Author Archives: author

Diabetic Foot Care in Patients with Mental Illness

DOI: 10.31038/ASMHS.2021515

Abstract

Foot disorder pathologies, caused by diabetes mellitus, result in diminishing the quality of life for patients and straining the economic fabric of both governmental institutions and private organizations. Patients afflicted with diabetes suffer from disabilities, which can in many cases lead to foot amputation and other various complications. Often, patients also suffer from chronic pain caused by diabetic foot neuropathy, which may make them unable to continue with their employment and have a negative effect on their daily lives. Patients with mental health disorders are adversely affected by diabetic foot pathologies due to their lack of timely follow-up and limited access to medical providers. The goal of this Practicum experience was to develop and deliver a PowerPoint presentation to provide clinical guidance and education to primary care clinicians who evaluate diabetic patients (many with mental health issues) who otherwise might not have an opportunity to be evaluated by a podiatrist in a timely manner. This author created the PowerPoint presentation based on the review of literature and the input from the committee members. The PowerPoint presentation on diabetic foot care was limited to the primary care clinical staff at the Queens County Medical Center in Queens, New York. The purpose of the practicum is for these clinicians to learn how to perform a comprehensive evaluation of the lower extremities in patients with diabetes, including awareness of risk factors prone to increasing risk of foot ulceration, screening for neurological foot deficits, analyzing treatment options for patients with diabetic foot maladies, andrevention strategies to prevent diabetic foot complications.

Keywords

Diabetic neuropathy, Diabetic foot care, Diabetic foot ulcer, Podiatry, Psychiatry and diabetes, Diabetes screening

Introduction

Nature of the Problem

Diabetes is a disorder, which can cause severe medical problems with the physiology of persons afflicted with it, and the silent nature of this malady can lead to medical disability in a manner where late intervention is futile. One of the greatest pathologies caused by diabetes is neuropathy in the peripheral lower limbs, which can cause not only physical injuries affecting mobility in patients but also issues with pain and poor healing, which can lead to chronic pain syndromes [1]. Diabetes occurs due to glucose not being properly regulated by either lack of insulin production by the pancreas or the inability of the body to use its own insulin in an effective manner. This process auses grave health consequences including lower-extremity amputations, a disease that is the seventh leading cause of death in the United States [2].

Patients, suffering from mental health problems, are especially harmed by diabetes as the lack of timely access to podiatric providers often leads to diabetic foot neuropathy. Neuropathy, which leads to loss of sensation in lower extremities of patients (due to the fact that these are longest nerves as they are involved in innervating all the way the bottom of the feet), can often cause ulcerations and foot sores, which are overlooked by these patients. The disorder of diabetic foot disease (DFD) is a combination of peripheral neuropathy and arterial disease, which often leads to an end result of foot ulceration and lack of appropriate management that can lead to lower extremity amputation complicated with an open wound infection or osteomyelitis [3]. Furthermore, this lack of foot malady awareness can cause these patients to not seek care for their feet and further compound these problems and, in many cases, lead to avoidable foot amputations. Additionally, these psychiatric patients face further barriers as they lack financial resources to see specialist clinicians promptly, are prone to increased risk by being on psychiatric medicines, which often increase their blood sugar levels, and lack proper housing and follow- up, which could enhance their medical care [4]. Proper screening, evaluation, and timely management and prevention of foot maladies in patients with diabetes have shown to significantly reduce the incidences of lower foot amputation and better health outcomes for diabetic patients [5].

Significance to Patients with Mental Illness

The provision of providing cutting-edge information to primary care practitioners, which includes screening, diagnosing, and treating psychiatric patients with diabetic fool maladies, facilitate the optimal goal of improving foot health care in this underserved population. The majority of mental health patients face challenges in seeing a podiatrist on a routine basis and thus, are at increased risk of diabetic foot pathologies due to the increased levels of hyperglycemia caused by psychiatric medications. The timely intervention of podiatric are provided by primary care clinicians will lead to positive health outcomes for patients afflicted with mental illness and improve their quality of life.

Review of Literature

Overview

The Centers for Disease Control and Prevention (CDC) defines diabetes as a disorder, which leads to increased blood glucose levels in the body (CDC, 2015). Diabetes occurs due to glucose not being properly regulated by either lack of insulin production by the pancreas or the inability of the body to use its own insulin in an effective manner. This process auses grave health consequences, including lower-extremity amputations, a disease that is the seventh leading cause of death in the United States (CDC, 2015). According to the CDC, approximately 29.3 million people in the United States (9.3% of the population) have diabetes with another 86 million people having a pre-diabetic condition (CDC, 2015). The incidence of diabetes mellitus is expected to increase from 382 million people in 2013 to 592 million by 2035 with the vast majority of cases present in developing countries, which will also see the greatest increase in the number of these cases [6]. It is ironic that as the world has developed exponentially in the fields of basic health care, disease and infection management, and improved diet for all in the last several decades, the elevated incidences of diabetes is a reminder of how overindulgence in this abundance of dietary choices and lack of exercise can lead to such a blood glucose malady [6].

Diabetic Neuropathy

DFD is a combination of peripheral neuropathy and arterial disease, which often leads to an end result of foot ulceration and the lack of appropriate management of DFD can lead to lower extremity amputations complicated with an open wound infection or osteomyelitis [3]. The World Health Organization (WHO) in conjunction with the International Diabetes Federation (IDF) have set a goal of reducing amputations related to diabetes complication by up to 50% by initiating a multipronged approach of increasing patient education about diabetes, forming a multidisciplinary team of various specialties involved with the patient, and timely patient monitoring, which has shown to decrease amputation rates from 49% to 85% [7]. Neuropathy leads to loss of sensation in the lower extremities of patients (due to the fact that the bottom of the feet are enervated by the longest nerves in the body) and can often cause ulcerations and foot sores, which are overlooked by these patients. Furthermore, this lack of foot malady awareness can cause these patients to not seek care for their feet and therefore further compound these problems; a tragic complication leading to avoidable foot amputations [3].

Central Nervous System Effects

Diabetes can cause significant damage to the organs of the central nervous system, primarily the brain. The increased levels of glucose present in the blood stream cross the blood-brain barrier leading to consequences, which include (a) encephalopathy due to problems metabolizing the increased glucose in the blood stream; (b) elevated risk of brain stroke due to elevated intracranial pressure as a result of chronic, uncontrolled diabetes; (c) potential of brain damage and white matter changes in the cerebral cortex due to the long term use of insulin and other hypoglycemic medications; (d) possibility of seizures due to elevated blood sugars decreasing the seizure threshold; and (e) potential of cognitive changes when hyperglycemia goes unchecked for long periods of time [8].

Peripheral Nervous System Effects

The effects of long-term elevated serum glucose levels have a deleterious effect on the nerves of the peripheral nervous system. The first effect, causing the most common nerve damage in diabetes mellitus, is called diabetic neuropathy, which impedes the sensation perceived by the sensory nerves as they relay messages to the brain [9]. Additionally, motor nerves are also affected as they slow down messages from the brain to move muscles in a timely manner affecting body reflexes to stimuli [10]. The second effect is autonomic neuropathy, which is a process whereby gastrointestinal functions such as digestion are affected by elevated blood sugar levels. Furthermore, autonomic involuntary functions such as blood pressure and heart pulse are often disrupted while also leading to sexual dysfunction (CDC, 2015). Another adverse effect is diabetic gastroparesis, which affects the passage of food through the stomach, as muscles in the colon do not interact in an effective manner, leading to multiple systemic medical complications [9]. Moreover, the process called focal diabetes-related neuropathy causes individual cranial nerves to transmit signals less effectively resulting in vision loss and hearing problems [9].

Diabetic Foot Effects

Epidemiology

There is an increased incidence of diabetes in the world, especially as the accessibility of medical care has improved [6]. The world population is living longer although enduring more diseases as people age with the latest estimate of 592 million people diagnosed with diabetes by 2035 [6]. Males, especially over the age of 60, are at the highest risk of developing DFD with the presence of foot ulceration a major indicator leading to risk of foot amputation, a lifetime risk of almost 25% prevalence in the general population [3]. The rate of foot ulceration increased by 700% in patients with diabetic neuropathy when compared with patients without diabetes and its associated conditions [3]. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD) estimated that about 60% to70% of the world population with diabetes suffers from neuropathy (age and disease duration causing increased risk) and the highest rates are among people with diabetes for over 25 years [11].

Etiology

The lack of knowledge regarding this disease, unable to see providers on time, lack of screening protocols, difficulty in managing blood sugar levels, and the limited follow-up options available for patients often led to this result of foot amputation [3]. The loss of sensation due to sensory nerves being initially unresponsive to light stimuli makes the patients unaware of any stressors affecting their lower extremities, which often results in foot injuries being unheeded. Gradually, this loss of sensory stimuli perception ascends into more proximal areas of both feet bilaterally, and by then, most of the damage has been done in terms of nerve neuropathy. Often, patient complaints gradually evolve from tingling sensations and shock-like lower extremity pain to abnormal hot and cold sensation to their feet; a process that eventually leads to foot cramping with anatomic changes like hammer toes, flat feet, and foot pressure ulcerations [3]. These anatomic results are directly from motor nerves being affected during the later phases of DFD after initial sensory foot deprivation. Another common malady leading to foot dysfunction includes autonomic changes in the feet, which can often manifest itself as dry skin, cracked skin changes, excessive foot sweating at times, and loss of deep tendon reflexes. The difficulty of blood to flow back from the veins in the feet against gravity leads to foot edema, which is another major risk factor of DFD [3].

Risk Factors

There are various risk factors which can make an individual prone to be diagnosed with diabetes mellitus relative to the general population. Family history plays a significant part in elevating a person’s chance of getting diabetes. The elevated risk can be as high as 2.3 to 5.5 times a person without a familial history of diabetes [12]. Multiple other risk factors include obesity, waist circumference, inactivity, and history of gestational diabetes. Additionally, American Indians, Hispanics, and Asians were noted to have elevated risk of being diagnosed with diabetes compared to the general population [10]. It was also noted that losing muscle mass, co-morbid medical conditions, and gaining weight due to inactivity also led to increased prevalence of diabetes in the older population [10]. High blood pressure, increased triglycerides, and elevated cholesterol levels also were noted to be risk factors in developing this illness [12].

Oral Medications

There are multiple medications used to mitigate the adverse effects of diabetes by attempting to keep blood sugar levels down with the goal being to prevent long term central and peripheral manifestations of this disease. The majority of these classes of drugs include metformin, sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase inhibitors, and glucagon receptor agonists, which are used as monotherapy and in combination, to treat adults with type 2 diabetes [13]. There was an average of 1% decline in Hemoglobin A1c (an indicator of blood sugar levels over the last three months) with these prescribed medications and there was no difference between a single drug or a combination.

Lifestyle

Patients with diabetes must adhere to a lifestyle, which includes awareness of risk factors prone to increasing their risk of foot ulceration, be aware of self-screening for neurological foot deficits, speak to their clinicians proactively regarding treatment options for diabetic foot maladies, andrevention strategies to prevent diabetic foot complications [14]. Additionally, patients must be encouraged to ensure compliance with foot care protocols and adherence to follow-up recommendations and appointments [14].

Diagnosis

History

A prominent risk factor, which leads to adverse effects from diabetes is the asymptomatic nature of this illness in its early stage. Patients are often not aware of their hyperglycemic status until they start experiencing symptoms. Early detection of diabetes leading to initiation of diet and exercise regimens with possible utilization of oral hypoglycemics has positive outcomes for patients. The signs and symptoms of diabetes include: (a) lethargy, (b) chronic feelings of hunger, (c) excessive urination with corresponding feelings of being thirsty most of the time, (d) dry skin, and (e) blurred vision [15]. Patients with diabetes are also prone to yeast infections due elevated blood sugars providing a nutritional source for yeasts and due to their immunocompromised status. Nerve damage associated with neuropathy can cause long duration for injuries to heal while also causing numbness and tingling in extremities. It takes a combination of factors, such as the patient history, family history, clinical foot exam, and the utilization of diagnostic exams, to best screen the patient for severity of DFD [15].

It is imperative that focused questions need to be asked during the history taking portion of evaluation which would include (a) is the patient’s blood sugar monitored by the patient on an ongoing basis and is it well controlled; (b) are the medications taken by the patient for diabetes causing any adverse side effects including episodes of hypoglycemia; (c) has the patient been referred to podiatrists, ophthalmologists, nephrologists to evaluate and manage systemic issues caused by their diabetes; (d) has the patient been involved in their diet management by exercising and eating in a health manner; (e) has the patient kept up-to-date with their immunizations including annual flu vaccine shots; and (f) has the patient made aware of all foot complications caused by diabetes and has the patient been educated in foot care, including keeping the foot area dry, examining the foot area on a regular basis for any bruises or injuries and ensuring that their toe nails are trimmed regularly by a podiatrist [3].

Physical Exam

The physical exam component of the evaluation of a patient with diabetes must ensure that the patient’s body mass index (BMI) is maintained in the normal range while also ensuring that the patient maintains a consistent exercise regimen (NIDDKD, 2008). Vital signs must be monitored for hypertension and orthostatic blood pressure must be performed regularly to rule out signs of autonomic neuropathy [7]. Physical exam techniques must also evaluate the foot of the patient regularly for injuries and pulses must be palpated to monitor for adequate blood flow to the extremities [7]. A combination of deep tendon reflexes, sensory lower extremity exams, and vibration tests must be performed to evaluate patient for any metabolic foot maladies [3]. An ophthalmology exam must be performed to rule out neo-vascularization in the retinal region and flame hemorrhages which are often noted in diabetic patients with poor blood sugar control (NIDDKD, 2008). A thorough skin examination must be performed to screen for skin atrophy, dryness, yeast infections and discoloration of the skin, which if often noted in diabetic patients [4].

Lab Studies

There are multiple scales, which can be used to measure foot maladies, and they might utilize measures, such as capillary refill, pedal pulses, foot deep tendon reflexes, pathological Babinski reflexes, and pedal edema on rating scales [15]. Commonly used screening diagnostic methods, such as neuropathy symptoms scores, Semmes-Weinstein monofilament, vibration perception on the lower extremities from distal to proximal, nerve conduction studies, and even nerve biopsy, are valid tools in the arsenal for diabetic neuropathy foot screenings [15].

Treatment

The mainstay of treatment is a coordinated approach by the patients and their clinicians regarding prompt screening, initial diagnosis of diabetes and subsequent awareness of systemic foot manifestations, and monitoring levels of blood sugars, ensuring that the foot is free of any added physical stress by managing weight and reducing risk factors, such as smoking and alcohol use and appropriate follow up with referral specialists [3]. A combination of clinicians would include the primary care clinician to coordinate care and refer to specialists, dietician to monitor weight and recommend food choices, diabetes educator who might suggest special techniques to care for the foot [3]. Additionally, an endocrine specialist is needed to follow up on glycemic control and management of medications, a podiatrist to ensure that the foot is evaluated thoroughly and recommend and fit podiatric shoes for the patient if necessary, and family support to help ensure that the patient is able to follow through with all his or her medical commitments [3].

Primary Interventions

In case of an open ulcer, there would be certain recommended treatments, which are considered standard protocols to include (a) debridement of the wound to help remove any foreign bodies and ensure that the food is free of infection; (b) changing the pressure points of the foot by utilizing podiatric foot inserts and making special leg casts as necessary; and (c) treatment of any infection by using topical and/or oral antibiotic agents to reduce opportunities for any spread of infection, which could lead to cellulitis and gangrene if unchecked [3]. Wound dressings also play a key role in maximizing the role of antibiotics and reducing chances of infection in patients with diabetic foot ulcers [3]. Common wound dressing techniques include wet-to-dry saline dressings; dressings with infused topical antibiotics covering the wound; and polyurethane dressings, which help ensure that the moisture conditions are optimal for wound healing [3]. Increasingly, there is greater use of growth factors in the treatment of diabetic foot ulcers that help with angiogenesis and increased cellular production, which can lead to more vascularization of the site. Furthermore, the role of vacuum-assisted closure, which can help remove redundant moisture in the wound, exposes wounds to rich oxygenated air therapy, and stem therapy is being studied in the quest to manage and treat diabetic foot complications [3].

Complications

Another common complication of diabetic neuropathy is peripheral artery disease (PAD), which manifests itself in the lower extremities by chronic leg pain, difficulty with healing of foot wounds, change in foot temperature, and lack of foot pulses bilaterally [16]. Commonly used screening tools for PAD include measuring the ankle-brachial index, foot ultrasounds, and contrast angiography [16]. Although these tools continue to be prevalent and utilization of these techniques have increased over the last several years, there continues to be increased rates of diabetic foot amputations due to a lack of timely screening and access to providers [3].

Prevention

The vast number of patients with diabetes are not initially seen by a podiatrist but rather by their primary care providers, including allied health professionals (physician assistants), and preventive strategies, screening, and treatment of foot ulcers has shown to decrease lower foot amputation rates by 49% to 85 % (NIDDKD, 2008). Physician assistants (PAs) can play a crucial role in mitigating the amputations connected with poor foot hygiene in diabetics by ensuring that their diabetic patients are screened in an appropriate fashion during their initial visit with an emphasis on thorough foot screening and follow-up referral to a podiatrist if available in a timely fashion (NIDDKD, 2008).

Patient Education

The screening criteria for DFD must include initial awareness and identification that a patient is vulnerable for foot ulcerations due to the diagnosis of diabetes. The patient must be made aware that routine inspection of the foot on a daily basis (while in the shower for example) is essential to prevent damage to the foot, shedding light on the symptoms to look out for in DFD, such as temperature changes in the foot, tingling, and painful feet [15]. It is important that the patient wears protective shoes, which helps reduce stress on specific parts of the foot and reduces exposure of the foot to outside risk factors, leading to foot trauma and keeping an eye out for any calluses, hammertoes, or hardening of certain areas of the foot [15]. There also needs to be regular follow-up by patients with their clinicians, depending on the nature of their DFD, which might range from a yearly foot examination to seeing a clinician every couple of months if there is already an ulceration present [15].

Patients and their families must be educated about checking that the shoes they wear do not provide excessive stress to the feet, provide adequate cushioning in their daily walking shoes, check daily between their toes for ulcerations, wash and then thoroughly dry their feet daily before bed, and use precaution if utilizing tools to cut toenails [15]. Active self-care and awareness of diabetic manifestation in feet, especially being vigilant in the presence of foot lesions and ulcerations, leads to positive long-term health outcomes for patients with diabetes [14]. The recommendations for foot care, which showed a potential decrease of lower foot amputations by almost 85%, included (a) always walking with comfortable shoes and not barefoot, (b) trimming toenails and not using abrasive items on feet, and (c) routine foot exams by a trained foot clinician [14-22].

Topics Based on the Literature

This author reviewed multiple research studies regarding the field of diabetic foot problems and the associated screening, diagnosis, treatment, and prevention protocols. It was imperative that the information regarding how prevalent diabetes is was included in the literature review of the topic, while also emphasize the frequency in which amputations occur in diabetic patients who neglect foot care [3]. The review of literature, after briefly touching on the definition of diabetes and related causes, focused on diabetic foot disorders. It was emphasized in the practicum review that screening and early diagnosis of diabetes can play a crucial role in reducing the frequency and intensity of foot infections [2].

The overarching theme of the practicum topics incorporated in the review of literature focused on complications of diabetes on a systemic manner, which primarily focused on the foot in this report. The importance of early intervention, including treatment with medication and emphasis of patient education, was dwelt upon as a compelling factor in decreasing the incidence of diabetic foot maladies. The author also emphasized the importance of referring patients to follow-up care with specialists due to the nature of diabetic disease and provided information for the primary clinician to implement treatment protocols during this initial treatment phase [15]. Finally, the review of literature accentuated the fact that early prevention, screening, treatments, and robust patient education would empower patients to take decisive steps in their diabetic foot care leading to positive health outcomes.

Discussion

Diabetic foot disorders can play a prominent role in affecting mobility in patients afflicted with this disease, which can often result in chronic pain and limited healing in the lower extremities [1]. The lack of insulin production by the pancreas in diabetic patients often lead to foot amputations, and this process is the one of the leading causes of death in the United States [9]. A combination of factors including lack of proper screening, timely evaluation, appropriate management and limited patient education work in conjunction to exacerbate this condition leading to poor patient outcomes [5]. Moreover, patients with limited financial and social resources can suffer additional negative consequences of this disease compared to the regular population due to their socio-economic circumstances [3].

Patients with mental health disorders encounter additional challenges due to psychiatric medications increasing blood sugar levels which further exacerbate their diabetic condition while also negotiating lack of proper housing and follow-up medical care [4]. This author focused on the barriers, which economically deprived patients face regarding diabetic care and the opportunities available to overcome them. The limited access to specialist foot providers, such as podiatrists, made it imperative that primary care clinicians, who after are the first to evaluate patients for medical purposes be educated in initial screening and management of diabetic foot maladies [7]. This author developed a PowerPoint presentation which was delivered to a group of primary care clinicians at the Queens County Medical Center, located in Queens, New York, which is at the front line of delivering care to indigent and socially deprived populations. It was the goal of this presentation that these primary care clinicians would be educated to treat patients early enough in the progression of diabetic foot disorders that diabetic related foot amputations will be minimized; a process leading to improved quality of life for these patients [5].

Conclusion

Lower extremity amputations lead to a decreased quality of life issues for patients with associated economic challenges and mobility issues. Timely screening, management, patient education, and appropriate follow-up can lead to mitigating the effects of diabetes not only on foot related problems, but on the overall health of patients. Patient education in conjunction with primary care provider education can play a crucial role in minimizing the devastating effects of this disease and lead to better health outcomes for patients, and reducing the financial expenses in the long term to the United States health care budget.

Appropriate and timely management of diabetes with its associated morbidities can lead to positive health outcomes for patients. The devastating consequences of diabetic related foot amputations not only leads to a poorer quality of life for affected patients but has caused increased economic harm to the community. Provider education regarding early screening and treatment of diabetes, which will lead to appropriate referrals to specialists, can help all the stakeholders affected by this disease on a personal and professional level. Governmental agencies, private institutions, and insurance companies will certainly benefit economically if there are more resources expended in the early phases of screening and patient education of diabetic patients. Finally, patients afflicted with this disorder would be able to be productive members of society without suffering the consequences of long-term foot pain and diabetic amputations.

Recommendations

Exploration of the diabetic foot disorders presents an opportunity for front line primary care clinicians to be leaders in the quest to reduce diabetic foot related morbidities. This innovative process would help enhance both patient and provider satisfaction while also providing economic savings to these institutions, which otherwise would be burdened by diabetic foot-related expenses. Further research could encompass patients not only suffering from psychiatric disorders, but also (a) patients with alcohol and substance abuse disorders, (b) native American and inner city populations without access to timely medical care, and (c) disabled patients who are unable to seek professional help due to mobility issues. Additional funding grants by governmental organizations and private charities to explore opportunities to expand diabetic care would certainly enhance research into this important topic. Finally, recognition about diabetic foot disorders and its horrendous consequences on patients can help pique further interest in researchers to explore alternative opportunities to improve patient care and provide a valuable service to society.

References

  1. Lazzarini P, Gurr J, Rogers J, Schox A, Bergin S. (2012) Diabetes foot disease: The Cinderella of Australian diabetes management? Journal of Foot and Ankle Research 5: 24. [crossref]
  2. Centers for Disease Control and Prevention (2015, December 28) Basics about diabetes: What is diabetes? Retrieved from http://www.cdc.gov/diabetes/basics/diabetes.html.
  3. Amin N, Doupis J (2016) Diabetic foot disease: From the evaluation of the “foot at risk” to the novel diabetic ulcer treatment modalities. World Journal of Diabetes 7: 153-164.
  4. Hoffman K (2016, March 21) Managing lower extremity conditions in patients with mental illness. Podiatry Today 29.
  5. Hsu CR, Chang CC, Chen YT, Lin WN, Chen MY (2015) Organization of wound healing services: The impact on lowering the diabetes foot amputation rate in a ten-year review and the importance of early debridement. Diabetes Research and Clinical Practice 109: 77-84. [crossref]
  6. Guariguata L, Whiting DR, Hambletonc I, Beagleya J, Linnenkampa U, et al. (2014) Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Research and Clinical Practice, 103: 137-149. [crossref]
  7. Bakker K, Apelqvist J, Schaper NC, International Working Group on the Diabetic Foot Editorial Board (2012) Practical guidelines on the management and prevention of the diabetic foot 2011. Diabetes Metabolism Research and Review, 28: 225-231. [crossref]
  8. Prasad S, Sajja R, Naik P, Cucullo C (2014) Diabetes Mellitus and Blood-Brain Barrier Dysfunction: An Overview. Journal of Pharmacovigilance 02: 125. [crossref]
  9. Tesfaye S, Selvarajah D (2012) Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes/Metabolism Research and Reviews 28: 8-14. [crossref]
  10. The Mayo Clinic (2016, September 25) Diabetes-Risk Factors. Retrieved from http://www.mayoclinic.org/diseases-conditions/diabetes/basics/risk-factors/con-20033091
  11. National Institute of Diabetes and Digestive and Kidney Diseases. (2016, June 18) Diabetic neuropathies: The nerve damage of diabetes. Retrieved from http://www.niddk.nih.gov/health-information/health-topics/Diabetes/diabetic-neuropathies-nerve-damage-diabetes/Pages/diabetic-neuropathies-nerve-damage.aspx#what
  12. Chan JC, Malik V, Jia W, Kadowaki T, Yajnik CS, et al. (2009) Diabetes in Asia. The Journal of the American Medical Association 301: 2129.
  13. Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, et al. (2011) Comparative Effectiveness and Safety of Medications for Type 2 Diabetes: An Update Including New Drugs and 2-Drug Combinations. Annals of Internal Medicine 154: 602. [crossref]
  14. Bonner T, Foster M, Spears-Lanoix E (2016) Type 2 diabetes–related foot care knowledge and foot self-care practice interventions in the United States: A systematic review of the literature. Diabetic Foot & Ankle 7: [crossref]
  15. Lechleitner M, Abrahamian H, Francesconi C, Sturm W, Kohler G (2016) Diabetischer FuB. Wiener Klinische Wochenschrift 128: 80-84.
  16. Beaney A, Nunney I, Gooday C, Dhatariya K (2016) Factors determining the risk of diabetes foot amputations–A retrospective analysis of a tertiary diabetes foot care service. Diabetes Research and Clinical Practice 114: 69-74. [crossref]
  17. Bartsch RA, Cobern KM (2003) Effectiveness of PowerPoint presentations in lectures. Computers & Education 41: 77-86.
  18. Boghossian P (2006) Behaviorism, constructivism, and Socratic pedagogy. Educational Philosophy and Theory 38: 713-722.
  19. Castillo M (2010) Making a Point: Getting the Most Out of PowerPoint. American Journal of Neuroradiology 32: 217-219.
  20. (n.d.) In Merriam-Webster’s online dictionary (11th ed.) Retrieved from http://www.merriam-webster.com/medical/diabetes
  21. National Institute of Diabetes and Digestive and Kidney Diseases. (2016, June 18) Diabetic neuropathies: The nerve damage of diabetes. Retrieved from http://www.niddk.nih.gov/health-information/health-topics/Diabetes/diabetic-neuropathies-nerve-damage-diabetes/Pages/diabetic-neuropathies-nerve-damage.aspx#what
  22. Neuropathy (n.d.) In Merriam-Webster’s online dictionary (11th ed.) Retrieved from http://www.merriam-webster.com/medical/neuropathy

Intellectual Capital in the Post COVID-19

DOI: 10.31038/ASMHS.2021512

Abstract

Social Work studies about entrepreneurship warn a process of deliberate, planned and systematic rational choice which promote intellectual capital formation are predominant determinants. Specify a model for the study of trust dimensions: experiences, knowledge, capabilities, emotions, and abilities. Not experimental, documentary and retrospective study with a nonrandom selection of sources indexed repositories, considering the keywords and the publication period 2015-2020. A model with eight hypotheses three paths dependency relationships between nine variables put forward in the state of knowledge was specified.

Keywords

Heads of family, Social work, Entrepreneurship, Specific-19ation, Model

Introduction

The aim of this study is to specify a model for the study of social entrepreneurship in household heads [1]. From a review of the literature, the variables that allowed the systematization of the determinants of entrepreneurship paths are extracted [2].

The study is part of the Division of Humanities and Social Sciences, Social Work discipline, area of health promotion and sub-area of promotion of reproductive rights, parental rearing styles and management of household heads [3].

However, the project also has interference in economic and administrative sciences, as it will recover in the second phase the effect of cooperative entrepreneurship in Human Development with an emphasis on reproductive health, family upbringing and training of entrepreneurs [4].

Theory of Intellectual Capital

The principles that guide the rational choice lie in the tastes and preferences crystallizing objectives of the actors [5]. Therefore, before taking any decision binding preferences strategies, achieve collect information that will determine the election [6]. If individuals rather have an indeterminate number of tastes, objectives and goals, then your preference swill no longer depend on their capacity of choice and action [7]. Therefore, they act in a non-rational way [8].

The rational choice theory also warns that a decision is a result of an estimate of the costs and benefits of carrying out an effort regardless of their degree of significance [9]. This is a utilitarian dimension in which control of a situation from establishing a favorable balance of benefits versus costs will determine the election [10].

More specifically, the benefits and costs translate into a ratio of risk, effort and reward [11]. This means that a choice be rational when the risks and efforts are minimal provided that the rewards are greater [12].

In contrast, when the recognition of an effort and risk not up to expectations, then the choice has not been entirely rational and rather approaches an irrational dimension if the risks and efforts are increasing and intense with respect to the absence of rewards [13].

This is because the individual who tries is committed to the risks that will be activated by profit expectations [14].

Integrating each of the variables represents a series of paths in which the correlations explain each choice [15]. In short, the rational choice explained in general terms the process by which preferences are the determining factor by other factors which generate information or sense an atmosphere of certainty when deciding and act accordingly [16]. To the extent such information is available, accessible and actionable, then the rational choice will emerge as an option, but rather proliferates ambiguity, then a non – rational decision will be generated with irrational consequences [17].

However, when information is not available or is very abstract, rational choice is replaced by a tighter option to culture; values and norms of people with respect to a contingency which no known precedent some, but people always react the same way [18].

Studies of Intellectual Capital

If rational choice is brewing from preferences based on information available to determine tastes and objectives, the prospective attitude suggests that the absence of information creates uncertainty that determine risk aversion or waiver of certain gains and risk appetite when losses are imminent [19]. Thus, the utility, benefit or happiness crystallize into losses or gains, circumventing the process of rational choice and legitimizing an irrational choice [20].

Therefore, a prospective is more than a decision lies in attitude and expectation of risk or certainty to gains and losses in the immediate future. In that sense, a retrospective is an attitude that is the same relations but compared to last [21].

In short, the prospective attitude is a hinge between rational choice and reasoned action. Each of these theoretical and conceptual frameworks based its scope and limits from the availability of information, if the individual is able to assume an attitude, make a decision or take an action that corresponds to the available information and representation that you have it [22].

Specification a Model for Study of Intellectual Capital

Unlike the rational choice theory that focuses on the usefulness of the information available and the theory of prospective attitude that focuses its interest in the certainty of the information, the theory of reasoned action assumes that information, any it is, it is a general environment that will influence the behavior to the extent that information is transformed into rules. This is because the theory of reasoned action considers that all information is cognitively process [23].

Therefore, an overview of the environment, their demands and opportunities conducive categories of accessible and abundant availability of information that will influence a spendthrift behavior such as believing that jobs, wages and financial credits significantly increase [24]. On the contrary, if one considers that the context is rather recession and economic crisis, then austere styles, cooperative and innovative life will be adopted [25].

However, the theory of reasoned action, like the rational choice theory and the theory of prospective attitude, pose a general scenario incident on a specific behavior without considering the current situation and specifies decision maker [26].

Method

Documentary work was carried out with a selection of sources indexed to international repositories such as Scopus and WoS, considering the keywords of “specification” and “intellectual capital” in the period from 2015 to 2020

A search for summaries was carried out in order to subtract the indicators of intellectual capital, considering equation (1). Then, once the indicators of empathy, trust, commitment, entrepreneurship, productivity, competitiveness, innovation, satisfaction and happiness were selected, experts on the subject rated these indicators in order of importance, being 10 of greater importance and 0 of zero or no some importance Data were processed in the statistical analysis package for social sciences version 20.0:

formula 1

Percentages, contingencies and proportions were estimated to establish risk thresholds in decision-making regarding intellectual capital indicators.

Results

The trust indicator obtained the highest percentage (25%) followed by commitment (22%), empathy (17%), entrepreneurship (13%), satisfaction (9%), innovation (6%), productivity (4%), competitiveness (3%), happiness (1%). This means that decision-making is a function of the level of trust, although the instrument does not specify the type of trust that can be organizational, interpersonal, intra-personal or technological.

The contingency parameters suggest significant differences between the decisions made based on intrapersonal trust with respect to interpersonal [ϰ2 = 16,27 (16 df) p < ,05]. In other words, as an educational process, intellectual capital is focused on internal capacities, experiences, skills, knowledge and emotions rather than their outsourcing when socializing knowledge.

The proportions of probability suggest that the formative process of intellectual capital, centered on the intra-personal confidence of abilities [OR = 17,21(13,24 to 19,20)], skills [OR = 18,21 (14,35 to 20,21)], knowledge [OR = 15,43 (13,24 to 21,23)], experiences [OR = 18,20 (14,32 to 23,45)] and emotions [15,46 (10,21 to 22,31)], is at an allowable threshold of risk. It means then that the intervention of social work can be cemented in the formation of intellectual capital and its indicators of intra-personal confidence.

Discussion

The contribution of the present work to the state of the matter lies in the specification of a model for the study of intellectual capital, considering the dimensions of intra-personal confidence in which skills, emotions, experiences, abilities and knowledge, in the qualification of experts, were located in tolerable risk thresholds.

In relation to the literature where the intellectual captain is approached from non-formative organizational dimensions such as cooperation, tasks, goals, objectives or innovations, this paper suggests complementing these dimensions with intra-personal ones to establish differences between professional training and job training.

Future lines of research concerning the structural models of intellectual capital, human capital and social capital will allow establishing a predictive explanation of academic, professional and labor training.

Conclusion

Given that the information is not available or is processable actors requiring immediate planning of their actions, the determinants of the planned behavior are those in which information can be delimited and specified depending on a particular situation or to an event which is the subjective control from decision-making and the information available and actionable [18].

The theory of planned behavior finds that perceived control is a significant determinant of behavior in direct and indirect mode. To interact with subjective norms and attitudes generate an intention that is also assumed as a determinant of behavior [19].

However, it perceived control, as the norm and attitude, depend on a set of beliefs about information availability. In this sense, the specification of a model would include variables that anticipate the behavior, but not from the beliefs of availability of information, but from provisions to cooperate by actors that form an entrepreneurial project to develop their skills, not only of choice, deliberation or planning, but innovation [20].

References

  1. Andersen HC (1945) Kejsarens nya kläder, (The emperors new clothes, authors transl.) in H.C. Andersen och hans sagor, Bokförlaget Norden, Malmö. Band 172-178: 1.
  2. Bonoma TV, Clark BC (1988) Marketing Performance Assessment, Boston: Harvard.
  3. Bontis Nick (1998) Intellectual capital: an exploratory study that develops measures and models. Management Decision 36/2: 63-76.
  4. Booth, Rupert (1998) The measurement of intellectual capital. Management Accounting 26-28.
  5. Boudreau, John (1998) Strategic Human Resource Management Measures: Key Linkages to the People Vantage Model. Journal of Human Resource Costing & And Accounting 3: 21-40.
  6. Davenport TH, Prusak L (1998) Working Knowledge: How Organizations Manage What They.
  7. Dinesh, David, Palmer, Elaine (1998) Management by objectives and the Balanced Scorecard: Will Rome fall again? Management Decision 36/6: 363-369.
  8. Eccles Robert (1991) The performance measurement manifesto. Harvard Business Review 131-138.
  9. Edvinsson Leif, Malone, Michael S (1997) Intellectual capital – Realizing your company’s true value by finding its hidden roots. Harper Business, New York.
  10. Edvinsson Leif, Malone, Michael S (1998) Intellectual capital – The proven way to establish your company’s real value by measuring its hidden brainpower. Piatkus Publ. New York.
  11. Frankfort-Nachmias, Chava; Nachmias, David (1992) Research methods in the social sciences. St Martin’s Press. Kent.
  12. Gröjer, Jan-Erik; Johansson, Ulf (1996) Human resource costing and accounting. Joint Industrial Safety Council, Stockholm.
  13. Hemmer, Thomas (1996) On the design and choice of ‘modern’ management accounting measures. Journal of Management Accounting Research 8: 87-116.
  14. Hollis, Martin (1994) The philosophy of social science. Cambridge University Press.
  15. Johansson U, Mabon, H (1998) The personnel Economics Institute After Ten Years: What Has Been Achieved and Where Are We Going? Journal of Human Resource Costing & And Accounting 3: 65-76.
  16. Johnson H, Thomas Kaplan, Robert (1987) Relevance lost the rice and fall of management accounting, Harvard Business School Press, cop. Boston.
  17. Kaplan, Robert Norton, David (1992) The Balanced Scorecard – Measures that drive performance. Harvard Business Review 1: 71-79.
  18. Kaplan, Robert Norton, David (1996a) Using the balanced scorecard as a strategic management system. Harvard Business Review 75-86.
  19. Kaplan, Robert Norton, David (1996b) The balanced scorecard. Harvard Business School Press, Boston.
  20. Leininger, Madeleine (1994) Evaluation Criteria and Critique of Qualitative Research Studies, Critical Issues in Qualitative Research Methods edited by Morse, Janice, Thousands Oak, Calif. Sage.
  21. Liberatore Matthew, Monaham, Thomas Tymon, Walter (1997) Linking a balanced scorecard to company strategy. Corporate Controler, Winter 24-29.
  22. Mason, Jennifer (1996) Qualitative research. SAGE Publ. London.
  23. Meindl James, Stubbart, Charles Porac, Joseph (ed) (1996) Cognition within and between organizations. SAGE Publ. London.
  24. Miles Grant, Miles Raymond, Perrone Vincenzo, Edvinsson Leif (1998) Some conceptual and research barriers to the utilization of knowledge. California Management Review 40: 281-287.
  25. Olve, Nils-Göran, Roy, Jan Wetter, Magnus (1997) Balanced Scorecard isvensk praktik. Liber Ekonomi, Malmö.
  26. Roos Johan, Roos Göran, Edvinsson Leif, Dragonetti Nicola C (1997) Intellectual capital- Navigating in the new business landscape. MacMillan Press. London?

 

A Therapeutic Equivalence of Two Formulations of the Fixed Combination of Benzydamine Hydrochloride and Cetylpyridinium Chloride in the Treatment of Sore Throat Associated with Upper Respiratory Tract Infection

DOI: 10.31038/JCRM.2021422

Abstract

Background: The combination of Cetylpyridinium chloride and Benzydamine hydrochloride (CPC/BH) has antiseptic, antimicrobial, anti-inflammatory and analgesic properties. We have investigated whether the fixed combination in the form of lozenges is therapeutically equivalent to the orosoluble tablet formulation in a randomized, parallel, partially double-blind, three-arm, placebo controlled clinical trial in patients with sore throat due to upper respiratory tract infection.

Methods: Clinical assessment was made within 3 hours after the initial single dose drug administration. Thereafter, subjects underwent the therapy according to the prescribed schedule for additional 4-7 days, primarily to assess the safety profile of CPC/BH. Multiple measurements using Visual Analogue Scale (VAS) were performed to assess sore throat pain intensity, while categorical Sore Throat Pain Relief Scale (STPRS) was used to assess sore throat pain relief within three hours after the initial dose administration. Tonsillopharyngitis Assessment Score was used to assess the resolution of upper respiratory tract infection after 4 and 7 days of therapy.

Results: Altogether 291 patients aged 39,6 ± 11,5 years with sore throat were randomly assigned to receive CPC/BH lozenges (118 patients), CPC/BH orosoluble tablets (116 patients) or placebo (57 patients). Both formulations were significantly more effective than placebo in reducing sore throat pain intensity at 1, 2 and 3 hours after the initial dose administration. The two formulations were found to be equivalent in terms of therapeutic efficacy at all three measurement points. Similarly, Total Pain Relief over the time interval of 15 minutes to 3 hours after the initial dose was greater in both formulations in comparison with placebo and no significant difference between the two formulations. Altogether 28,1% of patients in placebo group, 59,3% in CPC/BH lozenges group and 47,4% in CPC/BH orosoluble tablets group were considered therapy responders. Again, both treatments were significantly better than placebo with no significant difference between the two formulations. The mean time to onset of sore throat pain relief was significantly shorter in both formulations with comparison to placebo. At day 5 of treatment, the disease was completely resolved in 31,6% of subjects in the placebo group and in 53, 4% patients treated with both CPC/BH formulations (p=0,007). At day 8, the disease was resolved in 66,7%, 89,0% and 81,0% of patients in placebo, CPC/BH lozenges and CPC/BH orosoluble tablets groups, respectively. There was similar statistical significance between the groups as at day 5. Altogether, 10 therapy-related adverse events have been reported. There were all of mild intensity, none of them was serious and they were relatively evenly distributed between the treatment groups.

Conclusions: The therapeutic equivalence between the lozenges and orosoluble tablets formulation of CPC/BH was demonstrated in terms of sore throat pain intensity reduction, sore throat pain relief, percent of responders and time to the pain relief onset after the initial dose and in terms of the disease resolution after 4 and 7 days of treatment. Both formulations were superior to placebo. Both CPC/BH formulations have similar safety profile to placebo.

Introduction

Upper respiratory tract infections are one of the most common acute infectious diseases including acute pharyngitis. The latter is one of the commonest complaints at the general practitioner level of medical care, even so, most of the people with pharyngitis do not seek medical help [1,2]. Predominantly, pharyngitis or tonsillopharyngitis is caused by viral infection. In less than 20% of cases bacteria are involved [3]. Hence, the use of antibiotics for the treatment of acute pharyngitis is questionable and in many cases inappropriate [4,5].

Cetylpyridinium chloride (CPC) belongs to a family of quaternary ammonium bases. It exerts its antimicrobial effect through non-specific interaction at the bacterial cytoplasmic membrane [6]. CPC is a broad-spectrum antiseptic that has both a bactericidal and virucidal effects. In addition to its antiseptic effect, it also has emulsifying and detergent properties and helps to lubricate and soothe the painful area. It penetrates the least accessible places on the mucous membrane. This is an important factor in the treatment of mouth and throat infections [7]. Benzydamine hydrochloride (BH), a non-steroid anti-inflammatory drug (NSAID) has analgesic, anaesthetic, anti-inflammatory and antimicrobial properties. It is a weak inhibitor of the synthesis of prostaglandins but it has several properties, which may contribute to its anti-inflammatory activity [8]. Clinical studies with benzydamine used for management of inflammatory oropharyngeal conditions have demonstrated results, mainly exerted as a more rapid resolution of pain and dysphagia and reduction of inflammation [9,10].

Krka, d. d., Novo mesto has developed the fixed dose combination of 3 mg CPC and 1 mg BH in the form of lozenges. The therapeutic regimen is one lozenge four times daily, i.e. each 3 hours. The principal aim of our study was to investigate whether the CPC/BH lozenges are therapeutically equivalent to the reference marketed fixed combination dose of 3 mg CPC and 1 mg BH in the form of orosoluble tablets, which has the identical dose regimen, in patients with sore throat due to upper respiratory tract infection. The second aim was to demonstrate the superior effect of both CPC/BH formulations over placebo.

Patients and Methods

This was a randomized, parallel, partially double blind, three arm, placebo-controlled, equivalence, multicenter, international trial conducted at 11 clinical sites in Russian Federation and Slovenia. Due to issues with the dissolution time, the blind was only assured for the lozenges (i.e. placebo was in the form of lozenges). Even so, orosoluble tablets were not on the market in participating countries at the time of the study conduct so the patients could not have recognized the reference product.

In order to be enrolled, male or female patients, aged 18 to 65 years, should have had the onset of moderate to severe sore throat six days or less before the screening/enrolment visit. They had signs and symptoms of acute tonsillopharyngitis. They have signed written informed consent to participate in the trial. Among the non-inclusion criteria were streptococcal tonsillitis assessed with rapid antigen detection test in patients with severe pathology of changes in pharyngeal region, increased body temperature that needed antipyretic treatment (more than 38, 5 degrees Celsius), oropharyngeal lesions such as tumours, purulent necrotic process or aphtous ulcers, any evidence of mouth breathing or coughing which could compromise respiratory function and worsen sore throat and concomitant therapy that could bias the assessment of therapeutic efficacy and safety.

Patients have undergone two or three visits at the outpatient clinics. At the first visit, the initial single dose of study therapy has been administered and measurements of pain intensity and pain relief performed over three hours. Thereafter, patients continued with the usual therapeutic regimen for 4 or 7 days. There were two additional visits on day 5 and 8 of the study to assess safety and efficacy of the treatments. Patient whose condition has resolved after 4 days of therapy, concluded the therapy on day 5, while those with persisting signs and symptoms of the disease have been treated for another three days.

The key parameter of the assessment of efficacy endpoints was Sore Throat Pain Intensity (STPI). It was assessed by Visual Analog Scale (VAS) that ranges from zero (not sore) to 100 (very sore) in millimetres [11]. The measurement points (in minutes) at the initial visit were zero (baseline at the time of the therapy intake), 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, and 180.

Primary efficacy endpoint was a difference between the STPI at one hour after the administration of the initial dose and baseline STPI value while secondary endpoints included the difference in STPI between STPI at two hours and three hours, and baseline STPI value. Another secondary endpoint was percent of responders defined by the threshold STPI reduction at first, second and third hour after the therapy administration.

At each of the two following visits, a single STPI measurement has been made to yield the combined tertiary efficacy endpoint of percent of patients with the disease resolution.

Another parameter of efficacy assessment was sore throat pain relief (STPAR) measured at the initial visit by the categorical Sore Throat Pain Relief Scale (STPARS) containing seven categories of pain relief description [12]. The measurement points with STPARS were identical to VAS except the baseline measurement where no relief could has been assessed hence no assessment with STPARS was made. A secondary efficacy endpoint Total pain relief (TOTPAR) was defined as the area under the curve (AUC) in the time interval from 15 minutes to 180 minutes after the initial dose administration. At each of the two following visits, a single STPRS measurement has been made to yield the combined tertiary efficacy endpoint of percent of patients with the disease resolution.

Tonsillopharyngitis assessment score (TPAS) [11,13] has been assessed to evaluate objective signs of the condition, which served as the assessment for the inclusion criterion and for two tertiary efficacy endpoints. It consists of five features assessed by the investigator: body temperature, oropharyngeal colour, oropharyngeal enanthemas, cervical adenopathy and cervical adenitis. To assess the safety profile, an interview and physical inspection were used.

Statistically, this study has been based on equivalence design. The null hypothesis for the primary efficacy endpoint is non-equivalence between the two CPC/BH formulations, and the alternative hypothesis is equivalence defined by pre-defined equivalence margin (δ) of 13 millimetres of VAS score [14]. Assessment of the hypotheses was based on a two-sided 95% confidence interval for the treatment difference. It was to be concluded that the two formulations are equivalent if the lower and upper bounds of the 95% confidence interval for the treatment difference lie entirely within (–δ, δ) interval. In order to assure the assay sensitivity as an inherent part of the equivalence design, a superiority alternative hypothesis of both formulations against placebo was tested. In order to achieve the study power of 80% and type I error (α < 0.025), minimally 273 subjects should have finished the primary point assessment. Due to expected minimal effect of placebo, a balanced treatment allocation of 1:2:2 was used for placebo, and each of the formulations, respectively.

Results

Altogether 291 patients were enrolled and underwent the single dose efficacy assessment. The baseline characteristics are displayed in the Table 1.

Table 1: Baseline characteristics.

Placebo

N=57

CPC/BH

Orosoluble tablets

N=116

CPC/BH

Lozenges

N=118

Total

N=291

Age (years)

Mean (SD)

Min/max

 

39,9(10,80)

24/62

 

40,5(12,23)

19/65

 

38,5(11,07)

19/64

 

39,55 (11,49)

19/65

Gender (%)

Male

Female

 

35

65

 

36

64

 

26

74

32

68

Body temperature (oC)

mean (SD)

min/ max

 

37,49 (0,3)

36,7/38,3

  

37,49 (0,4)

36,6/38,4

 

37,49 (0,4)

36,4/38,4

37,49 (0,4)

36,4/38,4

TPA score-baseline

mean (SD)

median

min/ max

 

5,1 (0,9)

5,0

4/8

 

5,1(1,1)

5,0

4/9

 

5,2(0,9)

5,0

4/7

STPI (mm)

mean (SD)

min/ max

 

80,0(10,28)

64/100

 

78,2 (10,02)

52/100

 

77,6 (9,89)

60/100

78,3(10,02)

52/100

Out of 291 patients, 143 successfully completed the treatment at Visit 2 with no major protocol violation, while 143 concluded the treatment at visit 3. There were 5 drop-outs.

The mean difference between the two formulations in STPI at 1 hour (primary efficacy endpoint) has been 3,38 mm in favour of CPC/BH lozenges. The corresponding 95% CI were – 1,73 and 8,49 mm and were therefore entirely within the equivalence margin. The mean difference between CPC/BH orosoluble tablets and placebo has been 19,74 mm. The difference was statistically significant (p<0,001). Likewise, the mean difference between CPC/BH lozenges and placebo was statistically significant. It has been 23,11 mm (p<0,001). The two secondary efficacy endpoints-STPI difference at 2 hours and STPI difference at 3 hours have shown similar results and therefore corroborated the outcome with the primary efficacy endpoint. The primary and secondary efficacy endpoints denoting STPI difference at hours 1, 2 and 3 are shown in the Figure 1.

fig 1

Figure 1: STPI difference at hour 1, 2 and 3.

The STPAR score values over the time interval of 15-180 minutes, which represent the basis for the TOTPAR calculation, are shown in the Figure 2. The TOTPAR over the corresponding time interval has been significantly higher in the therapeutic groups who were administered the two CPC/BH formulations in comparison with placebo group. There were no significant differences between the two formulations.

fig 2

Figure 2: TSPAR score over the time interval of 15-180 minutes.

Altogether, 59.2 percent of patients who have taken CPC/BH lozenges and 47.7 percent of those who were treated with CPC/BH orosoluble tablets have responded adequately to the therapy. There were no significant difference between the two therapeutic groups, whereas both formulations were significantly better that placebo (Figure 3).

fig 3

Figure 3: Percent of responders after the initial dose therapy administration.

After 4 days of treatment, sore throat and signs of tonsillopharyngitis have resolved in 31,6% of patients in placebo group, and in both CPC/BH formulation groups in 53,4% of subjects. The difference between placebo and active treatments was significant (p= 0.007). After 7 days of treatment, the disease was resolved in 66,7%, 89,0% and 81,0% of patients in placebo, CPC/BH lozenges and CPC/BH orosoluble tablets groups, respectively. There was similar statistical significance between the groups as after 4 days of therapy.

There were altogether 10 drug-related adverse events reported. The overall incidence per treatment group was 3,51%, 4,31% and 2,54% for placebo, CPC/BH orosoluble tablets and CPC/BH lozenges, respectively. Due to a low number of drug-related adverse events, a comparative analysis was not performed.

The summary of drug-related adverse events is displayed in the Table 2. There were no patients who would be unable to finish the assessment due to clinically significant adverse events. There were no deaths or any other serious adverse events in this study.

Table 2: Drug related adverse events.

Treatment

 

Total

N=291

Placebo

N=57

Orosoluble

tablets

N=116

Lozenges

N=118

 

 

 

 

 

 

 

Gastrointestinal disorders

Diarrhoea

0

1(0,9%) 0

1(0,3%)

Dry mouth

0

0 2(1,7%)

2(0,7%)

Heartburn

0 0 1(0,9%)

1(0,3%)

Meteorism

1(1,8%)

0 0

1(0,3%)

Nausea

0

1(0,9%) 0

1(0,3%)

Numbness of tongue

0

1(0,9%) 0

1(0,3%)

Parageusia

0

1(0,9%) 0

1(0,3%)

Stomach pain

0

1(0,9%) 0

1(0,3%)

Total

1(1,8%)

5(4,3%) 3(2,5%)

9(3,1%)

Skin and subcutaneous tissue disorders Erythema facial

1(1,8%)

0 0

1(0,3%)

Total

1(1,8%)

0 0

1(0,3%)

Discussion and Conclusions

In this clinical trial, two formulations containing fixed combination of CPC 1 mg and BH 3 mg have been tested to establish the therapeutic equivalence of the two formulations with respect to efficacy and safety profile. The Orosoluble tablets have already been on the EU market at the time of the trial conduct contrary to lozenges pharmaceutical form of lozenges that was developed by Krka, d. d. Clinical data on the fixed combination have been rather scarce [15] including lack of placebo controlled studies. In order to assure essay sensitivity to established efficacy of the marketed pharmaceutical form, we had to include placebo arm to demonstrate the superiority of the reference drug [16].

As for the study methodology, all the key parameters of efficacy assessment including Sore throat pain intensity and Sore throat pain relief scales and Tonsillopharyngitis assessment score are well-established methods to assess efficacy in the setting of the claimed indication. They are corroborated with the research which has established their value as an assessment [11,17,18] as well as with studies of different medicinal products with similar indication profile [12,19].

The principal and decisive endpoint in the efficacy equivalence assessment in this trial was a single one. It represents the difference in pain intensity at the pre-determined time point as recommended by the EU Note on guidance on clinical trials of nociceptive pain.

The results of the comparison analysis, which included alternative hypothesis of equivalence, has demonstrated unequivocally that the two formulations are equivalent. The assay sensitivity has been assured by a clear-cut superiority of both active treatments over placebo in the primary efficacy endpoint analysis. The superiority of both CPC/BH formulations over the placebo in the pain intensity reduction persisted also after 2 and 3 hours as assessed by secondary efficacy endpoints. The secondary endpoint TOTPAR is an indicator of the pain control throughout the entire dosing interval. It is one of the main endpoints of sore throat pain model for the assessment of sore throat pain, which is commonly used in the comparative therapeutic intervention trials [17,20]. The percent of patients that respond adequately to the therapy is a very relevant endpoint in the trials that investigate the comparative effect between the two drugs and is proposed by the EU note on guidance as a primary efficacy endpoint of choice. The definition of the responder status is different throughout the studies. However, in most cases, the change in pain score that defines a clinically important difference for the individual patient is the most appropriate cut-off value [20,21]. Hence, we defined the equivalence margin (13 mm) of sore throat pain intensity difference at 1 hour, 2 hours and 3 hours after the initial dose as a cut-off point between the responder and non-responder status. In this respect, the responders maintain sustainable pain relief over the key points of the dosing interval.

As for the safety part, the number of drug-related adverse events was too low to justify a reasonable comparable analysis of the events. Low incidence was expected since both compounds are relatively safe, do not have a systemic effect in the recommended doses and have many years of safe use in their life cycle history. Furthermore, the incidence of individual drug-related adverse events was in majority of cases under 1% of the study population. Mostly, there were solitary cases of mild intensity. All of them abated by the end of the treatment. Lack of any severe or serious adverse events further corroborates the safety of both formulations and advocate their broad use in the supportive upper respiratory tract infections treatment setting.

In conclusion, this clinical trial has demonstrated that CPC/BH lozenges are therapeutically equivalent to CPC/BH orosoluble tablets in terms of sore throat treatment. The superior effect of both drugs persisted and was significantly better than placebo over the entire recommended dosing interval. These results were corroborated with the assessment of the percent of subjects who adequately responded to the therapy as well as with disease resolution after 4 and 7 days of treatment. Both drugs turned out to be relatively safe with the low incidence of adverse reactions and lack of severe or serious events.

References

  1. Bisino AL (2011) Acute pharyngitis. N Engl J Med 344: 205-211 [crossref]
  2. Hannaford PC, Simpson JA, Bisset AF, et al. (2005) The prevalence of ear, nose and throat problems in the community: results from a national cross-sectional postal survey in Scotland. Fam Pract 22: 227-233 [crossref]
  3. Addey D, Shephard A (2012) Incidence, causes, severity and treatment of throat discomfort: a four-region online questionnaire survey. BMC Ear Nose Throat Disord 12: 9 [crossref]
  4. Little PS, Wiliamson I, Warner G, et al. (1997) Open randomised trial of prescribing strategies in managing sore throat. BMJ 314: 722-727 [crossref]
  5. Butler CC, Rollnick S, Kinnersley P, et al. (1998) Reducing antibiotics for respiratory tract symptoms in primary care: consolidating ≫why≪ and considering ≫how≪. Br J Gen Pract 48: 1865-1870 [crossref]
  6. Merianos JJ (1991) Quaternary ammonium antimicrobial compounds. In: Block SS, ed. Disinfection, sterilisation and preservation. 4th ed. Philadelphia, London: Lea & Febiger 225-255
  7. Pitten FA, Kramer A (2001) Efficacy of cetylpyridinium chloride used as oropharyngeal antiseptic. Arzneimittelforschung 51: 588-595 [crossref]
  8. Quane PA, Graham GG, Ziegler JB (1998) Pharmacology of benzydamine. Inflammopharmacology. 6: 95-107 [crossref]
  9. Sardella A, Uglietti D, DemarosI F et al. (1999) Benzydamine hydrochloride oral rinses in management of burning mouth syndrome: A clinical trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 88: 683-686 [crossref]
  10. Wethington JF (1985) Double-blind study of benzydamine hydrochloride, a new treatment for sore throat. ClinTher 7: 641-646 [crossref]
  11. Schachtel BP et al. (1984) Rating scales for analgesics in sore throat. Clin Pharmacol Ther 36: 151-156 [crossref]
  12. Schachtel BP et al. (2002) Demonstration of dose response of flurbiprofen lozenges with the sore throat pain model. Clin Pharmacol Ther 71:375-80 [crossref]
  13. Schachtel BP, Fillingim JM, Beiter DJ, Lane AC, Schwartz LA (1984) Subjective and objective features of sore throat. Arch Intern Med 144: 497-500 [crossref]
  14. Todd KH. Et al. (1996) Clinical significance of reported changes in pain severity. Ann Emerg Med 27: 485-489 [crossref]
  15. Herrera D, Santos S, Ferrús J et al. Efficacy of a 0.15% benzydamine hydrochloride and 0.05% cetylpyridinium chloride mouth rinse on 4‐day de novo plaque formation. J Clin Peridonto 32; 595-603 [crossref]
  16. CPMP/ICH/363/96. Note on guidance on statistical principles for clinical trials.. Available at: https://www.ema.europa .eu/en/documents/scientific-guideline/ich-e-9-statistical-principles-clinical-trials-step-5_en.pdf, (accessed March 8, 2021).
  17. Schachtel BP et al. (1988) Sore throat pain in the evaluation of mild analgesics. Clin Pharmacol Ther 44: 704-711 [crossref]
  18. Stahmer SA, Shofer FS, Marino A, Shepherd S, Abbuhl S (1998) Do quantitative changes in pain intensity correlate with pain relief and satisfaction. Acad Emerg Med. 5: 851-857
  19. Schachtel BP, Fillingim JM, Lane AC, Thoden WR, Baybutt RI (1991) Caffeine as an analgesic adjuvant. A double-blind study comparing aspirin with caffeine to aspirin and placebo in patients with sore throat. Arch Intern Med 151: 733-737 [crossref]
  20. Schachtel BP et al. (2007) Utility and Sensitivity of the Sore Throat Pain Model: Results of a Randomized Controlled Trial on the COX-2 Selective Inhibitor Valdecoxib. Journal of Clinical Pharmacology 47: 860-870 [crossref]
  21. Farrar JT, Berlin JA, Strom BL (2003) Clinically important changes in pain outcome measures: a validation study. J Pain Symptom Manag 25: 406-411 [crossref]

Airline Service Features: A Mind Genomics Cartography Incorporating Emotions

DOI: 10.31038/ASMHS.2021511

Abstract

Respondents evaluated unique sets of 48 different combinations of elements (so-called vignettes), describing airline services, first rating interest, and second, selecting the emotion closest to their feel, from a list of five feelings/emotions. The test stimuli comprised mixtures of elements, features of the airline’s service, combined according to an experimental design. Each of 54 respondents evaluated a unique set of vignettes arrayed to ensure that the ratings could be analyzed by OLS (ordinary least-squares) regression. Two mind-sets emerged, MS1 being travel process and MS2 being fun and entertainment. The individual elements were linked to the emotions as well, providing a nuanced view of the elements beyond the ability to drive interest in the airline. The paper ends by introducing the PVI, personal viewpoint identifier, to assign a new person to a mind-set, providing a prescription of the specific words to say to the respondent to break through the everyday clutter, and excite interest in the offering.

Introduction

The world of travel and leisure collapsed during the 2020 Covid-19 pandemic [1-3]. Earlier in the decade, as travel was surging, the issues emerged about just ‘what’ the customer wanted in what was becoming a highly competitive environment. The period from 2009 to 2019 saw the emergence of the world from a financial debacle, the melt-down of 2008. Companies began to compete on what they could offer the customer. The emergence of e-commerce, and -shopping for travel changed the balance of knowledge, making the travel agent less important. Customers could use the Internet with programs like Kayak, Orbitz, and so forth to discover and piece together prices, amenities, schedules, etc. [4,5].

Within this world of information and increased customer demand, as well as direct to consumer, issues began to emerge about what features are important to acquire and satisfy customers [6]. In addition, however, interest in consumer requests was accompanied by a growing understanding that emotions play a role in decision making as well [7]. The question emerged about how to link elements to emotions as well, providing two pieces of information; how the element drives decisions, and how the element drives emotions, respectively In papers published by author Moskowitz and colleagues, introduced an approach using experimental design to design test stimuli, and a method to assess liking responses to these test stimuli, and especially determine the acceptance of the the underlying individual phrases, elements, the building blocks of the vignettes [8,9].

The study reported here presents one of the early studies in the use of the emerging psychological science of Mind Genomics to understand how people think about the features of travel, both in terms of motivation to act, and in terms of the linkage of emotion to the specific element. The ingoing assumption was that through the approach of Mind Genomics, explained below, it would be possible to do a simple study to understand the mental ‘valence’ of ideas in the mind of the consumer.

Understanding the Mind of the Consumer through Systematics (Mind Genomics)

Mind genomics is an emerging science with heritage from psychology, consumer research, statistics, and anthropology [10]. The objective of a Mind Genomics study is to understand how people make decisions about the everyday aspects of their lives. Mind Genomics works at the level of the granular, at the simplest levels of experience, which we might call ‘bottom-up’. This means that the information is specific, g expressed in the language of the person who is doing the experiencing, rather than in a summarizing, detail-sparse, high level language that might be used for a professional report.

The study reported here represents one of the earliest mindset cartographies, defined operationally as small studies which take a snapshot of an experience or a situation, with relatively few people. The objective of cartography is to map out the area, rather than confirm/falsify a hypothesis in the way Karl Popper and his associates might do so [11]. Mind Genomics reveal patterns which suggest a hypothesis, rather statistically test a hypothesis. The reason for that seemingly bold statement is that the conventional ways scientist to test hypothesis involve focusing the study, minimizing the noise so that the ‘signal’ can come through. Mind Genomics works in the opposite way, inserting ‘noise’ by testing the stimulus in y different ways, akin to the MRI (magnetic resonance image). It is the set of patterns generated by the MRI, and recombined, which lets the signal come through clearly.

Applying Mind Genomics to the Customer-facing Aspects of an Air Flight

We illustrate how Mind Genomics reveals the responses to an ordinary situation of the 21st century, specifically what people want as amenities on an airline. As the case study unfolds, we will see how Mind Genomics deals with what is interesting at a cognitive, interpretation level, and then at an emotional level, viz., the emotions selected by the respondent while reading a vignette.

The objective of the study was to identify the features of a flight as might offered by an airline seeking to burnish its image. Among the many offers that an airline could provide, in the language of the airline, how does Mind Genomics reveal the importance of the different offers, identify the emotions which relate or link to those offers, and uncover new mind-sets, groups of people showing different, even radically different responses to the same stimuli?

The process follows a series of steps, which we now explicate, showing the step, the data, and the conclusions emerging from each step.

Step 1: Select the Topic, Ask 6 Questions Relevant to the Topic, and for Each Question Provide 6 Answers

The original study was done in 2012. At that time, the primary design was the so-called ‘6×6’, or six questions, each with six answers, and a unique set of 48 combinations or vignettes for each respondent. The reason for the larger design can be traced to the early years of internet-based research. The respondents were recruited from a panel (Open Venue, Inc.,) located in Toronto Canada, but servicing the United States. Respondents at the time were not yet ‘oversampled’ by having every internet transaction followed by a short survey for satisfaction, or so it seems today.

During the first 15 years of these past two decades, it was possible to get consumer respondents to participate in interviews on the web lasting 15 to 20 minutes each. The dropout rate was low, around 33%, and the cost was modest. One benefit of the early introduction of Mind Genomics into internet-based research was the possibility of larger, longer studies, the current 6×6 design, and two rating questions. Today, with the shortening of attention span, with the various media and social media competing for attention, it is no longer possible to do the types of studies reported here. The studies can be of the same type, but significantly shorter. The new approach comprises 4 questions and four answers to each question and is known by the phrases ‘4×4’ or ‘four by four’.

Table 1 shows the 36 elements, arranged by question, and then the six answers (elements) to each question. It is important to keep in mind that the selection of elements need not be perfect. Most researchers are accustomed to thinking a great deal about the choice of elements. Some of that thinking comes from the fact that the researcher fails to perceive research as an iterative process and assumes that the research of this type is always final, conclusive. When the researcher realizes that one can do these early-stage cartographies quickly, inexpensively, and iteratively, the attitude changes from ‘getting the right elements for the not-to-be repeated study’ to ‘getting into the field, getting a feel of what ‘works’, and the iterating a few more times during the next day or two.’

Table 1: The six questions and the six answers to each question.

Question A: What are travel perks?
A1 Fly with us and your bags will fly free
A2 Extra carry-on bags….No extra charge when choosing our airline
A3 Special monthly offers
A4  Enjoy VIP perks with our executive club membership
A5 Frequent flyers of our airline get frequent flyer miles
A6 Special holiday deals
Question B: What are personal travel conditions?
B1 Comfy leather seats
B2 Extra legroom with your seat
B3 Wider seats in both coach and first-class sections
B4 Enjoy peaceful privacy with unlimited luxury in first-class
B5 Adjustable personal heating and air conditioning
B6 Private area for nursing infants
Question 3: How do you make travel easier/more fun?
C1 Ticket fees updated online every 24 hours
C2 Unlimited in-flight shopping with payment options available
C3 Book flights through our NEW mobile app
C4 City guide scouts HOT SPOTS for each destination
C5 Largest number of planes with WiFi
C6 Book car rental and hotel reservations all from one website
Question D: What type of club facilities do you offer?
D1 Club members gain access to private lounge in terminals
D2 FREE club membership
D3 Open bar in Pre-flight lounge
D4 Priority boarding privileges for club members
D5 When joining our club your 1st flight is 9 Dollars!
D6 Frequent flyers get extra carry-on bags
Question E: What type of food do you feature?
E1 Fresh food prepared daily
E2 Affordable meals
E3 Large variety of snacks
E4 Baby Formula available on menu for nursing mothers
E5 International cuisine
E6 Meals prepared to your preference
Question F: How do you relieve the schedule & baggage related anxieties?
F1 Mobile app reminds you of your flight 24 hours before boarding
F2 Gift card given if flights are late
F3 24/7 baggage assistance
F4 Live status for the whereabouts of incoming flights
F5 30min guarantee for incoming baggage
F6 Top Security guaranteed at airports

Step 2: Create Combinations of Answers (Vignettes), Present Them to the Respondent in Sets of 2-4 Answers, the Set Evaluated as a Single Offering

The underlying experimental design creates 48 unique combinations for each person. 36 of those combinations comprising four answers (elements), and 12 of those 48 combinations comprising three answers. No vignette can ever comprise two answers from one question to avoid combinations which could be mutually contradictory. The combinations are dictated by a single basic underlying design. The design is permuted so that the mathematical structure is the same, but the specific combinations differ for each respondent. The beauty of the design permutation strategy is that we know ahead of time that each respondent will have evaluated the precisely correct combinations to create an individual level model for that person. In the world of statistics, Mind Genomics uses a within-subjects design, which can be analyzed down to the level of a single respondent, that respondent level analysis becoming relevant for clustering the respondents into mind-sets.

The fact that each respondent evaluates a full experimental design makes Mind Genomics metaphorically akin to the MRI (magnetic resonance imaging). The MRI tool takes different snapshots of an underlying tissue, 2-dimensional, but puts them together afterwards by a computer program. The result is a three- dimensional represent Obtained by combining many-2 dimensional representations. The same holds for the Mind Genomics approach. We get a better understanding of the nature of responses to a situation by having many snapshots or many respondents looking at different combinations of the same topic. Rather than worrying about being correct in our initial choice of the stimuli to test, we create a pathway requiring absolutely no knowledge, although it does require that the researcher to identify phrases to use.

Before leaving this underlying experimental design, it is worth reinforcing the state above regarding Karl Popper’s view of the need to work with hypotheses. Mind Genomics differs from the conventional science which is interested in falsifying or confirming a hypothesis. To falsify with confidence, one would like to make the measures as free of variability as possible. In such a case, the strategy is to test the same stimuli many times to suppress by variability by averaging. Mind Genomics prescribes measuring the entire space, even with noise, letting the pattern emerge out of the seeming noise. Mind Genomics suppress the noise by averaging the underlying patterns, so that the noise drops out. The happy result is that Mind Genomics experiments (viz., studies, surveys) cover a great deal of the ‘design space,’ and reveal inherent patterns in a clear way. The underlying ‘story’ is easy to discern.

Step 3: Present the Test Stimuli, Vignettes, and Get Ratings

Figure 1 shows an example of four steps in the process, these steps manifesting themselves in screen during the Mind Genomics experiment. The four steps are shown as a single slide.

fig 1

Figure 1: Example of the respondent experience, who sees instructions, a vignette and two ratings scales, use the airline, and select an emotion.

The top portion of Figure 1 shows the orientation/instructions. The instructions say as little as possible about the topic. The goal is to have the elements convey the information because it will be the reactions to the elements which make all the difference.

The second section of Figure 1 shows a four-element vignette, viz., and a vignette comprising four answers.

The third section of Figure 1 shows the first rating scale; ‘use this airline’ (expected action)

The fourth section of Figure 1 shows the second rating scale, ‘select an emotion.’

Often critics complain that it is impossible for a person to make a judgment unless the vignettes are complete. Experience over the last 35 years with Mind Genomics shows this criticism to be invalid, although there is some need for instruction. People have no problem once the vignette is put into context with a few relevant pieces of information. A vignette having only one piece of information is hard to evaluate. An example is a vignette presenting only the brand name, or a price or a benefit. There is no sense of a ‘something’ being evaluated. By the time we get to two and certainly three elements things become a lot easier. The ‘something’ emerges, although the something is simply a set of ideas strung together without connectives. Nonetheless, respondents very rarely say that they have a difficulty answering the questions when there are several elements in the same vignette.

A great deal of the criticism of Mind Genomics comes from individuals who are looking at the process as a long, tortuous process. Most of the people who complain are either academics or marketers. The typical run-of-the-mill person has no problem going through 48 of these vignettes, when the vignettes are properly presented. The respondent is instructed to rate the vignette, doing so by ‘intuition’ and ‘gut feel’. It is here that respondents occasionally begin by trying to be consistent, but since these vignettes come and go so quickly, a typical respondent simply stops trying to be consistent, goes into almost an automatic state, and responds honestly to the combinations. The respondent cannot game the system. That is exactly what is desired, in an honest evaluation. The mind genomics approach forces the respondent to be honest because no human being could follow this combination rapidly enough when the combinations come once a every 8-12 seconds each, in an unrelenting fashion. This evaluation time suffices for the respondent to read the vignette, or at least glance at the vignette, and assign two ratings.

After the respondent completed the evaluation of the 48 vignettes, they completed a second questionnaire, comprising a self-description, in terms of who they are, what they do, and what they think about traveling and airlines. The respondents also were asked to list one feature that they feel to be most important.

For Mind Genomics studies, the best practice is to work with a professional company which specializes in getting respondents to participate on these online studies, whether the studies are called surveys, experiments, or some other label. The respondents may not be totally representative of the entire population, but they are as close as one is going to get to a representative population of the ultimate consumer or relevant party. Efforts to get free panelists may work in some rare situations, but over the past two decades it has become the norm to use panel providers, who incentive the panelists to participate in these studies. In this way the data come in quickly, at relatively low cost.

Step 4: Prepare the Data for Analysis by Transforming the Rating to Create New Variables

The 9-point Likert Scale may be used in the way it is, but it will be far more relevant to create a new binary scale for question #1 (use the airline), and five new binary scales for question #2 (select the emotion from a set of five).

The rationale for creating a binary scale is the effort needed to understand and then to explain the meaning of each scale point on a 9-point scale. Managers make yes/no decision, and prefer black and white answers, or at least black and white measures (viz., not use the airline vs. use the airline). When the 9-point scale is transformed to a binary scale, no/yes, it becomes easier for the manager to understand and use the data. Managers can understand yes in know quite easily. It does not take a lot of effort to explain the results. There is of course a loss of granularity, but that is to be expected and welcomed because it also reduces the confusion in interpreting the results.

The first transformation is the binary transformation using scale #1, the 9-point rating scale. By convention, viz., long term processes in consumer research, the scale is divided between 6 and 7. Ratings of 6 and below are assigned the value 0. Ratings of 7 and above are assigned the rating 100.

The second transformation is done using scale #2, the emotion. Each of the five emotions becomes its own scale. When the emotion is selected (and the other four not selected), the newly created variable corresponding to the selected variable is assigned the value 100. The other four newly created variables, viz., those not selected, are assigned the value 0. It should be kept in mind that this second ‘scale’, viz., select the emotion, is not a rating scale in the way we think of scales, but rather the lowest form of measurement, called the nominal scale by psychophysicist SS Stevens [12]. The five scale points, 1,2,3,4, and 5, do not have any metric value. They are simply placeholders to tell us what was selected.

The two transformations j prepare the data for OLS (ordinary least squares) regression analysis, which link the transformed ratings to the presence/absence of elements.

One final note is in order. OLS regression requires variation in the dependent variable, viz., variation in the transformed rating. This variation can be vanishingly small, but it must be in the data to prevent the regression analysis from ‘crashing.’ A prophylactic measure adds a random number around 10-5 to each newly transformed variable, a low number which does not material affect the OLS regression but prevents the OLS regression program from ‘crashing.’

Step 5: Create an Equation for Each Person, and Cluster People Based on the Pattern of Their Coefficients

The underlying experimental design enables the researcher to relate the presence/absence of the 36 elements to the responses, even at the level of the individual. This so-called ‘within-subjects design’ allows the estimation of the following equation at the level of each respondent, even though each respondent evaluated a unique set of 48 vignettes or combinations:

Binary Response Variable = k0 + k1(A1) + k2(A2) … k36(F6).

The foregoing equation uses the transformed variable from question #1, which had been transformed from a 9-point Likert Scale [13] to a binary scale (see Step 4 above).

Each respondent generates a vector of 37 numbers, an additive constant and 36 coefficients, one coefficient for each of the 36 elements. We ignore the additive constant, focusing just on the 36 coefficients. These coefficients show how the respondent weights the information to drive the judgment of ‘use.’

Through the statistical methods known as cluster analysis [14], we divide the respondents into two and then three groups, based upon the pattern of coefficients. In this case, with a small base size of 54 respondent we isolate two large clusters that were interpretable (MS1 and MS2), and a small cluster of 4 respondents that could not be interpreted. We thus selected a three-cluster solution, but do not pay attention to the third cluster, or third group (MS3). Note that the terms MS1, MS2, and MS3 are short-hand versions for the phrase mind-set, whose meaning will become clear.

At this point it is important to note that the entire clustering operation except for rejecting clusters or naming them is a purely mathematical operation, based upon creating groups of objects (respondents) showing mathematically ‘similar patterns.’ There is no attempt to name the mind-sets. Up to now everything is ‘objective,’ at least in the mathematical sense.

Step 6: Create an Equation for All Respondents, for Total, for Mind-sets, and for Genders

Step 5 showed the equation, estimated by OLS regression. The equation comprises both an additive constant (k0), and 36 individual coefficients.

Binary Response Variable = k0 + k1(A1) + k2(A2) … k36(F6).

Table 2 shows the parameters of the equations, first estimated for all vignettes evaluated by the total panel, and then estimated for all vignettes evaluated by respondents assigned to MS1, and then respondents assigned to MS2. Table 2 shows only the positive coefficients. To show all coefficients (viz., 36 for each subgroup) overwhelms the reader, and prevents patterns from emerging clearly. Neither zero coefficient nor negative coefficients teach us as much as do the positive coefficients.

Table 2: Performance of the strong performing elements by Total Panel and by the two larger mind-sets.

table 2

The parameters are interpreted as follows:

Additive constant – This is the parameter k0. The additive constant is the expect proportion of responses of value 7, 8, or 9 in the absence of elements. By design, all vignettes comprised three or four elements, so no vignettes ever comprised zero elements. The additive constant can be estimated, however, and represents the ‘baseline’ interest in using the airline, in the absence of any additional information. A simile is a statue. The additive constant is the base of the statue.

The elements, in turn, are the additive or subtractive values. We do not show the negative coefficients, which would subtract from the additive constant. We do show the positive coefficients because they are the more important for understanding the nature of the respondent’s thinking.

Table 2 shows a low additive constant, values 21-22, meaning that in the absence of elements (a theoretical situation, as noted above), we expected only one in five ratings to be ‘use the airline.’ It will be the elements, especially those with high coefficients, which drive the choice. These are the elements which ‘perform strongly.’ The operational definition of ‘perform strongly’ is a coefficient of +8 or higher, corresponding to a ‘t’ statistic of about 2 or higher, and a probably of randomness of 0.05 or lower. These cut-off points are obtained by an analysis of variance of the regression model data from the total panel. The strong performing elements are shown as shaded cells.

The strong elements for each mind-set tell the story, whether travel efficiency (MS1) or travel as fun and adventure (MS2). The names for the mind-sets are the major contribution in the interpretation. The creation of the elements requires critical thinking. The mind-sets themselves, however, emerge without any input from the researcher, other than being named.

The elements in Table 2 sorted by strongest to weakest, first by those elements which perform strongly among both mind-sets, then those elements which perform strongly among Mind-Set 1 (valuing travel efficiency (business travelers)), and then those elements which perform strongly among Mind-Set 2 (valuing travel as fun (leisure travelers)).

The data suggest strong performing elements, some performing well in both mind-sets. Two elements should not surprise, one dealing with price, the other with comfort:

When joining out club your 1st flight is 9 Dollars!

Extra legroom with your seat

One element has virtually no appeal at all

Baby Formula available on menu for nursing mothers

It is important to emphasize at this point that what seems obvious, namely the two different groups of respondents appear to emerge seamlessly, is in fact not so obvious at all. Consider, for example, another way to divide the respondents, viz., by gender. Table 3 shows radical differences between genders in their responses to the elements. The genders differ in terms of the elements which score highly. Yet, there is no clear story which summarizes the differences between the genders regarding the elements which perform strongly.

Table 3: Performance of the elements by Total Panel and by gender.

table 3

Step 7: Link Emotions to Elements

Question #2 required the respondent to select a single emotion/feeling to describe how the respondent felt after reading vignette. As described above, we can link the elements to each emotion/feeling by creating five new variables, as well as two summary variables (positive, negative)

The ordinary least-squares equation fits the same type of equation as we have seen above, without, however, the additive constant. In these analyses, coefficients of 10 or higher, are operationally considered to be strong.

We get a sense of the linkages for the Total Panel from Table 4. The Summary linkages suggest five strong linkages with positive emotions (comfortable, confident, and curious):

Table 4: Linkage of elements with emotions. Data from the Total Panel. Strong linkages of 10 or higher are shown in by the shaded cells.

table 4

When joining our club your 1st flight is 9 Dollars!

Extra carry-on bags….No extra charge when choosing our airline

Wider seats in both coach and first-class sections

Extra legroom with your seat

Comfy leather seats.

The summary also suggests five strong linkages to negative feelings/emotions (anxious, indifferent)

Private area for nursing infants

Baby Formula available on menu for nursing mothers

Book flights through our NEW mobile app

Mobile app reminds you of your flight 24 hours before boarding

Unlimited in-flight shopping with payment options available

It is important to recognize the potential power of linking elements to emotions. Knowing the linkage of an element with an emotion gives a sense of why the element performs the way it does and may increase the ability to fine tune the message to eliminate the negative feeling/emotion.

Step 8: Generalize the Results by Assigning a NEW PERSON to One of the Two Mind-sets

The data presented here provides an in-depth look at responses to offerings of amenities by airlines. The effort to create the study is relatively small; a day or even less should suffice to pick the topic, discuss the questions, select the answers, and run the study on the internet with 100-200 respondents. The newer versions, with four questions and four elements are even faster. The time for running the experiment is also short; 17-20 minutes for a panel or group of 50-100 people, who can run the study on the internet. Finally, the data analysis is automatic, with the researching getting the report within 1-2 minutes after the study is completed.

The issue is not the study, but rather the generalizability of the results, and the use of the data, both for knowledge-building and for direct marketing. Studies using 50-100 respondents can be set up and executed quickly, especially within the ‘new’ framework of 4×4, viz., four questions, each with four answers. The templated approach (www.BimiLeap.com) makes that effort simple. Yet, at the end of the single Mind Genomics experiment or iterated set of experiments, there is still the need to ‘use’ the data to solve real-world issues, perhaps involving hundreds, thousands, or even millions of people. How then can the researcher generalize the results?

A great deal of ‘foundational research’ regarding attitudes works from the top down, identifying general patterns of responses, so-called personas, which are akin to the mind-sets, but usually for a broader topic area, such as travel in general [15,16]. The objective of the research is to assign a new person to one of these general personas, and then attempt to offer that ‘persona’ (and thus the individual) the appropriate message. The effort is cumbersome, expensive, open to a great deal of interpretation. All too often the effort ends up with the researcher and the marketer ‘guessing’ what to communicate to and what to offer to each persona, viz., each overarching general ‘mind-set.’ The personas may be clear as general descriptions, but the descent from the general to the particular remains a stumbling block. That is, knowing the ‘general’ does not automatically mean knowing ‘the particular in this instance.’

Mind Genomics approaches the problem in a different fashion. Mind Genomics works at the granular level, from the bottom up, remaining in the granular. Here, the granular comprises the relevant, limited aspects of travel, represented by 36 different, concrete ideas, ideas which can be instantiated in specific actions. The emergent mind-sets are quite different from each other. Time after time, these mind-sets emerge as the key to both to better understand the customer, and to better put that understanding into action.

The focus on granularity has led to a simple, virtually algorithmic approach which assigns new people to the appropriate mind-set. The data from the mind-sets (Table 2) prescribe the appropriate messages. During the past several years, authors Gere and Moskowitz have developed the PVI, the personal viewpoint identifier. The PVI comprises a set of six specific statements, taken from the set of statements shown in Table 2. The statements are those which best differentiate among two or three mind-sets, when artificial and disturbing ‘noise’ or random variability in inserted into the data table, in a so-called Monte Carlo simulation [17]. The PVI works by creating six questions (six elements from the study), each rated on a two-point scale. The pattern of responses to the six questions generates the information need to assign a person to one of the two (or three) emergent mind-sets, discovered through the Mind Genomics experiment.

The PVI set-up is templated and uses the Mind Genomics output. Table 5 shows the set-up section for the PVI. Not shown are the inputs for the three optional questions about why the PVI respondent travels, and the full set of data from which the PVI will created the algorithm to assign the respondent to a mind-set.

Table 5: The first part of the set-up for the PVI template.

  Question Text Mindset1 Mindset2 Mindset3
  Air1-2021      
1 Mind Set Name MS1 Organized MS2 Fun  
2 Mind Set Feedback Look at flight to be organized, safe, efficient Look at flight as fun and adventure  
3 Mindset Page Possible Links Possible Links  
4 Mindset Video Possible Links Possible Links  
5 Question to be asked in the PVI (High Anchor) Seriously consider the airline (Low Anchor) Not a good enough offer  

Table 5 shows the five initial steps requiring judgment. This information is not automatically provided by the PVI algorithm.

1. The first step requires the researcher to provide the names for the mind-sets.

2. The second step requires the researcher to provide feedback to the respondent who fills out the PVI, with the feedback sent in an email, as well as placed into a database. Respondents are not only interested in the mind-set to which they belong, but want to know about their mind-set, and the other mind-sets.

3. The third step, an optional one, allows the researcher to drive the respondent to a landing page, based upon the mind-set to which the respondent has just been assigned.

4. The fourth step, also optional, optional one, allows the researcher to drive the respondent to a video, based upon the mind-set to which the respondent has just been assigned. Either the respondent is guided to a landing page, to a video, or neither.

5. The fifth step shows the two questions to be used when the respondent rates each of the six elements in the PVI.

Figure 2 shows the actual PVI created for this study from the viewpoint of what the respondent receives to complete. The PVI link is shown below, and is current as of Spring, 2021.

fig 2

Figure 2: The PVI screen as the respondent see it.

https://www.pvi360.com/TypingToolPage.aspx?projectid=1271&userid=2018

The PVI begins with a short orientation about the project, and then requests the respondent to answer several background questions, such as age, gender, etc.

The second part of the PVI comprises three questions about the respondent as a flier (viz., frequency, reason for flight, passenger class).

The third part of the PVI presents six questions, and the two answers. The order of these six questions varies from respondent to respondent. The pattern of answers assigns a respondent to one of the two mind-sets.

The respondent who participates in the PVI questionnaire devotes approximately 60-90 seconds to the study. The objective is to identify WHO the respondent is, WHAT the respondent thinks or does, and then the mind-set to which the respondent BELONGS. This knowledge can be used to understand what to offer to the person through a designated landing page or video ‘fine-tuned’ to the mind-set, or to understand the mind-sets of people in different populations regarding the topic. It is important to keep in mind that once the mind-set is determined, the data can be used to select the precise words to use in advertising, or for research.

The feedback emerging from the study might well be incorporated into the landing page or video, to which the newly ‘mind-typed’ respondent is directed as part of the search process. The prospect, no longer a respondent in the PVI, would be led to one of the two different landing pages or videos, constructed according to Figures 3 or 4, respectively.

Discussion and Conclusions

fig 3

Figure 3: The structure of information for the landing page or video: Mind-Set 1: Business Travelers.

fig 4

Figure 4: The structure of information for the landing page or video: Mind-Set 2: Leisure Travelers.

As presented here, the Mind Genomics method provides a fast, easy to use, inexpensive  knowledge creation and knowledge deployment system. The worldview of Mind Genomics differs from the worldview of applied research in that the data can be archived and directly integrated in a bigger database. The coefficients have ratio-scale properties (a 20 is twice as much as a 10), the coefficients are scale-independent since they come from a binary transform, and the coefficients can be stored for comparison across years, topics, and even disciplines. In a sense, the coefficients comprise the basis of a ‘wiki of the mind’.

The important thing to keep in mind is that the data are cognitively rich, and self-evident. That is, there is no tortuous experiment to tease out the way ‘nature works.’ The patterns emerge quite simply. The patterns which emerge are either meaningful or not meaningful. Mind Genomics simply restructures parts of everyday life, giving the information a numerical value based upon the linkage with either a rating question, or an emotion. Instead of those questions, the questions can deal with price, with occasion, and so forth, in which case the results emerging from the cartography would provide the foundation for a ‘cognitive economics,’ or ‘cognitive anthropology.’ Finally, the ability to mind-type many people on many mind-sets provides a unique opportunity to create a true ‘wiki of the mind’, linked with actual people, so that one may understand more fully how the ‘mind type’ manifests itself in the behavior of the everyday.

Acknowledgment

Attila Gere thanks the support of the Premium Postdoctoral Researcher Program of the Hungarian Academy of Sciences.

The authors wish to thank the late Steven Onufrey, Ms. Janna Kaminsky, and Prof. Martin Braun of Queens College for their help on this project, in Mathematics 101, Queens College of the City University of New York.

References

  1. Neuburger L, Egger R (2020) Travel risk perception and travel behaviour during the COVID-19 pandemic 2020: a case study of the DACH region. Current Issues in Tourism 1-14.
  2. Nicola M, Alsafi Z, Sohrabi C, Kerwan A, Al-Jabir A et al. (2020) The socio-economic implications of the coronavirus pandemic (COVID-19): A review. International Journal of Surgery 78: 185-193.
  3. Wilson ME, Chen LH (2020) Re-starting travel in the era of COVID-19: preparing anew. Journal of Travel Medicine 27: 108.
  4. Choi K, Wang Y, Sparks B (2019) Travel app users’ continued use intentions: it’sa matter of value and trust. Journal of Travel & Tourism Marketing 36: 131-143.
  5. Lu J, Mao Z, Wang M, Hu L (2015) Goodbye maps, hello apps? Exploring the influential determinants of travel app adoption. Current issues in Tourism 18: 1059-1079.
  6. Cheyne J, Downes M, Legg S (2006) Travel agent vs internet: What influences travel consumer choices? Journal of Vacation Marketing 12: 41-57.
  7. Andrade EB, Ariely D (2009) The enduring impact of transient emotions on decision making. Organizational Behavior and Human Decision Processes 109: 1-8.
  8. Levin LA, Langer KM, Clark DG, Colquhoun TA, Callaway JL et al. (2012) Using mind genomics® to identify essential elements of a flower product. Horticultural Science 47: 1658-1665.
  9. Moskowitz H, Silcher M, Beckley J, Minkus-McKenna D, Mascuch T (2005) Sensory benefits, emotions and usage patterns for olives: using Internet-based conjoint analysis and segmentation to understand patterns of response. Food Quality and Preference 16: 369-382.
  10. Moskowitz HR (2012) ‘Mind genomics’: The experimental, inductive science of the ordinary, and its application to aspects of food and feeding. Physiology & Behavior 107: 606-613. [crossref]
  11. Wilkinson M (2013) Testing the null hypothesis: The forgotten legacy of Karl Popper? Journal of Sports Sciences 31: 919-920. [crossref]
  12. Baker BO, Hardyck CD, Petrinovich LF (1966) Weak measurements vs. strong statistics: An empirical critique of SS stevens’ proscriptions NN statistics. Educational and Psychological Measurement 26: 291-309.
  13. Joshi A, Kale S, Chandel S, Pal DK (2015) Likert scale: Explored and explained. Current Journal of Applied Science and Technology 396-403.
  14. Dubes, Richard, Anil K. Jain (1980) Clustering methodologies in exploratory data analysis. Advances in Computers 19: 113-228.
  15. Brower M (2017) Claritas (formerly Nielsen) Segmentation and Market Solutions. The Charleston Advisor 18: 15-20.
  16. Zhang Y, Mohammadian A (2006) An Exploratory Analysis of the Household Travel Behavior and Lifestyle Choices. Applications of Advanced Technology in Transportation 665-670.
  17. Rubinstein RY, Kroese DP (2016) Simulation and the Monte Carlo method. John Wiley & Sons 10.

Is the Rational Design of Viral Vaccines a Realistic Enterprise?

DOI: 10.31038/JCRM.2021421

Abstract

The development of molecular biology in the 20th century fostered the expectation that biology could be reduced to chemistry and this blurred the distinction between the chemical nature of antigen-antibody binding and the biological nature and capacity of the immune system to elicit the formation of neutralizing antibodies able to protect against viral pathogens. Belief in the rational design of viral vaccines is problematic because the complex notions of human rationality and of design are rarely described or defined accurately, which leads investigators to overestimate their capacity to solve inverse problems. Vaccinologists are often confronted with such problems which consist for instance in identifying what were the multiple biological causes in the past that give rise to a wanted beneficial result in the future, such as the absence of deleterious HIV infection in human elite controllers. In addition to the impossibility of investigating past immunological events by doing scientific experiments in the future, the common failure of rational vaccine design is also due to the fact that vaccinology is essentially an empirical science that needs to rely on the results of immunogenicity trials that must necessarily be based on trial-and-error experimentation rather than on bounded rationality.

Review

A scientific procedure is said to be rational if it is based on reason and accepted scientific theory and successful rational vaccine design in virology usually implies that researchers are expected to be able to predict the outcome of an immunization process aimed at inducing the production of neutralizing antibodies (Abs) that abolish the infectivity of a viral pathogen. The concept of structure-based vaccine design is derived from rational drug design which relies on knowledge of the 3D structure of a biologically active target molecule in order to discover candidate molecules that will bind with high activity and selectivity to the target and abolish its biological activity [1]. Such computer-assisted strategies based on structural bioinformatics and molecular docking are usually considered to be superior to the empirical screening and trial-and error approaches commonly used in the past [2,3] although they mostly failed when they were applied to the rational design of viral vaccines. The reason for this is that vaccinologists mostly tried to improve the antigenic binding capacity of their candidate viral immunogens instead of investigating whether superior immunogens could be designed that would be able to generate protective Abs in vaccinees [4-7]. Improving immunogenicity would have required an investigation of the numerous factors, extrinsic to chemical epitope-paratope recognition, that control the biological capacity of human immune systems for eliciting the induction of protective antibodies which depend on the Ab gene repertoire and antigen processing ability of the host, the specificity of helper and suppressive immune cells and various other immunoregulatory mechanisms. Even when a vaccine has been “designed” on the basis of computer-based predictions, there is in fact no guarantee that it will necessarily be able to induce protective Abs if it has not been tested empirically in the human biological context in which it is expected to be effective. The remarkable development of molecular biology in the 20th century did foster the expectation that all biological phenomena may eventually be understood by reducing biology to chemistry and such reductionist thinking did blur the distinction between the chemical nature of antigen-antibody binding and the biological nature of the capacity of immune systems to elicit the production of neutralizing Abs. The structure-based reverse vaccinology (SBRV) approach introduced by Burton [8] was based on a confusion between antigenicity and immunogenicity which led many vaccinologists to expect that if a structurally defined HIV epitope was able to bind strongly to a broadly neutralizing monoclonal Ab, this epitope would also be able to induce similar neutralizing Abs in a vaccinated human host [9]. However, all Abs are both polyspecific (i.e. they always contain a variety of different paratopes) as well as heterospecific (i.e. they are able to react more strongly with other antigens than with the one that was used in the immunization process that elicited the Ab); these properties explain why the antigenic and immunogenic properties of proteins are often located in different regions of the molecule which is the reason why immunogenicity is not necessarily accompanied by an antigenic reactivity of the immunogenic epitope that would allow it to bind to the induced Ab [10]. Many vaccinologists are not aware that most problems they need to solve are so-called inverse problems. Solving inverse problems consists in proposing a theory that is able to explain the multiple past causes that produced an observed beneficial effect, for instance the absence of deleterious HIV infection in elite controllers [11]. An inverse problem thus starts with a result and requires that the investigator must try to imagine what are the multiple causes that could have produced it. Since scientific experimentation cannot investigate past events, it is necessary to develop a theoretical model of HIV immunity that could account for what has been observed and then to demonstrate that what the model predicts actually does occur. Since the human immune system is extremely complex and consists of numerous subsystems that are currently only poorly understood, it has been impossible to solve the numerous inverse problems posed by each subsystem and to develop plausible models that could be tested experimentally. In the absence of testable hypotheses, the only alternative was to rely on trial-and-error investigations which are the classical tools that have been used by vaccine developers in the past. These consist in selecting plausible vaccine candidates as well as appropriate vaccine formulations, schedules, adjuvants and routes of administration and testing these empirically since there was no knowledge of how the immune system induces the formation of neutralizing rather than non-neutralizing Abs.

Burton and Topol [12] have argued that since HIV infection elicits in patients broadly neutralizing Abs that recognize many HIV strains, it should in principle be possible to design an HIV vaccine, although they acknowledged that investigators would have to know how the immune system is able to induce neutralizing antibodies! This self-evident truth regarding the consequences of our ignorance of the mechanism of neutralizing Ab induction is of course one of the main reasons why the rational design of an HIV vaccine did not succeed although many other reasons for this failure have been well documented [7,13]. Burton and Topol [12] nevertheless stated that a rationally designed HIV vaccine may perhaps only be a decade away. They also suggested that rational vaccine design could be successfully applied to a virus like SARS-CoV-2 and that a pan-virus vaccine able to protect against more severe and antigenically distinct coronavirus variants that could appear during any epidemic, may in future be obtained by rational design, even before such variants had emerged or had caused considerable damage. They envisaged that this could be achieved by investing hundreds of millions of $ for stockpiling enormous quantities of vaccines for future use although they did not clarify which rational design strategies would make it possible to produce effective vaccines against new viruses of unknown pathogenicity.

In fact, rational vaccine design is actually problematic for two reasons that are linked to the concepts of both rationality and of design. The economist and Nobel laureate Herbert Simon introduced the notion of “bounded rationality” to explain the intrinsic limitations of human cognition and rationality that are due to the many unavoidable constraints that always limit the ability of humans to achieve a complete analysis of complex systems [14]. Such limitations exist because our information is always insufficient or inaccurate, we have limited time and resources for investigating the countless numbers of interacting components in any complex biological or immunological system and we cannot reach entirely rational decisions that would require a complete knowledge of all the relevant parameters. Instead of guaranteeing that a correct solution to complex problems can be reached, bounded rationality inevitably forces us to make tentative decisions that always remain uncertain.

Physicists and chemists used to believe that the universe was ruled by mathematical laws that would make it possible to predict the future behavior of a system if one had an intimate knowledge of all its initial conditions. However, in spite of our enormous modern computational power, we were actually unable the predict the 2008 world financial crisis and we also fail to be able to make long-term weather predictions. Chaos theory has reconciled us with the reality that extremely small differences in the initial conditions of a dynamic biological complex system prevents us from making accurate predictions about its future state [15,16].

The concept of design which implies the deliberate and intentional conceiving of an artificial, novel object or process by an intelligent being is equally ambiguous.

Adepts of so-called “intelligent design” for instance argue that a mythical, intelligent deity is responsible for having designed all living forms on our planet according to a preconceived plan and they do not accept that evolution took place through the filter and pressure of Darwinian natural selection. The design metaphor is also equally inappropriate for explaining the evolution of living organisms on earth as it is for describing the activity of scientists when they try to achieve a particular intentional goal in the form of a discovery or invention since their intentional design activities in most cases are not successful [6]. Intentional successful design remains as mysterious as the indispensable contributions of human imagination, intuition and talent that are needed for producing artistic as well as scientific creations and success is not obtained by simply following the numerous steps of a design procedure as if they were the obvious rules of a conceptual recipe book.

The popular paradigms of rational design and reductionism led many HIV vaccinologists to assume that the detailed structural knowledge of HIV spikes would allow them to design complementary binding antigens capable of inducing neutralizing Abs by vaccination [7]. This strategy failed because it was not appreciated that the structures observed in HIV complexes of spikes bound to Abs resulted from a process of mutually induced fit between the two partners and did not correspond to the structures present in the free, mobile and frequently disordered partners before they had interacted. For instance, the HIV-1 p17 matrix protein possesses an intrinsic protein disorder of 70% that reverberates across the viral membrane and produces a shell disorder that prevents the HIV immunogens used as vaccine from inducing a protective immune response [13,17]. It is well-known that although segmental mobility in proteins does enhance the binding capacity of epitopes and paratopes, extreme disorder in a protein antigen on the other hand can prevent antigen recognition and vaccine effectiveness [18].

The common failure of rational vaccine design is in line with the well-known fact that vaccinology is essentially an empirical science that relies more on trial-and-error experimentation than on available fundamental scientific knowledge of immunological phenomena. As emphasized by Hacking [19] in his book Representing and Intervening, we need to interfere with the material world (for instance immune systems) in order to obtain knowledge about it and our understanding increases when we are able to intervene successfully in it, for instance by achieving protective immunity by immunization. An understanding of the immune system is thus achieved because of a prior successful intervention and effective vaccines have often been obtained empirically in the past even before their mode of action had been elucidated. During the last ten years innumerable unsuccessful attempts have tried to identify which series of successive HIV immunogens should be used in a vaccine in order to mimic the Ab maturation pathway that is required for eliciting neutralizing protective Abs [20,21].

Since we know very little about which features of human immune systems regulate the production of protective antibodies, it seems evident that empirical vaccination trials will remain a prerequisite for developing effective vaccines against HIV and many other viral pathogens.

References

  1. Kuntz ID (1992) Structure-based strategies for drug design and discovery. Science 257: 1078-1082. [crossref]
  2. Amzel LM (1998) Structure-based drug design. Curr Opin Biotechnol 9: 366-369. [crossref]
  3. Bramwell VW, Perrie Y (2005) The rational design of vaccines. Drug Discov Tod 10: 1527-1534. [crossref]
  4. Douek DC, Kwong PD, Nabel GJ (2006) The rational design of an AIDS vaccine. Cell 124: 677-681.
  5. Walker LM, Burton DR (2010) Rational antibody-based HIV-1 vaccine design: Current approaches and future directions. Curr Opin Immunol 22: 358-366. [crossref]
  6. Van Regenmortel MHV (2016) Structure-based reverse vaccinology failed in the case of HIV because it disregarded accepted immunological theory. Int J Mol Sci 17: 1591-1625. [crossref]
  7. Van Regenmortel MHV (2019) HIV/AIDS: Immunochemistry, Reductionism and Vaccine Design: A Review of 20 Years of Research. Springer Nature Switzerland AG 364.
  8. Burton DR (2002) Antibodies, viruses and vaccines. Nat Rev Immunol 2: 706-713. [crossref]
  9. Van Regenmortel MHV (2012) Basic research in HIV vaccinology is hampered by reductionist thinking. Front. Immunol 3: 194. [crossref]
  10. Van Regenmortel MHV (2014) Specificity, polyspecificity, and heterospecificity of antibody-antigen recognition. J Mol Recognit 27: 627-639. [crossref]
  11. Van Regenmortel MHV (2018) Viral species, viral genomes and HIV vaccine design: is the rational design of biological complexity a utopia? Arch Virol 163: 2047-2054. [crossref]
  12. Burton DR, Topol EJ (2021) Variant -proof vaccines – Invest now for the next pandemic. Nature 590: 386-388.
  13. Van Regenmortel MHV (2020) What does it mean to develop an HIV vaccine by rational design? Arch Virol 166: 27-33.
  14. Simon H (1996) The Sciences of the Artificial. 3rd ed. Cambridge, MA: MIT
  15. Du Sautoy M (2016) What we Cannot Know. Harper Collins Publishers 36-73
  16. Green S (2015) Can biological complexity be reverse engineered? Stud Hist Philos Biol Biomed Sci 53: 73-83. [crossref]
  17. Goh GK, Dunker AK, Foster JA, Uversky VN (2019) HIV vaccine mystery and viral shell disorder. Biomolecules 9(5):178. [crossref]
  18. Uversky VN, Van Regenmortel MHV (2020) Mobility and disorder in antibody and antigen binding sites do not prevent immunochemical recognition. Crit Rev Biochem and Mol Biol
  19. Hacking, I (1983) Representing and Intervening. Cambridge University Press: Princeton, NJ, USA 1-304.
  20. Van Regenmortel MHV (2018) Development of a preventive HIV vaccine requires solving inverse problems which is unattainable by rational vaccine design. Front Immunol 8 :2009 [crossref]
  21. Uversky VN (2021) On the irrationality of rational design of an HIV vaccine in light of protein disorder. Arch Virol, [crossref]

The Organization of the Dental Service in the Voronezh Region

DOI: 10.31038/IMROJ.2021613

 

In the article, on the territory of a large subject of the Russian Federation, the features of the organization of dental care for adults and children are considered. During the meetings in the autonomous health care institution, in accordance with the action plan of the Department of Health of the Voronezh Region, the issues of primary prevention of dental diseases among the population of the Voronezh Region within the framework of the state program of the Russian Federation “Development of Health Care”are highlighted. When considering the current state of scientific medicine and the practical direction of preserving the health of the population, the relevance of dental research remains unchanged. The analysis of literature sources and reporting materials showed the importance of dynamic observation of medical and social indicators, conditions and lifestyle, the level and structure of dental morbidity, and the demographic situation. The author of the work is well aware of the importance of the background of dental measures aimed at prevention (first of all) and treatment (if necessary). Speaking about the indicators of morbidity in dentistry, the author emphasizes the need to study it to assess the public health of the entire population. The data of the social and hygienic monitoring of the Voronezh Region for 2017-2019 were used.

Keywords

Curatorship, Dental service, Perspective directions of development

In recent decades, the broadest powers to provide medical care to the population have been transferred to the level of the constituent entities of the Russian Federation, including the dental service. The broad capabilities of specialized medical organizations operating in legally permitted forms of ownership are provided by a significant number of personnel, high external and internal resources, and constant updating of prescriptive directives on professional activities in relation to all personnel with explanations on the implementation of effective and high-quality provision of medical care. The dental service in the health care system of the Voronezh Region is currently characterized by the availability and quality of care to the population, the introduction of modern dental technologies into practice, and constantly improving the professional level of specialists [1].

Materials and Methods

In order to analyze and evaluate the results of preventive and curative work to reduce the incidence of diseases among the population in the dental profile, it is extremely important to consider the shortcomings available in the official accounting documents. Therefore, every year the results of the work are summed up through the preparation of an analytical review of the activities of the dental service of the Voronezh Region. It is such a study that creates the possibility of forming a strategy for organizing work on the part of a dentist working in outpatient clinics (APU) and managing the health care vertical at the regional level. At the beginning of 2020 in the Voronezh region, the number of initially applying for dental care fell by 3.9%, while initially seeking children at 6.5%. There is no doubt about the information that crisis situations in various spheres of society aggravate social and hygienic factors that affect the dental morbidity in the direction of deterioration. This constantly directs the theoretical and practical parts of the work carried out to re-evaluate the forces of these factors, as well as to find ways to optimize the ongoing preventive work.

We have studied and used the data of the reports, conducted a comparative analysis concerning the personnel potential of the dental service of the Voronezh region in 2017-2019. (report forms No. 17, 30, 47), the availability of resources, as well as the opinion that the health of the population is directly related to medical and demographic indicators against the background of the results of preventive work included in the main indicators of the dental service. This work, carried out in the Voronezh Region, is fully comparable with the existing world experience in planning preventive programs to reduce the dental morbidity of the population, for the strategic unity of science and practice.

Results of the Study

At the beginning of 2020, the dental service of the Voronezh Region, as a subject of the Russian Federation, has 13 dental clinics, including one for children, 19 dental departments, 10 dental offices at district hospitals (RB), 293-at other medical organizations of the Voronezh region, including dispensaries, sanatoriums, general education institutions, enterprises. The structural composition of dental specialists has remained virtually unchanged over the past years. In 2019, 1156 doctors of the dental profile (in state medical organizations) and 607 doctors of the non-state dental profile provided outpatient dental care in the region. The share of dentists in the structure of the region’s dental specialists working in the public sector was 8.8% in the reporting year (9.1% in 2018).

In recent years, the stability of the personnel potential of public sector dental doctors has been noted. In state medical organizations in the region as a whole, in 2019, 1308.5 full – time positions of dental doctors were allocated (in 2018 – 1319), employed – 1151 (in 2018 – 1164.25), individuals – 1156 (in 2018-1156). The percentage of staffing for occupied positions was 88% (in 2018 – 88.3%), for individuals-88.3% (in 2018-87). The percentage of dental doctors in 2019 by position (public sector) is shown in Figure 1.

fig 1

Figure 1: Percentage of dental doctors in 2019 in the Voronezh Region.

Of course, the focus is on the work of the therapeutic APUs of the region, both in the adult and in the child population, the figures show the indicators of the availability of dentists-therapists for 2017 – 2019 (Figure 2 and 3, respectively). The priority remains to work with the younger generation on the basis of the principle “prevention is better than treatment” [2]. But with the staff at pediatric dentistry of the medical organizations of the districts in a difficult situation: a low security child population by dentists for children (1.7 while the recommended ratio of 5.0) due to insufficient staffing and lack of them in a few areas (in 2019 is not entered into the appointment with a dentist in BUZ VO “Nizhnedevitskiy RB”) (Figures 2 and 3).

fig 2

Figure 2: The provision of dentists-therapists per 10 thousand adults in the region in 2017-2019.

fig 3

Figure 3: Provision of dentists-therapists for 10 thousand children in the region in 2017-2019.

Children’s dentists actively participated in the medical examination of the children’s population of the region [3]. The school preventive program is carried out in all general education institutions of Voronezh and the districts of the region. The activities of the dental service of the Voronezh Region are carried out in accordance with the Procedures for Providing Medical Care to Adults and Children with dental diseases, as well as in accordance with the Clinical Recommendations (treatment protocols) of major dental diseases. The proportion of sanitized patients from primary referrals in the region in 2019 was 59.85% (in 2018 – 60.1%), in the regions of the region decreased from 60.5% in 2018 to 57.62% in 2019, in Voronezh increased from 63.1% in 2018 to 63.4% in 2019. The indicator of those examined for preventive purposes from the number of primary applicants in the region decreased from 50.1% in 2018 to 47.36% in 2019, in Voronezh also decreased from 46.2% in 2018 to 45.16% in 2019, in the regions of the region there was also a decrease – from 52.4% in 2018 to 50.04% in 2019.

In all schools, gymnasiums and lyceums of Voronezh, hygiene lessons are held in primary school classes on the rules of oral care, and health schools are open. Despite this, the number of people with a healthy oral cavity per 1000 children under the age of 14 years, 11 months and 29 days in the whole region decreased and amounted to 548.73 (in 2018 – 575.42), in the districts of the region the indicator increased slightly – from 477.04 in 2018 to 477.66 in 2019, and in Voronezh it decreased – from 695.28 in 2018 to 627.13 in 2019 [4].

Discussion

The implementation of the financial plan for 1 dentist-orthopedist for 2019 was 98.5% in the region (in 2018 – 99.4%), including 98.5% in the regions of the region (in 2018 – 104%), 100.8% in Voronezh (in 2018 – 97.6%). Kantemirovskaya RB (92%), Repyevskaya RB (93.7%), Rossoshanskaya RB (91.2%), Ternovskaya RB (95.97%), Ertilskaya RB (86%), VOKB No. 2 (34.3%), VSP No. 2 (86.7%), VSMU Dental Polyclinic did not meet this indicator.. N. N. Burdenko (92.6%), BUZ VO “VSP No. 5” (99.1%). ganizations of the dental profile of the Voronezh region actively participate in the actions held within the framework of the regional interdepartmental project “Live long!”, with the support of the Department of Health – the program “Kaleidoscope of Health”, with the support of the Dental Association of Russia in the person of the VROO “Dental Association” from 01.03.2019 to 31.03.2019, the campaign “A dazzling smile for life” was held for schoolchildren of the Voronezh region. And on May 23, 2019, the departure of 3 specialists of the AUZ VO “VOKSP” was carried out in the city of Liski for participation in the review-competition within the framework of the specified project. This event was attended by representatives of all dental clinics in Voronezh. In 2019, the specialists of the regional clinical dental polyclinic (AUZ VO “VOKSP”) carried out 17 visits to medical organizations in the region (in 2018 – 17).

Supervision is in AUZ IN “WAXP” a huge breakthrough in the provision of organizational and methodological assistance to the heads of the dental service areas. In 2019, 1710,438 visits were made to the doctors of the dental profile of the region, which is 2.8% less than in 2018 (1759,157 visits). In order to improve dental knowledge in the field and in accordance with the work plan of the dental service of the region, together with the specialized departments of the Burdenko State Medical University, 6 events were held in 2019 (7 in 2018): inter – regional events – 3, regional workshop – 2, city event – 1. Annually, the staff of the regional clinical dental clinic publishes information and methodological materials for dentists of the region. The program of state guarantees for dentistry for 2019, according to preliminary data, was implemented in the region by 101.3% in the UET, in Voronezh-by 100.9%, in the regions of the region-by 100.5%. Below the control values, the PGG was performed by the dental services of the Bogucharskaya RB, Petropavlovsk RB, Podgorenskaya RB, and Ternovskaya RB dental hospitals.

The development and implementation of the main directions of development of stoma-tragicheskoi services, and coordination of dental medical organizations of all forms of ownership in the field provides organizational and methodical study of the regional clinical dental clinic.

The priority areas of organizational and methodological work are defined as:

  • providing organizational, methodological and advisory assistance to the heads of dental services
  • field forms of operational control over the activities of dental units
  • systematic analysis of the activities of the dental service of the region, the implementation of analytical work on the assessment of the state and dynamics of the development of its individual structures
  • development of current and long-term plans for the activities of the dental service of the region, strategic planning
  • organization of activities in priority areas of development of the dental service of the region, their implementation, monitoring and evaluation of the effectiveness of implementation
  • conducting permanent training of specialists of the dental service of the region of the middle and senior level (conferences, seminars)
  • information support (issue of methodological recommendations and information letters).

Insufficient provision and understaffing of staff in the districts of the region, especially secondary medical personnel, weak material and technical base of a number of facilities for providing dental care to the population of the districts of the region remain problematic [5]. The best performance has reached the dental service of BUZ VO “Anna RB”, BUZ VO “Bobrovskaya RB”, BUZ VO “Kalacheevskogo RB”, BUZ VO “Liskinsky RB”, BUZ VO “Pavlovskaya RB”, BUZ VO “Ramon RB”, BUZ VO “Buturlinovskiy RB”, BUZ VO “Novousmanskiy RB”. Last rank place in the rating table of the medical organizations of the districts is a dental service BUZ VO “Bogucharskaya RB”, BUZ VO “Vorob RB”, BUZ VO “Ternovskaya RB”, BUZ VO “Kantemirovskaya RB”, BUZ VO “Novokhoperskiy RB”.

Among the dental clinics in Voronezh, the best indicators were achieved by the VSP No. 6 and VKSP No. 4 dental clinics [5].

Conclusion

The priority directions of the development of the dental service of the Voronezh region can be considered:

  • strict implementation of the Program of state guarantees to the population of the region for the provision of dental care
  • equipping dental departments and offices in accordance with the standards of equipping Procedures for providing medical care to adults and children with dental diseases
  • improving the availability, safety and quality of dental care to the population
  • priority of prevention in the field of health protection, including in the organization of the work of the school dental service of the districts of the region
  • entry into the continuing medical education program.

References

  1. Antonenkov Yu E, Chaikina NN, Saurina OS (2020) About the dental service of the Voronezh region. Problems of social hygiene, health care and the history of medicine 28: 239-242.
  2. Korolenkova MV, Khachatryan AG, Harutyunyan LK (2020) Perinatal risk factors for caries of temporary teeth 99: 47-51.
  3. Pervushina OA, Antonenkov Yu E, Chaikina NN (2014) On the issues of optimizing the work of secondary medical personnel with the adult population in the dentistry of the Voronezh region. Current Issues of Education and Science 1: 99-100.
  4. Chubirko MI, JM Chubirko, Yu e He (2019) Internal quality control of medical care in scientific publications and normativnyh legal acts of the Russian Federation (review). Saratov Journal of Medical Scientific 15: 928-930.
  5. Golikova LO, Yu E Antonenkov, Yu Yu Bortnikova (2020) Formation of a health-saving environment in youth educational organizations as a basis for the prevention of morbidity, Based on the materials of the international scientific and practical conference. Modern Society, Education and Science 64: 76-80.

Comparison of a Single Dose Fibrinogen Concentrate with Placebo and Blood Transfusions after Surgery on the Aortic Arch: A Prematurely Ended Randomized Controlled Trial

DOI: 10.31038/IJAS.2021214

Abstract

Background: Aortic replacement surgery is often complicated by significant bleeding due to perioperative coagulopathy. Data regarding the effectiveness of treatment with fibrinogen concentrate to reduce perioperative blood transfusion in aortic replacement surgery in prior studies have shown conflicting results.

Methods: A randomized, placebo-controlled, double blind, clinical trial of a single dose fibrinogen concentrate versus placebo for treatment of post-cardiopulmonary bypass coagulopathy in patients undergoing elective surgery for thoracic arch aneurysm with deep hypothermic circulatory arrest.

Results: Twenty patients were randomized to fibrinogen concentrate (N=10) or placebo (N=10). The recruitment of study patients was prematurely ended due to a low inclusion rate. Five (50%) patients in the fibrinogen group and two (20%) patients in the placebo group had at least one perioperative blood transfusion (P=0.196). The 5-minute bleeding mass after study medication was 65 g [39-104] in the fibrinogen group and 61 g [40-108] in the control group (P=0.910). Postoperative blood loss was 450 ml [300-655] in the fibrinogen group and 510 ml [415-650] in the control group (P=0.405). After study medication, maximum clot strength and time from initial clot formation until maximum firmness improved significantly in the fibrinogen group but not in the control group.

Conclusions: Due to small volumes of postoperative blood loss and premature study termination, a beneficial effect of fibrinogen concentrate on the number of blood transfusions after aortic replacement surgery could not be established. However, treatment with fibrinogen effectively restored the postoperative fibrinogen concentration to preoperative levels and increased maximum clot strength after cardiopulmonary bypass.

Keywords

Hemostasis, Fibrinogen, Point of care systems, Thoracic aorta surgery

Introduction

Aortic replacement surgery is often complicated by significant bleeding due to perioperative coagulopathy. Consumption and dilution of clotting factors, inflammation and fibrinolysis, Hypothermic Circulatory Arrest (HCA) and long Cardiopulmonary Bypass (CPB) time increase the need for blood transfusions to treat perioperative blood loss [1]. Although blood transfusion is increasingly safe, evidence suggests that it remains associated with adverse clinical outcomes [2]. To reduce the risk of transfusion associated complications, perioperative coagulopathy can be treated with coagulation factor replacement therapies, but adequate powered randomized studies on the efficacy and safety of such therapies are scarce [3,4].

Plasma fibrinogen plays an important role in perioperative hemostasis, but is often reduced to low concentrations during cardiac surgery [5]. Low plasma fibrinogen levels reduce clot firmness and have been associated with bleeding complications [6]. Plasma fibrinogen initiates clot formation and enhances platelet aggregation by binding platelet glycoprotein IIb/IIIa receptors found on platelets [7,8]. To prevent depleted plasma fibrinogen levels, cardiac surgery patients can be substituted by plasma transfusion, Fibrinogen Concentrate (FC) or cryoprecipitate. Transfusion with plasma immediately supplies all essential coagulant factors, but requires large volumes to restore plasma fibrinogen levels, with risk of circulatory overload.

Data regarding the effectiveness of treatment with FC to reduce perioperative blood transfusion in aortic replacement surgery in prior studies have shown conflicting results. A landmark randomized trial in 2013 showed that blood transfusion was significantly reduced by FC compared to placebo [9]. However, a follow up multicenter study in 2016 could not confirm these results [10]. Fibrinogen concentrate did not reduce blood loss in studies that included a cardiac surgery population with lower bleeding risk (i.e. <20% of included patients had aortic replacement surgery) [11]. We therefore conducted a double blind randomized controlled trial in patients with aortic arch replacement surgery with HCA to investigate if intraoperative FC administration reduced the need for allogeneic perioperative blood transfusion within 24 h after surgery.

Patients and Methods

Study Design

A randomized, placebo-controlled, double blind, clinical trial of FC (Hemocomplettan P, CSL Behring, Marburg) versus placebo for treatment of post CPB coagulopathy in patients undergoing elective aorta replacement surgery with HCA for thoracic aneurysm at a large tertiary hospital for cardiac surgery. Ethical approval was provided by the local ethics committee (Medical Ethics Research Committee United, no. NL45370.020.13) on July 16th 2014. The study protocol was registered at the US National Library of Medicine (NCT02299947) and performed in accordance with the Declaration of Helsinki. All patients gave written informed consent prior to entering the study. On July 2015 the protocol was amended after a serious adverse event (one patient died of mesenteric ischemia) and a history of severe atherosclerosis or type B aortic dissection was added to the exclusion criteria.

Study Population

Adults with thoracic aneurysm scheduled for aortic replacement surgery were eligible for study participation. Patients with the following medical conditions were not recruited: prior thrombosis or myocardial infarction, congenital coagulation disorder, use of antiplatelet therapy or vitamin K antagonists within 5 days preceding surgery, a history of severe atherosclerosis or type B aortic dissection, prior thoracic surgery, pregnancy and pre-operative fibrinogen concentration <1 g/L. Patients were informed by telephone at least one week prior to the planned surgical procedure and with their permission written study information was sent by mail. Informed consent was retrieved by a trained research professional one day before surgery. Inclusion took place between August 2014 and July 2018.

Data Collection and Study Procedures

Patient characteristics were collected from routine preoperative anesthesia assessment and consisted of medical history, current drug use, laboratory tests and echocardiography results. Surgical characteristics and study data were prospectively collected and started at time of hospital admission. Anesthesia and Intensive Care Unit (ICU) management were conducted following local standard operating procedures for cardiac surgery. For Cardiopulmonary Bypass (CPB), non-pulsatile perfusion was used with a flow of 2.0 to 2.4 l/min/m2 and unfractionated heparin was used to target the kaolin Activated Clotting Time (ACT) >400 s. After aortic cross-clamping, cardiac arrest was initiated using a cold crystalloid cardioplegia solution (St. Thomas cardioplegia, Pharmacy ‘Haagse Ziekenhuizen’, The Hague, The Netherlands). Deep HCA with a core temperature of 25°C and bilateral antegrade, selective, cerebral perfusion preserved organ function during aortic replacement surgery. Patients were weaned from CPB after rewarming (temperature >35.5°C). Heparin was reversed with protamine sulfate (0.75 mg per 100 U of heparin) and tranexamic acid was administered to each patient.

Blood Product Transfusion Algorithm

Blood product transfusion was performed according to a local transfusion protocol. The trigger for Red Blood Cell (RBC) transfusion was a Hematocrit (Ht) <0.20 during CPB or <0.25 after CPB; a Hemoglobin (Hb) <4.4 mmol/l (7.1 g/dl) during ICU stay. Plasma transfusion was based on intraoperative blood loss (i.e. the number of transfused cell saver units or clinical signs of coagulopathy after protamine administration) or ongoing blood loss and an international normalized ratio of prothrombin time (INR) >1.5 after ICU arrival. Platelet transfusion depended on clinical signs of coagulopathy and/or low Platelet Count (PC) <100 x 109/l.

Blood Sampling and Coagulation Tests

Blood samples were collected from an arterial line at five perioperative time points: T1. At baseline after induction of anesthesia; T2. During CPB after initiation of rewarming; T3. Post-CPB, after protamine administration; T4. Post-CPB, after treatment with study medication and T5. At ICU arrival. Whole blood was sampled in K2EDTA and 3.2% sodium citrate tubes (BD Vacutainer) for conventional blood tests and coagulation assays at the hospital laboratory (Hb, Ht, PC, Fibrinogen (Clauss assay, STA-R Evolution analyzer, Diagnostica STAGO, France), activated partial thromboplastin time (aPTT)). Viscoelastic Point-of-Care (POC) testing was performed on a TEG 5000-analyzer (Haemonetics Corp., USA). Whole blood POC tests were performed at the operation room complex by a research professional within 5 minutes after sampling. Viscoelastic POC tests included: kaolin initiated clotting time (R; min.), time from initial clot formation until maximum firmness (Alpha Angle (AA); degrees), maximum clot strength (MA; mm) and Functional Fibrinogen (FF).

Intervention

Study medication was prepared by a trial pharmacist after aortic arch reconstruction during CPB rewarming. Fibrinogen Concentrate (FC) was dissolved in a blinded infusion bag with sterile water (1 gram per 50 ml). Fibrinogen dose was based on patient weight, using the following dosing regimen: 4 g/200 ml for weight <70kg=;6g/300ml for weight 70-90 kg; 8 g/400 ml for weight >90 kg) [12]. Placebo was a weight adjusted equivalent volume of sodium chloride 0.9% (Freeflex, Fresenius Medical Care Nederland B.V). All study medication was administered through an 18-gauche peripheral coloured intravenous line.

Study medication was only administered if clinically relevant bleeding occurred after CPB and when completion of surgical hemostasis for focal bleeding was accomplished by the surgeon. The 5-minute intraoperative bleeding mass was determined by weighing dry surgical gauzes, applying them into the surgical field for 5 minutes with no touch or irrigation and weighing them again. Blood volume weight between 60 and 250 grams was classified as clinically relevant coagulopathic bleeding [9]. After administration of study medication, 5-minute bleeding mass was measured again.

Outcomes

The primary outcome parameter was number of perioperative transfused allogeneic blood products within 24 h after surgery. Secondary outcome parameters were blood loss after surgery (chest tube drainage volume 24 h after surgery), re-operation (30 days) and postoperative mortality (30 days). Tertiary outcome parameters included the course of perioperative plasma fibrinogen levels and viscoelastic POC coagulation parameters.

Randomization and Blinding

Before surgery patients were randomly allocated by a clinical pharmacist to receive FC or placebo using block randomization (eight patients per block). Blinding of the investigators and surgical team was ensured by maintaining equivalent volumes of study medication in an infusion bag wrapped in aluminum foil.

Sample Size

Based on historical transfusion data in patients with aortic replacement surgery from our institution (median number of 24 h blood transfusions 9 ± 7) we hypothesized that two groups of 39 patients were required to demonstrate a 50% reduction of blood transfusion products in 60% of patients.

Statistical Analysis

Descriptive statistics were calculated for all parameters. Categorical variables were described as numbers and percentages. Continuous data were described as mean (standard deviation) and median [interquartile range] for normally and non-normally distributed data. Normality was tested using visual inspection of histograms. To compare categorical variables between groups Pearson chi-square test or, in case of small sample sizes, the non-parametric Fisher’s exact test was used. Statistical comparison of continuous variables was performed using the Student’s t-test for normally distributed data and the Mann-Whitney U test for non-normally distributed data. The sign test was applied for directional changes in paired coagulation parameters before and after administration of study medication. For estimating a difference in the primary outcome parameter between FC group and control group, Mann-Whitney U test was conducted on the number of transfused allogeneic blood products according to study medication treatment. Exploratory analysis was performed for secondary endpoints postoperative 24 h blood loss, re-operation and postoperative mortality. There were no missing data for the primary outcome. Missing data for secondary and tertiary outcome parameters were assumed missing completely at random and were excluded from analysis. No adjustment for multiple statistical comparisons was used.

Results

Study Population

Between August 2014 and July 2018, 171 patients with a thoracic aneurysm were screened for study participation and 73 patients were considered eligible and received study information (Figure 1). Twenty-seven patients provided informed consent and were randomized to receive FC or placebo. During surgery two patients were excluded because aortic replacement surgery was performed without HCA and five patients had insufficient intraoperative bleeding. On November 2014 the data and safety monitoring board was consulted early for a serious adverse event (one patient died of mesenteric ischemia) and concluded that the study should be continued based on the results of an interim analysis. The recruitment of study patients was terminated in December 2018 due to a low inclusion rate.

fig 1

Figure 1: Patient flow diagram.
Legends; HCA; hypothermic circulatory arrest.

Twenty patients were treated with FC (N=10) or placebo (N=10). Mean age was 63 (±12) years, mean weight was 87 (±20) kg and six (30%) patients were female. Baseline characteristics are listed in Table 1. Fibrinogen concentration at the end of CPB and before study medication was 1.5 [1.4-1.7] g/l for the fibrinogen group and 1.6 [1.4-2.1] g/l for the control group (supplementary Table 1). The mean decrease in plasma fibrinogen concentration compared to baseline was 47% (±7) and 18 (90%) patients had a fibrinogen concentration <2 g/l. After FC administration the plasma concentration increased from 1.5 [1.4-1.7] g/l to 3.1 [2.8-3.3] g/l (P=0.005). At time of ICU arrival fibrinogen concentration was 3.0 [2.6-3.3] g/l in the fibrinogen group and 1.8 [1.5-2.2] g/l in the control group (P=0.001). The difference in plasma fibrinogen concentration was no longer present at 24 h after surgery (4.4 [3.4-4.7] g/l for the fibrinogen group and 3.6 [3.2-4.4] g/l for the control group, P=0.267).

Table 1: Baseline and clinical characteristics.

Demographics Fibrinogen n=10 Placebo n=10 Missing
Age, median [IQR], y 67 [55-74] 64 [50-67] 0
Female, No (%) 4 (40) 2 (20) 0
Weight, mean (SD), kg 86 (24) 89 (15) 0
EuroSCORE, median [IQR] 7.5 [5-10] 6.5 [5-8] 0
Diabetes, No (%) 0 (0) 0 (0) 0
Hypertension, No (%) 6 (60) 6 (60) 0

LVEF %, No (%)

<30

30-50

>50

 

0

3 (30)

7 (30)

0

3 (30)

7 (70)

0
Aortic Valve surgery, No (%) 4 (40) 8 (80) 0
CPB time, median [IQR], min 198 [174-225] 222 [195-259] 0
Cerebral perfusion time, median [IQR], min 30 [26-47] 33 [27-57] 0
Transfusion autologous blood, median [IQR], ml 833 [600-1700] 1100 [550-1300] 1
5-min bleeding mass before SM, median [IQR], ml 131 [90-188] 142 [79-158] 0
5-min bleeding mass after SM, median [IQR], ml 65 [39-104] 61 [40-108] 0
Laboratory
Hb, mmol/l 8.0 [7.3-8.7] 7.8 [6.7-8.9] 0
Ht, % 0.38 [0.35-0.40] 0.37 [0.33-0.41] 0
Platelet count x109/l 191 [163-212] 208 [161-249] 0
Fibrinogen g/l 3.1 [2.7-3.2] 3.1 [2.7-4.0] 0
Aptt, s 34.9 [32.3-36.9] 34.4 [31.9-38.7] 3
Viscoelastic POC
TEG-MA, mm 67.4 [65.2-69.8] 68.5 [64.6-72.7] 0
TEG-R, min 7.2 [4.7-8.9] 6.9 [3.9-8.6] 0
TEG-AA, ° 62.1 [59.7-68.3] 65.8 [63.4-71.8] 0
FF-MA, mm 26.7 [22.5-40.6] 30.9 [27.5-38.7] 1

CPB: Cardiopulmonary Bypass, SM: Study Medication, TEG: Thromboelastography, R: Kaolin initiated Clotting Time, AA: Angle from Initial Clot Formation Until Maximum Firmness, MA: Maximum Clot Strength, FF: Functional Fibrinogen.

Blood Transfusion and Blood Loss

Five (50%) patients in the fibrinogen group and two (20.0%) patients in the placebo group had at least one perioperative blood transfusion (P=0.196). Number and types of perioperative blood transfusions are presented in Table 2. Intraoperative bleeding after CPB was not different between both groups (5-minute bleeding mass 131 [90-188] g for the fibrinogen group and 142 [79-158] g for the control group, P=0.821). After study medication 5-minute bleeding mass was reduced by 52% [33-67] in patients that received FC compared to 32% [16-80] in patients treated with placebo (P=0.705). Median postoperative blood loss was 490 ml [393-635]. Postoperative blood loss was 450 ml [300-655] for the fibrinogen group and 510 ml [415-650] for the control group (P=0.405).

Table 2: Perioperative blood transfusions.

 

Fibrinogen

Placebo P

Missing

Intraoperative blood transfusions, units (range)
RBC

3 (1-2)

1 (1) 0.503

0

Plasma

1 (1)

2 (2) 0.942

0

Platelets

2 (1)

1 (1) 0.542

0

Postoperative blood transfusions (24 h), units (range)
RBC

1 (1)

0 0.317

0

Plasma

2 (2)

0 0.317

0

Platelets

1 (1)

0 0.317

0

RBC: Red Blood Cells.

One patient in the fibrinogen group had a reoperation because of mesenteric arterial occlusion. In both groups one patient died during hospital stay, cause of death was mesenteric ischemia in the fibrinogen patient and sepsis in the placebo patient. One patient in the placebo group suffered from a non-fatal stroke (Figure 2).

fig 2

Figure 2: Perioperative fibrinogen concentrations in fibrinogen (purple) and placebo (grey) group.
Legends; Median values and error bars, IQR. Dashed lines indicate reference lines. Pre; baseline, post; post CPB, PM; post study medication. *P<0.05.

Viscoelastic POC Tests

Perioperative viscoelastic POC test results are presented in Figure 3. Values at baseline, post-CPB and after study medication were similar between both groups (Supplementary Table 2). A reduction in maximum clot strength between baseline and post-CPB (ΔTEG-MA) was related to intraoperative blood loss (r=-0.468 for 5-min bleeding mass, P=0.043). After study medication maximum clot strength and time from initial clot formation until maximum firmness improved significantly in the FC group but not in the control group (Figure 3). Test results for maximum clot strength and functional fibrinogen returned to baseline in the FC group (-7% difference compared to baseline for TEG-MA (P=0.203) and -15% difference for FF-MA (P=0.241)) but did not in the control group (-16% difference compared to baseline for TEG-MA (P=0.005) and -53% difference for FF-MA (P=0.008)).

fig 3

Figure 3: Perioperative viscoelastic POC test results.
Legends; Data markers indicate median and error bars, IQR. Dashed lines indicate manufacturers reference lines. Pre; baseline, PM; post study medication. *P<0.05.

Discussion

This study aimed to determine the effect of intraoperative treatment with FC on perioperative blood product transfusion in patients with elective aortic arch replacement surgery with HCA. A difference in number of blood transfusions after treatment with FC could not be demonstrated because the recruitment of study patients was prematurely ended due to a low inclusion rate and sample size was insufficient to answer our primary research question. Patients treated with FC showed an improvement in fibrinogen concentration, maximum clot strength and time from initial clot formation until maximum firmness directly after CPB, compared to patients treated with placebo.

Prior studies on the effect of treatment with FC to reduce blood transfusions in cardiac surgery patients have shown conflicting results [9-11,13-15]. A single-center randomized trial published in 2013, demonstrated that intra-operative treatment with FC resulted in an 85% reduction of blood transfusions in patients undergoing aortic replacement surgery [9]. Total avoidance of transfusion was achieved in almost half of the FC patients compared to none of the placebo patients. However, the number of blood transfusions in the control group was very high (median 13 units vs. 2 units in the FC group) and the favorable effect of FC treatment on blood transfusion after aortic replacement surgery could not be confirmed in a follow up multi-center study in 2016 with a similar design [10]. In that study, the number of transfusions in the placebo group declined to a median of 3 units [0-7] and was even lower than the number of transfusions in the FC group (median 5 units) [2-11]. A clear explanation for the higher transfusion rate in the FC group was not found, but could have been the result of poor protocol adherence [16]. The large decline in perioperative blood transfusions over time in patients undergoing aortic replacement surgery, irrespective of FC treatment, was also witnessed in our institution. Our historical transfusion data that were used for sample size analysis in 2014, showed a much higher number of transfusions than the control group of our randomized trial (median 9 ± 7 vs. median 0 ± 0). Therefore, it seems unlikely that our sample size would have been sufficient to demonstrated a significant difference in transfusions between both groups, if patient recruitment had not been prematurely ended. The implementation of a patient blood management program in 2015 that consisted of lower transfusion thresholds, an intraoperative POC transfusion algorithm, modified surgical and CPB techniques to reduce blood loss and limit intraoperative anemia could explain the overall reduction of transfusions over time in patients undergoing aortic replacement surgery in our institution.

Our results showed that treatment with FC resulted in an improvement of maximum clot strength and time from initial clot formation until maximum firmness compared to placebo. This finding is relevant as a reduction in maximum clot strength between baseline and post-CPB was correlated to intraoperative blood loss. In surgical patients, viscoelastic coagulation tests are used for the early diagnosis of coagulation disorders, to guide transfusion management and consequently reduce postoperative bleeding and blood product consumption [17-19]. In cardiac surgery patients monitoring of fibrinogen function with viscoelastic tests showed a better clinical performance than routine coagulation tests as a standardized, more reliable and valid laboratory tool for monitoring of the fibrinogen contribution to the clot formation [3]. Maximum clot strength was found to be the best viscoelastic predictor of postoperative blood loss, while none of the routine coagulation tests showed any correlation with postoperative bleeding [19,20].

Fibrinogen plays a key role in hemostasis and a negative association exists between plasma fibrinogen levels and blood loss after cardiac surgery [8,21-23]. Studies have shown that patients with normal or elevated fibrinogen levels experience fewer bleeding complications than patients with low fibrinogen levels [23,24]. In post-CPB hemostasis, fibrin formation is significantly more deteriorated than the platelet component of whole blood clot strength, suggesting that initial management of coagulopathy following cardiac surgery should focus on improving fibrin formation [25]. While the critical level of plasma fibrinogen, in relation to perioperative blood loss, remains subject of debate, there are experimental and clinical data describing that fibrinogen improves clot strength dose dependently [26,27]. In our study the median fibrinogen concentration after CPB was below the reference range in 90% of patients but most patients had little blood loss and a beneficial effect of FC treatment to reduce the number of blood transfusion products could not be established. However, we were able to demonstrate that FC treatment effectively restored fibrinogen levels and maximum clot strength to preoperative levels. Considering the relationship between maximum clot strength and bleeding, viscoelastic testing can guide the physician in the primary replacement of fibrinogen to reduce postoperative blood loss.

Limitations

Our trial was prematurely ended due to low inclusion rates. More than expected, patients were not eligible for study participation due to use of anticoagulants or a history of thrombosis. Also, we overestimated the willingness of high-risk cardiac surgery patients to participate in a clinical intervention study. The main reasons to refrain from study participation were anxiety for surgery and fear for adverse outcome. We aimed to include patients at high risk for postoperative bleeding based on type of surgery, use of HCA and historical data. However, overall blood loss was low. This may be the result of a Hawthorne effect. Also, different aspects of a patient blood management program could have influenced blood loss in favor of patient outcome.

Conclusion

This study demonstrated that low fibrinogen levels are common after elective aortic replacement surgery with HCA. Treatment with FC effectively restored fibrinogen levels, improved maximum clot strength and time until maximum firmness but a reduction in blood loss compared to patients treated with placebo could not be demonstrated.

References

  1. Görlinger K, Shore-Lesserson L, Dirkmann D, Hanke A, Rahe-Meier N, et al. (2013) Management of Hemorrhage in Cardiothoracic Surgery. J Cardiothorac Vasc Anesth 27: S20-34. [crossref]
  2. Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgery (EACTS) and the European Association of Cardiothoracic Anaesthesiology (EACTA), Boer C, Meesters MI, Milojevic M, Benedetto U, Bolliger D, Heymann C, et al. 2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery. J Cardiothorac Vasc Anesth. 2018; 32: 88-120.
  3. Erdoes G, Koster A, Meesters MI, Ortmann E, Bolliger D, et al. (2019) The Role of Fibrinogen and Fibrinogen Concentrate in Cardiac Surgery: An International Consensus Statement from the Haemostasis and Transfusion Scientific Subcommittee of the European Association of Cardiothoracic Anaesthesiology. Anaesthesia 74: 1589-1600. [crossref]
  4. Fitzgerald J, Lenihan M, Callum J, Mc Cluskey SA, Srinivas C, et al. (2018) Use of prothrombin complex concentrate for management of coagulopathy after cardiac surgery: a propensity score matched comparison to plasma. Br J Anaesth 120: 928-934. [crossref]
  5. Karkouti K , Callum J , Crowther MA , McCluskey SA, Pendergrast J, et al. (2013) The Relationship Between Fibrinogen Levels After Cardiopulmonary Bypass and Large Volume Red Cell Transfusion in Cardiac Surgery. Anesth & Analg 117: 14-22. [crossref]
  6. Essa Y, Zeynalov N, Sandhaus T, Hofmann M, Lehmann T, et al. (2018) Low Fibrinogen Is Associated with Increased Bleeding-Related Re-exploration after Cardiac Surgery. Thorac Cardiovasc Surg 66: 622-628. [crossref]
  7. Levy JH, Goodnough LT (2015) How I use fibrinogen replacement therapy in acquired bleeding. Blood 125: 1387-1393. [crossref]
  8. Levy JH, Welsby, Goodnough LT (2014) Fibrinogen as a therapeutic target for bleeding: a review of critical levels and replacement therapy. Transfusion 54: 1389-1405. [crossref]
  9. Rahe-Meyer N, Solomon C, Hanke A, Schmidt DS, Knoerzer D, et al. (2013) Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery: a randomized, placebo-controlled trial. Anesthesiology 118: 40-50. [crossref]
  10. Rahe-Meyer N, Levy JH, Mazer CD, Schramko A, Klein AA, et al. (2016) Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE): a double-blind phase III study of haemostatic therapy. Br J Anaesth 117: 41-51. [crossref]
  11. Bilecen S, de Groot JA, Kalkman CJ, Spanjersberg AJ, Bruinsma GJBB, et al. (2017) Effect of Fibrinogen Concentrate on Intraoperative Blood Loss among Patients With Intraoperative Bleeding During High-Risk Cardiac Surgery: A Randomized Clinical Trial. JAMA 317: 738-747. [crossref]
  12. Collins PW, Solomon C, Sutor K, Crispin D, Hochleitner G, et al. (2014) Theoretical modelling of fibrinogen supplementation with therapeutic plasma, cryoprecipitate, or fibrinogen concentrate. Br J Anaesth 113: 585-595. [crossref]
  13. Ranucci M, Baryshnikova E, Crapelli GB, Rahe-Meier N, Menicanti L, et al. (2015) Randomized, double-blinded, placebo-controlled trial of fibrinogen concentrate supplementation after complex cardiac surgery. JAHA 4: e002066. [crossref]
  14. Jeppsson A, Waldén K, Roman-Emanuel C, Thimour-Bergstrom L, Karlsson M (2016) Preoperative supplementation with fibrinogen concentrate in cardiac surgery: A randomized controlled study. Br J Anaesth 116: 208-214. [crossref]
  15. Lee SH, Lee SM, Kim CS, Cho HS, Lee JH, et al. (2014) Fibrinogen recovery and changes in fibrin-based clot firmness after cryoprecipitate administration in patients undergoing aortic surgery involving deep hypothermic circulatory arrest. Transfusion 54: 1379-1387. [crossref]
  16. Rahe-Meyer N, Levy JH, Mazer CD, Schramko A, Klein AA, et al. (2019) Randomized evaluation of fibrinogen versus placebo in complex cardiovascular surgery: post hoc analysis and interpretation of phase III results. Interact Cardiovasc Thorac Surg 28: 566-574. [crossref]
  17. Serraino GF, Murphy GJ (2017) Routine use of viscoelastic blood tests for diagnosis and treatment of coagulopathic bleeding in cardiac surgery: updated systematic review and meta-analysis. Br J Anaesth 118: 823-833. [crossref]
  18. Meco M, Montisci A, Giustiniano E, Greco M, Pappalardo F, et al. (2020) Viscoelastic Blood Tests Use in Adult Cardiac Surgery: Meta-Analysis, Meta-Regression, and Trial Sequential Analysis. J Cardiothorac Vasc Anesth 34: 119-127. [crossref]
  19. Welsby IJ, Jiao K, Ortel TL, Brudney CS, Roche AM, et al. (2006) The kaolin-activated Thrombelastograph predicts bleeding after cardiac surgery. J Cardiothorac Vasc Anesth 20: 531-535. [crossref]
  20. Sharma S, Kumar S, Tewari P, S Pande, Murari M (2018) Utility of thromboelastography versus routine coagulation tests for assessment of hypocoagulable state in patients undergoing cardiac bypass surgery. Ann Card Anaesth 21: 151-157. [crossref]
  21. Levy JH, Szlam FAHA, Tanaka KA, Sniesienski RM (2012) Fibrinogen and Hemostasis: A Primary Hemostatic Target for the Management of Acquired Bleeding. Anesth & Analg 114: 261-274. [crossref]
  22. Gielen C, Dekkers O, Stijnen T, Brand A, Klautz R, et al. (2014) The effects of pre- and postoperative fibrinogen levels on blood loss after cardiac surgery: a systematic review and meta-analysis. Interact Cardiovasc Thorac Surg 18: 292-298. [crossref]
  23. Kawashima S, Suzuki Y, Sato T, Kikura M, Katoh T, et al. (2016) Four-Group Classification Based on Fibrinogen Level and Fibrin Polymerization Associated With Postoperative Bleeding in Cardiac Surgery. Clin Appl Thromb Hemost 22: 648-655. [crossref]
  24. Blome M, Isgro F, Kiessling AH, Skuras J, Haubelt H, et al. (2005) Relationship between factor XIII activity, fibrinogen, haemostasis screening tests and postoperative bleeding in cardiopulmonary bypass surgery. Thromb Haemost 93: 1101-1107. [crossref]
  25. Solomon C, Rahe-Meyer N, Sørensen B (2011) Fibrin formation is more impaired than thrombin generation and platelets immediately following cardiac surgery. Thromb Res 128: 277-282. [crossref]
  26. Velik-Salchner C, Haas T, Innerhofer P, Streif W, Nussbaumer W, et al. (2007) The effect of fibrinogen concentrates on thrombocytopenia. J Thromb Haemost 5: 1019-1025. [crossref]
  27. Schenk B, Lindner AK, Treichl B, Bachler M, Hermann M, et al. (2016) Fibrinogen supplementation ex vivo increases clot firmness comparable to platelet transfusion in thrombocytopenia. Br J Anaesth 117: 576-582. [crossref]

China’s Direct Air Capture Potential

DOI: 10.31038/GEMS.2021314

 

China has been a major contributor to worldwide climate mitigation efforts. As the world’s largest emitter, the estimated emissions from fossil fuels in 2016 was said to be equivalent to approximately 1% of the remaining carbon budget under a 2°C scenario [1]. Key targets for lowering carbon dioxide (CO2) emissions set forth in China’s Intended Nationally Determined Contribution (INDC), under the Paris Agreement, includes peaking CO2 emissions by 2030, lowering CO2 emissions per unit of GDP by 60–65% from 2005 levels by 2030, and increasing the share of non-fossil fuels in primary energy consumption to around 20% by 2030 [2]. President Xi further restated this commitment during his speech to the UN General Assembly [3], including an ambitious goal to achieve net zero emissions by 2060. The INDC outlines a portfolio of low-carbon technologies and mechanisms to reduce greenhouse gas emissions, including setting up a national carbon market. However, the latest speech by President Xi gave very few details on how the net-zero goal for 2060 will be met.

To achieve true carbon neutrality by 2060, various notable scholars propose the use of negative emissions technologies (NETs) [4]. A specific capture technology gaining widespread attention among scientists is direct air capture (DAC), which enables the direct extraction of CO2 from the atmosphere. Fuhrman et al., (2020) [5] used the Global Change Analysis Model (GCAM 5.3) to simulate how negative emissions technologies, in general, and direct air capture (DAC), in particular, will contribute to China’s meeting this target. Their results confirmed the need to deploy NETs at very large scales, up to 1.5 GtCO2 per year of DAC.

In order to make a meaningful contribution to CO2 emissions reduction, we require carbon-neutral energy and/or heat to operate DAC. Due to the variation in DAC separation technologies, there is a disagreement on the actual amount of energy required. However, we know that DAC is an energy-intensive operation [6]. The energy requirement varies between 0.32 and 4.73 MWh per tonne of CO2 [7] removed from air. 35 DAC also requires considerable water input (1 t of Ceq, DAC (e.g. amines) requires approximately 90 m3 of water [8]). These considerations may limit the selection of possible DAC locations in China to areas where these resources are available in order to reduce costs. Research on the best locations to site DAC facilities in China is still relatively sparse. However, considering the energy requirements would suggest that co-location with renewable facilities such as wind or solar farms for supply of energy is a good route [9].

Research on efficient adsorbents, and DAC location studies are currently ongoing at the Energy Plus Laboratory affiliated with Shanghai Jiao Tong University. We hope to harness the favourable policy environment and recent technological advances in the field of carbon capture to design a prototype system capable of being upscaled to capture 1ton/day of CO2!

References

  1. Janssens-Maenhout, Greet, et al. (2017) Fossil CO2 & GHG emissions of all world countries. Luxembourg: Publications Office of the European Union 107877.
  2. NDRC Enhanced actions on climate change: China’s intended nationally determined contributions. 2015.
  3. The Guardian China pledges to become carbon neutral before 2060 (2020) The Guardian. Available: https://www.theguardian.com/environment/2020/sep/22/china-55 pledges-to-reach-carbonneutrality-before-2060.
  4. Haszeldine RS, Flude S, Johnson G, Scott V (2018) Negative emissions technologies and carbon capture and storage to achieve the Paris Agreement commitments. Phil Trans R Soc A. [crossref]
  5. Fuhrman J, Clarens AF, McJeon H, Pralit Patel, Scott CD, et al. (2020) China’s 2060 carbon neutrality goal 60 will require up to 2.5 GtCO2/year of negative emissions technology deployment [R].arXiv.org: 2020.
  6. Realmonte G, Drouet L, Gambhir A, James Glynn, Adam Hawkes, et al. (2019) An inter-model assessment of the role of direct air capture in deep mitigation pathways. Nat Commun 10.
  7. Brandani S (2012) Carbon dioxide capture from air: a simple analysis. Energy Environ 23: 319-328.
  8. Smith P, Steven JD, Felix Creutzig, Sabine Fuss, Jan Minx, et al (2016) Biophysical and economic limits to negative CO2 emissions. Nat Clim Chang 6: 42-50.
  9. Wang J, Sun, Zeng X, Jianxin Fu, Jun Zhao, et al. (2021) Feasibility of solar-assisted CO2 capture power 70 plant with flexible operation: A case study in China. Applied Thermal Engineering 182.

Bringing Light – Addressing the Sexual and Reproductive Health and Rights (SRHR) of People Living with Physical Disabilities (PWDPs)

DOI: 10.31038/AWHC.2021423

Abstract

In Pakistan, there is a ‘culture of silence’ around disability and Sexual and Reproductive Health (SRH) rights. Therefore, SRH needs and rights of people living with disabilities remain unaddressed because of prevailing cultural norm and traditions that stigmatize sexuality of People Living with Disability (PWD) and prevent them from claiming their sexual rights and taking control of their reproductive lives. Furthermore, people with disabilities are unable to access quality and tailored SRHR information and services.

The aim of this project was to build the capacity of People Living with Physical Disabilities (PWPD) on their Sexual and Reproductive Health and Rights (SRHR). The project was also aimed at increasing awareness among the general public on the SRHR needs of PWPDs as they are generally considered asexual, hence not needing access to SRHR information and services. To achieve this, Aahung planned to build capacity of the caregivers, and trainers who work with/for people living with disabilities and develop user-friendly resource material to aid them to teach people living with physical disability about their SRH needs and rights which is an innovation within itself. The approaches discussed here, however, apply broadly to all aspects of health programming for people with physical disabilities. Aahung envisioned transforming these trainers into advocates for SRH needs and rights of PWPDs in their respective workspaces and/or communities and integrate the newly-designed SRHR-related resource material into their activities.

Introduction

Sexual and reproductive health and rights (SRHR) fulfillment is essential to an individual’s overall wellbeing and prosperity, but collectively, it plays a greater and much more crucial role in the development of a nation [1]. Progressive SRHR attitudes and behaviours in general population are critical for sustainable human development, especially in a developing country like Pakistan [2,3]. SRHR encompasses comprehensive information and services directed toward tackling gender biases, rights violation, sexual and gender-based violence, and concerns regarding adolescence, puberty, and sex and sexuality; it also ensures provision of reliable information and services around family planning, contraception, and post-abortion care in order to promote safe and healthy SRHR behaviours [1,4]. However, strong stigma is associated with these topics in the country, resulting in none to limited conversation and consequent low general knowledge, misinformation, negative perceptions and attitudes, and unhealthy practices around SRH.

People living with physical disabilities are further distanced from SRH resources owing to the common misconception that they are not sexual beings or sexually active [5]. Researchers have found that People with Physical Disabilities (PWPDs) are usually stereotyped as asexual, which can lead to significant sexual and reproductive disparities when compared with the population living without any disability [6,7]. Several other studies further highlight the different kinds of neglect and discrimination faced by PWPDs. A research found that they are less likely to receive higher education and are usually socially isolated. Impaired interpersonal relations and social communication can lead to reduced self-esteem and confidence in physically disabled people, which can prevent them from claiming their sexuality and sexual concept and from accessing desired Sexual and Reproductive (SRH) services [8]. The lack of self-esteem in PWPDs has also been vastly reported to result in significantly low sexual esteem, low sexual satisfaction, and high sexual distress [7,9].

According to Pakistan Bureau of Statistics, there are 3.3 million people with disabilities in the country, which is 1.6% of the total population [10]. However, the country’s data on PWPDs is insufficient and unreliable, major reasons being non-cooperation of respondents and inconsistency in the definition of ‘disability’. Currently, there is no widely accepted definition of ‘people with disabilities’ in Pakistan’s national policies [11]. In Pakistan, there is a ‘culture of silence’ around the needs of people that are living with physical disabilities, especially their sexual and reproductive health, needs, and rights. The prevalence of discouraging cultural norms and traditions that stigmatize sexuality of people with disabilities leaves an essential component of their lives largely unaddressed and prevents them from claiming their sexual health and rights and taking control of their reproductive lives. Furthermore, PWPDs face a greater challenge when they are unable to access quality SRHR information and services that are exclusively tailored to their needs. The success or usefulness of any programme relies largely on the shared needs and wishes of the beneficiaries and key stakeholders. In Pakistan, however, no effort has been made to scientifically assess genuine SRH needs and problems of the PWPDs [11].

It is imperative to realize that the main reason for the disconnect between PWPDs and their access to SRHR is not the disability itself, but the prevailing assumptions regarding their needs among service providers, communities, and the policy makers [12]. The ignorance that pervades our society with regards to sexuality and disability renders the SRH needs and rights of PWPDs absent [13]. The misrepresentation and social exclusion combined with lack of access to the necessary resources, results in increased vulnerability of the physically disabled people to Sexually Transmitted Infections (STIs); they are also more likely to experience physical, sexual, and emotional violence and mental health issues [14,15]. To overcome the breach in equal provision of SRH information and services, it is recommended to increase the competency and capacity of organizations and care/service providers working for PWPDs, as well as the PWPDs themselves. Additionally, there is a strong need to conduct researches to identify, explore, and effectually employ evidence-based solutions [12]. Aahung designed a comprehensive module to build capacity of the caregivers and trainers working with/for PWPDs, to inform their attitudes and perceptions around the various themes of SRH with physical disability as a cross-cutting theme. Aahung envisioned transforming these trainers into advocates for SRH needs and rights of PWPDs in their respective workspaces and/or communities and integrate the newly-designed SRHR-related resource material into their activities.

Methods

Intervention

Aahung established partnerships with four different organizations working for the welfare and wellbeing of PWPDs, namely NOWPDP, Center for Inclusive Care, BINAE foundation and Connect Hear. From these partner organizations, 19 participants were identified to be trained as Master Trainers on the SRHR needs of PWPDs. Participants included trainers working in relevant organizations, care givers, and PWPDs.

Aahung developed user-friendly resource material and training modules for capacity building after consulting with organizations working for the people living with physical disabilities; data and results from Aahung’s previous programmers were also taken into consideration to strengthen the training module. For people with hearing impairments, animated videos were dubbed into sign language on SRHR issues including gender, puberty, sexual abuse, early age marriage, family planning, and abortion. The content was translated into braille, by experts, for people with visual impairments and videos were dubbed into sign language for people with hearing impairments. The translations were verified by the receivers themselves; when introduced to the material, individuals with seeing or hearing disabilities were able to understand the content. Additionally, interpreters and training facilitators were also made part of the training. The facilitators were identified and employed on the basis of their expertise in SRH. Training facilitators also included PWPDs to improve communication with participants. Trained participants reached out to approximately 200 people, sensitizing them on the SRHR needs of PWPDs.

Study Design and Setting

Training was held in Karachi in June, 2018. It spanned over three days, covering topics including Social Determinants of Health, Value Clarification and Attitudinal Transformation (VCAT), Gender, Sex and Sexuality, Sexual and Reproductive Health and Rights, Puberty Changes, and Family Planning. The objective of training was to increase comfort of the participants for addressing issues related to SRHR and physical disability, to enhance knowledge of the participants on SRHR and physical disability, and to enhance skills of the participants to discuss issues related to SRHR and physical disability with other people.

Data Collection and Management

To assess the effectiveness of the intervention, participants’ knowledge and beliefs were assessed through a pre- and post-test questionnaire. The questionnaire was developed in English and was translated to Urdu and Pakistan Sign Language for the hearing-impaired participants. Qualitative feedback was gathered as well from the participants to understand the experiential aspect. Questions focused on participants’ understanding of puberty, gender, sexual and reproductive health rights, and family planning.

Ethical Considerations

All participants were given detailed information, verbally and in sign language, about the training including; objectives, anticipated benefits, expectations from the participants, the time that the training session will take, the pre- and post- tests, the fact that they may choose not to participate or to withdraw from it at any time, without reprisal. Verbal and sign language consent was taken from all participants. Measures were taken to ensure confidentiality and anonymity of the information provided by the participants.

Results

There was a substantial increase in the knowledge and attitude of participants post-training. 82% caregivers reported that they had insufficient information, and, therefore, felt unprepared to appropriately address the SRHR issues of the people living with physical disabilities. However, upon being reinforced with accurate knowledge and appropriate language after the training, 91% of the participants felt confident enough to interact of the matter with PWPDs and other relevant stakeholders.

At pre-test, 55% participants were able to identify the differences between sex and gender, however, at post-test, all participants were able to identify the differences.

“I thought “Sex” and “Gender” are the same thing before coming to this training, but now I understand that they are conceptually distinct.” – Training Participant

Knowledge related to girl’s puberty was 0% before the training and increased to 64% afterwards. Similarly, knowledge about boy’s puberty was 1% and increased to 73% after the training.

“I did not have any idea about pubertal changes when I was in my puberty age. This session should be attended by every child who is entering their pubertal age, so that they don’t face difficulty in understanding the physical and emotional transitions.” – Training Participant

The training was able to debunk misconceptions around sexual health as well. The greatest change in perception was seen for the myth stating ejaculation is unhealthy and causes weakness. 54% of the participants believed that ejaculation causes weakness and infertility whereas after the training no participant agreed with this.

Overall, the trainings were well-received by the participants.

“SRHR is not something that is spoken about in the disabled community (hearing and visually impaired), therefore this training was an opportunity to learn something new and share with others.” – Training Participant

The Master Trainers produced as the result of Aahung’s training directly reached out to a total 200 PWPDs. The new trainees were from within the master trainers’ organizations, communities, and social networks, and comprised PWPDs as well as caregivers. Aahung monitored and supported three of these trickledown trainings conducted by CIC, Connect Hear and BINAE foundation.

A telephonic follow-up was also conducted with the master trainers from the first training. They reported that the module introduced to them had immensely helped them in trickling down the message with other people living with physical disability and those providing services to them.

Discussion

Participants felt that the videos and activities were an effective way to understand and apply the knowledge learned, however, the interactive activities were more useful than those involving writing, because for those with physical disabilities, discussions were easier and a more effective way of communicating than writing their responses. Furthermore, interactive and user-friendly resource materials designed for specific disabilities played a vital role in sensitizing PWPDs on SRHR subjects generally considered to be taboos. Given that PWPDs are reluctant to reach out to service providers for fear of being mocked and judged, these interactive materials are an effective strategy to address their SRHR-related myths and misconceptions.

The intervention served as a pilot unveiling potential for scaling up the SRHR program with PWPDs on regional and national levels. Introducing educational material around SRHR in the forms of braille books and AV tools among people with various disabilities, allowed the researchers to learn regarding the extent of ease or difficulty of its receptivity by the target audience, as well as the measure of impact the specially designed module was able to produce. These findings will serve to further inform and update the program, which is then planned to be integrated into schools and other organizations and/or departments working for the benefit of PWPDs. Organizations that will be approached and involved for the integration of SRHR education for PWPDs of all ages and backgrounds, on state level, include, People with Disabilities Network Department of Health, Department of Education (especially the wing working on Life Skills Based Education (LSBE)), Pakistan Associations of the Blind (PAB), and Pakistan Association of the Deaf (PAD). Welfare organizations that provide vocational training for PWPDs will also be approached with the proposal to include SRHR module among their other forms of training. In Punjab, a civil society organization is working on a similar cause, but the organization primarily works around LSBE with younger individuals with disabilities, which can provide the window for Aahung to propose a similar program for their audience’s SRHR needs.

Apart from involving public and private organizations in this cause by collaborating or partnering with them on state and local levels, an essential purpose for piloting the SRHR program with PWPDs was to study how eventually it could be mainstreamed into Aahung’s regular LSBE and SRHM programmes. In the future, all Aahung trainings done by Aahung with students, parents, teachers, and healthcare providers among others are planned to have a segment on building awareness and destigmatizing the SRHR service and knowledge needs of PWPDs.

Limitations

Catering to people with different physical disabilities within one training was a challenge, since different disabilities require different and unique means to be addressed. During the trickle-down trainings, however, the MTs were able to overcome this challenge by conducting separate trainings for people with different physical disabilities. Furthermore, since there isn’t any precedent for a similar programme in Pakistan and the exploratory nature of this intervention, a rigorous evaluation could not be done. Therefore, future studies should explore methodologies for evaluation with PWDs while incorporating different types of data collection methodologies suited to each disability.

References

  1. Temmerman M, Khosla R, Say L (2014) Sexual and reproductive health and rights: A global development, health, and human rights priority. The Lancet 384: e30-e31. [crossref]
  2. Adinma J, Adinma E (2011) Impact of Reproductive Health on Socio-economic Development: A Case Study of African Journal of Reproductive Health 15: 7-12. [crossref]
  3. Pillai VK, Maleku A (2015) Reproductive Health and Social Development in Developing Countries: Changes and Interrelationships. British Journal of Social Work 45: 842-860.
  4. Braeken D, Rondinelli I (2012) Sexual and reproductive health needs of young people: Matching needs with systems. International Journal of Gynecology & Obstetrics 119: S60-S63. [crossref]
  5. DeBeaudrap P, Mouté C, Pasquier E, Mac-Seing M, Mukangwije P, et al. (2019) Disability and Access to Sexual and Reproductive Health Services in Cameroon: A Mediation Analysis of the Role of Socioeconomic International Journal of Environmental Research and Public Health 16: 417. [crossref]
  6. Chance RS (2002) To Love and be Loved: Sexuality and People with Physical Journal of Psychology and Theology 30: 195-208.
  7. Rowen TS, Stein S, Tepper M (2015) Sexual Health Care for People with Physical The Journal of Sexual Medicine 12: 584-589. [crossref]
  8. Aron L, Loprest P (2012) Disability and the Education The Future of Children 22: 97-122. [crossref]
  9. McCabe MP, Taleporos G (2003) Sexual Esteem, Sexual Satisfaction, and Sexual Behavior among People with Physical Disability. Archives of Sexual Behavior 32: 359-369. [crossref]
  10. Pakistan Bureau of Statistics (2017) 6th Population and Housing Census-2017 (Population and Housing Census). Government of
  11. Ahmed M, Khan AB, Nasem F (2011) Policies for Special Persons in Pakistan Analysis of Policy Berkeley Journal of Social Sciences 1.
  12. Oosterhoff P (2018) Sexual and Reproductive Health Rights of Persons With Disabilities (IDS Disability Briefing). Institute of Development Studies.
  13. Addlakha R, Price J, Heidari S (2017) Disability and sexuality: Claiming sexual and reproductive Reproductive Health Matters 25: 4-9. [crossref]
  14. Aragão J da S, França ISX de, Coura AS, Medeiros CCM, Enders BC (2016) Vulnerability associated with sexually transmitted infections in physically disabled Ciência & Saúde Coletiva 21: 3143-3152. [crossref]
  15. Krnjacki L, Emerson E, Llewellyn G, Kavanagh AM (2016) Prevalence and risk of violence against people with and without disabilities: Findings from an Australian population-based Australian and New Zealand Journal of Public Health 40: 16-21. [crossref]

BMK Blood Test Result as Evaluation of Bisphosphonates Used for the Treatment of Osteoporosis

DOI: 10.31038/AWHC.2021414

 

There has been long use of Bisphosphonates for bone antiresorption; for example,

Alendronate 10 mg: 1 tablet/day

Alendronate 70 mg: 1 tablet/week

Risedronate 5 mg: 1 tablet/day

Risedronate 35 mg: 1 tablet/week

Risedronate 150 mg: 1 tablet/month

Ibandronate 150 mg: 1 tablet/month

However, effectiveness of the recommended dosage and appropriate length of time have never been evaluated. After blood test for Biological Bone Marker, studies have been gathered for more than 10 years or since 2005-2017, and surprisingly, remarkable results have been found out.

First of all, BMK blood test must be correct throughout its process, for reliable and accurate results [1].

  1. No food is allowed for patients from 8 pm to 8 am (12 hrs)
  2. Blood sample is taken between 8 am to 9 am only (normal values specified by Prof. Dr. Narong B)
  3. Blood Test by the Laboratory needs to be done immediately as result value varies by time.
  4. Solution used for running the BMK blood test must be calibrated every morning.

This report covers evaluation on bone resorting value which is CTx or Beta Cross Laps only. Normal value specified by Prof. Dr. Narong B. is 0.31 for female [2].

If CTx or Beta Cross laps as measured = 0.31 for female, there will be 100% bone resorption, as normal, for female. If CTx is more than 100% bone resorption is faster or higher than normal. If CTx is less than 100%, bone resorption is slower or lesser than normal.

Example CTx value of a patient = 0.45

  CTx 0.31 = 100%

If 0.45 = 100 x 0.45 = 145% 45% more than normal bone resorption

     0.31

    Or

CTx value of a patient = 0.21

CTx 0.31 = 100%

If 0.21 = 100 x 0.21 = 67.7% 32.3% less than normal bone resorption

     0.31

This report covers 708 patients on 5th floor, King Bhumibhol Building, Chulalongkorn Hospital from 2005-2017 having been controlled the dose of bisphosphonates by BMK Blood Test, but only 480 patients or 66.8% having been given Bisphosphonate.

196 patients have had Ibandronate 150 mg and 27 ones have taken it several years before treatment = 223 patients

148 patients have had Alendronate 70 mg and 16 ones have taken it several years before treatment = 164 patients

26 patients have had Alendronate 10 mg and 12 ones have taken it several years before treatment = 38 patients

15 patients have had Risedronate 35 mg and 5 ones have taken it several years before treatment = 20 patients

12 patients have had Risedronate 150 mg and one has taken it several years before treatment = 13 patients

The result has turn out, astonishingly, opponent for patients, costing a lot as well even though both doctors and patients have been confident treatment was in the right direction. Consequently, there is in depth analysis of 480 patients using Bisphosphonates as shown in the followings.

Result of one month administration of Bisphosphonates [3].

Comments One month course of all bisphosphonates have so effective:

  • Ibandronate 150 mg can reduce CTx from 181.8% to 49.8%
  • Alendronate 70 mg can reduce CTx from 140.3% to 31.9%
  • Alendronate 10 mg can reduce CTx from 157.2% to 37.1%
  • Risedronate 35 mg can reduce CTx from 158% to 62.5%
  • Risedronate 150 mg can reduce CTx from 154% to 47.4%

If there had not been BMK blood test and dosage had been given to patients continuously, CTx would have been reduced to the point that the bone will have no bone resorption. So, there would have been only old bone cells, prone to degeneration and necrosis. Only light or minor injury, bones are easily broken. For example, when a tooth is extracted, mandible is also broken.

Basically, there are differences of effective period of dosage used for patients. So, each patients is required to have BMK blood test once a month after being treated with Bisphosphonate, and will continue until effectiveness period for 1 tablet is evaluated (CTx 70-100%)

For example, Mr. A has 1 tablet of Ibandronate monthly as instructed by the pharmaceutical manufacturer. In fact, he needs only 1 tablet per 3 months which is accurate and costs him 3 times less. This result shows Bone resorption is between 70-100% in control forever.

When discontinued bisphosphonates, it will take months to resume bone resorption until the acceptable safe level which means CTx 70% up to 100%:

  • Ibandronate 150 mg: average of 4.1 months resuming acceptable rate of bone resorption
  • Alendronate 70 mg: average of 3.5 months resuming acceptable rate of bone resorption
  • Alendronate 10 mg: average of 6 months resuming acceptable rate of bone resorption
  • Risedronate 35 mg: average of 4 months resuming acceptable rate of bone resorption
  • Risedronate 150 mg: average of 2.8 months resuming acceptable rate of bone resorption

It shows that there are inconsistent results for each bisphosphonate, no matter how much dosage given to each patient in one month, even the same medicine. CTx after one month of treatment shows in consistent effectiveness deepening on each patient condition such as genetic background, food, illness, other treatments with herbs or jinseng and fruits. Those can give different CTx results. Initially, BMK blood test is needed once a month, later on once in 3 month or 6 months. However, it should not wait too long. Eventually, once in 6 month or once a year is an appropriate. When change is found, root cause should be analyzed to help CTx to resume.

Moreover, there are 1 or 2 dosages for each medicine. Adjustment for early patient seems to be difficult; for example, Alendronate should be adjusted from 70 mg to 10 mg, but there isn’t such a small dosage sold. So, length of time of effectiveness for one tablet needs to be evaluated so that CTx will be in 70-100%. In the future if different dosages are produced, it will help patients to resume their CTx to 70-100% within days instead of months, giving not so effective result; too long of low CTx.

It was found that one month of drugs administration will last longer than recommendation.

  • Ibandronate 150 mg: 1 tablet has an average of 4.1 months in effectiveness.
  • Alendronate 70 mg: 4 tablets has an average of 3.5 months in effectiveness.
  • Alendronate 10 mg: 30 tablets has an average of 6 months in effectiveness.
  • Risedronate 35 mg: 4 tablets has an average of 4 months in effectiveness.
  • Risedronate 150 mg: 1 tablet has an average of 2.8 months in effectiveness.

No matter which medicines given in a month according to the manufacture, similar results will come out. When stopping the use of those medicines, it will take 3-4 months to resume CTx to 70-100% . The results for all medicines are similar. Effectiveness length of time of medicine prescription for each patient can be different depending on patient‘s conditions whether to resist or accept dosage, their illness conditions, their other treatments, as well as fruits they eat. We can see that all mentions including some herbs or supplements will affect CTx, increasing 100+% of which data has been collected.

Average length of time of CTx after long administration of bisphosphonate resume to normal for each medicine :

  • Ibandronate 150 mg: 27 patients had an average of 25.18% CTx only, waiting for 13.3 months to resume to normal.
  • Alendronate 70 mg: 27 patients had an average of 21.2% CTx only, waiting for 16.8 months to resume to normal.
  • Alendronate 10 mg: 27 patients had an average of 25% CTx only, waiting for 13.3 months to resume to normal.
  • Risedronate 35 mg: 6 patients had an average of 10.8% CTx only, waiting for 10.1 months to resume to normal.
  • Risedronate 150 mg: 2 patients had 0% of CTx without resuming.

There are cases that patients having Bisphosphonate for years, but from BMK blood test, CTx is too low or 0% showing no Bone resorption at all: So, Bisphosphonate given to patients for years can turn out disadvantages due to low rate of bone resorption and high cost of treatment until they require long time to resume to normal. Especially for those 2 patients who had no recovery at all.

It is important to control CTx value in 70-100% besides what was mentioned in 1, Bone life cycle range is considered safe. If CTx is higher than 100%, bone resorption will be more than normal, or bone age will be shorter. Micro fracture can easily happen. It can remarkably decrease bone structure, causing bone fractures more easily. Therefore, CTx or Bone resorting needs to be 70-100%, and if this is controlled, a little longer bone life cycle means Micro fracture prevention.

Conclusion

BMK blood test is required to evaluate if bone antiresorptive medicine used for osteoporosis treatment is appropriate for patients; dosage amount, tablet effectiveness in months, weeks or days, and adjustment must be accurate and patient can save a lot of money.

References

  1. Bernardi D, Zaninotto M, Plebani M (2004) Requirements for improving quality in the measurement of bone markers. Clin Chim Acta 346: 79-86. [crossref]
  2. Bunyaratavej N, Kitimanon N, Boonthitikul S (2001) Study of the level of biochemical bone markers: NMID osteocalcin and bone resorptive marker (beta CTx) in Thai women. J Med Assoc Thai 84: S560-565. [crossref]
  3. Aksaranugraha S (2011) Observation: Application and Advantages of BMK in OP by Monitoring the Dose of Antiresorption Drugs with CTx. J Med Assoc Thai 94: S 65-66. [crossref]