep in mind that the researcher guided the AI by giving the AI specifics. These specifics describe the topic (get patients to come back), the specific problem (how can we communicate that it’s important), how to shade the question (make the questions more of explanations than just a list), how to ensure the question is understandable (understandable to a 10-year-old), and readable (20 words or fewer). Table 1 shows the success of this effort as well as the aforementioned summarization by AI. It is important to note that the actual effort generated several of these pages, because the research was geared both to answering a question and to learning about the topic. Table 1 is meant just as an example; the final four questions were selected from different iterations of Idea Coach, each iteration taking about 15 seconds.

The final questions selected were then used as inputs to Idea Coach. Once again, each iteration focused on generating 15 answers to the specific question. The answers were obtained from Idea Coach, put into the study, and then edited manually to correct the grammar, and to make the answer simple. Table 2 show a set of answers to one question.

Table 2: Results from the first effort to create 15 answers to the first question

It is important to keep in mind that that the Idea Coach, empowered by AI, becomes itself a tool to teach the researcher. Thus, what had started as a seeming insurmountable obstacle at the time Mind Genomics was born, the issue of thinking about questions and answers, ended up generating an additional and powerful benefit, viz., education at the early stage of thinking, even before the experiment is actually run with real people.

The final set of questions and answers appear in Table 3. Keep in mind that Table 2 presents the actual questions used to generate the different answers, as well as presenting the edited answers; the editing was done by the researcher before the study was run. This process ensures simple questions, simple answers, both short, and understandable to the respondent. In the actual experiment the respondent will only see combinations of answers, and never see the questions. The role of the question is only to generate the answers, either from AI or from the mind of the researcher. One final note is relevant here. Experience shows that this process ends up educating the researcher quickly on the topic, often resulting in the desire for the researcher to put in her or his own ideas rather than relying on the AI. That itself, the creation of confidence and excitement, becomes a strong reason for using the Idea Coach.

Table 3: The four questions and their four sets of answers used in the study

The Rating Scale

The main focus of this study is on the degree to which the messages motivate the respondent, at least within this format. We do not know what the respondent will actually do when giving the messages, although previous studies in the medical world have shown that the proper messages can double the number of colonoscopies [4] , as well as substantially reduce the number of within-30-day-readmissions to the hospital for patients who were suffering from CHF (congestive heart failure) [5].

The opportunity to investigate two aspects of messaging, e.g., motivation and believability, has emerged as a way of increasing the usefulness of the Mind Genomics experiment. To this end, the research used a two-sided five-point scale, a new approach in Mind Genomics. The points on the rating scale enable the respondent to rate both motivating (no/yes) and believable (no/yes). The scale below shows these two sides, and the frequency of their selection across the 2424 vignettes, evaluated by the 101 respondents.

Rating question: Think about going to the doctor. Here’s a paragraph about a visit. How do you feel personally when you read this paragraph Choose how you feel.

Scale Points

1=Does not motivate me…AND…I have no emotional response to it 11.7%

2=Does not motivate me…BUT…I get an emotional response when I read it 10.8%

3=I can’t answer 18.8%

4=Motivates me…BUT…I have no emotional response to it 28.2%

5=Motivates me…AND…I get an emotional response when I read it 30.4%

A separate part of the Mind Genomics experience required the completion of a self-profiling questionnaire, allowing the research to obtain information about the attitudes and behaviors. These questions and answers are shown in Table 4. The respondent was present with each question separately, in a ‘pull down menu’, showing the question and the different answers. The respondent was instructed to select one answer for each question.

Table 4: The self-profiling classification questions

Executing the Study

The actual study is executed in a straightforward manner. The Mind Genomics platform, BimiLeap, enables the researcher to select the respondents, their location, age, etc., through a built-in API linked to the panel provider, Luc.id, Inc., located in Louisiana. Luc.id is actually an aggregator, sourcing respondents from different online providers, located around the world. Thus, it is possible to work with defined respondents, viz., ‘survey takers’, from anywhere in the world. These respondents have already volunteered to participate, knowing that their data is entirely anonymized. The only information obtained about them is from their self-profiling, the questions shown in Table 4, along with age and gender.

Analysis

The data from each respondent is stored in the form of a vector or row of data, one row for each vignette. Thus, each respondent generates 24 rows of data. The first sets of columns are reserved for study identification and respondent identification. The information here includes the answers to the respondents self-profiling questions, this information repeated 24 times, once for each vignette. The second set of columns shows the specific composition of the vignette, starting with the order of testing (1-24), and then 16 columns, one for each of the 16 elements. The cell for each element is given the value ‘0’ when the element is absent from the vignette and the value ‘1’ when the element is present in the vignette. By design, each row will have shown a minimum of two ‘1’s’, and a maximum of four ‘1’s.’ The third set of columns show the rating, and the response time. The last set of columns show transformed rating data, defined and described in the next paragraph.

To prepare for an appropriate analysis, the rating scale data must be transformed to present the data appropriately for subsequent regression analysis using OLS, ordinary least squares regression [6]. The objective of Mind Genomics is to relate the presence/absence of the elements to the response. There are actually two responses here: motivating (vs not motivating), and believable (vs. not motivating). The research here focuses primarily on motivating vs not motivating, but it is also interesting to find out the messages which are believable vs not believable.

The strategy to decouple motivating from believable consists of creating a new set of binary variables through simple transformations:

R5=Motivates and believable. R5=100 when the rating is 5. Otherwise R5=0.
R54=Motivates. R54=100 when the rating is 5 or 4. Otherwise, R5=0.
R52=Believable. R52=100 when the rating is 5 or 2. Otherwise R52=0.
R3=Don’t know. R3=100 when the rating is 3. Otherwise, R3=0.
R41=Not believable. R41=100 when the rating is 4 or 1. Otherwise, R41=0.
R21=Does not motivate and not believable. R21=100 when the rating is 2 or 1. Otherwise R21=0.

RTSeconds=Response time in seconds. The BimiLeap program measures the elapsed time between the appearance of the vignette and the rating assigned by the respondent. The time is measured with a resolution of hundredths of seconds.

To each of the newly created binary variables, viz., those given a value of either 100 or 0, a vanishingly small random number is assigned, this number less than 10^-5. OLS, ordinary least-squares regression, requires that the dependent variable have some minimal variable. In the case that the dependent variable has no variability, either for a given individual or for what will be the relevant subgroup, the OLS regression will ‘crash.’ For example, this might well happen when a respondent avoids the rating ‘3’. For that respondent, R3, Don’t Know, will always have the transformed value of 0. Any effort create a model or equation relating the ratings of that respondent to the presence/absence of the 16 elements will end up with the OLS regression program ‘crashing.’ To avoid that problem is simple; add this vanishingly small random number to every transformed rating, ensuring that all newly created binary values (e.g., R5 …. R21) ends up with some minimum variation. This prophylactic step ensures that all of the equations will run when OLS regression is used.

OLS Regression – Relating the Presence/Absence of the Elements to the Binary Variables and Response Time

The objective of Mind Genomics is to quantify the contribution of the individual ideas or elements as they drive a dependent variable. The key variable in this study is ‘motivates’, captured by the newly created binary variable, R54. Whenever the vignette is rated as motivating (rating 5 or 4), R54 becomes 100. Otherwise, R54 becomes 0. Given this information, can we determine the degree to which each of our 16 elements ‘drives’ that rating of ‘motivates’? The answer to the foregoing question is a simple YES, due to the effort made in the set-up of the vignettes according to experimental design. The permuted experimental design ensures that each of the 16 elements appears statistically independently of every other one of the 16 elements, that there are some ‘incomplete vignettes’, lacking an answer from question or an answer from two questions. These properties enable the OLS regression to estimate the absolute value of the driving power of the element.

The driving power of the element is the magnitude of the coefficient in the equation below:

DV (dependent variable)=k₁A1 + k₂A2 … K₁₆D4

The additive model does not depend upon an interpretation of the data. Rather, the OLS regression simply uses the mathematical properties of the data to estimate the 16 coefficients. The additive constant is not calculated for the simple reason that it is important to be able to compare the coefficients from one study to another, in terms of their absolute values. The only way this comparison can be ensured is to force all of the information to be embedded in the coefficient. By having an additive constant, a baseline, the researcher has to first account for differences in baseline, and then account for differences in coefficients, considering the baseline. That effort is not productive when one is attempting to create a large-scale database across topics, across culture, and across time. It is more reasonable to estimate the coefficients without the complications caused by the additive constant. This change in the computation formula has been slowly emerging, prompted by the desire to understand the ‘stories’ embedded in different studies as they are revealed by the coefficients

Creating the Models or Equations for the Total Panel for the Different Dependent Variables

The Mind Genomics effort ‘comes alive’ when we look at the ‘meaning’ of the strong performing elements, if indeed we do have these elements. For Mind Genomics studies, the notion of ‘strong performing’ has been reserved for those elements of a positive nature with coefficients 21 or higher, and for those elements of a negative nature with coefficients of 15 or higher. Table 5 shows only one strong performing positive element, for motivating (D4: Lifestyle guidance: They can teach you to choose water over sugary drinks, which is better for your body), and only two strong performing negative elements, both for believable (D4: Lifestyle guidance: They can teach you to choose water over sugary drinks, which is better for your body, and C4. For children: They check if the child’s teeth are growing well).

Table 5: Coefficients for models (equations) relating the 16 elements to the newly created binary variables, and for response time (RT), The table is sorted by the values of coefficients for ‘motivate’ (R54).

The foregoing results are confusing. There is clear differentiation across elements in Table 5, both in terms of ‘motivating’ and in terms of ‘believable.’ Thus, the results are not due to the lack of differentiation across the elements, but perhaps to a deeper issue, e.g., the type of respondent. It may be that the 101 respondents comprise different groups of respondents with varying levels of interest and belief in what could be said and done in a routine doctor’s examination. If so, then the specific patterns might be elusive. The next analysis addresses this possibility by focusing on the way people describe themselves.

Responses of Key Subgroups in Terms of Motivate

The Mind Genomics process generates a great deal of data. The most practical way to deal with the plethora of information is to focus on one dependent variable, using that variable as the lens through which to examine the mind of the respondent as the respondent evaluates the vignettes. Once we focus more precisely, using one dependent variable, we will end up with many more strong performing elements, as we see in Table 6, where we focus on one variable (motivates, R54), and were we have divided people by what they say about some of their motivations and activities pertaining to health and lifestyle.

Table 6: Coefficients for the 16 elements for ‘motivates’ emerging from separate analyses of respondents self-defining themselves by their pattern of behavior and thinking (defined by the columns).

Table 6 is more gratifying because it shows many elements driving motivation, not just one element as we saw for the total panel in Table 5. Yet, in this increased number of strong performing elements it is difficult, indeed almost impossible, to synthesize a meaningful pattern. Knowing the way, a person answers questions about her or his attitudes and behaviors regarding the world of health and social interaction does not really allow the doctor to deeply understand the patient, at least in a formal, structured level. There may be some clues in the different classifications, but once again the lack of a clearly interpretable pattern emerges, this time with the plethora of strong performing elements, a plethora which seems to be incapable of simple definition. Face with this type of pattern, it is not surprising that many practitioners fail to understand their patients, at least in a structured way. The literature may be filled with data about specific medical conditions and their correlation with indices, but we fail to see tight connections.

Mind Sets

A hallmark of Mind Genomics is the focus on the search for basic groups in the population defined by the way they think about specific, granular topics. The ‘regular visit to the doctor’ is such a granular topic. The introduction to this paper talked about the general issue of what patients want from their doctors. The topic of a regular visit to the doctor puts the person’s thinking into a far more concrete realm. The material that the respondent may have to examine and evaluate need not be large scale issues, but may paint concrete ‘word pictures’, describing a very ordinary situation. Thus, as a research tool to understand the mind of the patient, or indeed of anyone, the Mind Genomics science provides a tool that can be honed and sharpened to a micro-focus on the minutia of a topic, minutia which might see irrelevant in the big picture, but might be exceptionally relevant to the topic.

The creation of mind-sets is a straightforward process. The researcher follows these steps, each transparent, each simple, using well-defined and statistically valid methods.

Step 1 – For each respondent create a model relating the presence/absence of the 16 elements to the binary transformed rating. The dependent variable here is ‘motivates’, R54. The model, estimated by OLS regression, is valid because the initial experimental design ensured that each respondent would evaluated a set of 24 vignettes, designed analysis by OLS regression [7].

Step 2 – Create the matrix of 101 rows (one row for each respondent) and 16 columns (one column for each element).

Step 3 – Use k-means clustering to divide the set of 101 respondents twice, first into two non-overlapping groups, and then into three non-overlapping groups [8]. The k-means clustering program used by Mind Genomics computes a ‘distance’ between pairs of respondents based upon the degree to which they are parallel, viz., the degree to which they trace out the same pattern. The measure of distance is the quantity ‘1-R’, where R is the Pearson correlation coefficient. R has a high value of +1 when the two sets of coefficients are perfectly parallel, and thus have ‘no dissimilarity’ or ‘no difference’ in their patterns. The value (1-R) is then 0. In contrast, when the two sets of coefficients move in opposite directions, then R has a value of -1, and the quantity (1-R) becomes 2.0. All pairs of respondents generate some number between 2 and 0.

Step 4 – The k-means clustering program assigns the respondents to the clusters so that the distances between pairs of respondents within a cluster are small, whereas the distances between pairs of centroids of the clusters are large.

The clustering is not exact, but rather a heuristic. The objective of the clustering is to discover presumably more meaningful groups of respondents. The clustering algorithm does not consider any meaning attached to the elements, but rather uses numerical magnitudes. That is, there is no effort to interpret the clusters.

Henceforth, this paper will use the phrase ‘mind-set’ instead of the term ‘cluster,’ in order to keep the spotlight on the effort to understand the way the person thinks about a topic.

Table 7 shows the coefficients estimated for Total Panel, for the three-mind-set solution, and for the two-mind-set solution, respectively, both emerging automatically from the BimiLeap program. The three-mind-set solution seems to be the more powerful solution, producing many more coefficients of high magnitudes (21+). The two-mind-set solution seems to be a bit weaker. Furthermore, the three mind-set solutions appear to be more interpretable, indeed quite easy to interpret:

Mind-Set 1 – Focus on visit to monitor the child
Mind-Set 2 – Focus on vitals and advice on eating
Mind-Set 3 – Focus on advice to lead a healthful lifestyle

Table 7: Performance of the elements by total panel, by three mind-sets, and by two-mind sets, respectively. The elements are sorted by the performance among the three emergent mind-sets.

The attraction of the mind-set solutions is undeniable because of its simplicity. Although the experience of participating in these Mind Genomics studies often exasperates professionals because they cannot ‘guess the right answer’, the reality is that ordinary people have no problem suspending their critical thinking, responding intuitively, and generating powerful results.

Identifying the Respondents by Attitude Versus by a ‘PVI’ (Personal Viewpoint Identifier)

A continuing finding in Mind Genomics is that who a person IS, or how the person says she or he thinks about a topic often does not co-vary with how the person responds when confronted with specific, granular issues relevant to the topic. This lack of correspondence between what a person ‘say’s and how the person actually responds can be seen from the pattern of percepts in Table 8. At the start of the Mind Genomics ‘experiment’, before evaluating the vignettes, the respondent completed a self-profiling classificaiton, comprising standard questions of gender and age, and then up to eight questions selected by the researcher, usually questions relevant to the topic.

Table 8: Distribution of answers to self-profiling questions by the total panel, and by the respondents in the three mind-sets.

Table 8 shows the self-profiling classification questions, and the percent of respondents selecting each answer. The clarity so evident in Table 7, based upon the response to the granular elements fails to emerge when the respondents separately profile themselves. Indeed, from Table 8 it would be difficult if not impossible to discern the presence of three radically different mind-sets

In recent years a new focus has been on the identification of individuals belonging to specific mind-sets, an effort which has ended up improving outcomes in the world of medicine. By knowing the mind-sets of patients discharged from the hospital after a bout with congestive heart failure, the results suggested a decrease in the within 30-day readmission from 17% down to 5% for the patients in the ward were ‘mind0typed’ after release and given the appropriate motivation material to put on their refrigerator [9]. The creation of the PVI, the personal viewpoint has been made available world-wide at the website www.pvi360.com. The program to create the PVI uses the output of the Mind Genomics study to create the PVI [10].

Figure 3 shows the first two parts of the PVI. Panel A comprises a set of questions about the respondent, with these questions ‘optional’. The rationale for these questions is primarily patient management, viz., the practical issue of picking up relevant patient data when the PVI data are included in a large-scale database. The PVI user can choose not to ask certain questions. Panel B comprises a set of six questions, coming directly from the results of the study, with the request for the person completing the PVI to choose one of two answers to each question. The six questions are randomized across the people who complete the PVI. The pattern of answers to the six questions map to the most likely of the three mind-sets, assigning the respondent to that mind-set. The important things to remember are that the language of the PVI questions is exactly the same language as that used to create the mind-sets, and that the PVI is an enhanced ‘guess’ about mind-set membership, but a guess based on actual response to relevant questions..

Figure 3: The first two parts of the PVI. Panel A shows the up-front questions about the respondent. Panel B shows the six questions and the two answer for each question.

The desire to know more about the patient and the medical experience has produced an additional feature of the PVI, so-called specialty or additional questions. These questions ‘tag along’ at the end of the actual PVI exercise. They enable the researcher to find out more information about a topic, and at the same time know the mind-set of the respondent who is answering the questions. The additional questions can be up to 20 in number, providing extensive additional information about the way mind-sets feel about other, related topics. These additional questions appear in Figure 4. The combination of additional questions with the PVI provides the researcher with a new tool to understand how to communicate with patients of different mind-sets, for a specific medical (or other) topic.

Figure 4: The third part of the PVI, the specialty or additional questions

How Good are the Data – The IDT (Index of Divergent Thought)

Up to now the focus has been on the use of Mind Genomics to understand how people think. During the years that Mind Genomics has been used, again and again it has become obvious that users of Mind Genomics go through a learning process. The researchers don’t really understand how to think creatively in the way Mind Genomics structures the process. At first the researchers grope around, often relying on Idea Coach to help them, but without a sense of what might be a strong question, and what might be cogent and meaningful answers. Creating a measure of ‘goodness of the study’ has become increasingly important as the use of Mind Genomics has evolved from consumer research professionals to young doctors, college students, and then high school and middle school students, and finally to grade school students.

The IDT (Index of Divergent Thought) is an attempt to quantify the ‘goodness’ of the study, through the summation of the weighted squares of the positive coefficients. Table 9 shows the computational formula. We already know the coefficient of each of the 16 elements for total panel, and for both the two mind-set solution and the three mind-set solution, respectively.

Table 9: The IDT (Index of Divergent Thought), measuring the performance of the study in terms of incorporating ideas which perform strongly.

The IDT is 74, very respectable for a study of this type. The IDT turns into a benchmark, as the researcher searches for elements which represent strong performers, especially for the total panel, or in the case of mind-sets, among at least one of the two mind-sets, and one of the three mind-sets, respectively. After all is said and done, in the end, the IDT can become a way for someone to measure progress in thinking.

AI Interpretation of the Three Mind-sets

At the start of the study, viz., when the elements were being created with the help of Idea Coach, one of the outputs of the process was the ‘Idea Book’, presenting the different sets of questions or answers, each set resulting from a query submitted to AI. After the BimiLeap platform used Idea Coach to develop the 15 questions or answers, these questions or answers were stored and ‘summarized’ set by set using a group of queries. The summarization generated a page of instructive output, shown in Tables 1 and 2, respectively.

The same approach was used for AI summarization of the results for each key subgroup of respondents. The summarization was done only for the elements with coefficients 21+ for positive variables (e.g., R54=motivates), and only for elements 15+ for negative variables (e.g., R21=does not motivate). When no element satisfied the threshold value the summarization was not done.

Table 10 presents the AI summarization for the strong performing elements for the three mind-sets, computed for the dependent variable R54. The AI summarization becomes a way for the researcher to better understand the results and perhaps the patterns emerging from the aspects and commonalities of winning elements.

Table 10: AI summarization for the strong performing elements for each of the three mind-sets emerging from the three-mind-set solution.

Discussion and Conclusions

Although one may often believe that years of experience with patients provides a strong sense of ‘what to say’ to each individual patient, the reality is that the proper communication with patients is necessary, but rarely well understood, and may require far more experience and guidance/coaching than might commonly be thought. Colloquially, some of this is encapsulated in what is colloquially called the ‘bedside manner’, but such a simple catch-all phrase can hardly do justice to the complexities presented in the visit of a patient with a doctor.. The literature about ‘what patients want from doctors’ recognizes the lack of deep information that is readily at the hands of the practitioner, can be sensed from some of these quotes from the public academic literature.

Although much has been written about what patients Then they contact their general practitioner (GP), there are no published data from large cohort studies of what patients expect…… most patients come to the consultation with a particular agenda. Failure to address this agenda is likely to adversely affect the outcome of many consultations [11].

The results showed that people ‘preferred’ the explanations based on what the participants in the earlier study wanted to know about their medicines, rather than those based on what the doctors thought they should be told. They also ‘preferred’ the explanations that did not convey negative information, rather than those that did convey some negative information. In addition, the inclusion of negative information affected ratings of likely compliance with the prescribed medication [12].

Most of the expectations in qualitative studies were related to the function “Fostering the relationship”. Similar expectations arose less often in quantitative studies. Conclusions Patients do have concrete expectations regarding each of the functions to be met in the medical encounters. The research approach tends to bias the results. Practice implications the collected expectations suggest how physicians may perform each of their tasks according to the patient perspective. Future research on patients’ communicative expectations needs to overcome the gap between qualitative and quantitative findings [13].

Patients want many things from their doctors, not all of which are possible. Below, however, is a list of things that patients seem to want from their doctor, and which should be possible. ….Eye contact… [14].

The study presented here is among the first to deal with the use of Mind Genomics to explore in detail the description of the interaction between the medical professional and the prospective patient. Mind Genomics provides the opportunity to describe the different facet of the doctor patient relationship in various conditions, with the descriptions emerging from the combination of AI (Idea Coach) and the doctor as co-generators of ideas, and the response of real people to these descriptions.

The ability to do these research projects with hours and days, from the generation of the topic to the creation of the study and finally to study execution and detailed analysis, promises to create a new corpus of knowledge about the world of everyday health and illness from the point of view of how a person perceives that world. The use of ordinary language, the ability of Mind Genomics to prevent guessing, the objectivity of the study was conducted on a computer, and finally the use of clustering to find mind-sets and typing tools to assign mind-sets, all promise a database of knowledge, at least interesting even if not eventually transformative.

References

Moskowitz HR (2012) ‘Mind genomics’: The experimental, inductive science of the ordinary, and its application to aspects of food and feeding. Physiology & Behavior. [crossref]
Moskowitz HR, Gofman A, Beckley J, Ashman H (2006) Founding a new science: Mind genomics. Journal of Sensory Studies 21: 266-307.
Gofman A, Moskowitz H (2010) Isomorphic permuted experimental designs and their application in conjoint analysis. Journal of Sensory Studies 25: 127-145.
Oyalowo A, Forde KA, Lamanna A, Kochman ML (2022) Effect of patient-directed messaging on colorectal cancer screening: A Randomized Clinical Trial. [crossref]
Gabay G, d Moskowitz HR (2019) “Are we there yet?” Mind-Genomics and data-driven personalized health plans. The Cross-Disciplinary Perspectives of Management: Challenges and Opportunities, pp.7-28.
Dismuke C, Lindrooth R (2006) Ordinary least squares. Methods and Designs for Outcomes Research 93: 93-104.
Gofman A, Moskowitz H (2010) Isomorphic permuted experimental designs and their application in conjoint analysis. Journal of Sensory Studies 25: 127-145
Ahmed M, Seraj R. and Islam SMS (2020) The k-means algorithm: A comprehensive survey and performance evaluation. Electronics 9(8): 1295.
Gabay G &d Moskowitz HR (2019) “Are we there yet?” Mind-Genomics and data-driven personalized health plans. The Cross-Disciplinary Perspectives of Management: Challenges and Opportunities, pp.7-28.
Davidov S, al Humaidan, M, Gere A, Cooper T, Moskowitz H (2021) Sequencing the ‘dairy mind’: Using Mind Genomics to create an “MRI of Consumer Decisions”. In: New Advances in the Dairy Industry. IntechOpen.
McKinley RK, Middleton JF (1999) What do patients want from doctors? Content analysis of written patient agendas for the consultation. British Journal of General Practice. [crossref]
Berry DC, Michas IC, Gillie T, Forster M (1997) What do patients want to know about their medicines, and what do doctors want to tell them? A comparative study. Psychology and Health 12: 467-480.
Deledda G, Moretti F, Rimondini M, Zimmermann C (2013) How patients want their doctor to communicate. A literature review on primary care patients’ perspective. Patient Education and Counseling. [crossref]
Stone M (2003) What patients want from their doctors. BMJ 326(7402): 12326doi: https://doi.org/10.1136/bmj.326.7402.1294 (Published 12 June 2003

The Significance of Sensory Disorders in Autism

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DOI: 10.31038/PSYJ.2023572

Abstract

Background: Autism is said to be a Neurodevelopmental Disorder which has a whole range of different strands. One of the most overlooked and misunderstood is the sensory differences – often referred to as Sensory Processing Disorder (SPD) or Sensory Integration Disorder (SID).

Aim: The aim of this study is to improve the understanding of the sensory differences and their implications in autism.

Methodology: Qualitative methods that include observation, personal accounts and ongoing research.

Current situation: Today unusual responses to sensory stimuli are recognized by many individuals with autism, their families and many professionals working in the field of Occupational therapy who work with them, although their significance is often overlooked by professionals working in other disciplines.

Summary: This study will show that both the sensory differences and their significance has been known for centuries. It will also propose that they are of great significance in autism for they affect every aspect ofindividual’s daily life.

Keywords

Autism, Neurodevelopmental delay, Sensory differences, Sensory processing disorder (SPD), Sensory integration disorder (SID), Soft neurological signs, Aberrant reflexes, Visual differences, Auditory differences, Tactile differences

The significance of our senses in development has been known for centuries, as was summed up by the German philosopher Immanual Kant in the 18^th century when he said, “All our knowledge begins with the senses, proceeds to understanding, and ends with reason.” During the 19^th century great doctors like Drs. John Langdon Down and the French physician Édouard Séguin worked with a range of children with learning disabilities of various kinds, while some of their other contemporaries worked with children who were blind, deaf or deaf-blind. As a group they were all keenly observant as can be seem from their books and papers, all having a real understanding of the sensory differences and their implications. During the time that Dr J.L. Down ran the Earlswood Asylum he noted that some of the children there fitted into different groups, some having savant skills and others having the “mannerisms and behaviour” that we would connect with autism today.

In a paper written in 1907 Dr Séguin made a comment worth repeating and, although his terminology is unpleasant to our ears, its importance is undeniable. As he noted, “Deafness and blindness from birth have the same effects as paralysis on ungifted children, by depriving them of the cognizance of a whole series of phenomena. But it is a fact curious enough to be noted, that partial obliteration of one of these channels of knowledge will produce the symptoms of superficial idiocy surer than its complete destruction.” Moving into the 20^th century we find that the importance of the sensory differences and their possible link to autism was highlighted by Bergman and Escalona in their [1] paper “Unusual Sensitivities in Very Young Children.” As they wrote “Colors, bright lights, noises, unusual sounds, qualities of material, experiences of equilibrium, of taste, of smell, of temperature, seemed to have an extraordinarily intensive impact upon these children at a very early age.”

In 1964 the seminal book Infantile Autism by Dr Bernard Rimland noted that many such children had unusual sensitivities in several, if not in all, their senses; an idea he supported by quoting from several studies that described peculiar reactions such as “ill focused eyes,” “functionally blind,” “blind while seeing, and deaf while hearing.”

Interest in this area has fluctuated over the decades. It gained attention in the 1960s and 1970s due to the work of several experts including the late Dr’s. Ornitz and Ritvo. In their 1968 paper they noted how common, and extremely important, those perceptual differences and their consequences were and postulating that the sensory differences could be the basis of autism [2-4].

In his book The Ultimate Stranger: The Autistic Child, Dr Carl Delcato detailed his research. While it was dismissed by many in the scientific community, his findings are importantbecause he found thatthere were three categories of sensory difference each with its own specific effects. Those three categories included children who were hypersensitive, others who were hyposensitive and a third category that he called White Noise in which those sensitivities were mixed. He also found that their mannerisms were directly linked to the sensory differences. He explained that “One or more of their intake channels (sight, sound, taste, smell, or feel) was deficient in some way. Their strange repetitive behavior was their attempt, through much repetitive stimulation, to normalize that channel or channels [5].

Delacato concluded that the sensory differences were “the most unique feature of autism.” Ornitz took that idea a stage further by suggesting that the seemingly unusual responses to sensory stimuli could be “used to identify autism in young children.”

In their book Deaf-Blind Children and Infants [6] Treffry and McInnes told us about the children they worked with, all of whom had a sensory impairment. The connection being that, as Treffry and McInnes told us, the result of those impairments was “… not a reflection of the child’s ability to process information and draw logical conclusions, but rather a measure of his ability to gather the information in the first place.”

By the late1970s personal accounts had begun to creep into the literature. One came from Jerry, a former patient of Leo Kanner who told Dr. Jules Bemporad about his childhood world which he said had consisted of confusion and terror and was “frightening” because it was full of “painful stimuli that could not be mastered.” Then there was Tony W. who recalled his childhood experiences telling us that “I was afraid of everything! I was terrified to go in the water swimming, [and of] loud noises; in the dark I had severe repetitive nightmares and occasionally hearing electronic noises with nightmares. I would wake up so terrified and disorientated” [7].

In “An Inside View of Autism” Temple Grandin noted that “My senses were oversensitive to loud noise and touch. Loud noise hurt my ears and I withdrew from touch to avoid over-whelming sensation.” She talked about her tactile problems saying that “When people hugged me, I stiffened and pulled away to avoid the all-engulfing tidal wave of stimulation. The stiffening up and flinching was like a wild animal pulling away.” She follows that by noting that “The nerve endings on my skin were supersensitive. Stimuli that were insignificant to most people were like Chinese water torture” [8,9].

Since the 1970’s some professionals (both inside and outside the world of autism) have been researching both neurodevelopment delay and the individual senses. That has led to a strong body of research that links neurodevelopment delay (and what are termed “soft neurological signs” which include aberrant reflexes) to the sensory differences. There is also a great deal of evidence that hearing can have a major impact on behavior from peoplelike Dr. G. Bérard, whose groundbreaking work continues to help many people worldwide, some with autism or other neurodevelopmental conditions [10].

Others work in the field of vision (an area in which the sensitivities are most complex). They include mild to severe Visual Impairment (VI) and what is often termed Visual Stress or Meares-Irlen syndrome. *Today research indicates that most children on the autism spectrum have severe visual stress which cause them to see the world around them as if everything is fragmented or distorted, with some even seeing faces as if they are totally blank. Since those early years there have been an increasing number of accounts (from individuals and families) about the sensory differences and the difficulties they cause. Many people are now taking those account seriously and today research is proving them to be true, as in “The pattern of sensory processing abnormalities in autism” by Janet Kern and her colleagues [11].

In 2007 the neuroscientists Henry and Kamila Markram came up with the Intense World Syndrome, based around hypersensitivity. Their initial interest in this topic was triggered by their son, who has autism. They and their colleague postulated that sensory overload interferes with social communication and language and that those obsessive and repetitive behaviors are the child’s attempt to bring order and predictability into a bewildering world. That led them to suggest that their hypothesis offers a unifying theory of autism. It is certainly a very positive theory and one that (in part) confirms previous research [12].

Comments

Research into NDD has shown that while the sensory differences and their effects are common among the neurodivergent community they are most severe in autism.
The Intense World Syndrome. The idea that sensory overload interferes with social communication and language and that those obsessive and repetitive behaviors are the child’s attempt to bring order and predictability into a bewildering world is certainly correct. The flaw being that it focusses solely on hypersensitivity whereas the sensory issues which are far more complex than that.

Conclusion

The link between sensory differences and autism is far clearer now that it has ever been. That is partially because of accounts by a range of different people from different countries across the world who are living with autism and because there is now a great body of evidence from reputable scholars working in a range of disciplines who confirm that neurodevelopmental delay can cause a range of sensory differences that have a major impact on people’s lives. In Lucy Blackman’s article “Reflections on Language” in [13-22] she asked “So, if one doesn’t have depth perception, what does that mean in terms of facial expression? If one hears the subtle sounds of speech out of order, which I do, how does one process language? If affection in the form of cuddles and kisses cause pain and discomfort in one’s infancy, how on earth does one develop interaction which might compensate for not interacting to speech and glance?” How indeed?

Conflict of Interest

The author has no conflict of interest to declare.

Funding

None

References

Bergman P, Escalona SK (1947) Unusual Sensitivities in Very Young Children. The Psychoanalytic Study of the Child 3: 1
Rimland B (1964) Infantile Autism. New York: Appleton-Century-Crofts.
Ornitz EM, Ritvo ER (1968) Perceptual Inconstancy in Early Infantile Autism: The Syndrome of Early Infant Autism and Its Variants Including Certain Cases of Childhood Schizophrenia. Arch Gen Psychiatry 18: 76-98.
Ornitz EM (1989) Autism at the interface between sensory and information processing. In G. Dawson (Ed.), Autism: Nature, diagnosis, and treatment .The Guilford Press.
Delacato C (1974) The Ultimate Stranger. New York: Doubleday.
McInnes JA, Treffry JM (1982) Deaf-Blind Infants and Children. Buckingham: Open University Press.
Bemporad JR (1979) .Adult recollections of a formerly autistic child.Journal of Autism and Developmental Disorders 9: 179-198.
Grandin T. An Inside View of Autism.
Grandin T., Margaret M. Scariano (1986) Emergence: Labelled Autistic Arena Press.
Berard G (1993) Hearing equals behaviour. New Canaan: Keats Publishing. (Original published 1982).
Kern J. et al. The pattern of sensory processing abnormalities in autism.
Markram K, Markram H (2010) The intense world theory–a unifying theory of the neurobiology of autism. Frontiers in Human Neuroscience 224.
Blackman L (2005) Reflections on Language” pp: 146-167 in Autism and the Myth of the Person Alone ed. by Douglas Biklen. New York University Press.
Mayoral M (2010) Neurological soft signs in juvenile patients with Asperger syndrome, early-onset psychosis, and healthy controls. Early Intervention in Psychiatry.
Parmar KR. et al. Visual Sensory Experiences From the Viewpoint of Autistic Adults, Front Psychol. [crossref]
Volkmar FR, Cohen DJ (1985) ‘The experience of infantile autism: A first person account by Tony W.’ Journal of Autism and Developmental Disorders 15: 45-54.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington: American Psychiatric Publishing, 2013.
https://www.disabilitymuseum.org/dhm/lib/detail.html?id=1531&page=11
http://auditoryintegrationtraining.co.uk/auditory-integration-training-ait-for-hearing-autism-adhd-add-dyslexia-and-other-special-needs-2/clinical-studies-for-auditory-integration-training/
https://blog.donnawilliams.net/2014/09/20/visual-perceptual-disorders-as-a-cause-of-autism/
https://www.brainbalancecenters.com/blog/retained-primitive-reflexes-sign-brain-imbalance
Neurodevelopmental delay – https://www.moveplaythrive.com/research/178-research-summaries-goddard

Pilot Results from the Ambulatory Electronic Health Record (EHR) Evaluation Tool: Lessons Learned

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DOI: 10.31038/JCRM.2023633

Commentary

Most studies focused on electronic health record (EHR) safety, specifically the ability of these systems to detect and prevent adverse drug events (ADEs), has been performed in the inpatient setting. To address this gap, the Ambulatory EHR Evaluation Tool was developed and piloted with seven clinics in 2019. Each of these clinics used one of the leading outpatient EHR systems, as identified by the Office of the National Coordinator (ONC) [1]. The tool consists of a medication safety test and a medication reconciliation module. For the medication safety test, it simulates a physician prescribing medications to their patients. The testing methodology closely follows the inpatient version of the tool, which is administered by the Leapfrog Group. For the medication reconciliation module, clinics were asked to electronically reconcile two medication lists.

To take the medication safety test, clinics downloaded a set of test patients and associated medication test orders to enter into their operational EHR using Computerized Physician Order Entry (CPOE). Included with these test patients were basic demographic details (e.g., age and weight), allergies, and relevant laboratory values. While entering these test orders, licensed prescribers recorded any advice or information they received (if any). The tool assesses basic and advanced decision support features [2]. Once finished with the test, clinics received an overall percentage score of unsafe orders detected, as well as individual order category scores. The test also included two subcategories: nuisance orders and fatal orders. Nuisance orders are low-priority medication combinations (i.e., drug-drug interactions and therapeutic duplications) that should be delivered un-interruptively, as they can contribute to alert fatigue [3]. These orders were reverse scored, in that clinics which alerted on these test orders were scored as “incorrect”. For fatal orders, these were high-priority medication interactions that if prescribed, can lead to serious injury and even death. Lastly, for the medication reconciliation module, we provided clinics with a test patient that was recently discharged from the hospital and is returning to their outpatient clinic for a follow-up visit. Clinics were provided with two medication lists: one from the recent hospitalization, and the most recent ambulatory medication list. These medication lists had the following discrepancies: removal and addition of a medication, and a change in the dose of a medication.

The mean overall score for the medication safety test was 54.6% (Table 1). The range was 42.5%, the minimum score was 37.5%, and the maximum score was 80%. Generally, clinics performed well in areas of basic decision support such as drug allergy (100%), drug-drug interaction (89.3%), drug dose (daily) (78.6%), and drug pregnancy (75%). In contrary, clinics performed poorly in areas of advanced decision support areas like drug age (39.3%). Most alarmingly, none of the clinics in the study had drug laboratory or drug monitoring alerts implemented. In terms of fatal order performance, the mean score was 67.9%. Only one clinic alerted on all the fatal orders in their test. For the nuisance orders, the mean score was 64.3%.

Table 1: Mean percentage scores for each order category

TAB 1

For the medication reconciliation module, three clinics (43%) had an EHR-based medication reconciliation functionality. However, only one clinic (14%) could demonstrate it during the pilot. In addition, none of the clinics’ EHR systems provided CDS during this process. Instead of electronic processes for medication reconciliation, most clinics compared medication lists manually, which was usually performed by a nurse or medical assistant.

The results from the initial pilot of the Ambulatory EHR Evaluation Tool revealed that while basic CDS features like drug allergy and drug interaction checking were widely implemented, areas of more advanced decision support were not implemented. A major commonality between all the clinics was that certain types of alerts were turned off completely. This occurred mostly in advanced decision support areas like drug laboratory, drug monitoring, and drug age; all of which are critical areas for patient safety. In addition, the mean fatal order score was only 68%, which is considered low given the severity of these medication orders. We expected all clinics to score a 100% in this subcategory. In terms of the results of the medication reconciliation module, only one clinic could demonstrate this functionality even though all the clinics were certified through Meaningful Use. Moreover, although most of the clinics understood the importance of medication reconciliation, the electronic processes at their individual facilities were poorly understood and thus unused.

In a broader context, the results from this pilot reveal significant gaps in the implementation of advanced CDS features in the outpatient setting. This is further magnified by the fact that commercial outpatient pharmacies are no longer routinely checking prescriptions for common medication errors, thus leaving the only effective medication safety net at the ambulatory clinic level. This leaves an enormous medication safety gap in the outpatient setting, where most medications are prescribed in the healthcare system. Hopefully, as this tool becomes more widely used, outpatient clinics will use it as a quality improvement tool to assess and identify gaps in the implementation of their medication related CDS, which as of now, is the only critical safety net for outpatient medication use.

References

Office of the National Coordinator for Health Information Technology. Office-based Physician Electronic Health Record Adoption. Published 2016. Accessed January 11, 2019. https://dashboard.healthit.gov/quickstats/pages/physician-ehr-adoption-trends.php
Kuperman GJ, Bobb A, Payne TH, Avery AJ, Gandhi TK, et al. (2007) Medication-related Clinical Decision Support in Computerized Provider Order Entry Systems: A Review. J Am Med Informatics Assoc 14: 29-40. [crossref]
Phansalkar S, van der Sijs H, Tucker AD, Desai AA, Bell DS, et al. (2013) Drug-drug interactions that should be non-interruptive in order to reduce alert fatigue in electronic health records. J Am Med Informatics Assoc 20: 489-493. [crossref]

Solving Epidemics of Lyme and Other Vector-Borne Infections through the Immune System

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DOI: 10.31038/IDT.2023415

“Le microbe n’est rien, le terrain est tout.” “(The microbe is nothing, the terrain is everything).” -Louis Pasteur

Abstract

Vector-borne infections such as Lyme disease and co-infections, rickettsiosis, dengue, West Nile fever, and malaria that are known for their high morbidity, and even mortality, have been globally on the rise due to several key factors. Among these are the increased population of and exposure to ticks and mosquitoes that are caused by climate change and deforestation, as well as a generally more health-compromised population as evidenced by skyrocketing prevalence of chronic diseases. The implicated factors in chronic sickness are continual rise in environmental pollution, unhealthy diet and substance abuse, overuse of antibiotics leading to microbial evolvement into more aggressive forms, disturbed biome, secondary fungal infections and antimicrobial resistance (AMR). Some of the most common vector-borne infections lack effective treatments, including chronic post-treatment Lyme disease with diagnostic tests not always being reliable. Additionally, Lyme’s Borrelia Burgdorferi, that is the most common vector-borne disease in North America and Europe, presents a particular challenge to its treatments by existing in many different genotypes with some being particularly aggressive. This article presents a different approach to vector-borne, and infections in general, based on several principal factors. These concern the increased focus on the host innate immunity to defeat infectious agents using a novel diagnosis to ascertain reasons for suboptimal immunity, treatment to address this and elicit proper immune stimulation by vaccine-like action. Both diagnosis and treatment concern energy medicine, which is formally recognized by the NIH, and based on the physics of the living, water, and all matter in nature.

Keywords

Lyme disease and co-infections, Vector-borne infections, West Nile encephalitis, Antimicrobial resistance, Bioresonance testing, Energy medicine, Homeopathy, Digital medicine

Introduction

According to the US CDC, the incidence of one of the most common vector-borne, Lyme disease has risen by 44% from 1999 to 2019 and has been responsible for almost a half-million new cases in the US annually, at a cost of some $1.3 billion a year. Studies have found that over 14% of the population worldwide in 80 countries, have contracted Lyme disease [1]. Yet, due to the presence of different strains of the bacteria, its ability to mutate, and the likely compromised immune response of the host, laboratory tests are not always reliable or drug therapies efficacious [2-6]. Consequently, as many as up to 20% of these patients remain chronically or post-treatment permanently ill with many seeking alternative treatments. Unfortunately, their shared experience and lack of published convincing results to the contrary, indicate that despite these treatments using prolonged antibiotic courses, antimalarial drugs, herbs, oxygen, ultraviolet light, electrocutions, and many supplements for immune support at the cost of up to six-digit out-of-pocket figures, their failure and harm prevail.

Many patient testimonials reveal unfortunate experiences with “progressive Lyme clinics” in the US or Europe, ending up feeling sicker and even being hospitalized. These treatments had in common the prevailing errors: excessive focus on “killing” the microbe and blinded attempts to stimulate immunity without knowing the fundamental causes of its malfunction. In light of the encountered failures with both conventional and integrative approaches, concerned Lyme specialists have called for seeking a different approach to the problem [7]. However, a true different approach, instead of usual “stronger” pharmaceuticals, must foremost involve the state of the terrain, as noted by the great Pasteur, or immunity that allows the evolvement of infection in the first place. Voluminous toxicological literature documents immunosuppressive effects of environmental pollutants which ae abundant in the modern environments, some 100,000 agents with hardly any safety testing [8-10]. According to Harvard University EPA Working Group 2007 Report, traces of hundreds of environmental pollutants have been found in the bodies of 100% tested Americans that roughly encompasses all industrialized nations.

Some of these, heavy and other metals, affect genetic and epigenetic mechanisms yet cannot be completely excreted or metabolized [11]. The exposure and pathologies commence since pre and postnatal periods and continue to accrue through food, water, and air from modern kitchens to Greenland [12-24]. Among metals, mercury that is the most toxic nonradioactive element exerts multisystemic, including immune invasion and harms through massive use of fossil fuels, and silver amalgam fillings [25-28]. Dental restorations, including silver amalgams, and ubiquitous toxic metals in the bodies of modern populations, also act as conducting receiving antennas for just as ever-present electromagnetic fields, resulting in their enhanced combined pathogenicity, further adding to the immune burden. Electromagnetic fields alone cause immune suppression, leading to chronic infections, cancer and numerous other diseases [29-36].

Also, just as prevalent and steadily rising are opportunistic fungal infections, due to a massive use of antibiotics and the high consumption of simple sugars, which cause increased immune burden, immunosuppression and immune invasion [37,38].

Additionally, antibiotics further impair the host resistance by altering immune response, damaging immune cells, the microbiome, and possibly the human genome that contains numerous bacterial remnants, thus exacerbating the vicious cycle and compromising overall health [39,40]. Consequently, they have been associated with many chronic diseases, including malignancies, with antibiotics produced AMR causing 700,000 global annual mortality that is expected to reach 10 million by 2050 [41,42].

Besides the known serious limitations of laboratory tests to diagnose toxicological agents where it counts the most, inside the internal organs in the living, infectious agents, including Lyme and co-infections bacteria, may elude these tests too [43-45]. Physics-based alternative medicine bioresonance test, applied kinesiology, has been used to address this diagnostic gap. Likewise, physics-based homeopathic or homeopathic-like copies of toxicological, infectious or any pathogen, isodes, have been employed for their established, based on hormetic effect, detoxification of toxicants, and antimicrobial vaccine-like immune stimulation [46-57]. The offered advantage of such immune enhancement therapeutics is the replacement of a direct microbicidal effect to avoid triggering mutations and antimicrobial resistance, with vaccine-like specific immune stimulation against infectious agents. Recently published studies and case reports presented the efficacy of this approach for COVID-19, and resolving pneumonia, and H Pylori infection without antibiotics [58,59].

In the long experience of this author, homeopathic remedies prepared from organs, sarcodes, indicated additional detoxifying and restorative effects likely due to enhancement of homeostatic function to expel xenobiotics. Remedies prepared from bodily fluids in order to dispel contained infectious or toxicological agents represent autoisodes. Isodes, sarcodes, and autoisodes have been registered with the American FDA and its many counterparts worldwide. Since homeopathic remedies largely represent energetic signals, not chemical substances, materials scientists and physicists deem that the prevailing portrayal of these remedies as overdiluted placebos, constitutes “distortion of and ignorance in science,” and “unnecessary confusion.” [60-72]. Considering that physics deems the living to be fundamentally electromagnetic systems, their response to meaningful energetic signals is obligatory [63-75].

Capitalizing on this premise, we can use the immune system, instead of drugs, herbs and other “killing” means, to dispense with infectious agents and also cultivate, unlike antimicrobial agents, future resistance against it, through vaccine-like energetic signals. Well-known matter-energy duality, natural resonance frequency phenomena in physics, and water science support imprint of energy fields of microbes in water, thus creating agent specific energetic vaccines. This approach utilizes the same immune stimulation principle as the pharmaceutical vaccines – delivery of a weakened microbe – but only in its energetic, instead of material molecular form (Figure 1).

Figure 1: Immune stimulation principle

Materials and Methods

The applied sarcodes and isodes were obtained from homeopathic pharmacies. Most of the time, sarcodes and isodes were used after adjusting their potencies by an automated water programming device* in order to better match the patient’s individual disease state, according to bioresonance testing.

The same water programming platform was used to prepare autoisodes. Scientific literature referred to energetically modified high-dilution homeopathic remedies as homeopathic-like [76]. Medical Nobelist Montagnier, among other researchers, produced positive biological responses with electronically modified high dilutions and immunologist Benveniste named this paradigm digital biology [77-81]. An automated platform can be particularly helpful in acute and life-threatening emergencies when effective antimicrobial drugs do not exist, or are available, and shortens the production of vaccines from years, for pharmaceutical ones, to minutes, for energetic ones.

Bioresonance testing, applied kinesiology, is based on phenomena of resonance, matter-energy duality, and natural resonant frequency of all matter in nature, including the living. The diagnostic tissue resonance interaction method has been used as a highly specific and sensitive technique for cancer detection [82]. The test is performed with a subject in a supine position on an examining table, holding a metal rod that is connected to a metal platform through a cable forming a conductive circuit between a testee and the platform. When glass vials with energetic imprints of body organs, toxicological, infectious, or other pathogens are separately placed on the platform, a person responds to their corresponding fields with an involuntary muscle stress response, if a tested substance is related to their pathology [83,84]. Muscle response displays a change of tone and a slight movement of the right leg. This reaction can be likened to self-awareness of meaningful information, as in a lie detector test through stressful brain wave pattern. Due to multiple intertwined connections between skin and internal organs, more than a single mechanism of response might be involved. The conduction circuit would encompass the brain and spinal cord with sensory and motor nerves, autonomic nervous system, widespread connective tissue, and biological water that possesses permittivity and connection with DNA [85-93]. A tester detects the muscle response by holding his/her hands on the subject’s ankles. In the event of a tested substance not being part of the pathology, muscle response is absent. The test can also determine the potential benefit, absence, or iatrogenicity of a tested therapeutic substance. On the whole, the test utilizes the same fundamental properties of the living, electromagnetism and electronics, as all biophysical tests such as ECG, EEG, and MRI.

Treatment of all of the cases was guided by bioresonance testing that also suggested otherwise, undiagnosed Lyme disease. Testing and treatment of the cases primarily focused on detection of toxicological agents, opportunistic fungal, parasitic, and viral infections, residues of antibiotics, endocrine impairment of excessive electromagnetic radiation, all of which have known immunocompromising effects. Basic healthy lifestyle guidance was provided in eliminating simple sugars, and reducing exposure to environmental pollutants and electromagnetic radiation that was not always optimally followed.

___________________________________________________

^*Therapeutic Frequency Imprinting Device, US Patent #10941061

Patient Cases

Case 1

Man in his forties with a recent diagnosis of Lyme disease, but suspecting having had it since his 20s. Complaints: poor memory, anxiety, neurological symptoms, decreased vision, poor energy, sex drive, with head and back pains. He tried many alternative treatments without success. After a fairly short series of remedies, he reported feeling the best he had in years and virtually free of symptoms.

Case 2

An alternative practitioner in her 40s with Lyme disease and head-to-toe problems for several years: decreased memory, burning mouth, fears, knee and back pain, headaches, hypoglycemic spells with sugar cravings, thyroid malfunction, poor energy, and an inability to lose excessive weight. After a few treatments, she reported feeling ‘the best ever in my life.’

Case 3

A woman in her 40s with massive body breakdown over the years, and a tentative Lyme diagnosis. Presented with periodic fevers, debilitating back pains, fatigue, headaches, photophobia, abnormal space perception, food allergies with cravings, multiple infections, parasitic, bacterial, viral, enlarged lymph nodes, and a neurological voice disorder. Many prior treatments did not help. By the end of her treatment course, she reported: “I feel so much better than when I started. I keep being amazed by it.”

Case 4

A woman in her thirties, with debilitating symptoms for years, was diagnosed with Lyme disease and Bartonella, two years prior to the visit. Neither prolonged multiple antibiotic treatments nor integrative treatments worked. She complained of intense pains with other neurological symptoms and fatigue. Other symptoms: excessive weight gain, food intolerances, respiratory and vaginal infections, severe mental impairment with brain fog, falling down after making even a few steps, auditory hallucinations of birds chirping, loose bowel movements, and depression. Her integrative MD was planning on implementing a special Alzheimer’s alternative and pharmaceutical drug program.

Besides Lyme, bioresonance testing detected other pathogens, especially affecting her brain: pesticides, herbicides, (she lived in a farm region), solvents, mercury, and flu virus. Following a single treatment, she reported that she stopped falling down, had a substantial increase in energy, disappearance of auditory hallucinations, and normalized bowel movements. Alzheimer-like mental state disappeared too, with an increase in mental clarity, word recall, and overall feeling much healthier and happier.

Case 5

A middle-aged woman complained of chronic facial pains and twitches, fatigue, anxiety, fears, and headaches. She was unsuccessfully treated by an osteopathic doctor and a pain specialist with a published book on the subject. Among other causes, bioresonance testing identified Lyme infection affecting her trigeminal nerve and TMJ. She responded to the treatment well, and regained a normal life. Her pain specialist doctor supported this approach.

Case 6

A nine-year-old girl was referred to a psychiatrist for psychotropic medications by a surrendered child psychologist, because of the therapist’s inability to remedy her progressing restlessness, OCD, aggressiveness, moodiness, and overall unpredictable behavior over the years. Bioresonance testing suggested mercury, Lyme, and strep infections in the brain. She was 90% cured after a single treatment and completely after the second one. “She is just normal. Huge change, huge, huge, since we came here,” said the mother.

Case 7

A woman in her sixties with generalized joint pains, chronic anemia, and fatigue. She was treated for years by her rheumatologist with two anti-inflammatory drugs for rheumatoid arthritis. Bioresonance testing detected Lyme infection and mercury in her joints and bone marrow. Within a year, she came off both drugs, had her anemia resolved, and quality of life restored to normal.

Case 8

A man in his fifties frequented emergency rooms with typical heart angina pains. All heart tests, including coronary artery catheterization performed at a prestigious university heart center, turned normal and his cardiologists offered no diagnosis. Bio-resonance testing suggested Lyme carditis and following brief treatment his chest pains ceased.

Case 9

A middle-aged woman suffered from debilitating migraine headaches for many years. The major cause seemed to be a missed Lyme infection in the brain. The outcome: resolved migraines.

Case 10

A woman in her sixties underwent a complete personality change with severe depression, anxiety, panic attacks with crying, compromised cognition, blurred vision, sensation of inflamed brain, arthritic pains, fatigue, dizziness, and inability to read due to poor focus, or retain information. After two years of unproductive treatments by conventional specialists, she was diagnosed with Lyme and co-infections by an integrative MD. Weeks of several antibiotic treatments along with supplements hardly helped. I advised her to stop all of her antibiotics and supplements, due to the detected side effects by bioresonance testing. Despite her fear of stopping the antibiotics, she had to discontinue one of these anyway, admitting to suffering its side effects. Following her first treatment she reported that her arthritis, panic attacks with crying, and inflamed brain were resolved; her energy and focus considerably progressed, with brain fog and dizziness being hardly present. She stated: “I can tell you that on your drops, especially the Lyme ones, I felt much more Herxheimer reaction than on my antibiotics.” Following the discontinuation of her second antibiotic and receipt of another treatment, she reported that her problems were gone.

Comment: The more intense Herxheimer reaction implies more intense apoptosis of bacteria, due to a potent immune response.

Case 11

A young woman with dozens of mental, emotional and physical symptoms combined, reluctantly followed my advice to discontinue her antibiotics for Lyme and co-infections. Following her first treatment, she reported no longer looking and feeling like a corpse, and even the return of her five-year absent sex drive since the onset of Lyme disease. She also reported much improvement in her pains leading to decreasing her opiate pain regimen, and internal body vibrations with muscle twitches that she had suffered after using some “Lyme electrocuting machine”. She too, noted stronger Herxheimer reaction to homeopathic-like Lyme drops, compared to all of her prior antibiotics.

Case 12

Man in his early sixties with multiple medical problems for years: sinusitis since infancy, fatigue in the afternoon for decades, brain fog, arthritic pains, and chocolate cravings. All these were resolved in eight-nine visits.

Case 13

Fifteen-year-old boy treated with several courses of antibiotics for Lyme infection. However, his complaints persisted: fatigue, headaches, arthritic pains, shortness of breath on walking, low appetite, difficulty with schoolwork. All of these have been resolved after a few treatments.

Case 14

Athletic man in his twenties, with fatigue, depression, panic attacks, body heaviness, brain fog, compromised short-term memory, motor speech problems, and a sense of body detachment for years. He received over a half dozen psychotropic drugs throughout the ordeal and was still consuming a few. After eight months of the treatment, reported being off psychotropic drugs for months for the first time in twelve years. Most of the problems were resolved, with others better or much better. He noted, “My workplace is so loaded with computers and fluorescent lights which I believe drain me and slow my complete recovery.”

Case 15

A woman in her thirties on a continuous 15-year antibiotics treatment. The latest regimen consisted of four antibiotics for chronic Lyme, Bartonella, sinus, and urinary tract infections. She was receiving other drugs for years, eleven in total, also for chronic Babesiosis, herpes and candida infections, a peptic ulcer, and countless other ailments. Virtually bedridden for many years, she was also receiving intravenous mineral and fluid infusions for severe fluid-mineral imbalance with dehydration and generalized edema. She was managed by prominent Lyme disease specialists who used multiple drug regimens, but her response was so poor that some of them even advised her to seek alternative treatments. The latter harmed her.

The initial bio-resonance testing indicated an even greater number of present chronic bacterial and viral infections, as well as systemic candidiasis. Mercury toxicity was also prominently present, likely due to silver amalgam fillings and a flu shot containing thimerosal received in the past that made her bedridden. Further follow-up testing indicated one of her cats as the Bartonellosis carrier which a blood test confirmed. The total iatrogenic damage in this case was so substantial that there were concerns about it taking years to mitigate. However, within the first two months of weekly treatments, she was able to discontinue all of the drugs and intravenous infusions that she was unable to do for years, since a cessation led to an increase in pain and all of her ailments. Nine months into the treatment, she reported having more energy, stamina, a positive outlook, and a far better quality of life.

Case 16

“My journey began working as an RN in a small rural hospital. During this time, I became a mother of six children and I started having reactions to nearly every medication I tried to put into my body, from lidocaine to antibiotics, to a Mantoux test. I would begin to shake and have involuntary body movements. Following a trip to the Mayo clinic, I was told it was all in my head. In 2009, I began to feel very fatigued and began to experience episodes of involuntary movements that lasted longer and were more dramatic. The naturopath found that I had elevated mercury in my system and then, during the process of removing my mercury fillings, I was introduced to FCT*. I was barely able to work most days, some days I had no ability to figure out how to prepare a meal, and I had no awareness where my limbs were in space. My first FCT testing found that not only did I have mercury in my system, but I also had Lyme and 2 or 3 other co-infections from the tick. This was later confirmed through laboratory blood work. The medical doctor recommended two antibiotics to be taken for a year. I chose to be treated with FCT which involved taking 1 drop of energized water, under my tongue, of each of the different causative agents that were making me ill, and also, ones that would support the tissues that were stressed. I made a complete recovery until I was bitten by a tick again in 2011 and once again chose to treat Lyme with FCT.

I am familiar with many other patients who have chosen the antibiotic route and they still have symptoms, or if they try going off them, their symptoms return. I know one gentleman who has been on antibiotics for 3 years with no resolution to his Lyme symptoms if he tries to go off them. I live a full and wonderful life, hiking, fishing, skating, skiing, and caring for my grandchildren. I am truly fortunate to have found FCT and have witnessed the benefits that many people can have as a result of using it.

As an RN, I appreciate all the science that is behind FCT, so if God would like me to serve others by offering FCT, I will be happy to do so.

Have a wonderful day!”

Annette Roiko, RN 1/17/14

*FCT–Field Control Therapy® expresses the concept that health, or disease, originates from corresponding cellular fields, as per retired Stanford University Professor of Materials Science, William A. Tiller, Ph.D.

Case of a Recovered Dying Dog from Apparently West Nile Encephalitis

Although the incidence of West Nile Virus infection is relatively low, it occurs worldwide, can be lethal due to CNS involvement, and has been on the rise lately [94,95]. According to the CDC, about 1 out of 10 people with severe CNS infection die and no known effective treatment is available. The disease also affects a number of animals, including dogs. In light of these facts, this presented case might be edifying.

An elderly dog of a patient of mine, Duke, was developing limb paralysis and lethargy. As the “control” group, several animals at the same farm treated by a veterinarian for the same pathology had to be euthanized months before. Duke’s evaluation suggested West Nile encephalitis virus infection, which is typical for that climate, as well as toxic metals and other pollutants in his body. My patient stated that the area was frequently exposed to chemtrails and their neighbor often burned some odorous materials outside. The veterinarian suspected the same infection and Duke was given its isode that resulted in a 50% improvement. Soon after, two immune organ sarcodes and two environmental isodes added further progress however, soon after the dog suddenly became completely paralyzed and comatose, with generalized body trembling. To add to the family’s misfortune, another dog suddenly died following a major seizure that was consistent with West Nile encephalitis. My patient notified me of the both events, without mentioning that a veterinarian with a lethal injection for Duke had arrived. I insisted on continuing the treatment but realized that the West Nile virus strain isode at my disposal was not matching his infection strain, as these mosquitoes and viruses vary greatly. My patient also reported another recent exposure to chemtrails. Under the circumstances of unavailable matching isodes, autoisodes can be very helpful. My patient was able to prepare an autoisode in a recommended potency using an automated water imprinting device, after drawing blood with an insulin syringe needle from Duke’s paw and placing a drop in his mouth. The next day the dog showed good progress and completely recovered several days later. Nine months since, he enjoys his daily chores.

A recent study indicated that autoisodes could be successfully used in the COVID-19 pandemic [58].

Conclusion

Since infectious diseases have and will continue their rise, parallel to environmental pollution and climate change, a different approach is compulsory due to the aforementioned limitations of the pharmaceutical paradigm in the treatment of all categories of infections, and to avoid further increases of antimicrobial resistance. As conventional medicine takes pride in being scientific, its neglect of the full body of science that, among others, strongly supports the interface of biology and physics, challenges this assertion [63,96].

Based on the physics of organisms and water, contemporary research demonstrated the effective application of energetic counterparts of environmental and microbial pathogens, as well as immune responses, and its potential to finally address Pasteur’s call for addressing a terrain–human petri dish [97,98]. The presented approach needs to be validated through proper clinical trials.

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A Short Comment on “1 Case Clinical Report of Cranium Aggressive Fibromatosis and Literature Review”

Leave a reply

DOI: 10.31038/JCRM.2023632

Short Commentary

Aggressive fibromatosis (AF) [1], known as a benign fibrous neoplasm arising from fascia, periosteum and musculoaponeurotic structures of the body, are rarely occurred in the head and neck region and tends to be locally aggressive, with nature to invade and erode skull and soft tissues, making excision much difficult. The presence of vital neurovascular structures in the head and neck makes it even more complicated. Owing to the features above mentioned, it is wise not to compromise on the vital structures considering the benign nature of the disease.

This clinical one case report revealed the clinical characteristics and appropriate therapeutic methods of aggressive fibromatosis (AF) in skull. In the meantime, it recommended the reasonable strategies for prevention and relatively favorable prognosis of AF, especially occurs in skull, which is very rare in neurosurgical clinic.

Findings and Significance of the Characteristics in Skull AF from this Work

It was indicated that the main manifestation of skull AF was headache and skull tumor. There was prominent osteolytic destruction found in X-ray plain film for skull AF. And CT scanning showed that skull sclerotin was disorganized and inhomogeneous, with widen diploe. The skull fibromatosis constituted by fibroblasts and myofibroblas, which were mainly spindle-shaped without heteromorphism. Immunohistochemistry showed positive expression of β-catenin and Vim in these cells. The enlarged incision was adopted for the strategy of operation in this patient of skull AF. After follow-up, there was no recurrence of AF discovered.

Taken together, it has been demonstrated from this study that skull AF is very rare in neurosurgical clinic. The clinical manifestation and iconography of AF were lack of specificity. Therefore, skull AF is hard to diagnose preoperatively. The effective diagnose is mainly dependent on histopathologic examination. As for treatment, operation is the most optimal method so far, which has a good therapeutic effect.

This work gave deeper insights into the distinctive elevation of the effects of AF clinical administration in a sooner future. From this case report, it therefore clearly can be seen that skull AF ought to be diagnosed by neuroimaging, such as CT and MRI. As for treatment, complete surgical excision of aggressive fibromatosis has been considered the only effective treatment. Chemotherapy may have a significant role, considering the possible hormonal etiopathogenesis of the condition. Radiotherapy, Other methods, expatiated as follows, are partially effective, already confirmed clinically previously.

Current Therapeutic Strategies and Future Prospect of Head and Neck AF

Head and neck fibromatosis is a rare condition with heterogeneity in presentation, proximity to vital structures, and locally aggressive nature. For the AF occurs in the skull, it is much rarer than any locations in the head and neck. These features make its treatment extremely challenging. Because of its rarity, variability in behavior, and the characteristics of these tumors, a standard treatment protocol has not yet been established. Although retrospective in nature, this study sheds new lights insight on various aspects of management of this rare entity. It has inherent limitations as it was retrospective, with a limited number of patients. However, as per our experience, we could conclude that surgery followed by multimodality management offers the best control, if not cure, for fibromatosis of head and neck region, may represent a superior strategy in AF administration clinically until now. Importantly, for differently special cases, unique therapeutic methods would be taken according to different types and locations of AF.

Apart from existing therapeutic strategies [2-4], such as complete surgical excision, chemotherapy post operations and antioestrogen therapy [5], etc., recently, therapies by using [6-8] non-steroidal anti-inflammatory drugs (NSAIDs) and interferon (IFN) α and tyrosine kinase inhibitor Imatinib have come to the fore. Some other novel and more effective treating methods are under studying.

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Not from Concentrate – An Exploration of the Minds of Consumers by Combining Experimental Design of Ideas (Mind Genomics) with Artificial Intelligence (AI)

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DOI: 10.31038/PSYJ.2023571

Abstract

AI (artificial intelligence) was used in the Mind Genomics platform (BimiLeap) to generate sets of messages about orange juice, not from concentrate. These messages, called ‘elements’ were edited slightly, and combined into vignettes comprising 2-4 elements, the combinations dictated by an underlying experimental design. Each of 100 respondents evaluated totally unique sets of 24 vignettes, with the vignettes created to allow statistical analysis by OLS regression and then clustering. Respondents rated each vignette on a two-dimensional scale; desire to drink, and believe the information, respectively. The key equation was the relation between the presence/absence of the 16 elements and the desire to drink. Two clear mind-sets emerged, MS 1=Stress better ingredients: MS2=Stress better functionality. AI was then used to summarize the results emerging from the two mind-sets, providing the summary based on themes, points of view, and opportunities for new products and services. The paper demonstrates synergies, viz., speed, simplicity, learning, and commercial opportunities currently available when one merges an information generating tool (AI) with rapid, hard-to-game evaluations by ‘real people.’

Introduction

The topic of NFC, not from concentrate, is an interesting issue in the change of the desirability of a product description over time. Where NFC was once the hallmark of quality for orange juice, the change in the world of citrus, especially in Florida, has eroded the value of NFC. Typical studies on these types of topics focus on limited aspects, such as the change in the dollar value of the slogan (viz., what are people willing to pay), or perhaps a historical retrospective of the business literature dealing with aspects of NFC.

The study reported here moves beyond a focused investigation of the topic into what might be more appropriately called an AI-enhanced exploration of the topic, coupled with the response of people. The approach used here, Mind Genomics, allows the researcher to explore how a person responds to various aspects of a topic, doing so in a way which moves towards the world of induction and so-called grounded-theory al. research [1]. Rather than developing a hypothesis emerging from a thorough understanding of the past, through published literature the emerging science of Mind Genomics encourages the exploration of a topic in a structured, templated fashion. The exploration is fast, inexpensive, disciplined, and almost always generates powerful new insights as it encourages research to explore and discover, rather than to confirm or falsify a hypothesis.

The origin of this specific study can be traced to the International Citrus & Beverage Conference, held in September 2023, in Clearwater, Florida. The conference brings together the various individuals involved in the world of citrus and allied products and services. The specific origin of the study was the conference presentation given by author Moskowitz to demonstrate the Mind Genomics method as a new technology. Discussions with authors Plotto and Sims about the best way to talk about Mind Genomics devolved into the notion that one could best explain the method by a live demonstration, from start to (almost) finish, in the allotted time of 50 minutes. Author Sims suggested the topic of ‘NFC’, and acted as the technical expert, to introduce the problem. Author Schneider, in turn, ran the computer, typed in the ideas or selected them when the ideas were presented as a group, from which one was to select messages (elements, ideas) to be tested. The output of the demonstration comprised both a book of information about NFC from different points of view (Idea book, produced by the embedded AI, called Idea Coach), as well as the results from the Mind Genomics ‘experiment’, after the 100 respondents participated.

Background to NFC

In the mid 1940s, in order to get a natural source of vitamin C to those in war-torn Europe, frozen concentrated orange juice was developed and became a leading seller once it hit the retail market. Evolving processing and storage techniques later allowed for the use of orange juice concentrate to develop refrigerated ‘Ready to Serve’ orange juice, creating a new segment in the market. Soon, this reconstituted ready to serve orange juice became the preferred choice of consumers over the frozen concentrate [2].

The reconstituted refrigerated 100% orange juice led the market until the introduction of not from concentrate, or NFC, orange juice to the market in the 1980s. Not from concentrate 100% orange juice is essentially made by extracting the juice, pasteurizing, and packaging. Though this juice was more costly to produce, store, and distribute, it was marketed as a ‘premium’ experience with superior flavor as it is not subject to the heat of evaporation.

NFC orange juice grew in popularity as consumers shifted from juice from concentrate to NFC, looking for more natural and healthier products [3]. Today, over 90% of Florida’s oranges are processed for NFC juice. However, due to challenges such as the state-wide devastation of citrus greening disease, juice production is declining [4]. Citrus greening has led to a decrease in Florida’s juice quality as infected oranges are described as bitter and sour and are lacking in sugar and orange flavor [5]. The lower sugar content and off attributes associated with infected oranges is making it more challenging for Florida orange juice producers to make 100% NFC orange juice with only Florida oranges. For example, companies such as Florida’s Natural, are now adding Mexican Valencia orange juice concentrate to their NFC juice to increase the sugar content of the juice and meet consumer demand. No studies have been done to assess what consumers think about not from concentrate orange juice versus from concentrate orange juice.

Background to Mind Genomics

Mind Genomics emerged from the confluence of three disciplines, psychophysics, statistics, and consumer research, respectively.

Psychophysics – provided Mind Genomics with the goal of measuring the strength of ideas. The origins of psychophysics lie in the pioneering work of scientists such as G.T. Fechner and S.S. Stevens, both focused on measuring the strength of sensations [6,7]. Their pioneering work, often called ‘Outer Psychophysics’ by Harvard’s S.S. Stevens, focused on the relation between the physical measurement of stimulus magnitude and the perceived magnitude. Stevens’ ‘Inner Psychophysics’ was to measure the strength of the percept. Mind Genomics used Stevens’ notion of the magnitude of an idea as the basis for the effort to measure the strength of our perception.

Statistics – provided Mind Genomics with a way to organize the ‘test stimuli’ into combinations, so that these combinations or vignettes could somewhat approximate the nature of information coming to respondents in the form of text information from which ideas would be generated in the mind of the person. The specific approach contributed by statistics is known as ‘experimental design.’ The contribution comprises the precise combinations needed to test, so that one can deconstruct the response to the combination (called vignettes henceforth in this paper) to the presence/absence of specific phrases. In this way it would be possible to create known combinations of test stimuli, present them to people, get the reactions, and finally use statistics to estimate the contribution of each component in the vignette to the response.

Consumer research – provided Mind Genomics with the recognition of the importance of the everyday. Rather than putting the respondent into an unusual situation, and then doing the experiment with the respondent now considered a ‘test subject’, consumer research focused on the quotidian, the ordinary. The goal was no longer to prove or disprove a hypothesis by experimentation, but rather to focus on the normal world, albeit from the eyes of someone who wants to know that world, in a quantitative fashion. Could numbers be put on the features of the ordinary world, to express the magnitude of different features of this world as they are perceived by people.

During the past three decades, the ‘emerging’ science of Mind Genomics has evolved to the point where it has become a DIY, do-it-yourself, research system, almost fully templated. The approach has evolved from the user creating one set of test vignettes (combinations of elements, viz., messages) to small, automatically created sets of vignettes, different for each respondent (study participant). In the most current version of Mind Genomics, each respondent evaluates sets of 24 vignettes, each vignette comprising a minimum of two and a maximum of four elements (messages). The underlying experimental design works with four topics, viz., questions, and with each topic generating four different elements, viz., answers. The experimental design puts together the answers into small, easy to read vignettes, the aforementioned combinations. The respondent reads each of 24 vignettes, and for each vignette assigns a response from a rating scale.

The objective of the Mind Genomics study is to make the effort easier, so that anyone can become a researcher. Indeed, elementary school students ages eight and above have found this templated approach to be fun, investigating topics such as the nature of third grade mathematics in ten years [8].

The Mind Genomics study continues to be enhanced. Current efforts, presented in this paper, include the use of AI (artificial intelligence) to help the researcher come up with the elements by suggesting questions and then answers to those questions, once the researcher describes the issue in the ‘Idea Coach’. Thus, it becomes far easier to investigate new topics, even with virtually no knowledge, because the embedded AI provides a true coach. Additional enhancements using AI include the summarization of results by AI using a number of queries to bring together the strong performing results in a user-friendly way.

Running a Mind Genomics Study on the Topic of NFC, not from Concentrate

The Mind Genomics study begins at the website (www.BimiLeap.com). After the researcher has created an account, the researcher begins a study by naming the study, selecting the language (currently only a few languages are implemented beyond English), and then agreeing to respondent privacy.

The next step requires the researcher to develop four questions, and for each question develop four answers. Figure 1 Panel A shows the request for the four questions. Figure 1 Panel B shows the request for four answers to one question, the question having been developed already by the researcher. Both Panel A and Panel B are shown ‘filled in’. For the researcher beginning the study, these screens are empty, requesting the researcher to fill them in, the researcher first creating the four questions and then afterwards filling four Panel B’s, one for each question.

Figure 1: Panels showing the input of the researcher. Panel A shows the request for four questions. Panel B shows the request for four answers to one of the four questions. Panel C shows the instructions to create a self-profiling classification question. Panel D shows the anchored five-point rating scale.

It is at this point that many researchers feel nervous. Idea Coach, embodying AI, was developed to decrease the nervous response, and push the study towards creation and then completion. Table 1 shows the first iteration of the Idea Coach, to provide questions. The researcher need only press the red oval in the formatted BimiLeap program to be taken to a screen which instructs the researcher to describe the topic in a box provided. The researcher then presses the request and receives a set of 15 questions. The researcher can select one or more questions, paste those questions into the appropriate screen (Figure 1 Panel A), edit the question if desired, add one’s own question, or run the request again for a mostly new set of questions. This process of requesting questions, selecting, and pasting, can go on for a while, but usually by four or five requests, and by thus 60-75 mostly different questions, the researcher will have selected the best questions and edited them. The same process happens for the request for four answers for each question.

While the researcher is using Idea Coach, both for questions and for answers, in the background the program is storing the guiding ‘squib’ for the development of questions, and the guiding question for the development of answers. When the researcher asks Idea Coach four times for questions, and three times for answers to each of four questions, the Idea Coach will produce 3 + 3 + 3 + 3 + 3 ‘pages’ of questions or answers. These are recorded for the researcher, along with a detailed analysis of the patterns uncovered on the particular page whether question or answer. The material is returned to the researcher in the form of an Excel book, the Idea Book, each page or tab corresponding to one of the different requests. Table 1 shows an example of what is returned after the first request to Idea Coach for questions.

Table 1: Results from the Idea Book, showing the 15 questions and AI summarization of those questions. Table 1 shows the results from the third time the Idea Coach was requested to provide 15 questions to address the topic.

The depth of information in Table 1 deserves a comment. One of the benefits of current AI is that the AI technology can be queried, as it was to develop the 15 questions, using the short paragraph, here really a sentence: Topic: Why would from concentrate orange juice be any less acceptable then NFC orange juice, please expand on this because I’m less than 12 years old. This single statement became a query, which generated the 15 Topic Questions listed. The AI then stored these 15 questions, while the Mind Genomics program, BimiLeap, continued to interact with the researcher, in order to select the four questions. After the four questions and four answers to each question were selected, BimiLeap used AI to ‘interrogate’ each set of 15 questions (and later each set of 15 answers). The results of the interrogation, viz., the summarization by AI, appears in Table 1, which shows the results from the third iteration, viz., the third time the researcher asked for the 15 questions to address the topic.

Once the researcher has selected the elements (the four sets of four answers), the next step is to add self-profiling classification questions. The now-standard version of BimiLeap automatically asks the respondent for gender and age, allowing the researcher to generate an additional eight questions, each with up to eight possible answers. Figure 1 Panel C shows the self-profiling classification question asked in this study. With up to eight classification questions, it is possible to use the first portion of the study, self-profiling, as a complete study in itself.

When the researcher has completed the setup of questions and answers (topics and elements), and then completed the self-profiling classification, it is time to create the rating scale. The rating scale for this study is unique in that it contains two parts, wanting to drink orange juice versus not wanting to drink orange juice, as well as believing versus not believing the material. Figure 1 Panel D shows the rating scale and the five answers.

How do feel about orange juice when you read this?
1=I don’t want to drink orange juice and i don’t believe what i just read
2=I don’t want to drink orange juice but i do believe what i just read
3=I can’t answer
4=I do want drink orange juice but i don’t believe what I just read
5=I do want drink orange juice and i do believe what I just read

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Marine-Biocement Promotes the Sustainable Eelgrass Meadows Protection at the Japanese Coastal Ocean

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DOI: 10.31038/GEMS.2023575

Abstract

In this study, we isolated five urease producing bacterial strains from coastal environment and create marine-biocement using Microbial Induced Calcium Carbonate Precipitation (MICP) procedure. It was shown that the wide range of urease producing bacteria could be isolated from coastal environment. The reinforcement effect of S1-1 strain showes the highest CaCO₃ amount and Unconfined Compressive Strength (UCS) level. The SEM-EDX results showed that S1-1 definitely precipitated calcium carbonate and bound the sea sand together. Therefore, urease producing bacteria S1-1 that can be newly used for biomineralization. Germination test showed that the marine-biocement retained its form in seawater for about one month, and then collapsed along with the eelgrass grew. This indicates that the marine-biocement has the strength suitable for the germination of eelgrass. After disintegrating, the marine-biocement returned to the sea environment as sea sand, suggesting that marine-biocement may be used as an innovative seeding medium for Zostera marina bioenvironmentally friendly.

Keywords

Marine-biocement, MICP, Eelgrass meadow, Blue carbon

Introduction

Japanese coastal area has typical biodiversity in the Asian ocean cause of two big ocean currents such as Japan current from southeast asia and Oyashio current from Arctic ocean. Moreover, one of the eelgrass “Zostera marina” habits around the Japanese coastal area and provide the life of marine biodiversity. This huge ecosystem services based on the feeding place, spawning ground and habitats for shells, squid and small fishes each other. Unfortunately, eelgrass meadows in Japan were significantly damaged by development of the coastal area and factory effluent in the 1960s, a period of high economic growth, and are expected to continue declining in the future [1]. These phenomena cause the coastal areas to lose their habitat for seaweed and to reduce important fishery resources that have been deprived of habitats. Because, Zostera marina support marine life, including epiphytic organisms as well as coastal fisheries resources and contribute to marine environments by stabilizing bottom sediment and maintaining coastal water quality [2]. In addition to this, it recently has been reported that Zostera marina absorbs not only CO₂ from the sea, but also about 17% from atmospheric CO₂ when exposed at low [3]. Thus, Zostera marina habitats are considered one of the most valuable marine ecosystems because they has both a supportive place for marine life and a very efficient storehouse of atmosphere-derived CO₂ as blue carbon [4,5]. In this study, we suggest the novel eelgrass protection technique applied with MICP technology. MICP has developed for the geotechnical applications such as liquefaction after earthquake, exchange heavy metal ions and self-repairing concrete for coastal erosion [6-8]. We modified the following MICP reaction mechanisms.

Marine bacterial urease catalyzes hydrolysis urea to ammonium and carbonate ion same as Sporosarcina pasteurii (eq1). After that, calcium carbonate precipitates from carbonate ion and calcium ion (eq2) between coastal sand particles. Then, coastal sand combines by calcium carbonate crystals and produces solidified marine-biocement (Kusube et al. 2020) [9]. The marine-biocement is harmless for several marine organisms cause of produced from marine bacteria and coastal sand. Therefore, we propose sustainable and convenience protection of eelgrass meadows with this marine-biocement.

Materials and Methods

Isolation and Identification of Urease Producing Bacteria

Urease producing bacteria were isolated from coastal sand collected from Shirahama-cho, Wakayama, Japan (33.692241°N, 135.336596°E) with Urea agar base (UAB) plate (Thermo Scientific Co. Waltham, Massachusetts, US) for screening culture media. The colonies with pinkish halo were pure cultured on a fresh UAB plates at least 5 times and were cultured at 30.0°C. After single colony culture, bacterial genomic DNA was extracted by 95.0°C boiling for 15 minutes. The 16SrDNA gene was amplified with universal primer 27F and [10] on the extracted each bacterial DNA. PCR program showed as denaturation at 94.0°C for 10 minutes and 25 cycles of denaturation (95.0°C, 30 seconds), annealing (55.0°C, 15 seconds) and extension (72.0°C, 30 seconds). And finally, gene extended at 72.0°C for 3 minutes. The elongated 16SrDNA sequences were determined by macrogen.co (Tokyo, Japan) and isolated marine bacteria was identified with Basic Local Alignment Search Tool BLASTN program [11]. A Phylogenetic tree was constructed by the neighbor-joining (NJ) method using MEGA X (ver.10.2.4) software with alimental sequenced data. An interior branch test was carried out (heuristic option and 1000 replications) to check the tree topology for robustness [12].

MICP Mechanism Applied to Marine-Biocement

Coastal sand 40.0 g was mixed for the making marine-biocement with isolated marine bacterial pellet from 100 mL culturing media and ionic solution 10 mL containing 0.75 M calcium chloride and 1.5 M urea [13-15] in the plastic tube (27 mm diameter and 50 mm height) with 2 mm mesh holes on the side of tubes to easy penetrate ionic solutions. The soaking materials placed at 25°C for 1 day to fully enzymatic reaction on the surface of the sand particles. To increase hardness of the marine-biocement, this treatment was repeatedly 2 more times. After this enzymatic reaction, marine-biocement was washed out excess ionic solution in distilled water and completely dried up at 110°C for 3 days to prevent hardening by quenching.

Measurement of Unconfined Compressive Strength of Marine-Biocement

In this study, Unconfined Compressive Strength (UCS) measurement was adopted to assess the strength for the purpose of determining the physical strength properties imparted on MICP. The UCS measurement have been used in most of the experimental programs reported in the literature in order to evaluate the effectiveness of the stabilization of marine-biocement [16] (Cheng, Shahin and Ruwisch 2014). UCS measurement is a compression test of a cylindrical rock specimens under confining pressure where the loading path is followed by a computer. After MICP curing, specimens were extruded from the mold, and it was sized 27 mm in diameter and 40 mm in height. And the strength properties of each marine-biocement were measured by UCS measurement, and shear strength were determined. Shear strength is a measure of how much stress (force/area) can be applied before the material undergoes shear failure.

Scanning Electron Microscopic (SEM) Observation and Energy Dispersible X-ray Spectrometry (EDX) Measurement of Marine-Biocement

The binding precipitate morphology and chemical component was analyzed with SEM-EDX analysis. Marine-biocement was dewatering treated with 50% acetone solution stepwise to 100% acetone in order to reduce the water molecules in the marine-biocement and completely vacuum drying with evaporator. After drying, marine-biocement for SEM-EDX specimens were stored in desiccator at room temperature. The binding precipitate morphology was observed by SEM (FlexSEM1000Ⅱ, HITACHI, Tokyo, Japan). The SEM specimens were coated 17 nm thickness platinum with AUTO FINE COATER (JFC-1600H) and SEM analysis was carried out at 15 kV and 62 mA. The chemical components of binding precipitates were analyzed by EDX system (AZtecOne, HITACHI, Tokyo, Japan). Kα spectra was used to analyze the surface precipitates.

Quantitative analysis of CaCO₃ in marine-biocement

To dissolve calcium carbonate, a calcite-acid reactor chamber was used [17]. The device consists of a reactor chamber, pressure meter and valve for the exhaust gas.

The ratio of binding calcium carbonate C is defined as:

The 1.0 g of marine-biocement was placed into reactor chamber, and binding calcium carbonate include the marine-biocement was measured under standard conditions (25.0°C, 1 atm). The 10 mL of 1.0 M hydrochloric acid added to generate the CO₂ gas from the calcium carbonate. The calibration curve was made with standard pure CaCO₃ reagent (FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan). The reactor chamber was sealed and gently shake to facilitate dissolve CaCO₃ in the reactor chamber. The binding calcium carbonate in marine-biocement was calculated from the calibration curve and the blank as non-treated coastal sand.

Germination test from Marine-Biocement with Zostera marina

In the creation process, a hole of φ 3 mm H 15 mm was dented on the upper part of the marine-biocement and three seeds of Zostera marina from Eiga jima, Hyogo prefecture provided by the NPO corporate seed of Zostera marina bank were embedded in marine-biocement of S1-1 which was most hardest of all specimens in UCS test. Only the seeds that showed high density in saturated saline were selected. Selected three seeds were planted each marine-biocement hole and covered with sea-sand and placed in a water tank (35 L) as germination condition irradiated for 10 hours for a day with LED light to accelerate germination, circulation of natural seawater controlled at 10°C constant [18]. As a control, seeds were sowed at 10 mm deep under the seasand and germinated spontaneously and compared with the germination rate from marine-biocement.

Results and Discussion

Phylogenetical Relation of Isolated Urease Producing Bacteria

Five isolated strains were identified from approximately 1,200 bp of 16SrDNA sequences. The results shown that they were closely related as well as to bacteria genus belonging to the Cupriavidus, Bacillus and Pseudomonas. These 16SrDNA sequences submitted on DDBJ and BLAST results suggested that the closest relatives of Cupriavidus basirensis S1-1 (Accession No. LC760339), Bacillus cereus S1-2 (Accession No. LC760340), Pseudomonas ceruminis S1-4 (Accession No. LC760341), Pseudomonas nitroreducens S1-5 (Accession No. LC760342) and Priestia megaterium S1-8 (Accession No. LC760343) cause of E value 0.0, 0.0,0.0 and 0.0, identified value 99.24%, 99.50%, 98.24% and 98.86% respectively. These sequences have been deposited in DDBJ are available under accession numbers LC760339-43). These strains included the urease producing bacteria isolated from marine environment previously reports (Figure 1). The relationship between isolates and previously reported marine urease producing bacteria showed in Figure 1. Phylogenetic analysis shows that the no specific species need for producing marine-biocement, it means that is able to isolate in every marine environment. Moreover, these bacterial species were already applied for industrial bio-remediation such as oil degradation, clean up for soil and water contaminated with heavy metals and/or chlorinated organic compounds [19,20].

Figure 1: Neighbor-joining tree based on bacterial 16S rRNA gene sequence data from different isolates of the current study along with sequences available in the GenBank database. Bootstrap values calculated from 1000 resamplings using neighbor-joining are shown at the respective nodes when the calculated values were 50% or greater. The phyla to which the strains belong are presented on the right.

Characterization of Marine-Biocement

The relationship between bacterial CaCO₃ (weight%) and UCS level (kPa) of the marine-biocement was shown at Figure 2. Isolated bacteria produced 1.7%-3.9% of CaCO₃ crystalline and then hardness showed 36-449 kPa in UCS level. Strain S1-1 showed the highest CaCO₃ amount and UCS level were 3.9% and 449 kPa, respectively. On the other hand, bacterial-free blank included 1.8% of CaCO₃ content and showed 106 kPa hardness. In addition, marine-biocement with strain S1-1 shows CaCO₃ content is 2.1 times higher than blank, and 4.2 times higher UCS level than that of blank. This result shows that was good related CaCO₃ content and UCS levels. Because CaCO₃ crystalline could be binding with each sea-sand particles to be strength enhancement (Figure 2). Moreover, CaCO₃ crystalline grew up on the surface of sand particles by urease producing bacteria. The important point is the urease producing bacteria was adsorbed on the surface of the sea-sand particles through the bacterial membrane electrostatic interactions. Previous studies have shown that bacterial cell surfaces are negatively charged and adsorb onto the particle surface [21,22]. The marine-biocement S1-1 induced ideal MICP system and was ocean-friendly materials cause of natural sea-sand and isolated bacterial species from the ocean. Biomineralization with S1-1 never reported. Therefore, it was suggested that S1-1 may be a urease producing bacteria that can be newly used for biomineralization.

Figure 2: Relationship between CaCO3 content of the marine-biocement and UCS. (S1-1: Cupriavidus basirensis, S1-2: Bacillus cereus, S1-4: Pseudomonas putida, S1-5: Psedomomas nitroreducens. S1-8: Bacillus megaterium).

Observation of Surface of Marine-Biocement Using SEM-EDX

SEM allows a direct and closer look at the CaCO₃ bonds developed at the interparticle soil particles and the EDX analyzer records the counts of representative elements from the elements’ spectrum for provides insights the MICP mechanism with coastal sand with local marine-bacteria [23]. The hardest marine-biocement with isolated strain S1-1 surface characteristics was shown in Figure 3. Figure 3(a) shows a SEM image of specimen of marine-biocement S1-1, and b, c, e and f show calcium and silica elemental mapping results by EDX analysis. EDX analysis was used to observe the elements included in marine-biocement. Figure 3(d) shows precipitated short rod like crystals on surroundings of the sand particle surfaces. The average of crystalline size was 10-20 μm in length and 5 mm in diameter, and this rod like shape agree with aragonite crystals [24]. The crystal phase (Figure 3(a)) and calcium phase (b) were overlapped in these SEM-EDX images, but silica phase was detected at the other region in Figure 3. Because of calcium from bacterial CaCO₃ and sand main silica compounded chemicals such as SiO₂ and Al₂O₃ for about 70% of the total in Japanese coastal sand. Furthermore, this is the evidence of CaCO₃ crystal layer could be bind another sand particle on the same frame of the sand particle surface. SEM image of bacterial free specimen was shown in Figure 3(g) and 3(h).

Figure 3: SEM images of marine-biocement with strain S1-1. CaCO₃ crystals on the surface of sand particle (a) and Enlargement of crystal region (d). Chemical composition analysis on the sand surface by Energy Dispersive X-ray (EDX) system (b, c, e) and (f). Blank as Marine-biocement surface without urease producing bacteria surface SEM image (a). And chemical composition by EDX analysis of blank.

There were observed flat phase on all surfaces and never confirmed rod like crystals as aragonite. Quantitative EDX results were provided to supplemental Figure 1 and shows that the composition ratio of marine-biocement that is mainly contained carbon (48%), oxygen (34%), silicon (7%) and calcium (4.3%) in bacterial one. In contrast that, no calcium detected in bacterial free specimen. Therefore, isolated urease producing bacteria begin to the MICP process in marine-biocement same as the other applied MICP materials (Supplemental Figure).

Zostera marina Germination Test with Marine-Biocement for the Blue Carbon Systems

Figure 4(a) shows the germinated two white coleoptiles from marine-biocement after 23 days after seed sowing. Green leaves started photosynthetic for some bubbles come from leaves surface in 30 days. After 2 months, green leaves growing up to 4.7 cm length and leaf vein formation was confirmed. This final germination rate was 26.7% of marine-biocement S1-1 and 23.3% from sea-sand. The maximum leaf length from the marine-biocement and sea-sand were 4.7 and 4.9 cm, respectively. The lack of difference in germination results between marine-biocement and sea sand conditions indicate that marine-biocement can be used to germinate Zostera marina. From these results, it means that this marine-biocement can be applied to the marine environment and ecosystem protection.

Figure 4: Germination image of Z. marina from seeds. (a)Two white coleoptiles from marine-biocement after 23 days after the germination test (b) 2 months after the test, they were grown green leaves up to 4.7 cm. The formation of parallel veins was confirmed.

Acknowledgment

This paper is a summary of work that under the Marine Challenge Program 2017 and Marine Tech grand prix 2018 andsupported by JSPS KAKENHI (JP18K05695), “Innovation inspired by Nature” Research Support Program from Sekisui chemical Co., Ltd, 20^th ESPEC for Global Environment Research and Technology and Mitsumasa Ito Memorial Research Grant. We would like to thank Mitsui Chemicals, Inc. for providing the technology for the mass cultivation of marine bacteria.

Data Availability

The data underlying this article are available in the GenBank Nucleotide Database at https://www.ncbi.nlm.nih.gov/nucleotide/ and can be accessed with following accession number as LC760339-760343.

Author’s Contribution

Yuki Nakashima, Momoka Miyasaka and Masataka Kusube were involved in study design and data interpretation. Koki Kusumoto, Keizo Kashihara, Kazuyuki Hayashi and Shinya Maki were involved in the data analysis. All authors critically revised the report, commented on drafts of the manuscript, and approved the final report.

Funding Statement

This work was supported by the Marine Challenge Program 2017 Leave a Nest Co., Ltd, JSPS KAKENHI under Grant JP18K05695 and 20^th ESPEC for Global Environment Research and Technology (Charitable Trust) and Mitsumasa Ito Memorial Research Grant.

Disclosure Statement

No potential conflict of interest was reported by the authors.

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The Evolution of Type 2 Diabetes Mellitus and Insulin Resistance

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DOI: 10.31038/EDMJ.2023732

Abstract

Over the past 25 years of studying type 2 diabetes mellitus, a working hypothesis has emerged to move the development of precision medicine for type 2 diabetes mellitus forward. Earlier studies using amplified genomic DNAs for genomic-wide searches of human genes have led many investigators astray. However, a recent study has taken a different approach, using next-generation RNA sequencing, revealing an essential down-regulation of two genes, TPD52L3 and NKX2-1. The current compendium focuses on describing all of the important priciples to clarify the hypothesis from the beginning: insulin sensitivity and glucose effectiveness, genetics, free fatty acids, cell membranes, atomistic glucose and glucose transport, β-cell functions, membrane flexibility and (pre-) diabetes type 2.

Furthermore, this study sheds light on the importance of considering membrane flexibility in the context of type 2 diabetes and questions the potential risk associated with using the term ‘insulin resistance’.

Keywords

Type 2 diabetes mellitus; Insulin sensitivity; Glucose effectiveness; Genetics; Free fatty acid; Cell membrane; Glucose transport; β-cell function; membrane flexibility

Introduction

While Falta and Boller introduced the concept of “insulin resistance” in their seminal work published in 1931, it was not until 1933, when MacBryde noted that scholars had not reached a consensus on its definition, leading to gaps in research and clinical care. Despite remarkable advancements in medicine, these gaps continue to exist, even after nine long decades [1,2]. Over the years, accumulating data on insulin resistance have been published, enabling reconsideration of its meaning. Another unresolved problem relates to the diabetes susceptibility loci in and around the CDKAL1, CDKN2A/CDKN2B, HHEX, KCNJ11, SLC30A8, and TCF7L2 genes, suggesting that the single-nucleotide polymorphisms within or near these genes most likely do not alter their expression or function [3]. A recent study reported that common variant studies of type 2 diabetes mellitus have identified more than 700 risk loci for type 2 diabetes, half of which have been discovered in the past three years [4]. The question is: Are we on the right track? Indeed, genes are normally copied exactly during chromosome duplication. Rarely, however, mutations occur in genes to give rise to altered forms, most –but not all– of which function less well than the wild-type alleles. One study, based on next-generation RNA sequencing, found that an inherited mitochondrial defect, reducing the mitochondrial respiratory chain complex activity, as well as a defect associated with alterations in lipid storage played a critical role in the onset of type 2 diabetes mellitus. Against the background of the above considerations, this type 2 diabetes mellitus compendium furnishes an overview of recent advances in biochemistry and molecular biology in the context of type 2 diabetes mellitus. The compendium will help physicians and/or students of medicine gain an in-depth understanding of the molecular mechanisms of this disease.

Insulin Sensitivity and Glucose Effectiveness

Computational modeling of glucose and insulin kinetics following intravenous glucose challenge has demonstrated that individuals with type 2 diabetes mellitus show significant reductions in insulin sensitivity (S_I) and insulin-independent glucose removal rate (S_G) compared with normoglycemic individuals (Table 1) [5]. Insulin sensitivity essentially reflects the ability of insulin to enhance the effect of glucose to normalize its own concentration, and glucose effectiveness refers to the ability of glucose, independent of a dynamic insulin response, to enhance net glucose disappearance. Thus, these individuals exhibit reduced responsiveness to circulating insulin as well as reduced glucose effectiveness.

Table 1: Measures of glucose effectiveness and insulin sensitivity for a two- compartment minimal model

Units	Control subjects	Type 2 diabetes individuals	P value	Δ (%)	Tracer
S_G
h^-1	0.41 ± 0.04	0.33 ± 0.02	< 0.001	19.5	¹³C
h^-1	0.52 ± 0.05	0.37 ± 0.02	< 0.001	28.8	²H
average				24.1
S_I
pmol x L^-1x h^-1	0.0082 ± 0.0012	0.0036 ± 0.0006	< 0.001	56.1	¹³C
pmol x L^-1 x h^-1	0.0098 ± 0.0013	0.0042 ± 0.0008	< 0.001	57.1	²H
Average				56.6

Data are based on the reference data listed by Weijers [5]. S_G: glucose effectiveness; S_I: insulin sensitivity

In the latter condition, glucose ⎼ independent of changes in the insulin concentration ⎼ is less able to facilitate its own uptake through a mass action effect and suppress its own release. A prospective study investigated the development of type 2 diabetes in normoglycemic offspring of parents who had type 2 diabetes. The study revealed that the offspring exhibited significant defects in both glucose effectiveness and insulin sensitivity more than a decade before disease development [6]. Moreover, a key feature in type 2 diabetes is an essentially larger defect in insulin sensitivity (56.6%) compared with glucose effectiveness (24.1%). What do these findings imply?

Genetics

In the ongoing research on the genetic basis of type 2 diabetes, earlier studies using amplified genomic DNAs for genome-wide searches of human genes have led many investigators astray. However, a recent study has taken a different approach, using next-generation RNA sequencing to examine genome-wide changes in gene expression in the skin of patients with type 2 diabetes, compared to non-diabetic patients [7]. This new study identified two previously unknown genes significantly downregulated in indivividuals.

The previous findings revealed that tumor protein D52-like3 (TPD52L3), a gene in the gene metabolism category, exhibited the most significant downregulation with a value of 3.7 × 10^-9 in the studied group, which consisted of individuals with type 2 diabetes. There is no established link between the gene TPD52L3 and type 2 diabetes or wound healing. However, a study involving exogenous expression of human TPD52 in cultured cells demonstrated a notable increase in lipid droplets [8]. Lipid droplets serve as storage organelles for excess fatty acids within adipocytes, which are fat cells. Tumor protein D52 is the founding member of the TP52-like protein family representing four paralogous mammalian genes, i.e. TPD52, TPD52L1, TPD52L2, and TPD52L3 [8,9]. When analyzing TPD52 and TPD52L3 genes, researchers found that the two sequencers shared 63 identical positions and 42 similar positions, resulting in an overall homology of 67.9% (Figure 1) [10]. Indeed, based on the high sequence homology with TPD52L3, it appears plausible that the primary function of TPD52L3 is lipid storage in adipose cells. A reduction in TPD52L3 expression could increase the release of free fatty acids into the bloodstream. The difference in the unsaturation index (number of cis carbon-carbon double bonds per 100 fatty acyl-chains) between the released free fatty acids from human white fat cells and the serum-free fatty acids in the healthy controls (85.5 versus 191.9, respectively) is significant [5]. The release of these saturated free fatty acids leads to a considerable decrease in the unsaturation index of erythrocytes and vascular membranes. As a result, the membrane flexibility of these cells is reduced. The decrease in membrane flexibility, in turn, negatively impacts the rate of glucose transport across the cell membrane, initiating the onset of type 2 diabetes.

Figure 1: Alignment of the human TPD52 (upper row) and the human TPD52L3 (lower row) protein sequences. Amino acid residues are indicated by single letters. Vertical lines indicate identical residues and colons/dots indicate highly/weakly conserved residues.

In the second scenario, the most downregulated gene in the gene regulation category was NKX2-1, and it exhibited a down regulation value of 3.7 × 10^-9 [7]. NKX2-1, a transcription factor, is associated with reduced mitochondrial respiratory chain complex activity, resulting in decreased ATP production, among other cellular functions [11]. This idea supports a study’s data proposing that the dysregulation of intramyocellular fatty acid metabolism in the offspring of individuals with type 2 diabetes is linked to an inherited defect in mitochondrial oxidative phosphorylation [12]. The β-oxidation of fatty acids plays a crucial role in compensating and restoring ATP production by increasing plasma-free fatty acids through hydrolysis. However, this increase in free fatty acids results in significant decrease in the unsaturation index of serum free fatty acids. Consequently, the reduction in the unsaturation index leads to decreased membrane flexibility and lowers the rate of glucose transport across the cell membrane, ultimately initiating the onset of type 2 diabetes. Notably, reduced mitochondrial activity is recognized as one of the key characteristics of type 2 diabetes [13].

Free Fatty Acids

After four billion years of evolution, the earliest protocells evolved to ‘modern’ cells enclosed by membranes consisting of phospholipids, the chief constituents of biological membranes. Glycerol-based phospholipids are the major class of naturally occurring phospholipids. Typically, a phospholipid consists of glycerol-3-phosphate, with a saturated fatty acid at position 1 and an unsaturated fatty acid at position 2 of the glycerol. Saturated fatty acids possess essentially linear alkyl chains with no double bonds. On the other hand, double bonds in unsaturated fatty acids are nearly in the cis configuration, which creates a bend in the fatty-acid chain. Molecules such as palmitoleic acid (C16:1) and oleic acid (C18:1) are bent at the cis double bond, and the two chain parts form an angle of 133 degrees [14,15]. This bend has important consequences for structure and functionality of biological membranes because, while saturated fatty acids are able to pack closely together, unsaturated fatty acids prevent such close packing.

Type 2 diabetes mellitus, gestational diabetes mellitus, and impaired glucose tolerance are characterized by elevated plasma free fatty acid levels [16,17]. This is confirmed by findings that the percentages of docosahexaenoic acid (C22:6 n-3) and arachidonic acid (C20:4 n-6), released from white adipocytes, are decreased by approximately 110-fold and 9-fold, respectively, compared with the human serum pool, and the unsaturation index of released free fatty acids from human white adipocytes is markedly lower than the unsaturation index of serum free fatty acids in healthy controls (85.5 and 191.9, respectively) [5]. Therefore, an increased release of free fatty acids from adipose tissue into the blood circulation elevates the plasma concentration of saturated fatty acids. Hence, a shift from unsaturated to saturated fatty-acyl chains in phospholipids of erythrocyte membrane and vascular endothelium is a hallmark of type 2 diabetes mellitus [18]. Borkman et al. in 1993 suggested that decreased insulin sensitivity is associated with decreased concentration of polyunsaturated fatty acids in skeletal-muscle phospholipids, raising the possibility that changes in the fatty-acid composition of muscle modulate the action of insulin [19].

Cell Membranes

Phospholipid bilayers form spontaneously and rapidly, when phospholipids are added to water. As evident in Figure 2, two acyl chains (the hydrocarbon chain region) yield a roughly cylindrical molecule with an area (A) that can pack in parallel arrays to form extended sheets of membranes composed of a mosaic of proteins and phospholipids in a fluid phospholipid matrix [20].

Figure 2: The most basic structural result obtained from x-ray scattering from oriented bilayers in model phospholipid membrane systems is the area (A) per lipid molecule (the cross-sectional area of the cylindrical part of the phospholipid). D_HHrepresents the membrane bilayer thickness.

The driving force behind this aggregation phenomenon is the weak, noncovalent bond (van der Waals force) between a pair of carbon atoms, which can be calculated with the Lennard-Jones potential [21]. The interaction energy (U) is related to the distance (r) between two carbon atoms, as illustrated graphically in Figure 3. This graph suggests that the minimum energy principle favors a carbon-carbon distance of about 4 Å, which is the most stable distance between the centers of two carbon atoms, with a minimum interaction energy of -0.77 kJ/mol. Furthermore, when the carbon atoms in two acyl chains of a phospholipid diverge, their interaction energy decreases as a function of distance r approximately with the sixth power, and when they approach each other, their interaction energy increases as a function of distance r approximately with the sixth power. Thus, the flexibility of a lipid bilayer is largely determined by the amount of weak noncovalent forces of carbon–carbon interactions, i.e., the number of -C=C- double bonds along the phospholipid unsaturated acyl chains.

Figure 3: The van der Waals interaction energy profile as a function of the distance (r) between the centers of two carbon atoms. The energy is calculated using the empirical equation U=B/r¹² – A/r⁶. Values for the parameters B=11.5 ⨯ 10^-6 kJnm¹²/mol and A=5.96 ⨯ 10^-3 kJnm⁶/mol for the interaction between two carbon atoms.

The unsaturation index is widely recognized as a useful parameter for describing the flexibility of a biological membrane. It is calculated by multiplying the mean number of cis double bonds per lipid acyl chain by 100 [22]. Therefore, an increase in saturated fatty acids of membrane phospholipids, as observed in erythrocytes, results in a decrease in membrane flexibility and is marked by a decrease in the unsaturation index. A number of studies of fully hydrated, fluid phase, model phosphatidylcholine bilayers have shown that introducing one or more carbon-carbon cis double bonds into the saturated acyl chains will increase the cross-sectional area A by about 18% and decrease the attraction energy by about 34% (Table 2) [23].

Table 2: Experimental data of fully hydrated fluid phase phosphatidylcholine lipid bilayers

	DLPC	DMPC	DPPC	DOPC	PDPC
Fatty acid structure	[C12:0)]₂	[C14:0]₂	[C16:0]₂	[C18:1]₂	C16:0,C22:6
Temperature (C°)	30	30	50	30	30
Area A per lipid molecule (Å)²	63.2	60.6	64.0	72.5	74.8
Mean Area A sat. unsat. (Å)²		62.6		73.6
Mean -C=C- interchain dist.(Å)		4.48		4.84
Mean interact. energy U (kJ/mol)		-0.59		-0.39
UI	0	0	0	100	300

Data are based on the original data listed by Weijers [40].
DLPC: Dilauroylphosphatidylcholine; DMPC: Dimyristoylphosphatidylcholine; DPPC: Dipalmitoylphosphatidylcholine; DOPC: Dioleoylphosphatidylcholine; PDPC: Palmitoyl-Docosahexaaenoic-Phosphatidylcholine; –C=C⎼: Carbon-Carbon double bound; UI: Unsaturation Index.

An important different method, compared to the number of studies of fully hydrated, fluid phase, model phosphatidylcholine bilayers, for quantifying the mechanical properties of a single cell, has recently developed, in which a spherical cell is aspirated into a micropipette aspiration channel with a controlled suction pressure [24]. The micropipette pressurization of giant diacylphosphatidylcholine bilayers demonstrated that poly-cis unsaturated chain bilayers are thinner and more flexible than saturated/monounsaturated chain bilayers. However, the most striking result was the major increase in bending flexibility, which occurred when two or more cis double bonds were present in one or both chains of the lipid [25].

Atomistic Glucose and Glucose Transport

Glucose tissue uptake is performed by different specific glucose transporters. Glucose transporter proteins are integral membrane proteins containing 12 membrane-spanning helices. The glucose channel of a glucose transporter comprises eight helices that are immersed in a box formed by the remaining four helices [26]. The cross-section of this box has a mean surface area of 1,100 Å², which covers an area of about 17 molecules of a phosphatidylcholine bilayer with saturated fatty acyl chains. Thus, the insertion of a glucose transporter molecule across a phospholipid cell membrane requires flexibility of the bilayer membrane.

β-Cell Functions

Variations in the lipid composition of cell membranes can profoundly impact the function of proteins embedded with them. Even small changes in the lateral pressure of a bilayer membrane can lead to significant alterations in the conformational distribution of the embedded proteins [27]. In type 2 diabetes mellitus, the redistribution process in membrane phospholipids can be triggered by a deficiency in cis carbon-carbon double bonds, compared to healthy individuals. A reduction in the area A of lipid molecules in the cell membranes leads to decreased flexibility. This reduction in flexibility can hinder the movement and conformational changes of proteins embedded in the membrane glucose transporters.

The collected information enables an exploration of ‘insulin resistance’ in the pathophysiology of type 2 diabetes. During the prediabetic phase, a crucial aspect of type 2 diabetes etiology is a decrease in unsaturation index of membrane phospholipids observed in erythrocytes compared to healthy controls. This reduction in the unsaturation index lowers flexibility of β-cell membranes, leading to a slower transmembrane glucose transport via GLUT2 in the β-cells. Consequently, the insulin granules inside the β-cells contain reduced insulin. Thus, instead of attributing the condition solely to ‘insulin resistance’, the primary factor behind decreased glucose levels within the β-cells and subsequent lower insulin production is the reduction in membrane flexibility.

Following the synthesis of monomer insulin within the β-cell, six monomer insulin molecules come together to form stable hexamers with a molecular weight of 36,000 [28]. These hexamers are then enclosed within mature intracellular vesicles and transported at any time to the β-cellʼs plasma membrane. A fusion pore is created upon the fusion of the intracellular vesicle membrane with the β-cell plasma membrane, releasing monomer insulin molecules into the bloodstream. Given the relative large size of the monomer insulin molecule (30Å wide and 35Å high), compared to the glucose molecule (overall size 10Å), both the vesicle membrane and the β-cell plasma membrane require significantly flexibility [29,30]. In individuals with type 2 diabetes, a reduction in the unsaturation index results in decreased membrane flexibility, leading to a slower rate of transmembrane insulin transport in the bloodstream. This phenomenon is in accordance with the data of individuals with type 2 diabetes, showing a reduction in insulin sensitivity by 57.9% and a much lower reduction in glucose effectiveness by 26.2% (Table 1). Thus, instead of using the term ‘insulin resistance’, the key issue lies in reducing flexibility in vesicle and β-cell plasma membranes, which impacts insulin release.

Membrane Flexibility and (Pre)diabetes Type 2

Table 3 records the biochemical outcomes of control individuals and individuals with prediabetes or type 2 diabetes mellitus. A study demonstrated that compared with healthy controls, individuals with gestational diabetes mellitus showed reductions in total polyunsaturated fatty acids (31.9 vs. 37.5; Δ=-14.9%), arachidonic acid (11.0 vs. 12.8; Δ=-14.1%), and unsaturation index (137 vs. 163; Δ=-15.8%) [31]. Another study revealed that compared with healthy controls, individuals with impaired glucose tolerance showed reductions, in total polyunsaturated fatty acids (25.8 vs. 30.7; Δ= -16.0%), arachidonic acid (11.1 vs. 12.5; Δ= – 11.2%), and unsaturation index (113 vs. 130; Δ= – 12.6%) [32]. Furthermore, a study found that compared with healthy controls, individuals with type 2 diabetes without retinopathy showed reductions in total polyunsaturated fatty acids (31.9 vs. 38.0; Δ= – 16.1%), arachidonic acid (11.3 vs. 13.0; Δ= -13.1%), and unsaturation index (134 vs. 155; Δ= – 13.6%) [33], whereas individuals with type 2 diabetes with retinopathy showed even lower values, compared to healthy controls, in total polyunsaturated fatty acids (29.5 vs. 38.0; Δ= – 22.4%), arachidonic acid (9.7 vs. 13.0; Δ= -25.4%), and unsaturation index (128 vs. 155; Δ= – 17.4%) [33].

Table 3: Erythrocyte acyl composition in phospholipids of control individuals, individuals with gestational diabetes, with impaired glucose tolerance, with type 2 diabetes without and with retinopathy, and type 2 diabetic men (study group).

	Total SFAs (%)	Total MUFAs (%)	Total PUFAs (%)	C20:4 n-6 (%)	UI
GDM
Controls (n=61)	33.6	15.9	37.5	12.8	163
Patients (n=53)	37.7	18.0	31.9	11.0	137
Δ (%)	+12.2	+13.2	-14.9	-14.1	-15.8

IGT
Controls (n=42)	42.4	22.6	30.7	12.5	130
Patients (n=28)	44.8	24.6	25.8	11.1	113
Δ (%)	+5.6	+8.8	-16.0	-11.2	-13.1

Type 2 diabetes ret.(-)
Controls (n=18)	42.1	18.8	38.0	13.0	155
Patients (n=14)	44.2	21.7	31.9	11.3	134
Δ (%)	+5.0	+15.4	-16.1	-13.1	-13.6

Type 2 diabetes ret.(+)
Controls (n=18)	42.1	18.8	38.0	13.0	155
Patients (n=46)	46.9	21.3	29.5	9.7	128
Δ (%)	+11.4	+13.3	-22.4	-25.4	-17.4

Type 2 diabetes (study group)
Controls (n=14)	44.0	20.2	28.8	11.1	126
Patients (n=21)	42.9	20.6	31.6	14.3	141
Δ (%)	-2.5	+2.0	+9.7	+28.8	+11.9

Ex-posed calculations performed by the author are based on the original data listed by Min et al. [31,32], Koehrer et al. [33], and Pelikánová et al. [40]. SFA: saturated fatty acid; MUFA: monounsaturated fatty acid; PUFA: poly-unsaturated fatty acid; UI: unsaturated index; C20:4 n-6: arachidonic acid. The values of gestational diabetes mellitus and impaired glucose tolerance are the means of phosphatidylcholine and phosphatidyletanolamine values. The values of type 2 diabetes mellitus with retinopathy are the means of mild, moderate, and severe diabetic retinopathy values [33].

These results imply that a decrease in the unsaturation index in individuals with prediabetes or type 2 diabetes mellitus has the potential to translate into an increase in attractive forces between the mutual membrane phospholipid acyl chains, which redistributes the lateral pressure profile of the cell membrane [27]. This redistribution induces alterations in mechanical and biochemical properties of the glucose transport channel proteins, i.e., it reduces the pore diameter, which in turn, reduces the rate of glucose transport across the cell membrane, and therefore causes the onset of type 2 diabetes mellitus [10].

These findings are substantiated by two surprising facts. First, Shulman et al. studied muscle glycogen synthesis in subjects with type 2 diabetes mellitus and matched controls using in vivo carbon-13 nuclear magnetic resonance spectroscopy [34-36]. They noted that the muscle glycogen synthesis rates in subjects with type 2 diabetes were about 50% lower of the rates observed in controls. The same group of researchers investigated, under hyperglycemic-hyperinsulinemic conditions, the pathway: transmembrane glucose transport into the muscle cell, conversion of intracellular glucose into glucose-6 phosphate, and then, after two more intermediates, the addition of the latter through glycogen synthase to the glycogen polymer. They concluded that their experimental results are consistent with the hypothesis that the transmembrane glucose transport into the muscle cell is the rate-controlling step in insulin-stimulated muscle glycogen synthesis in patents with type 2 diabetes, and the delivery of insulin is not responsible for the insulin resistance. This idea is in agreement with a constriction of the glucose channel within the three-dimensional structure of glucose transporter-4, which reduces the rate of transmembrane glucose-transport in type 2 diabetes [37]. Second, epidemiological evidence suggests that human plasma free fatty acid levels are generally elevated during the course of a pregnancy, probably with vital functions on fetal energy metabolism [38,39]. It is not unlikely that this increase also leads to an additional reduction in membrane flexibility and increases the amount of maternal glucose as an additional source of energy for the fetus.

The problem with the hypothesis is the lack of evidence of the healing power of an increase in unsaturation index in relation to type 2 diabetes. There is, however, an overlooked study with a surprising result. In 1991, Pelikánová et al. described, among others, a study group of 21 men with mild-to-moderate type 2 diabetes and 14 control men matched for age, sex, bodyweight, and dietary intake [40]. In this study, type 2 diabetes was defined by the criteria of the National Diabetes Data Group. The individuals were enrolled within 1 year after diagnosis, treated only with a diet, were less than 45 years of age and free of signs of atherosclerotic complications, and had a BMI < 30 kg/m² [41]. The amount of saturated fatty acids in the diet was lower for the type 2 diabetes individuals than for the healthy controls (35.4 ± 12.2 g/d vs. 47.7 ± 10.8 g/d). Table 3 presents the ex-post calculations based on the original data of erythrocyte phospholipids, described by Pelikánová et al. [40]. The salient points in the data of the individuals in the study group show essential increases, compared with healthy controls, in the total polyunsaturated fatty acids (31.6 vs. 28.8; Δ=+9.7% ), arachidonic acid (14.3 vs. 11.1; Δ=+28.8%), and unsaturation index (141 vs. 126, Δ=+11.9%).

For the first time in the type 2 diabetes literature, individuals with mild-to-moderate type 2 diabetes have been treated successfully with diet alone in combination with a rise in the arachidonic acid level. The authors of the Pelikánová-study suggested that the increase in arachidonic acid level could be diet-induced or represent an increased incidence of atherosclerotic complications. A third option, however, arises in the use of arachidonic acid as a supplement in training adaptations among resistance-trained males [42]. However, the crucial biochemical outcome of this study concerns, independent of the provenance of arachidonic acid, the experimental result of an increase, compared with healthy controls, in the number of carbon-carbon double bonds in the cell membranes of the 21 men of the study group. This increased the unsaturation index, which is intricately linked to a rise of membrane flexibility and therefore led to an additional increase in the rate of glucose transport across the cell membrane. In addition, the increase in membrane flexibility resulted in an improved transmembrane insulin transport from pancreatic β-cells into the blood circulation. The influence of arachidonic acid on membrane flexibility is particularly important because arachidonic acid with four carbon-carbon double bonds is an important molecule in the field of membrane flexibility.

The most important steps of the hypothesis are diagrammatically illustrated in Figure 4 and predict that using RNA sequencing, the most essentially downregulated regulation-related gene, NKX2-1, and the most essentially downregulated metabolism-related gene, TPD52L3, cause an increase in plasma saturated free fatty acid levels, which leads to a decrease in the membrane unsaturation index and thereby reduces the rate of transmembrane glucose transport, resulting in type 2 diabetes mellitus. The reliability of the ideas is supported by the understanding of the observations that, first, the reduced glycogen synthesis rate in subjects with type 2 diabetes mellitus was about 50% of the rate observed in healthy controls; second, the normoglycemic offspring of parents, who had type 2 diabetes, exhibited significant defects in both insulin sensitivity and insulin-independent glucose removal rate; and third, the key feature of type 2 mellitus is an essentially larger defect in insulin sensitivity compared with glucose effectiveness.

Figure 4: Hypothetical pathway of the development of type 2 diabetes

Attention to this hypothesis was very tastefully articulated by late Denis McGarry in his article “What if Minkowski had been ageusic…” [43]. He argued that hyperglycemia and insulin resistance might be better explained when viewed in the context of underlying abnormalities of lipid metabolism.

Obesity and Type 2 Diabetes

Obesity is a chronic metabolic disease that has become the main risk factor for various non-communicable diseases, in particular, type 2 diabetes. Obesity has been reported to account for 80-85% of the risk of developing type 2 diabetes, while recent research suggests that obese people are up to 80 times more likely to develop type 2 diabetes than those with a BMI of less than 22 [44]. The concentration of free fatty acids is elevated in obese individuals [45]. The increased release of free fatty acids from adipose tissue into the blood circulation elevates the plasma concentration of saturated fatty acids because the unsaturation index of released free fatty acids from human white adipocytes is markedly lower than the unsaturation index of serum free fatty acids in healthy controls (85.5 versus 191.9, respectively). This phenomenon causes a shift from unsaturated to saturated fatty-acyl chains in phospholipids of erythrocyte membrane and vascular endothelium with all the associated consequences (Figure 4). There is no question of suggesting that free fatty acids cause insulin resistance, as suggested by Boden, but a decrease in the unsaturation index reduces the pore diameter of the glucose transporter protein, which in turn, reduces the rate of glucose transport across the cell membrane [45].

Insulin Resistance

The findings presented above propose a potential solution for the importance of ‘insulin resistance’ in the pathogenesis of type 2 diabetes. Specifically, the significant downregulation of NKX2-1 and TPD52L3 appears to be the main cause of the reduction in cis carbon-carbon double bonds of phospholipid membranes. This reduction decreases the cross-sectional area A of the cylindrical part of the phospholipid molecule. As a result, there are increased attractive forces between the phospholipid acyl chains, causing a redistribution of lateral pressure in cell membranes. This, in turn, induces a cross-sectional contraction of all Class1 GLUT proteins, ultimately leading to a lower rate of transmembrane glucose transport. The idea aligns with observations from biophysical and structural studies, highlighting the critical role of interactions between membrane proteins and lipid molecules in their folding and stability [46-48]. Clinically, the results of a study by the Diabetes Prevention Program Research group, are quite exciting. They indicate that among high-risk individuals, lifestyle intervention resulted in a 50% reduction in the incidence of type 2 diabetes development, while metformin led to a 31% reduction, compared to placebo [49]. This valuable insight into treating type 2 diabetes according the Diabetes Prevention Program Research group deserves wider recognition and attention.

The consistent findings from various studies strongly support the conclusion that lifestyle change treatment can effectively compensate for the loss of membrane flexibility by inducing an increase in the membrane unsaturation index. Therefore, it is advisable to incorporate the assessment of the unsaturation index into the treatment protocol. By doing so, we can better address the needs of individuals with type 2 diabetes and work towards normalizing membrane flexibility. Furthermore, it is essential to reconsider the notion of ‘insulin resistance’. The original interpretation that cells do not respond to insulin is inaccurate. Instead, the correct understanding is that the amount of carbon-carbon double bonds of cell membrane regulates the rate of glucose transport. Thus, the concept of ‘insulin resistance’ loses relevance, especially considering the significant role of membrane flexibility in glucose transport.

Conclusions and Future Recommendations

The proposals of the Diabetes Prevention Program Research group remain the method of choice for the treatment of type 2 diabetes. The key to lifestyle modification consists of increasing the patient’s unsaturation index level, which would promote a phospholipid shift from saturation to unsaturation, and thus reduce the incidence of type 2 diabetes. Clinical evidence has demonstrated that all of the 21 men in the study group managed their disease by increasing the level of the unsaturation index without taking metformin. Based on the considerations described above, one could conclude that considerable clinical benefit would accrue by the essential concept: saturated fatty acids makes the human cell membrane more rigid, while unsaturated fatty acid increases its flexibility, which ultimately postpones the onset of type 2 diabetes mellitus.

Two different techniques quantifying the mechanical properties of cell membranes came to the same conclusions: an increase in carbon-carbon double bonds by poly-cis unsaturated chain bilayers creates more membrane flexibility than saturated/monounsaturated chain bilayers.

A substantial difference can be made in extending the quality of type 2 diabetes mellitus treatment by introducing the unsaturation index assessment, because the regulation of membrane flexibility represents a great step forward in the development of precision medicine for type 2 diabetes mellitus.

The investigation of the genetic origin of type 2 diabetes mellitus must be moved from chemistry of DNA to chemistry of RNA.

Physical activity, as a part of standard lifestyle intervention, needs to be accompanied by the following official instructions throughout the disease period:

– Increase the rate of glucose transport and insulin transport across cell membranes through caloric restriction and walking 3 to 3.5 miles per hour, for at least 150 minutes per week.

– Replace “insulin resistance” by “reduction in membrane flexibility”.

Conflict-of-Interest

The author declares that the research was conducted in the absence of any commercial of financial relationships that could be constructed as a potential conflict of interest.

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