Monthly Archives: March 2021

fig 1

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.

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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]
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  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]
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  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
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  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]

Disease, Duration and Death

Abstract

Life has always been threaten by diseases, calamities, catastrophes leading to death caused by various known or unknown, animate or inanimate objects in human’s relatively medium life span. Ever since the documentation of the human history, it is well known that man loved their body and prefer to live in accordance with their wishes. When rationale judgment became prominent after the experiences and observations of life and death events, they started searching remedies such as medicine. This is how medicine evolved since our early civilization. With the development of reason, logic, observation, experimentation and practical application, we learned tremendous ways of saving body, brain and behavior. However, as time passes human environment changes unpredictably leading to change in human behavior and attitude towards objects/materials and living beings. It is not only a matter of physical, biological or cosmic change but also behavior of everything that brought unprecedented events such as unexpected war, epidemic, catastrophes etc. leading to death [1,2]. Measurement of several physical parameters of human and universal bodies has become routine but various functions/characters in relation to time has yet to measure fully. This is the point we fall short to save humans promptly resulting high number of unexpected loss of life such as in COVID-19 pandemic. Among 1554960 covid-19 infected population in more than 209 countries, territories and two conveyances 5.9% died, and among the deaths more than 80% occurring in just 10 countries (USA, Spain, Italy, Germany, France, China, Iran, UK, Belgium, Netherlands) of the world in the last three months duration [2].

Disease is an abnormal architecture/anatomy, function, condition of the body and mind in a specific duration. Many times and circumstances death occurs due to unprecedented cause, behavior or ignorance. Therefore, it is essential to know the unknown environment and diverse nature and behavior of human beings to diagnose epidemicity of the disease. Despite vast scientific discoveries and new achievement, there is a big hole in the measurement of core human behavior and intelligence. Human body, intelligence and behavior plays a great role in the defense mechanism as well as association in the causation, development, cessation of disease in specific duration in specific place/s. So far we are devoid of the precise knowledge on the creation of covid-19 however many scientists have been trying to explore the mystery of the occurrences, nature and impact on the human population of the globe [3].

The duration or natural course of illness or diseases is important in the management of cases, carrier as well as prevention of complications and death [4]. Alert researchers identify the key factors of the disease when there is sudden rise of cases of similar features in a short period. Ignorance about the nature of pathogen and ignorance of the general population about the disease leads to higher number of deaths in a very short duration. Lack of alertness in changing behavior and environment of the disease in the population further complicates its management and increases the number of deaths. The challenge of the new disease, ignorance on the part of environment and human behavior help to expand disease dimensions in terms of time, place and person.

Opportunities such as chance, experience, observation and experimentation lead to discovery and development of medicine and care system that can make our life easier, comfortable and lengthier. This is the beauty of medical discipline, research and practice in human population. A dynamic patience where a body and brain searches a remedy continuously in response to disease is probably the best stimulus to initiate new knowledge, skills, practice to cure patient and prevent death. Lack of precise knowledge of duration and the nature of the disease is biggest obstacles in managing covid-19 at present and many more diseases that are possible in the future. Following the spread of disease and management of the patient (source) meticulously in global environment, recording the evidences and continuous sharing among the fellow researchers and responsible individuals are the most important aspects of pandemic control.

Alertness, continuous searches, dynamic patience can help humans to increase its capacity to deal with covid-19 pandemic. Change in seasonality in different geographical regions may affect duration of the diseases and distribution of death in humans. This demands thinking globally and acting globally.

Keywords

Covid-19, Death, Disease, Duration, Pandemic

References

  1. Riedel S (2004) Biological warfare and bioterrorism: a historical review. BUMCProceedings17: 400-406. [crossref]
  2. Covid-19 Coronavirus Pandemic, Worldometer. Accessed on April 09, 2020, 16:30 GMT.
  3. Zhou P, Yang X, Wang X, Hu B, Zhang L, et al. (2020) A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature579: 270-273. [crossref]
  4. Rothan HA,ByrareddySN (2020) The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. Journal of Autoimmunity109: 102433. [crossref]
fig 3

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.
fig 2

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

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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]

Lonomia obliqua Accident and Anesthesia

DOI: 10.31038/IJAS.2021212

Abstract

The case of a 45-year-old man who presented with extreme pain and edema after having touched a Lonomia obliqua caterpillar is described. Accidents due to the brief contact with this caterpillar may lead to a severe coagulopathy, hemorrhage, and death. Thus, it is important to discuss the mechanism of envenomation caused by the caterpillar. Antivenom treatment serum most commonly used to treat Lonomia accidents is highlighted and further described.

Keywords

Lonomia obliqua, Coagulation

FIG 1

Images from Science Museum of URI Erechim (RS)-Brazil

Introduction

Lonomia obliqua is a species of caterpillar most commonly found in the Southern part of Brazil. This caterpillar is also known as the “fire insect” because the hair covering its body contains toxic venom that is absorbed through the skin of a victim when its spine is broken. This envenomation causes intense pain in the location of absorption, disseminated intravascular coagulation, renal failure, and a consumptive coagulopathy, which can lead to a hemorrhagic syndrome and death [1-4].

Case Report

The patient who entered the emergency room was a 45-year-old man with extreme pain and edema in the ankle and left calf. He had no history of trauma and his symptoms started slowly two days prior. The patient had no foot pulse, the compartment syndrome diagnosis was made, and a fasciotomy was necessary. The anesthesiology staff did not know that the Lonomia accident had occurred and performed a 27 gauge pencan spinal anesthesia. The surgery went well and the blood flow returned to the foot. Six hours after the surgery, the patient had fully recovered from anesthesia but started presenting extreme blood loss in the leg wound. Blood samples showed 9.3 RNI, 130 000 platelets and 4.3 creatinine. Neurological examination was performed every 6 hours without alterations. The patient was in anuria since he was admitted to the hospital. Despite the efforts of volume resuscitation, he had the effect of the venom in association with muscle damage in the leg, causing rhabdomyolysis and leading to renal failure. After a long inquisition, it was discovered that he worked with wood, where this type of caterpillar resides, and treatment with Lonomia Antivenom (LAV) began. The antivenom is the most effective treatment for Lonomia obliqua accidents and is only produced by the Butantan Institute in Sao Paulo. This antivenom is made by the filtration of immunoglobulins produced by horse serum [2,5-7]. The vitals of the patient became stable, the bleeding stopped, and all his test results were normal in 36 hours, including renal function [2].

Discussion

Lonomia accidents are very dangerous and can lead to disseminated intravascular coagulation. This happens because the venom modulates the expression and phosphorylation levels of migration-related proteins, making the cells show an increased membrane ruffling (meaning a decreased cell adhesion), a decrease in the velocity of cell protrusions, and a more rounded shape, all resulting in a lower polarity index [5]. Spontaneous bleeding shown by the patient is due to systemic vascular and inflammatory disorders generated by the venom [5]. The venom is composed of molecules that may act directly or contribute to the generation of endogenous mediators, such as kinins, chemokines, and cytokines, that can induce vascular injury. The venom also has a direct effect on Vascular Smooth Muscle Cells (VSMC), inducing oxidative stress and the modification of the functionality of these cells [6]. Specifically, the venom consists of procoagulant toxins, such as factors II and X activators, but studies have shown that it does not consist of fibrinolytic activity. These toxins produce a coagulation cascade involving a prothrombin activator known as Lopap, which activates prothrombin, resulting in the production of thrombin that may cause fibrinogen to promote clot formation [3,8,9]. Previous research has revealed that an increase in intravascular thrombin concentration due to a Lonomia accident may disrupt endothelial cells, resulting in a hemorrhagic condition [5].

As the lethality of the venom is 1.5 to 2.0%, the patient is likely to die or suffer from systemic complications if no treatment is provided [1]. The antilonomic serum therapy has shown to be the most effective treatment for lonomic envenomation because previously tested therapies, including whole blood replacement, have revealed that there is an increase in coagulation due to the higher amount of clotting factors and toxins in the bloodstream. The antigen provided in the antivenom (antilonomic serum) only uses the scoli extracts and is effective in neutralizing the toxins involved in the envenomation by triggering lgG antibody production [7,9]. Precisely, the antivenom is an isotonic solution that has been purified by enzymatic digestion. The serum antibodies bind specifically to the venom, which is not yet fixed in the cells, causing it to be neutralized [10].

Several studies have determined that the serum aids in the recovery of fibrinogen and normalizes levels of thrombin, prothrombin, and activated partial thromboplastin, reverting hemostatic complications [8]. Patients who are diagnosed early and treated within the first 12 hours are less likely to develop severe coagulopathy and are able to recover within 20 hours of treatment [1,9]. Additionally, neuraxial block is contraindicated in these patients. If a patient came from this endemic region and started showing spontaneous bleeding, it is always important to remember that this accident may have occurred before anesthesia or surgery [3].

References

  1. Sano-Martins IS, Duarte AC, Guerrero B, Moraes RHP, Barros EJG, et al. (2017) Hemostatic disorders induced by skin contact with Lonomia obliqua (Lepidoptera, Saturniidae) caterpillars. Rev Inst Med Trop Sao Paulo 59: e24.
  2. Caovilla Jairo, Barros Elvino (2004) Efficacy of two different doses of antilonomic serum in the resolution of hemorrhagic syndrome resulting from envenoming by Lonomia obliqua caterpillars: A randomized controlled trial. Toxicon: official journal of the International Society on Toxicology 43: 811-818. [crossref]
  3. Alvarez Flores M, P Zannin M, Chudzinski-Tavassi A (2010) M: New Insight into the Mechanism of Lonomia obliqua Envenoming: Toxin Involvement and Molecular Approach. Pathophysiol Haemos Thromb 37: 1-16.
  4. Zanon P, Pizzato SB, da Rosa RL, Terraciano PB, Moraes JA, et al. (2021) Urine proteomic analysis reveals alterations in heme/hemoglobin and aminopeptidase metabolism during Lonomia obliqua venom-induced acute kidney injury. Toxicol Lett 341: 11-22. [crossref]
  5. Bernardi L, Pinto AFM, Mendes E, Yates JR 3rd, Lamers ML (2019) Lonomia obliqua bristle extract modulates Rac1 activation, membrane dynamics and cell adhesion properties. Toxicon 162: 32-39. [crossref]
  6. Moraes João A, Rodrigues Genilson, Nascimento-Silva Vany, Renovato-Martins Mariana, Markus B, et al. (2017) “Effects of Lonomia obliqua Venom on Vascular Smooth Muscle Cells: Contribution of NADPH Oxidase-Derived Reactive Oxygen Species” Toxins 9: 11: 360. [crossref]
  7. Sano-Martins IS, Gonza´lez C, Anjos IV, Dı´az J, Gonc¸alves LRC (2018) Effectiveness of Lonomia antivenom in recovery from the coagulopathy induced by Lonomia orientoandensis and Lonomia casanarensis caterpillars in rats. PLoS Negl Trop Dis 12: e0006721. [crossref]
  8. Gonçalves LRC, Sousa-e-Silva MCC, Tomy SC, Sano-Martins IS (2007) Efficacy of serum therapy on the treatment of rats experimentally envenomed by bristle extract of the caterpillar Lonomia obliqua: Comparison with epsilon-aminocaproic acid therapy. Toxicon 50: 349-356. [crossref]
  9. Chudzinski-Tavassi AM, Carrijo-Carvalho LC (2006) Biochemical and biological properties of Lonomia obliqua bristle extract. Journal of Venomous Animals and Toxins Including Tropical Diseases 12: 159-171.
  10. INSTITUTO BUTANTAN. Coordenadoria de Ciência, Tecnologia e Insumos Estratégicos de Saúde. Secretaria de Estado da Saúde. Governo do Estado de São Paulo. Soro antilonômico: bula profissional.

The Role of Atezolizumab in the Treatment of Triple- Negative Breast Cancer

DOI: 10.31038/AWHC.2021422

Abstract

Triple-Negative Breast Cancer (TNBC) is commonly treated with chemotherapy. However, immunotherapy has been widely suggested as a treatment option for patients with TNBC, including atezolizumab. The present narrative article aims to fully understand the evidence of atezolizumab in the treatment of TNBC. Newer and better biomarkers are needed to select patients with TNBC that are more likely to benefit from immunotherapy.

Keywords

Atezolizumab, Immunotherapy, Breast cancer, Tumor-infiltrating lymphocytes

Introduction

Triple-Negative Breast Cancer (TNBC) consists in a very aggressive breast cancer, often including earlier recurrence and metastasis, that is essentially characterized by the lack of progesterone, estrogen, and human epidermal growth factor receptor-type 2 (HER2), accounting for about 15% up to 20% of all the breast cancers. The most common therapy for the metastatic TNBC is chemotherapy, even though it refers to a short-lived type of responses, considering that patients frequently present a median overall survival of 12 up to 18 months. Hence, there is a certain need to develop further studies to improve the existing therapies or to introduce innovative ones [1].

According to previous studies, immunotherapy actually represents a very promising treatment for TNBC mainly due to the fact that TNBC has more tumor-infiltrating lymphocytes (TILS), higher levels of Programmed Death Ligand 1 (PD-L1) expression on immune cells and the tumor, and a greater number of nonsynonymous mutations [2-4]. Atezolizumab consists in an Fc-engineered, humanized immunoglobulin G1 monoclonal antibody which is expressed on tumor cells and on tumor-infiltrating immune cells. Basically, this agent directly binds to PD-L1 and blocks its interaction with the Programmed Death Protein 1 (PD-1), while simultaneously enabling the reactivation of the anti-tumor immune response without the antibody-dependent cytotoxicity [5]. The present article reviews some of the main studies that suggest the use of atezolizumab in the treatment of TNBC due to its efficiency and positive outcomes among patients with this disease. The main goal is to fully understand the evidence of the use of atezolizumab in the treatment of TNBC, as well as the main outcomes of this specific immunotherapy.

Atezolizumab in the Treatment of Metastatic TNBC

The first relevant clinical trial of immunotherapy in TNBC was Impassion 130. This trial included 451 patients (median follow-up, 12.9 months). In the intention-to-treat analysis, the median Progression-Free Survival (PFS) was 7.2 months with atezolizumab plus nab-paclitaxel, as compared with 5.5 months with placebo plus nab-paclitaxel (hazard ratio for progression or death, 0.80; 95% Confidence Interval [CI], 0.69 to 0.92; P=0.002); among patients with PD-L1–positive tumors, the median PFS was 7.5 months and 5.0 months, respectively (hazard ratio, 0.62; 95% CI, 0.49 to 0.78; P<0.001). No difference was observed in overall survival (OS) in the intention-to-treat analysis [21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel (hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P=0.08)]; among patients with PD-L1–positive tumors, the median OS was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86).

At ESMO Virtual Congress 2020 an update of overall survival analysis was presented for the PDL-1 + population which confirm the benefit of immunotherapy (3-year survival rates with atezolizumab–nab-paclitaxel versus placebo were 36% and 22%). These results have been widely debated since the study design did not allow drawing these conclusions in PDL1 positive patients and it was only planned to verify the OS in PDL-1 positive patients if the data were positive in the intention to treat population.

The Impassion131 trial also contradicts the findings of the IMpassion130 trial which corroborates the need for further investigations in terms of the use of atezolizumab in the treatment of TNBC [6-9]. In this trial patients were randomly assigned to atezolizumab plus paclitaxel at or to placebo and paclitaxel. The primary endpoint was PFS in the PD-L1-positive population. A statistically significant result (based on a HR of 0.62 and median progression-free survival increasing from 5 to 8 months) would lead to testing in the intent-to-treat population. Secondary endpoints, including overall survival, would be formally tested only if previous tests were significant. PFS was not significantly improved by atezolizumab plus paclitaxel vs paclitaxel alone in either the PD-L1–positive (6.0 vs 5.7 months; HR = 0.82; P = .20) or the intent-to-treat population (5.7 vs 5.6 months; HR = 0.86; significance not formally tested for hierarchy). The combination also did not improve OS in the PD-L1–positive group (22.1 vs 28.3 months; HR = 1.12) or the intent-to-treat population (19.2 vs 22.8 months; HR = 1.11).

Reasons for the discrepancy between the studies maybe related to the use of steroids in the premedication for paclitaxel in IMpassion 131. We also must wait for the publication of this trial to check subsequent therapy lines in both arms since an overall survival of 28.3 months in patients treated with chemotherapy was never seen in other trial.

Atezolizumab in Neoadjuvant Context

NeoTRIP [10] randomly assigned 280 women with early or locally advanced TNBC to receive neoadjuvant therapy with either atezolizumab plus carboplatin/nab-paclitaxel or placebo plus the same chemotherapy. All patients underwent surgery and then received four further cycles of anthracycline-based chemotherapy. pCR rates were not significantly different between the two study arms: 43.5% with atezolizumab vs 40.8% with chemotherapy alone. A multivariate analysis showed that the only variable associated with pCR rate was PD-L1–positive status (P < .0001).

According to this trial, the addition of atezolizumab to the neoadjuvant chemotherapy for patients with TNBC did not improve the rate of the Pathologic Complete Response (pCR) but we will have to wait to see if there is a long-term benefit. Nonetheless, the IMpassion031 trial [11] has proved that the addition of atezolizumab to the neoadjuvant chemotherapy significantly improved the rates of pathologic complete response, regardless of PD-L1 status with an acceptable safety profile. This phase III, randomized patients to receive atezolizumab or placebo with nab-paclitaxel followed by atezolizumab or placebo with dose-dense doxorubicin and cyclophosphamide. pCR was seen in 57.6% (95% CI: 49.7, 65.2) of patients in the atezolizumab arm and in 41.1% (33.6, 48.9) in the placebo arm (Δ16.5%; 5.9, 27.1; 1-sided P = 0.0044 [significance boundary, 0.0184], P = 0.0085 for the intersection hypothesis of ITT and PD-L1+ populations). In PD-L1+ pts (n=152), pCR was seen in 68.8% (57.3, 78.9) vs 49.3% (37.6, 61.1) of pts (Δ19.5%; 4.2, 34.8; 1-sided P = 0.021; not significant). Median EFS was not reached in either arm, but follow up is short (20 months)

One of the possible explanations for the difference seen in these two trials may at least in part be related to the chemotherapy backbone. In the IMpassion031 study, patients received anthracyclines in the neoadjuvant phase, whereas this was given after surgery in NeoTRIP

Atezolizumab in Adjuvant Context

Regarding the role of atezolizumab in an adjuvant chemotherapy context, there is a trial that is currently being developed, the IMpassion030 [12], which consists in a global, prospective, randomized, open-label, phase 3 trial that aims to investigate the safety, efficacy, and pharmacokinetic profile of the adjuvant atezolizumab plus standard taxane adjuvant chemotherapy in contrast to the chemotherapy alone in an early stage of TNBC. Essentially, in these specific trial 2300 patients with operable stage II or III TNBC will be randomized. The adjuvant treatment will consist of weekly paclitaxel for 12 weeks, followed by dose dense anthracycline and cyclophosphamide for 4 cycles every 2 weeks or the same chemotherapy regimen given with atezolizumab every 2 weeks, up to a total period of 1 year. The primary endpoint refers to the invasive disease-free survival, while the secondary endpoint also includes the node and lymph status, as well as the overall survival, safety, patient functioning and health related quality of life.

Conclusion

The main goal of the present study is to fully understand the benefits of atezolizumab during the treatment of TNBC, as well as the main outcomes of this specific immunotherapy. After reviewing several studies, it is possible to conclude that better biomarkers are needed in order to select patients that are more likely to benefit from Immune Checkpoint Inhibitors (ICIs) and to develop new combination therapies to overcome ICI resistance. The existing biomarkers at the moment are basically four, more precisely: PD-L1, Mismatch Repair (MMR) deficiency, Tumor Mutational Burden (TMB), and Tumor Infiltrating Lymphocytes (TILs) [13]. The PD-L1 expression on tumor cells is the most used biomarker to predict immunotherapy benefit in most clinical trials, despite presenting several limitations. We still don’t know which cut-off is best, if it should be measured in tumor cells and / or immune cells or in the primary tumor or metastatic lesion. The MMR deficiency rarely occurs in breast cancer, being more common in early-stage diseases. TMB is a measurement of the number of nonsynonymous mutations carried by tumor cells [14]. Still, a high TMB alone does not seem to represent the optimal predictor for immunotherapeutic response in breast cancer, since definition of high TMB lacks standardization, with different thresholds adopted across studies. Lastly, TILs are a well-known prognostic factor in early and advanced stages TNBC, and their assessment is being implemented as a stratification factor in breast cancer immunotherapy trials [13,15]. In sum, further investigations are needed, especially with the goal of presenting better biomarkers in order to select patients with TNBC that are more likely to benefit from immunotherapy, including the usage of atezolizumab.

References

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