Monthly Archives: March 2019

Ethics of Belief and Ethics of Ambiguity: Demystifying the Ethics of the USPHS Syphilis Study at Tuskegee [1]

DOI: 10.31038/AWHC.2019222

Abstract

One of the lead physicians defending the “United States Public Health Service Study at Tuskegee of Untreated Syphilis in the Negro Male” was Dr. John C. Cutler. His defense of the study was (roughly) because the benefits to society in general, and the black community in particular, far outweighed any corresponding risks or harms. His moral judgment controverted the large number of thoughtful essayists decrying the Study as a straightforwardly and racist dehumanizing of men, women, and families. In this essay, I seek to show two things. First, I seek to show how an action or event done at a particular time may lack the objectivity that comes with distanciation, thus a (malicious) systemic distortion may be ambiguously reducible to a historical error, especially if there is no critical theory borne from critical reflection to hold the action or event morally accountable. Second, I show how two things should be apparent with disambiguation of the historical narrative and with critical reflection: 1) an ethic of ambiguity (and the integrity thereof) should demand that moral propositions be critically assessed at the time of an action or event from more than one angle to ensure the protection of all humans, especially historically marginalized individuals and groups; 2) an ethic of belief, given its Intentionality and intentions, should understand its inherent vulnerabilities and accentuate the import of evidence in moral epistemology.

Keywords

Ethics of Belief, Ethics of Ambiguity, Intentionality, Moral Epistemology, Syphilis Study, Tuskegee, USPHS

A young boy and his mother stood viewing a museum art piece depicting a man slaying a lion. Looking incredulous, the boy argued, “Mama, everyone knows that a man can’t beat a lion.” The mother prudentially responded, “Yes, but remember son, it was a man who painted the picture.” – anonymous source

there can be mutual reinforcement between an explanation and what it explains. Not only does a supposed truth gain credibility if we can think of something that would explain it, but also conversely: an explanation gains credibility if it accounts for something we supposed to be true. – Quine and Ullian The Web of Belief.

Introduction

There is a uniquely discursive and unexpected feature of the notorious United States Public Health Service Study on the effect of Untreated Syphilis on the Negro Male at Tuskegee (the Study), one that points to either a weakness in the structure of ethical arguments or the propensity of agents to put forth invalid ethical arguments due to an accentuation of fallacious propositions, maniacal beliefs, or justifiable ambiguities. This paper shows that an in-principle attempt to justify the treatment (or non-treatment, as it were) of 623 Negro men (and their families) survives no credible moral epistemology or justification, cannot rely on an ethic of ambiguity to demonstrate its veracity, and cannot avoid its inherent racism. We are almost five decades since the Study, and almost nine decades since its inception. Given this near half-century of critical reflection, analysis, and moral inferences, I look at the force of predominant ethical theories to see whether an ethic of ambiguity is a sustainable defense for the Study’s protagonists.

In this essay, I use Dr. John Cutler as a symbol of the primary protagonists. Born in 1915, Dr. John Cutler, finished Western Reserve University Medical School in 1941 at the age of 26, and one year later, ten years after the Study began, started his career at the United States Public Health Service—the government organization that authorized the Study. His participation in the Study as one of the primary doctors, his furtherance of a similar study in Guatemala, and his unswerving commitment and defense of the Study decades after its public revelation, are all indicative of why he surmounts several others as the Study’s protagonist. There’s a prima facie sense in which his words can be perceived as genuine empathy: “The Tuskegee Study has been grossly misunderstood and misrepresented this way. And the fact was it was (our) concern for the black community, trying to set the stage for the best public health approach possible and the best therapy, that led to the Study being carried out” [2]. Defensive terms like “grossly misunderstood,” “misrepresented,” “concern for,” “best…approach,” and “best therapy” suggest the deep lack of empathy and care that the United States Public Health Service visited upon the families of Macon County, Alabama between 1932 and 1972 [3]. If Dr. Cutler is correct, that ambivalence surrounding the Study was only a gross “misunderstanding” and that there was nothing duplicitous about it, then the last half-century of critical analysis amounts to nothing more than the subjective misinterpretation that is (potentially) commonplace to all historical events. The “historical events” to which I refer are those events that come into being—that occur—due to actions caused by Intentional mental states (beliefs) and intentional (deliberate) actions. In this regard, I am not referring to anything environmental; [4] rather; I am referring to a particular narrative that was imposed upon one group of humans by another group of humans. Historical events of this ilk, such that they are the consequence of human actions, are themselves narratives—they occurred because of (1) particular Intentional mental states, attitudes, beliefs, etc. (2) and intentional, planned out/premeditated actions. Thus, the historical event of my present concern is the USPHS Syphilis study at Tuskegee

Undergirding many mental states (beliefs, desires, etc.) is the property of Intentionality. [5] All beliefs are mental states having certain properties: 1) beliefs (because they have Intentionality) have aboutness or directedness. “If I have a belief, it must be a belief that such and such is the case” [6]. Not all mental states have aboutness. I may have an attack of nervousness, for example, that is not about anything in particular. Beliefs, on the other hand, is not of that kind. It is a mental state that is about something. This notion that my beliefs have aboutness (or directedness), i.e., that my beliefs are always traveling towards something is philosophical jargon for inferring that my beliefs have Intentionality. Also, beliefs have 2) intentions. In this regard, I am referring to intentional in the classical, non-philosophical sense of having goals, objectives or purposes. Intentions of this sort cannot exist independent of background mental states. To speak of Intentionality, then, is to speak in a discursive and reflective way on a necessary property of belief. One can’t speak of the ethics of belief without acknowledging the belief’s Intentionality, i.e., “what is it about?” If I say I have a certain belief, the very next question would (or should) be “what is your belief about?”

The Study didn’t just happen, like say, an accident of history, void of an Intentional human narrative. The Study was a non-natural act, the result of intentional mental state, attitudes, and belief. Such states need a (mind-to-world) direction of fit. This direction of fit disqualifies interpretations that are inconsistent with an agent’s belief. On this account, there are two kinds of beliefs worthy of mention: de dicto and de re. A de dicto belief is essentially a “belief,” i.e., it is a mental state with content and Intentionality. I am not going into the richness of this discussion, which would take me too far afield of my present concern, except to say, very roughly, that a de dicto belief is an a priori belief, the kind of belief that can be had (arguably) by a brain in a vat, independent of experience. Thus, there is a redundancy in uttering a term like “de dicto belief” [6].

On the other hand, a de re belief is far more fundamental to my present concern. A de re belief is a belief that denotes something existential—or external. One can say that a de dicto and a de re belief have the same starting point. They have the same initial properties for sure. However, de re beliefs interacts with the actual, real world. Commonly, these distinctions are of no significant consequence beyond the philosophy of mind and the philosophy of language but given my showing of how contextual beliefs can function to marginalize fellow humans, this distinction helps in clarifying the ethics of belief. Thus, we will start with a clarification of belief, namely, what it means to have an ethical belief and how an unethical belief can yield ambiguous concern and render harm to others and self. Concerning the Study, unethical beliefs began as de dicto mental states and ended with the (de re) marginalization of 623 black men in Macon County, Alabama, then extended to their families.

The Ethics of Belief

Historical events, caused by intentional actions, happened because human minds made them happen. Beliefs about the historical narrative, if they are untrue, don’t count for anything ethical. If the trajectory of their beliefs is to do good, then the truth value of their beneficent proposition is ethical. If, on the other hand, the trajectory of their belief is to harm, then their actions are maleficent and unethical.  I. L. Humberstone surmises, “Beliefs aim at being true, and their being true is their fitting the world; falsity is a decisive failing in a belief, and false beliefs should be discarded; beliefs should be changed to fit with the world, not vice versa” [7]. Facts about the world (e.g., the grass is green, snow is white, Nigeria is in Africa, and water is wet) should always be prioritized over individual opinions about the world, both epistemically and ethically. If the beliefs we have aren’t fortified by facts (i.e., don’t correspond to facts about the world) and good evidence (or valid arguments in defense of facts and evidence) we should set them aside. First person authority of one’s beliefs—i.e., the fact that I have access to my beliefs in a way that no one else is able—tends to render a superiority (or perhaps even an arrogance) that is not necessarily justifiable [8]. It is a special positioning, with special access, but it is not sacrosanct or devoid of error. A person, for good or for ill, may feel fully justified in believing her beliefs—and that makes perfect sense (unless one knows oneself to be delusional)—but if that belief is taken to be perfect, free from error, hubris may prevail. Donald Davidson reminds us that “Error is possible” [8]. Error, mistakes and miscalculations are always possible, “Though there is first person authority with respect to beliefs and other propositional attitudes, an error is possible; this follows from the fact that the attitudes are dispositions that manifest themselves in various ways, and over a span of time” [8]. Thus, beliefs (both de dicto and de re) are vulnerable to error and doubt, “For first-person attributions are not based on better evidence but often on no evidence at all” [8]. Fashioning one’s actions based on uncritical beliefs, therefore, is hubris. It is the beginning of personal folly, bigotry, and unethical behavior. It seems rather difficult for the protagonists in the Study to discount the word-evidence of the credible, namely, one of the primary participants in the Study and the one who brought the lawsuit, Charlie Pollard when he said, “And when this first started up, I didn’t know nothing—just a country boy, as they say. And when they got down here in Alabama, they found what they wanted—they just went to doctoring on us. And said they gon treat us. They just said, ‘bad blood’” [2]. It is clear that Pollard’s words, once juxtaposed with the goal and title of the Study, “the Effects of Syphilis in the Untreated Negro male” (italics mine), successfully refute Dr. Cutler and the other protagonists’ intentions. So long as their de dicto beliefs were only beliefs, there were no objective ethical issues. The moment their beliefs became de re (actual), i.e., the United States Public Health Service came to Macon County, Alabama and objectively fulfilling their beliefs, they were officially involved in unethical behavior. It’s time now to distinguish the two types of beliefs more clearly.

A de dicto belief is not necessarily of moral consequence. Indeed, I cannot be held morally responsible (or reprehensible) for thinking an act that I don’t commit. My subjective beliefs are of no moral consequence unless they are de re beliefs—i.e., my beliefs are of no consequence unless they are beliefs that are imposed upon real external objects. The external objects of our present concern are 623 black men and their families. If it was the case that Cutler and other protagonists of the Study opined privately—like a brain in a vat—nothing ethically hung on their beliefs (or the content thereof). But the moment their beliefs were imposed upon the men (and ostensibly, their spouses and children), causing unjustifiable harm, their beliefs in correspondence with their actions became unethical [9]. Beliefs remaining in one’s head may be metaethical moorings—analogical attempts at resolving puzzles, for instance. On a regular basis, philosophers ponder counter-intuitions, counterfactuals or expedient analogies, everything from pedophilia to murder to genocide are considered. None of these ponderings (or moorings) are considered unethical as such. They are just thoughts, even though some of these thoughts may rise to the level of beliefs. But if their beliefs move from private to public, impacting real human (or non-human) animals in the real world, their beliefs, and their corresponding actions are susceptible to (normative) moral judgement. Let’s say, for example, that a certain man (Paul) dislikes his father-in-law (Sam), which is not abnormal. Paul so dislikes Sam that he regularly ponders murdering him. He envisages a myriad of scenarios about how to kill Sam, and he even practices shooting at an effigy of Sam pinned to a tree stump in the woods. However, because Paul’s ponderings are de dicto—words and thoughts only—he committed no ethical wrong. [10] If he murders his father-in-law through premeditation, he has committed a moral and a legal de re wrong. But is there a possibility of ambiguity here? Perhaps. Imagine that Paul is so angry that with Sam that he goes to the woods and continues his vitriolic target practice with Sam’s effigy attached to a tree stump. As Paul aims at the effigy, unbeknownst to him Sam is taking a walk in the woods and crosses Paul’s line of fire precisely as Paul pulls the trigger. Sam is killed immediately. This is a homicide, but is it murder? Certainly, there is a great likelihood that Paul may be convicted, especially after the jury hears how much he despised Sam, wanted him dead, and often premeditated his murder even to the point of practicing it.

The truth of the matter is that this is a case of accidental death because there is no causal relationship between Paul’s de dicto beliefs and Sam’s death. The de re direction of fit is absent in Paul’s mind. In short, de re beliefs are subject to ethical judgement due to their interaction with the real world in ways that de dicto beliefs do not. Cutler’s (et al.) beliefs moved from de dicto to de re, and, as such, their uncritical analysis of their actions make them susceptible to the prevailing evidence against the Study and made them susceptible to moral judgement. Paul can legitimately plead ignorance of his father-in-law’s presence when the homicide/death took place. Cutler, however, fully believes that his beliefs were justified, and his actions were of no negative consequence. But he is wrong—again. He was wrong with his participation in the Study and he is wrong in the way he frames and delivers his reflections. The evidence is against him. Let me say why.

W. K. Clifford poignantly claimed in the 19th century,

He had no right to believe on such evidence as was before him. He had acquired his beliefs not by honestly earning it in patient investigation, but by stifling his doubts. And although in the end he may have felt so sure about it that he could not think otherwise, yet inasmuch as he had knowingly and willingly worked himself in that frame of mind, he must be held responsible for it [11].

The most compelling function of the ethics of belief is an epistemic one: one is never justified in making assertions in the absence of evidence. Evidence is sacrosanct. Also, justification for believing is intimately connected to evidence. Certainly “whether or to what degree a person is justified in believing something may vary with time” [12]. The protagonists, when faced with mounting evidence, over 40 years, chose to believe corrupted beliefs and false truths rather than good evidence. Once again Clifford makes excellent ethical sense, “However convinced you were of the justice of your cause and the truth of your convictions, you ought not to have made a public attack upon any man’s character until you had examined the evidence on both sides with the utmost patience and care” [12].  There was never intent to treat these men. When penicillin was discovered as a treatment for syphilis they were never administered this potentially curative antidote. And as an aside, in 1932, the same year the Study began, notorious gangster Al Capone was incarcerated in the Atlanta U.S. Penitentiary with syphilis and gonorrhea. When penicillin was found to be curative for syphilis, the ruthless, alleged murderous gangster and convicted income tax evader, was offered the medication though he refused it thinking it was poisonous [13]. Then hard-working black men in Macon County, some of whom were share-croppers, were given less consideration than an acrimonious gangster. Speaking with respect to his honest feelings about the Study, Pollard quietly said, “It did make me, you know, I might have said some curse words-when I was by myself-but they ought to have been ashamed of themselves. I wouldn’t have done them like that” [1, 46:00]. Experimenting on humans without letting them know, and without their consent, is unethical. The men thought they were patients. The protagonists knew they were objectifying these human subjects. If the Study had any integrity they would have been told them the truth; they would have asked for their consent. Whether we like it or not, beliefs, if they are to be regarded as ethical, have social constraints. Clifford offers the following refrain, “And no one man’s belief is, in any case, a private matter which concerns him alone. Our lives are guided by that general conception of the course of things which were created by society for social purposes” [11]. Social justice should never be a privilege—it is an ethical responsibility that begins with doing the good.

The Ethics of Ambiguity

Beliefs are said to be ambiguous or false if they are derived from an interpretation of a historical event in which the mind-to-world direction of fit is somehow fuzzy or unclear. Ambiguity takes place in the mind. It is a confusion of beliefs—justifiably or without justification—based upon evidence and the interpretation of evidence derived from a historical event. As a result, the ethics of ambiguity boils down to what a person believes to be ethical truths based upon his or her interpretation (assuming there are no guiding moral absolutes). If there are no moral absolutes or if there is no objective moral truth, any person seems entirely justified in his or her beliefs, even if said beliefs lead to moral relativism, moral skepticism, or even more extremely, moral nihilism—and ethical ambiguity has room to thrive. Facing this quirk in the complexity of moral philosophy, Fyodor Dostoyevsky’s (The Brothers Karamazov) way of inveighing against such views is to couch his own beliefs as a religious ethic, “Without God everything is permitted.” This relativistic view, which is also found in the Hebrew Bible, “In those days there was no king in Israel; every man did what was right in his own eyes” (Judges 17:6), was refuted by Plato in the Euthyphro over two millennia ago. On Plato’s account, the rightness or wrongness of an action is not contingent upon a Divine Commander who makes an action right because it is “loved by the Gods.” An action tends to be right or wrong for other (more human) reasons (e.g., reason, consequences, sentiments, virtues or caring relations). Nevertheless, there is something that the relativists and the Universalists have in common: they are both necessarily conjoined by the fact that there is no way to construct an argument independent of beliefs. Belief (or having a belief) is a necessary (but not sufficient) condition for having knowledge. If I say I know any particular thing I must also believe it. It makes no sense to say “I know that my mother’s name is Alice, but I don’t believe it.” With respect to moral epistemology (i.e., moral knowledge), the same rule applies. I can’t say, for example, “I know that murder is wrong, but I don’t believe it is wrong.” The challenge question in making such a moral inference, particularly with respect to analytic philosophy, is do I have a supporting argument in defense of my belief and my moral knowledge? [14] So, a legitimate question for John Cutler and others of his ilk could be, “How did you understand the nature of your beliefs and the nature of your ethics during and after the Study? Also, in the face of moral outrage, lawsuits, personal objections and a demand for social justice, why did you hold fast to your beliefs?”

Something is said to be ambiguous if its’ significance is such that more than one interpretation can be offered. Immediately it is clear that ambiguity has something to do with mind and language—mind in the sense that it is here that interpretations are done, and language in the sense that this is the medium through which interpretations are played out both in the mind and in conveyance to others. These terminologies are governed through both cognitive meanings and emotive meanings. From a logical point of view, and in order to get to the particular ends of which I see in this essay, I am more concerned with the cognitive meaning than the emotive one. Cognitive meanings demand evidence to determine the truth-value of particular statements/propositions, but emotive meanings tend to allow emotions and feelings that are vulnerable to biases in a way that facts aren’t. An act or an event is never ambiguous—They are facts. They occurred. The motivations that brought about a particular event may need unpacking, but the act or the event can be independently verified. Acts or events take place in the presence of certain irreversible contingent properties; therefore, “with regard to the past, no further action is possible” [15]. Interpretations of the actions or events are certainly all we have—interpretations. Interpretations such can be correct or incorrect, wrong or right—They can be ambiguous based upon several human factors. But the action itself, or the event, is a fact. It occurred. It represents a historical reality—it is not ambiguous—our interpretations are.

Thus, since an action or event lacks the property of ambiguity, and are, as such, factual or evidentiary, the true focus of our investigation lies in the nature of interpretation—for it is here that the ethics of ambiguity truly finds itself. The nature of interpretation must begin, in logical form, with the truth value of propositions. Such that a proposition is true, it has sustainability in valid and sound logical arguments. There is no ambiguity here. Susan Haack pointedly articulates what propositions can and can’t be if they are to have unequivocal truth-value as premises in a valid argument: “For it is valid if it couldn’t have, not just doesn’t have, true premises and false conclusions” [12]. So the proposition, “The men in the Syphilis study were inhumanely violated,” is true if and only if this proposition can be shown to be true. It is false otherwise—so says the Law of Non-Contradiction. And if this conclusion is true, and if the major and minor premises are constructed with truthful propositions, then the logical dictum—there is no conclusion that is false if all of the premises are true—remains. Every argument such is valid and sound, having true premises (none of which are false) and a true conclusion. This is quite straightforward and an irrefutable philosophical yardstick, especially in analytic philosophy, from Aristotle to today. The strength of any successful refutation would have to show a compromise (or weakness) in any of the propositions (either in the premises or the conclusion) such that either one is less formidable making the premises indeterminable, the argument (potentially) unsound, and is thus ambiguous.

Propositions, then, must be of such disambiguation that they are inaccessible to falsification or pliability. To this end, Scott Soames says the following about propositions, “The key constraint shaping the account is that real propositions are not things we, or other cognitive agents, interpret; they are not instruments we or they use to carry information; they are not entities we or they endow with Intentionality. Rather, propositions are inherently representational entities that are capable of being true or false, independent of any actual use to which we or other agents put them” [16]. The key to Soames benchmark definition is “real propositions”—i.e., as opposed to, say, unreal, artificial, fake, or illusory propositions. The latter has cognitive meaning buttressed by unequivocal evidence, the latter is suspect—suspicious even—a fantasy of sort that seems to render an historical event ambiguous, if it were able—more open to (subjective) interpretation. But again, with respect to the ethics of ambiguity, de Beauvoir says, “With respect to the past, no further action is possible. There have been war, plague, scandal, and treason, and there is no way of our preventing their having taken place; the executioner became and executioner and the victim underwent his fate as a victim without us; all that we can do is to reveal it, to integrate it in the human heritage…” [16]. The only way, it seems to me, to reveal the facts of human history, especially those facts that rise to heinous acts against others, given human tendency toward tribal revisionism, is to disambiguate the propositions of those promoting dehumanization as a matter of course,

I need to be clear: Cutler did not commence the Study, neither is he its only defender, he is more of a metaphor for its advocates. As historian Susan Reverby avers, there were some, even blacks, who saw “nothing wrong with what was done” [17]. But the preponderance of evidence suggests a malicious complicity. The researcher/playwright David Feldshuh of Miss. Ever’s Boys, the fictionalized account of the Study, usefully argues, “Here’s this reprehensible study that very caring people partook in that made me wonder what guidelines would you follow…If our intention are good, how are we to be certain that we’re not engaged in something that will in the future prove to be morally reprehensible or at least morally questionable” [17].  Ambivalence of this sort often hurries to a kind of consequentialism—a utilitarian defense that would concede moral rightness if a reprehensible (or sacrificial) act is such that it produces a greater good, yay, a greater happiness overall. On this account, there is no moral uncertainty; there is no ethical ambiguity. An action is right—not intrinsically, but consequentially—if it tends to promote a better state of affairs overall. Cutler, then, is not at all ambivalent about the Syphilis Study. He quite clearly states, “We were dealing with a very important study that was going to have the long term results of which was to actually improve the quality of care for the black community—so that these individuals were actually contributing to the work towards the improvement of health toward the black community, rather than simply serving as merely guinea pigs for the Study. And, of course, I was bitterly opposed to cutting off the Study for obvious reasons” (italics mine) [2].

The amount of rational, learned professionals, mostly employed by the Centers for Disease Control (CDC) or other parts of the USPHS, who were deeply lacking in human empathy, is so astounding that one may ask why choose Cutler as the metaphor for the Study? His words, as I’ve already shown, in the wake of an escalating moral epistemology decrying the Study, seems heartless—“It was important that they were supposedly untreated, and it would be undesirable to go ahead and use large amounts of penicillin to treat the disease, because you’d interfere with the study.” His willingness to make these claims on camera for the Nova documentary Deadly Deception is instructive, and his responses to the views of others in the USPHS is confirming. Sidney Olansky, Chief of the Division of Venereal Disease Research Laboratory, wrote to Cutler, “Dear John…We agree wholeheartedly with your premises for the validity of the study, your arguments for the importance of this follow-up, and your recommendations for the clinical examination” [17].

Cutler’s argument that it would be “undesirable” to use “large amounts of penicillin to treat the disease” is in itself a violation of the Hippocratic Oath as a physician he vowed to uphold, particularly the stanza, “I will abstain from all intentional wrong-doing and harm, especially from abusing the bodies of man or woman, bond or free.” Do no harm is the common phrasing. But in the minds of Cutler et al, were they committing harm? Not according to their interpretation of their actions or the event. On their account, “the validity of the study” (i.e., the argument that the Study should be prioritized over all other interpretations) or the economy of the Study was sacrosanct—it was an investment in something noble, regardless of other interpretations. Olansky continues in 1951, one-year shy of two decades into the Study, “We have an investment of almost 20 years of Division interest, funds and personnel; a responsibility to the survivors both their care and really to prove their willingness to serve, even at the risk of shortening life, as experimental subjects. And finally, a responsibility to add what further we can to the natural history of Syphilis” [17].

The protagonists of the Study were very clear: the Study was a noble act; there was no ambiguity with respect to their interpretation, even when it meant the direct infliction of pain for no curative end, which is entirely in view with Olansky’s words to Cutler, “Careful studies of spinal fluid and neuromuscular system are advised.” The trauma associated with this kind of invasive medical procedure was not only extremely painful, but it was also dangerous during its early 20th Century usage, which was only a few decades in use before the Study’s conception. Charlie Pollard’s testimony clearly and heroically states, even during the associated agony of the spinal tap, “It was pretty bad—that spinal tap—course, I did along pretty well with it, but uh…I stayed in the bed a week or two” [1]. These men were told that the spinal tap was a “special free treatment.” It is clear that the men saw themselves as patients receiving special care from the United States Public Health Service and the scientist who conducted Syphilis Study at Tuskegee saw the men as “experimental subjects” (and falsely) with a “willingness to serve.” Any willingness they may have had was based upon deception.

The key words in Olansky’s letter to Cutler, which served to affirm and congratulate him, were all given in the best interest, not for the men, but of the Study. Terms like “investment,” “Division interest, funds and personnel,” as well as the paternalistic ambiance of their tone, “their willingness to serve,” “at the risk of shortening [their] life,” and “experimental subjects” are omniscient language in which they offered no unadulterated evidence. Their “willingness to serve” begs the question; did they know they were serving some grand humanitarian end? And if they did know, did they know they were “experimental subjects” and that their lives (and their families’ lives) were at risk? The omniscient, omnipresent and omnipotent languages of these doctors bespeak their God-complex in the lives of an extremely vulnerable population of Negro men in Macon County, Alabama. One year after Olansky’s letter, Eleanor N. Walker, writing to Cutler, continues to encourage him to keep the course: “It seems to me that after 20 years we have too much at stake in this study to let it slide now for the sake of a few dollars.” And, as for those “lost” men who were able to slip through the idiomatic cracks, “In the case of those residing in Alabama it should be simple enough to have them located and examined.” Once again it is clear: the administrators of the Syphilis Study wanted nothing to do with its ceasing, even after two decades of watching misery and death. Their empathy for this population of black had either eroded or never existed. And their urgency didn’t recede—it abounded as we see in Walker’s search for options to ensure the Study’s continuance, “Would it be possible to think about tying in more closely with the [Tuskegee] Institute staff in some way. Certainly, something should be done right now to put the study on a firmer foundation if it is determined it should be continued.” Apparently, the firmer foundation was solidified since the Study continued for another two decades.

The Ethics of the Study

With the help of Simone de Bouveur et al., I have tried to show how that the Syphilis Study wasn’t at all ambiguous—it was a straightforward historical event. Any potential ambiguity would have to hang on a misinterpretation of the Study—a misinterpretation that I take to be wholly unjustified given the level of deception and harm. If the doctors in the Study desired moral salvation, it would have had to be because they thought they weren’t doing something morally prohibited. In their minds, their interpretation of the Study was the correct one. There was no moral or ethical ambiguity in their imagination. I believe that Cutler’s beliefs were morally groundless and unjustifiable, but what of his/their actions? Cutler says, “The fact was it was a concern for the black community.” The morality of the Study rests on the truth-value of this proposition. I think I’ve shown this proposition to be false. And I’ve also showed how Clifford’s scourge against false beliefs, especially when used as propositions in the construction of an argument, is also embraced by Bertrand Russell, “It is undesirable to believe a proposition when there is no ground whatever for supposing it true.”

The USPHS Syphilis Study at Tuskegee was an experiment with (objectified) human subjects, but for these black men in rural Alabama it was an unconscionable disrespect of their freedom and bodies by none other than their government—the United States of America, the “land of the free.” Their basic human liberty was denied and for four decades empathy was an irrelevance. This “study” was anti-black racism. There can be no gainsaying the fact that the USPHS Study on Untreated Syphilis in the Negro Male at Tuskegee was an intentionally racist study; it wasn’t simply a human rights violation. It was an antiblack racist act. None of the men in the Study were white. It was titled as a study on Negro males. An argument could be made that the Study would not have been done with black slave men, because during slavery commodified black bodies had value. But free black men of the Deep South were disposable (this is clear from the post-slavery lynchings), thus the nomenclature of “anti-black racism” of which I give Lewis Gordon’s reflection a generous quote.

In this explicit foregrounding of the self, Gordon’s focus is on the ontology (not the psychology) of everyday black and white egos, the interactive dynamics between these ontologies, and their relations to the origins and maintenance of antiblack racism. The interactive dynamics between these ontologies have trapped black and white ego formation in classic imperial battles for ontological space. By ontological space, I mean space to be, to posit oneself and realize that self-positing. The imperial nature of this battle derives from the fact that Europeans and Euro-Americans have defined the ontological space of white ego genesis in a way that requires the evading of the humanity of Africans. This evasion is effected through the racial redefining of Africans as blacks, Negroes, or more pejoratively as “niggers.” The result is an imperial ontology that restricts the space of black ego genesis and appropriates its ego-formative resources in the interest of white self-formation. (italics mine) [18].

Black men in 1932 Alabama lacked the power and the resources to defend themselves against the imperial threat of a United States government sanctioned, white supremacist ideology. They had nothing with which they could resist the invasion of whiteness—they knew that many of their family members were sick with “bad blood” so they trusted their bodies (and their ontology) to those whose interest was self-centered. The men deserved an ethic of empathy and care. Instead, they were the recipient of ethical egoism—the USPHS did what was right in their own rational self-interest, regardless of the collateral damage in the form of devalued black bodies (and later, Guatemalan brown bodies).

The underlying conceptual scheme facilitating the Study was a white supremacist, anti-black racism that envisioned black lives and black bodies as non-free property, void of any significance or import that whites were duty-bound to respect. Truly antiblack racism envisaged black bodies as non-free regardless of time or space. Consider for a moment the case of Dred Scott, the black slave who accompanied his master, Army officer Dr. John Emerson, to various northern Free states, where it was decided in 1852 by Chief Justice Roger Taney that

…a negro, whose ancestors were imported into the [United States of America], and sold as slaves…had for more than a century before been regarded as beings of an inferior order, and altogether unfit to associate with the white race, either in social or political relations; and so far inferior, that they had no rights which the white man was bound to respect; and that the negro might justly and lawfully be reduced to slavery for his benefit. He was bought and sold, and treated as an ordinary article of merchandise and traffic, whenever a profit could be made by it. This opinion was at that time fixed and universal in the civilized portion of the white race. It was regarded as an axiom in morals as well as in politics, which no one thought of disputing, or supposed to be open to dispute; and men in every grade and position in society daily and habitually acted upon it in their private pursuits, as well as in matters of public concern, without doubting for a moment the correctness of this opinion [19].

The Dred Scott decision, among other things, set the stage for the white supremacist arrogance that would eventually enable hideous actions like the Syphilis Study. Chief Justice Taney’s conceptual scheme was not based upon a parochial decision—it was the overarching decision with only two members of the Court dissenting. The Civil War may have put an end to physical (body) enslavement, but the white supremacist conceptual scheme promoting black inferiority through a pervasive anti-black racism was institutionalized in many white minds through their beliefs, creating the kind of patriarchal white supremacist culture that would make the Syphilis Study a possibility among enlightened, rational people who lived in the United States. The correlation of Scott and the men of the Study accentuates the absence of two values in the overarching conceptual scheme: freedom and empathy.

Conclusion

In conclusion, de Beauvoir, writing on what it means to be free, says, “But if man is free to define for himself the conditions of a life which is valid in his own eyes, can he not choose whatever he likes and act however he likes?” [15]. I am not binding myself to the French existentialism Beauvoir is defending here, but as a definition of freedom, I find much purchase. In other words, 1932 Macon County, Alabama had an unusually high rate of syphilis, roughly one-third of the men tested had the sexually transmitted disease. This “fact” caught the attention of the USPHS, whereupon they commenced a study—and experiment—of what would happen if these black men were untreated. To our present knowledge, the USPHS didn’t give the men the syphilis virus, neither through injection nor any other form (though we can’t discount this possibility that they may have, given the nefarious action was done a few years later in Guatemala by some of the same scientists, including Dr. Cutler), but what they did was of such deceitfulness that it interrupted history. The force of history is such that, in the words of theologian David Tracy, [20] “it is not only contingent; history is interruptive” [19]. The historical interruption seems clear enough:

The men thought that they were patients of a joint federal and local medical and nursing program at the Tuskegee Institute and the Macon County health department for their “bad blood,” a local idiom that encompassed syphilis as well as anemias. They did not consider themselves subjects since they did not know the study existed. The PHS followed the men for forty years (from 1932 to 1972), actively keeping them from many forms of treatment (including penicillin when it became available in the 1940s), never giving them a clear diagnosis, but providing them with the watchful eyes of a nurse as well as exams (including a diagnostic spinal tap), placebos, tonics, aspirins and free lunches. Burial insurance became an additional inducement for their participation. In exchange, the men or their families agreed to allow for autopsies without knowing that the researchers needed to confirm the ravages of syphilis on the men’s organs and tissues. [17].

Among the many pieces of evidence of what seems somewhat sadistic, or apathetic is the organizational structure derived from the conceptual scheme. There is no happenstance in this socio-scientific-medical construction. Instead, we see the properties of what injustice demands: an abuse of power by those who were in structurally powerful positions to halt the freedom of the powerless. The ethical violations, the human rights violations and the racism that hovered over this successful effort to constrain the vulnerable is clarified further by Tracy’s critique, “To be an American is to live with pride by participating in a noble experiment of freedom and plurality. But to be a white American is also to belong to a history that encompasses the near destruction of one people (the North American Indian, the true native Americans) and the enslavement of another people (the blacks)” [19].

In contrast to Dred Scott, a slave, the syphilitic (as well as the controlled group) men of Macon County were not slaves, but they were deceived just the same. They thought the actions of the doctors were noble. Herman Shaw, one of the men in the Study, said, “The way I heard about it was through a rumor that the people, and this came out of Macon County, said that you can get free medicine for yourself, and things of that kind. And therefore, I went. On that Saturday afternoon when we went over there, they said we would get free medicine, that wouldn’t cost us anything and the doctor… We will get free doctoring” [2]. They went to become patients of medical doctors. They were made interruptions of history as objectified experimental subjects. There is no way that deception of this kind can be morally prudential.

References

  1. A non-digitalized version of this article was previously printed without open access as a commentary in Journal of Healthcare, Science and Humanities. Vol. VIII, Number 1, Spring 2018.
  2. Deadly Deception: https://www.youtube.com/watch?v=qNa8CnC4sSU Deadly Deception 3:31
  3. Guatemala Syphilis Experiment https://www.britannica.com/event/Guatemala-syphilis-experiment; Recent questions regarding the existence of the specimens gives good reason to doubt the Study’s 1972 termination. See,
    1. Roy, Benjamin (1987) The Tuskegee Syphilis Experiment: Biotechnology and the Administrative State. Journal of the National Medical Association 87: 1;
    2. Spector-Bagdady, Kayte and Paul A. Lombrardo (2018) From in vivo to in vitro: How the Guatemala STD Experiments Transformed Bodies into Biopecimens” The Milbank Quarterly 00:1–28.
  4. Such as hurricanes. In 2017 Hurricane Irma and Maria devastated the Caribbean, but there were no underlying mental states. Though we tend to use generic language like “acts of God” to contextualize a certain kind of phenomenon, hurricanes and other kinds of environmental events are natural historical events having no import for my present concerns.
  5. The “I” is capitalized to differentiate between “Intentionality” as a function of mind in which mental states are very often about something and “intentions” or to “intend.”
  6. Searle, John. R. (1983). Intentionality: An Essay in the Philosophy of Mind. Cambridge, New York, Oakleigh, Melbourne: Cambridge University Press.
  7. Humberstone L (1992) Mind, New Series. Cambridge University Press 101: 59–83..
  8. Davidson, Donald (2001). New York: Oxford Press.
  9. Slote, Michael (2001) Morals from Motives. New York: Oxford University Press, Inc.
  10. There are some ethical theories, like Christian ethics, for example, “For as he thinks in his heart, so is he” (Proverbs 23:7) and other words spoken by Jesus on his Sermon on the Mount, that take motives and other de dicto beliefs to be on the same level of committing the action.  But this doesn’t work rationally. It is hard to envision an argument that would put thinking about pedophilia as being equivalent to actual pedophilia. Doing an act requires far more commitment than thinking an act. Either way, Christian ethics would also decry the Study even to a greater extent than other non-cognitivist and cognitivist approaches.
  11. Clifford, William Kingdon (2008) The Ethics of Belief, A. J. Burger.
  12. Haack, Susan (1995). Evidence and Inquiry Malden: 1995.
  13. Al Capone dies in Florida villa”. Chicago Sunday Tribune. Associated Press. January 26, 1947.
  14. As well as, to what degree am I justified in believing my beliefs? It does make good sense to believe my beliefs—even if they are ambiguous, but I am justified to a lesser degree—because if I don’t believe my beliefs, I would believe nothing at all, unless I find that my beliefs are delusional or fail to correspond to the “experts” or facts about the real world.
  15. de Beauvoir, Simone. (1948). The Ethics of Ambiguity. New York: Philsophical Library.
  16. Soames, Scott. (2015). Rethinking Language, Mind, and Meaning. Princeton, Oxford: Princeton University Press.
  17. Reverby, Susan M (2000) Tuskegee’s Truths: Rethinking the Tuskegee Syphilis Study.Chapel Hill, London: University of North Carolina Press.
  18. Gordon, Lewis R. (1995). Bad Faith and Antiblack Racism. Amherst: Humanuty Books.
  19. Scott v. Sanford, 60 U.S. (19 How.) 393 (1857).
  20. Tracy, David (1987) Plurality and Ambiguity. Chicago: University of Chicago Press.

The Pregnancy Ecological Momentary Assessment Pilot Study: Applications of Mobile Technology

DOI: 10.31038/IGOJ.2019215

Abstract

The Pregnancy Ecological Assessment (PregEMA) Pilot Study was designed to apply EMA approaches (i.e., capturing experiences in real time in the natural environment) among a population of pregnant women.  A total of 28 women completed EMA surveys on their smartphone over a 4 week period during their second and third trimester.  We assessed mood, eating, physical activity, stress, location and context at the beginning of the day, end of day, and randomly throughout the day and week.  The majority of participants completed EMA surveys (average 76% completion rate) with limited missing surveys. Key findings from the EMA data were that on average, women indicated having trouble sleep 71% of the time, were taking prenatal vitamins 73% of the time, were physically active 55% of the time, and spent 5.7 hours per day sitting. The innovative approaches employed in PregEMA allowed us to understand women’s experiences in real-time and in women’s natural environments.  Future work could consider how these methods may be integrated into larger population studies, trials and clinical or community-based interventions.

Keywords

Pregnancy; Ecological Momentary Assessment (EMA); mobile technology

Background

Ecological momentary assessment (EMA), the repeat assessment of experiences, behaviors, and mood in real time within one’s own environment has been applied in multiple studies, particularly in areas related to health [1].  EMA has been applied in numerous contexts including but not limited to studies related smoking cessation[2, 3], eating patterns[4], and cardiovascular activity[5]. EMA has been useful in addressing limitations in data collection methods that rely on recalling previous experiences over long periods of time as well as capturing dynamic processes that may fluctuate or change over short periods of time. EMA has rarely been applied in studies of pregnant populations; however some prior examples include the use of technologies such as personal digital assistants (PDA) to assess the psychological state of pregnant women to predict the length of human gestation [6, 7] and repeat collection of saliva samples and psychological distress questionnaires administered at short intervals to assess psychological distress and pregnancy outcomes [8].

Previous studies have used mHealth (mobile health) approaches among pregnant populations. However, there are no known published studies to date that specifically use mobile technology or smartphones coupled with EMA data collection to assess the health and experiences of pregnant women in real time. The application of EMA through current technologies such as smartphones can be useful for data collection among pregnant women given the dynamic, complex nature of pregnancy [9].

As a result, we developed the Pregnancy Ecological Momentary Assessment (EMA) Pilot Study (PregEMA), which was designed to examine the central question of whether EMA data collection through smartphone technology could be applied among a pregnant population to understand their contexts, behaviors/lifestyle factors, and psychosocial well-being. As a secondary aim, we explored the possibility of collecting location data in real-time, an extension of EMA known as geographical momentary assessment (GMA), in order to assess context/environments [10]. Assessment of location and environment in real time provides an avenue to capture women’s multiple environmental exposures outside of their residential neighborhood as typically measured in prior studies. Today, the smartphone allows for instant access to participants for real time data collection and transfer of information, and the GPS built into smart phones permits collection of information on subject location. Data from Pew show that smartphone use is common enough to support applications and are feasible among the proposed study population with a high percent of smartphone ownership[11]. These approaches can remotely capture women’s daily experiences and provide insight into effective strategies and interventions for addressing health during pregnancy. This paper presents the methods and design of PregEMA and some descriptive data of the study population.

Methods

Recruitment and Sample

PregEMA is a pilot ancillary study to the GDM2 Trial, a randomized controlled trial designed to assess two screening approaches for diabetes in pregnant women (i.e., gestational diabetes)[12, 13].  Participants recruited for GDM2 are a diverse sample of pregnant woman between the ages of 18–45 with singleton pregnancies between 18–24 weeks of gestation.  Exclusion criteria are preexisting type 1 or 2 diabetes, hypertension requiring medication, inability to complete or already completed glucose testing, advanced HIV or liver disease, and recent steroid use. The study takes place at a hospital in Pittsburgh, PA. Women are recruited directly through the hospital clinic, flyers, electronic announcements, social media advertisements,  and through other physicians’ offices.  Study recruitment for GDM2 began in July 2015.  Recruitment for PregEMA began October 2015 and ended in Jan 2016.  Women from GDM2 were approached during their first or second study visit (between 24 and 28 weeks gestation) to gauge their interest in participating in PregEMA. After their GDM2 visit, in which they were either completing their initial glucose tolerance test (visit 1) or randomized to take the follow-up glucose tolerance test (visit 2), women were asked if they were interested in hearing about PregEMA; and if so, the research coordinator would describe the study, review the eligibility criteria, and review informed consent.  Women also received the study coordinator’s contact information if any technical issues or other problems were to arise. Eligibility criteria for PregEMA included having a smartphone and willingness to use their own smartphone for completing EMA surveys. We approached 37 women from GDM2, and 3 did not have a smart phone and 2 were not interested. A total of 32 women completed consent forms while 31 initiated the web-based application. Our final analytic sample included 28 women who completed at least 16 surveys over the 4-week study period. The Institutional Review Board for the University of Pittsburgh approved this research study.

Study Design and EMA Data Collection

PregEMA is a prospective study where women were followed over a 4-week period. Over the 4-week period, women received prompts through the smart phone via text, linking them to time-specific surveys through an online system.  Participants would receive prompts to complete surveys at the beginning of the day (BOD), the end of day (EOD), and at a random day and time. Participants received prompts to complete the BOD and EOD surveys 3 times a week (various days) as well as a random prompt twice per week. Participants set the times for which they would like to receive their BOD and EOD, with the times being at least twelve hours apart.  Participants are given 30 minutes to complete the BOD and EOD surveys with reminder text messages sent every 10 minutes. They were given 60 minutes for the random survey with reminder text messages sent every 20 minutes. After that time period, the survey would cancel and would be considered missing.  Figure 1 includes example screen shot of the EMA prompts as they appear on the smartphone.

After the initial protocol was set up on the participant’s phone through the online system, their information was stored in their browser’s cookies.  The cookies were then sent to a secondary server, which was separate from the primary server used for the back-end program designed to send the survey prompts. Information was communicated back to this secondary server, which included a program designed to check when surveys were available.  Once the participant completed and submitted their survey, that information was also sent back to the secondary server, where the data was loaded into a database. Each time the participant completed a survey, their GPS coordinates (longitude and latitude) were also recorded. Participants had the option of turning on/off their location services. After the 4-week period, women were invited to complete a 20–30 minute exit interview over the phone for feedback about the protocol and overall study. Women were compensated $35 if they completed 3 surveys per week over the 4-week study period and an exit interview. Women did not receive direct payment for their phone or data charges.

IGOJ 2019-104 - Dara Mendez USA_F1

Figure 1. Screenshot of EMA Prompts on Smartphone

Measures

PregEMA included a variety of measures for the BOD, EOD, and random surveys. Many of the measures had parallel items from existing tools and scales. For example, the Cohen Perceived Stress Scale is a validated scale with multiple measures [14]. Although not developed for the EMA context, we adapted measures from this scale and others for this study. Some other measures were derived from other EMA studies [15].

BOD Survey. The BOD survey was designed to assess women’s mood and experiences in the morning and what may have occurred overnight. We collected measures on sleep, eating patterns, and mood. Example questions were “Did you have trouble falling asleep” with a yes or no response; “Rate how well you slept last night” with a response of 0 = poor to 4 = excellent; and “How are you feeling” with various options that they could check all that apply such as Happy, Angry, Stressed and Content.

EOD Survey. The EOD survey was designed to assess women’s experiences during the day and was only collected once per day, not throughout the day. Once again, we asked questions about rest, sleeping patterns, physical activity, and eating patterns. Exampled questions included “Were you able to eat today” with the option of yes or no. There were several follow up questions such as “How many meals and snacks did you eat today?”; “Did you eat anything before 12 noon”; “Did you change what you ate today because of weight gain?” Additionally, we asked that if participants purchased foods for the day, that they take a picture of the receipt. They had an opportunity during the EOD day prompt to upload pictures of receipts of foods they purchased. This could have been food purchased at any convenience or grocery store, including anything eaten a restaurant.

Random Survey. The random survey questions were sent at a random time during the waking hours (between times of the BOD and EOD alarm prompts) and any day of the week. They received a maximum of two random surveys per week. The random survey included items of discrimination, stress, and experiences in healthcare settings [16]. Example questions were “In the past week, have you seen a doctor, nurse or other healthcare worker for this pregnancy?” with follow-up questions such as “How satisfied were you with the care you received” on a scale of 1–5; “In the past week, were you treated unfairly because of your race or ethnic group?” If they answered yes, the follow-up question was “Where?” with options such as at the doctor/healthcare clinic, at a restaurant, at work.

Direct questions about context were sent with each EMA prompt: “Where are you?” (e.g., home, work, outside). “Who are you with?” (e.g., alone, with partner/spouse, other family member, other). GPS (longitude, latitude) capabilities are embedded in the current technology for smartphones allowing us to collect location as participants complete the various EMA prompts.

Analyses

The primary analyses are descriptive and show trends and prevalence of the core survey questions as well as location. Location information (longitude/latitude) were mapped using ArcGIS version 10.5 (ESRI; Redlands, CA). Since participants were completing the same survey questions multiple times over the 4 week period, univariate analyses were conducted by taking an unweighted average within subject and then averaging responses across subjects. Descriptive analyses were completed using SAS version 9.4 (Cary, NC).

Results

Table 1 includes characteristics of the population of women who completed a minimum number of EMA surveys. The characteristics of women in the pilot PregEMA were similar to the overall characteristics of the source population from the GDM2 Study.

A total of 880 surveys were sent to the 28 participants.  In total, 665 surveys were attempted/completed (BOD=278 out of 388, EOD=292 out of 372, RAND=95 out of 120) for completion rates of 72%, 78%, and 79%, respectively, and an overall completion rate of 76%. The total number of responses varied from a low of 12 to a high of 28 with a mean of 23 and a median of 25 data collection points.On average participants completed 9.7 BOD and 10.4 EOD surveys over the month period.  Subjects had good compliance with random surveys. Only two participants completed 1 or 2 random surveys while the remainder completed 3 or 4.  Within each time point, participant’s tended to have answered all the survey questions.  An examination of the main questions of each time point (excluding the food receipt upload option) shows high response rates within each BOD, RAND, and EOD time point with the average number of answered questions as follows: BOD 8 + 0.8 (out of 9 questions), RAND 8 + 0.5 (out of 9 questions), and EOD 9 + 0.9 (out of 11 questions). The most commonly missed BOD question was BOD6 which asks subjects to rate their level of hunger.  The most commonly missed RAND question was RAND3 which asks subjects about unfair treated today because of her race or ethnic group.  In part this was driven by one subject who never answered this question.  There was not a pattern of missing questions within the EOD surveys. Table 2 includes each type of survey completed per participant.

Table 1. Characteristics of the Population (N = 28)a

Estimate

Age, M (Range)

26 [19–37]

Pre-Pregnancy BMI, M (Range)

29 [22–41]

Weeks Gestation, M (Range)

27 [20–34]

Race, %

   Non-Hispanic Black

48%

   Non-Hispanic White

43%

   Mixed Race

9%

Income (yearly), %

   <$20K

57%

   $80K+

13%

Education, %

   HS/GED

35%

   Some college

22%

   College degree

22%

a. Height and weight (to calculate BMI) were all taken at participant’s 1st visit, while gestation was collected at the start of the surveys. There were several income and education categories, but only a few are presented. Yearly income was not adjusted for family size.

Table 2. Surveys Completed Per Participant (N = 28)

Time Category

Minimum count per person

Maximum count per person

M (SD)

Across all time categories

12

30

23 (3.9)

BOD

4

16

9 (2.5)

EOD

5

13

10 (0.6)

R

1

4

3 (0.7)

Participants in the study had the option to allow location data to be included with their survey responses. The majority of surveys included location data (80.3%).  Missing location data were subject dependent rather than time point dependent.  Missing location information for the three time periods (BOD, RAND, and EOD) occurred on 20.7%, 20%, and 18.6% of surveys respectively.  However, 65.1% of the missing location data occurred in just 4 participants.  No information is known about device or cellphone provider so it could not be determined if one of these factors contributed to missing location data. Participants were not restricted to any particular area during study participation, but the subject’s location data was predominantly within Allegheny County with a few locations outside of Allegheny County in PA, OH, and FL.  The location data revealed that very low location variability was collected, both overall and between time points (BOD, RAND, and EOD).    Three extreme location outliners, 2 in Florida and 1 in Ohio, were removed before examining the data.  Minus these locations that were far out of the subject’s normal pattern, the maximum range between survey points within subject was between 0.0171 and 96.7 km with an average (standard deviation) of 24.0 ± 24.7 km.  A given subject’s location data is predominantly found within 10 km of other location data from that same subject.

Tables 3–5 include descriptive analyses of the overall population by taking the within person unweighted average and then averaging across all participants for the study time frame (i.e., 4 weeks). In table 3, the beginning of day responses indicate that a majority of participants had trouble falling asleep but on average slept 7 hours each night. The rating of their sleep quality was average although a majority indicated being tired when asked about mood/feelings. In table 4 at the end of the day, on average, women at almost 4 meals or snacks per day, with a majority eating a meal/snack prior to noon. Not many participants indicated changing what they ate due to concerns with weight gain. About half of the participants indicated being physically active on average while 65% of the population spent 5 hours or more sitting in a given day.  As indicated in Table 5, which were random prompts, women were around 28 weeks pregnant when they participated in the study. About 41% saw a healthcare provider within the past week; and out of those, a great majority were satisfied with their care.  No one in the population indicated being treated unfairly due to their race (racial discrimination). Two core question related to perceived stress were queried and indicated that women have a sense of control over important aspects of their life and the ability to handle important life issues.

Table 3. Beginning of Day Responses

Survey Question

Estimate

Did you have trouble falling asleep last night? (yes)

71.9%

How many hours of sleep did you get?

7.0

Rate how well you slept last night (0=poor, 4=excellent)

                         0

7%

                         1

19%

                         2

34%

                         3

31%

                         4

9%

Do you feel nauseous or ill? (yes)

16%

Please rate your level of hunger (0=not hungry, 4=very hungry)

                        0

16%

                        1

30%

                        2

27%

                        3

15%

                        4

12%

Have you had anything to eat or drink this morning? (yes)

62%

Did you eat overnight or late at night after dinner? (yes)

31%

How are you feeling?  (check any that apply)

Selected items

Tired: 88%

Happy: 29%

Content: 40%

Table 4. End of Day Responses

Survey Question

Estimate

Were you able to eat today? (yes) a 

99%

(if yes) How many meals and snacks did you eat today?

3.8

(if yes) Did you eat anything before 12 noon? (yes)

62%

(if yes) Did any pain, fatigue, or other symptoms of pregnancy affect how you ate today?

16

(if yes) Did you change what you ate today because of concern about weight gain? b

7%

Did you take a pre-natal vitamin today? (yes)

73%

Were you physically active today? (yes)

55%

How many hours did you spend sitting today? c

5.7

Did you sleep or rest during the day today? (yes)

32%

(if yes) How many hours?

2.6

a. Only two records where a subject reported not eating for the day
b. Only 4 participants changed eating due to concerns about weight gain
c. 65% spent 5 or more hours sitting

Table 5. Random Survey Responses

Survey Question

Estimate

How many weeks pregnant are you?

28.1

In the past week, have you seen a doctor, nurse or other healthcare worker for this pregnancy? (yes)

41%

(If yes) How satisfied were you with the care you received (on a scale of 1–5, with 5 being most satisfied and 1 being least satisfied)?

                  1

3%

                  2

11%

                  3

13%

                  4

15%

                  5

58%

(If yes) Please select the topics you discussed (check all that apply)

Top topics:

Weight gain: 73%

Gestational diabetes: 37%

Medicines: 37%

Preterm labor signs: 34%

Breastfeeding: 24%

In the past week, how often have you felt like you were unable to control the important things in your life? 0=never; 1=almost never; 2=sometimes; 3=fairly often; 4=very often

                          0

41%

                          1

27%

                          2

18%

                          3

12%

                          4

2%

In the past week, how often have you felt confident about your ability to handle your personal problems? 0=never; 1=almost never; 2=sometimes; 3=fairly often; 4=very often

                          0

9%

                          1

3%

                          2

20%

                          3

27%

                          4

41%

Based on some results from the exit interview, we identified several ways in which we could tailor a future protocol and learned of participants’ perceptions of using mobile technology in order to assess pregnancy health and well-being in real time. A few key themes emerged: participants discussed dividing questions about food intake by meals and snacks rather than one question on meals; tailoring questions related to physical activity  and amount of sitting each day; eliminating the feature to upload pictures of participants food and restaurant receipts as many participants did not collect paper receipts. We also asked women during the exit interview about the potential burden of receiving EMA prompts at least 4 times per week, and no participant cited this as a major burden or deterrent from participating. The majority of participants also said they would have been willing to completed surveys for longer than four weeks. Further analyses from these exit interviews will be useful in continuing to tailor protocols for EMA data collection among pregnant women.

Discussion

PreEMA is an approach to advancing EMA data collection during pregnancy with the goal of understanding some of the dynamic processes women undergo extending beyond the physiological changes typically assessed in biomedical research. The innovative approaches employed in PregEMA allows us to understand women’s pregnancies in real-time and in women’s natural environments.  This is the first study of our knowledge that incorporates real-time measurements of behavioral, psychosocial, and environmental factors and processes during pregnancy and over a 4-week period.

The measures collected in this study allows us to apply multi-level frameworks to complex processes by integrating individual and environmental level data. The psychosocial measures of mood, stress, and discrimination have been collected in previous EMA studies, including assessment of diurnal patterns of salivary alpha amylase in pregnant women via PDA prompts for women to collect their own saliva samples while also completing mood assessments using paper and pencil methods [17]. However, no studies of our knowledge collect EMA data of stress as well as mood and experiences of discrimination via mobile technology and beyond the short 1 week intervals that are typical of EMA studies. Additionally, the collection of women’s location via the GPS capabilities embedded in the smartphone allowed for the implementation of geographical momentary assessment to understand location in tandem with participants’ reports of their environments. These location measurements present an opportunity to uncover patterns of mobility among pregnant women over an extended period of time and implementation of geospatial analyses that can aid in identifying clustering and patterning of health risks and behaviors in space and time.

There are some limitations in EMA data collection that are not characteristic just to this study. Although EMA methods allow for data collection in real time, repeat, intensive measurement can be burdensome over long periods of time. EMA helps to minimize recall bias, particularly among items that are dynamic and change within shorter intervals. However, the items from longer, validated scales have not been necessarily validated for EMA data collection nor designed to capture micro-processes. The technology developed for this pilot study is similar to other applications outside of EMA data collection. However, there is a challenge of developing an application that may not be transferable across operating systems. In order to address this, our pilot included a web-based application that required the participant to be connected to Wi-Fi either directly or through their data plan. This sometimes posed as a challenge for participants who did not always  have a data plan or who could not connect to Wi-Fi. A future protocol should include a phone-based and web-based component that allows the participant to complete EMA prompts when they are not connected to Wi-Fi or a data plan but then automatically uploads data whenever connected.

This pilot has also informed future research for a larger EMA cohort as well as continuation of EMA data collection to understand real-time micro-processes during the postpartum period, a time when mothers are going through tremendous changes, including taking on new maternal roles. The results of this pilot will aid in providing new research questions and hypotheses related to the multiple pathways between context and health among childbearing women to develop future interventions, programs and policies. Furthermore, the use of mobile technology to assess women’s health in real-time during pregnancy can directly inform a future intervention designed to address the multiple demands and challenges women face during pregnancy and beyond. Future work using mobile technology should apply person-centered design coupled with supportive services in real time and when necessary (just-in-time interventions) as well as support current modes of clinical and social service care for women and their children.

Acknowledgement

We would like to thank the women who agreed to participate in the pilot study. We would also like to thank the staff and co-investigators of the GDM2 Trial, including Dr. Esa Davis (PI). We would like to thank the PregEMA pilot study staff and students; including the recruitment and retention team, Jessica Duell and Rashaa Brown; and the technology team Er Wang and Dr. Hassan Karimi. We would also like to thank Dr. Lora Burke for her guidance in developing the protocols for the EMA mobile application and using her EMPOWER study as a prototype. Finally, this pilot study was made possible in part from funding from the Academy Health/Aetna Foundation Scholars-in-Residence Fellowship. The PI, Dr. Dara Mendez was funded by a Diversity Supplement NIH/NHLBI R01HL107370-S1 (Mendez/Burke) while she was conducting this pilot study. This pilot study led to the development of the NIH/NHLBI funded Postpartum Mobile Mothers Study (PMOMS).

References

  1. Shiffman S, Stone AA, Hufford MR (2008) Ecological momentary assessment. Annu Rev Clin Psychol 4: 1–32. [crossref]
  2. Shiffman S, Gwaltney CJ, Balabanis MH, Liu KS, Paty JA, et al. (2002) Immediate antecedents of cigarette smoking: an analysis from ecological momentary assessment. J Abnorm Psychol 111: 531–545. [crossref]
  3. Hufford MR, Shields AL, Shiffman S, Paty J, Balabanis M (2002) Reactivity to ecological momentary assessment: an example using undergraduate problem drinkers. Psychol Addict Behav 16: 205–211. [crossref]
  4. Engel SG, Kahler KA, Lystad CM, Crosby RD, Simonich HK, et al. (2009) Eating behavior in obese BED, obese non-BED, and non-obese control participants: a naturalistic study. Behav Res Ther 47: 897–900. [crossref]
  5. Kamarck TW, Shiffman SM, Smithline L, Goodie JL, Paty JA, et al. (1998) Effects of task strain, social conflict, and emotional activation on ambulatory cardiovascular activity: daily life consequences of recurring stress in a multiethnic adult sample. Health Psychol 17: 17–29. [crossref]
  6. Spicer J, Werner E, Zhao Y, Choi CW, Lopez-Pintado S, et al. (2013) Ambulatory assessments of psychological and peripheral stress-markers predict birth outcomes in teen pregnancy. J Psychosom Res 75: 305–313. [crossref]
  7. Entringer, S, Buss C, Andersen J, Chicz-DeMet A, Wadhwa PD (2011) Ecological Momentary Assessment of Maternal Cortisol Profiles Over a Multiple-Day Period Predicts the Length of Human Gestation. Psychosomatic Medicine 73: 469–474. [crossref]
  8. Giesbrecht GF, Poole JC, Letourneau N, Campbell T, Kaplan BJ, et al. (2013) The Buffering Effect of Social Support on Hypothalamic-Pituitary-Adrenal Axis Function During Pregnancy. Psychosomatic Medicine 75: 856–862. [crossref]
  9. Newham JJ, Martin CR (2013) Measuring fluctuations in maternal well-being and mood across pregnancy. Journal of Reproductive and Infant Psychology 31: 531–540.
  10. Epstein DH, Tyburski M, Craig IM, Phillips KA, Jobes ML, et al., (2014) Real-time tracking of neighborhood surroundings and mood in urban drug misusers: application of a new method to study behavior in its geographical context. Drug Alcohol Depend 134: 22–29. [crossref]
  11. Pew (2013) Internet and American Life Project.
  12. Abebe KZ, Scifres C, Simhan HN, Day N, Catalano P, et al. (2017) Comparison of Two Screening Strategies for Gestational Diabetes (GDM(2)) Trial: Design and rationale. Contemp Clin Trials 62: 43–49. [crossref]
  13. Scifres, C.M., et al., (2015) Gestational diabetes diagnostic methods (GD2M) pilot randomized trial. Matern Child Health J 19: 1472–1480. [crossref]
  14. Cohen S, Kamarck T, Mermelstein R (1983) A global measure of perceived stress. J Health Soc Behav 24: 385–396. [crossref]
  15. Burke LE, Shiffman S, Music E, Styn MA, Kriska A, et al. (2017) Ecological Momentary Assessment in Behavioral Research: Addressing Technological and Human Participant Challenges. J Med Internet Res 19: 77. [crossref]
  16. Williams DR, Yan Yu, Jackson JS, Anderson NB (1997) Racial Differences in Physical and Mental Health: Socio-economic Status, Stress and Discrimination. J Health Psychol 2: 335–351. [crossref]
  17. Giesbrecht GF, Campbell T, Letourneau N, Kooistra L, Kaplan B, et al. (2012) Psychological distress and salivary cortisol covary within persons during pregnancy. Psychoneuroendocrinology 37: 270–279. [crossref]

Gene Machine: The Race to Decipher the Secrets of the Ribosome by Venki Ramakrishnan, Basic Books, 2018

DOI: 10.31038/JMG.2019212

Book Review

When I was a Yale Graduate student in the Department of Molecular Biophysics and Biochemistry, from 1972 to 1978, there were several notable scientists in the department including Joan Steitz, her husband Tom Steitz, Don Engelman, Peter Moore, and Sidney Altman. In 1978, just as I received my Ph.D. from Yale, a new postdoctoral student named Venki Ramakrishnan was starting work in Peter Moore’s lab. Joan Steitz was studying ribosomal RNA binding sequences. Tom Steitz was using X-ray crystallography to study the three dimensional structure of large proteins like hexokinase. Don Engelman and Peter Moore were using neutron diffraction to study distances between deuterated pairs of ribosomal proteins. Sidney Altman was investigating the chemical properties of tRNAs. Venki Ramakrishnan’s work with Peter Moore on the ribosome would, three decades later, lead to a path of Ramakrishnan winning the Nobel Prize in Chemistry, along with Tom Steitz and Ada Yonath.

Finding Ramakrishnan’s book for sale at Barnes & Noble, and knowing some of the principals involved in this story, I had to read it. It is a beautifully written, riveting book. In some ways, Gene Machine bears similarities to another seminal scientific memoir The Double Helix written by James Watson, describing his race with his partner Francis Crick to decipher the secrets of DNA. In other ways, Ramakrhishnan’s narrative is different.

As related by the author in his book, Ramakrishnan received his undergraduate degree from Baroda College in India and his Ph.D. from the University of Ohio. After his post doc in Moore’s lab, Ramakrishnan landed his first independent job as a biophysicist at Brookhaven National Laboratory in 1983. In 1988, to learn X-ray crystallography, he took a two-week course in the subject at Cold spring Harbor Laboratory. In 1989, to learn more about crystallography, Ramakrishnan took a sabbatical year at, and several years later, took a staff position in the famous MRC Laboratory of Molecular Biology (LMB), where Watson and Crick had deduced the structure of DNA after Watson had looked at her Rosalind Franklin’s X-ray photographs of DNA, and for which Watson and Crick won a Nobel Prize shared with Franklin’s supervisor Maurice Wilkins in 1962. Sadly, Franklin died before that Nobel Prize was given.

In the early 1980s, Sidney Altman and Tom Cech discovered that RNA can catalyze chemical reactions much like protein enzymes, for which they won a Nobel Prize. Such RNA catalysts are called ribozymes and led to the speculation that life on earth originated in a RNA World where the first catalysts were ribozymes instead of proteinacious enzymes

Also, in the 1980s, Harry Noller at the University of California, Santa Cruz, was noticing that the ability of the ribosome to translate the genetic code written in messenger RNA into proteins seemed to be largely resistant to enzymes that cut up the ribosomal proteins, implying that ribosomal synthesis of protein from amino acids was catalyzed by ribozymes within the ribosome rather than ribosomal proteins. It was also around this time that Ada Yonath, of the Weizmann Institute in Israel, demonstrated that it was possible to obtain crystals of the ribosome which produced X-ray diffraction patterns. From these it would be theoretically be possible to determine the precise three dimensional map of the structure of the ribosome to atomic scale precision.

Finally, in this period, Tom Steitz and Peter Moore teamed up to begin studying the three dimensional structure of the ribosome by X-ray crystallography.

Thus, at the end of the millennium, the stage was set for race to discover the complete three dimensional structure of the ribosome, the organelle inside the biological cell that translates the genetic code into proteins that form the structures and enzymes of each cell. As Ramakrishnan’s scintillating narrative shows, this race was not going to be easy. In fact, all of the groups of researchers studying the structure and chemistry of the ribosome employed many grad students, post docs, and collaborators with enormous talents and skills in biomolecular analysis. The human character and brilliant contributions of these diverse molecular biologists are told with a considerable charm by Ramakrishnan in his book. Ramakrishnan is excellent at giving credit where credit is due, something which does not always happen in the modern competitive scientific world. It is very nice to see it here.

Not that there was any lack of tension in the race to the ribosome structure. Each of these researchers was working full speed in the hope of scooping the opposition. In the way that things worked out, the Steitz & Moore group concentrated on deciphering the structure of the 50S subunit of the ribosome, Ramakrishnan’s group concentrated on the structure of the 30S subunit, while Noller’s group and Yonath’s groups concentrated, by differing methods, on the whole 70S ribosome. All of these people who worked on the ribosome were friends and knew each other and met regularly to talk and compare notes at various conferences. Throughout his book, Ramakrishnan describes the honorable illuminating competition that goes on in science everyday and that is the glory of this subject. By the end of the millennium the thrilling race told by Ramakrishnan was essentially over, and the different research groups displayed their results in a really beautiful Volume LXVI of the Cold Spring Harbor Symposium in 2001.

The ribosome is one of the most complicated cell organelles ever studied. It is a monstrously complex concatenation of RNA and protein, having a diameter of approximately 200 Angstroms and a total molecular weight of about 3 million Daltons. It is comprised of 80 ribosomal proteins, making up 35% of its weight and 4 large ribosomal RNAs (rRNAs), making up 65% of its weight. A picture of the ribosome at atomic scale, shown on the cover of Ramakrishnan’s book, looks like an extremely complicated tangle of spaghetti. Most of the proteins are on the surface of the ribosome. Most of the interior is comprised of RNA. Thus, the synthesis of most proteins that goes on in cells is catalyzed by ribozymes, not enzymes. In this regard, the RNA World currently lives on in every biological cell on Earth.

As is often the case, the Nobel Committee in Sweden took several more years, until 2009 to award the Nobel Prize in Chemistry to Tom Steitz, Venki Ramakrishnan, and Ada Yonath. The rules of the Nobel Foundation limit the prize to three recipients. If there were no such limitation, then Peter Moore and Harry Noller would undoubtedly also have also shared in the Nobel Prize. While appreciating the great honor given to him by his peers, Ramakrishnan takes distinctly philosophical point of view by pointing out that winning a Nobel Prize in science is largely a matter of luck and of being in the right place at the right time. He also points out that many prestigious science prizes now bestow much more money than the Nobel Prize. Still, I have to give Ramakrishnan much credit for writing a book that is as riveting as The Double Helix but told with a natural grace and honesty that is lacking in Watson’s triumphal memoir.

 Strangely enough, the classical era of X-ray crystallography in molecular biology that began with Watson and Crick’s use of Rosalind Franklin’s X-ray photographs of DNA in 1953 and ended with Ramakrishnan’s X-ray photographs of the ribosome half a century later may finally be over. In 2015, I attended the 5th Zing Nucleic Acids conference in Tampa, Florida. I was amazed to see that on the slides of most presenters that the backgrounds of the nucleic acids shown always showed the immediate protein surroundings of the nucleic acids to atomic level resolution. Several scientists told me that such atomic scale resolutions of proteins (and nucleic acids) were now seen with atomic electron microscopes on single molecules without the need for crystals or X-rays. Biomolecular structures that used to take years by X-ray crystallography are now routinely being solved in weeks. In this sense, with the new millennium, molecular biology has entered a brand new era in which molecular biologists struggle to decipher the exceedingly intricate mechanism by which such complicated biomolecular machines as the ribosome operate.

I have just one complaint about Gene Machine. It lacks an index. Hopefully this will be added in future editions. Otherwise, it is a very fine book, well worth reading.

Understanding the Macroscopy of Malignant Lesions of the Female Internal Genital Tract

DOI: 10.31038/IGOJ.2019214

Abstract

Communication and agreement between pathologists and gynecologists and oncologists and others experts is important for a good understanding of patient management and further diagnostic decision and complementary surgical conduct. On some occasions, there may be doubts about reports or even diagnoses from a transoperative examination. Hence, we deem an interdisciplinary action to be important, where we can explain the diagnostic procedures of pathology in order to elucidate doubts and review basic principles of the macroscopy of genital folds. We describe step by step, in an uncomplicated way, the macroscopic examination of the female internal genital tract.

Keywords

Macroscopy, Female Internal Genital Tract, Neoplasms

Introduction

With previous diagnosis of neoplasms the uterine body (adenocarcinoma) or uterine cervix (epidermoid carcinoma), ovaries, uterine tubes and vagina are examined by pathologists is of fundamental importance to the prognostic assessment and therapy.

Many gynecologists, oncologists, radiotherapists and other specialist have doubts about the data described in an anatomopathological report. Therefore, we listed a few steps in the macroscopy routine of a pathological anatomy laboratory in an attempt to explain the data supplied in the reports.

Hysterectomy

The first step in the macroscopic examination of a hysterectomy is the opening of the uterus for fixation, with the introduction of a probe, The weight of the organ without the adnexa, which should be assessed separately; the measurements of the uterus, such as height (from the bottom to the cervix) and latero-lateral and antero-posterior diameter; and measurements of the cervix (height, diameter of the cervix and diameter of the external (orifice) are checked. The thickness of the myometrium, endometrium and endocervix are also checked. If the piece presents a vaginal border, the height of the vaginal component should be measured and the posterior columns identified [1–3]. (Figure 1)

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Figure 1.

A fundamental step is the examination of visualized lesions, detailing number, measurements (three dimensions in the neoplasm), outline, consistence, and color, relationship with adjacent and measured structures. Exception situations for exams of hysterectomies are represented by uteruses sent lacerated and fragmented in more than portions. The portions will be heavy in set; and measurements will be performed on the largest and smallest portions in the three dimensions. However, the approach to the neoplasm is impaired, especially with respect to the resection margins. The pathologist can make this reference in the final report, justifying, like this, the impossibility assessing the margins of surgical resection.

Endometrial Adenocarcinoma

Endometrial cancer is biologically and histologically diverse, being divided in two types: low-grade estrogen-dependent (well or moderately differentiated); frequently associated toendometrial hyperplasia; and type II which occurs more frequently after menopause has a high histological grade, as the serous carcinoma and clear cell carcinoma subtypes [3-5].

Usually, adenocarcinomas are located in the high and medium body. In some cases, they originate in the lowest segment of the uterine body. Often, in the macroscopic examination, they are dominant masses. They can be diffuse and superficial in the endometrial cavity. Many times, they extend to the internal or external half of the myometrium or to the serosa. It is important to assess the extension to the endocervical cavity and establish whether it is superficial or deep in the stroma [3, 5].

Therefore, specimens of the tumor with myometrium and painted serosa, the endometrium endocervical canal transition (isthmus) and the endocervix are collected for histology [1, 3]. (Figure 2)

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Figure 2.

Each selected slice will be embedded in blocks, producing slides for microscopy and the final report in agreement with the macroscopic examination approach, describing the type endometrial lesion, its location: body, bottom, isthmus, penetrating the endocervical canal. The measurements of the neoplasm are taken in the three dimensions. The depth of the invasion in the myometrium and serosa is assessed, as well as the invasion of the isthmus, endocervical canal and ectocervix [1, 2].

This sampling procedure is important for the anatomopathological staging of type I and II adenocarcinomas and malignant mixed Mullerian tumors [5].

In possession of these data, a surgeon will be allowed to define survival and complementary therapies.

Invasive carcinoma of the cervix

The invasive carcinoma of the cervix can be, predominantly, vegetating or exophytic, papillary, polypoid or endophytic. When the neoplasm surrounds the cervix of the uterus and penetrates the underlying stroma, it produces a barrel shaped cervix, which can be identified by direct palpation. It may reach parametric soft tissues. In advanced stages, it extendsby directly spreading to contiguous tissues, such as the bladder, ureters, and vagina [3-5].

Therefore, in hysterectomies due to invasive carcinoma of cervix, we proceed by defining the lips and quadrants of the cervix that are involved by the neoplasm and the type of lesion (ulcerated, vegetating, infiltrating). The measurements of the lesion includediameter, extension towards the endocervical canal and lesion in the stroma. The invasion of the endocervix and right and left parametria, as well as the invasion of the endometrial cavity and vaginal cuff when present, should be described [1, 2].

The following specimens are collected for histology: lesion (both lips) with ectocervix or vaginal cuff painted withink; tumor and endocervix; assessing the thickness of the lesion; right and left parametria painted with ink, endocervix, endometrium transition, myometrium and other secondary lesions that may be found in the uterine body [1, 2, 3]. (Figures 3 and 4)

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Figure 3.

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Figure 4.

Uterine Cervix X conization

Cone macroscopy: for a satisfactory final result, it is recommended that the surgeon use a repair (12 hours) site to position the piece (cone). A good understanding between pathologist and surgeon is necessary. The surgical ectocervical and endocervical margins are painted with ink and fixed with acetic acid. The piece will be opened during the repair, when present or randomly.

The best way to fix the material is to stretch it out on cork or styrofoam, using pins to secure it, favoring thus its fixation without retraction and with a better sample of the squamocolumnar junction section [2].

The macroscop ic examination begins by measuring the height and diameter of the cervix (amputation or cone). The ectocervical surface is evaluated for the presence of rosy, ulcerated areas, with vegetations, light brown areas of leukoplasia, and the measurements of these and the determination of the quadrant in which they are located should be reported, as well as the distance of the endocervical and ectocervical margins [1, 2, 5, 6].

If the cone is higher than 2, 0cm, it is possible to cut the endocervical margin and include it separately. On the other hand, when irregular and short slices are cut without separating the two margins, with the first, second, third and fourth quadrants being initially cut [1, 2].

The conization specimen should be included altogether, in radial (pizza) sections.1 Another option for cutting the cone is in parallel sections: cuts are performed in the anteroposterior direction. This type of cut is more difficult to be done when the cone cannot be previously stretched out and is already fixed [1].

Generalities of macroscopy of the uterine tubes

Neoplasms are rare, but we cannot forget them during the macroscopic examination. The carcinoma of the tubes usually occurs in their ampulla or fimbriae, the right tube being more affected than the left one. Macroscopically, in the lesion area, the tube is round, of showing a fusiform or hotdog shape. The surface is reddened, lumpy, with necrosis and blood content, or a raspberry color. The fimbriae can be closed, if the neoplasm spreads, the ovary and the uterus can be adhered, forming a mass. Cutting sections from the lesion (surface painted with ink) area, from the three portions of the tube, including the uterine ostium, is crucial. The full inclusion of the fimbriae is recommended. The tubal canal should be resected from the isthmus to the ostium.

Ovaries

Macroscopy of the Ovaries

In the macroscopy of the ovary, the presence of cystic, solid or solid-cystic lesions should be established. The first step consists of weighing the piece before opening it and measuring its three dimensions (including thickness and diameter) [1, 2].

 Subsequently, the configuration of the ovaries is observed, and the tunica albuginea is assessed. This can be complete, or lacerated, showing vegetations and nodules. The surface can be flat, bossy, light brown, dark brown, hemorrhagic and translucent.

Ovaries with abscesses or torsion show a dark brown external hemorragic surface with necrosis foci and fibrin deposits. Tumoral ovaries with laceration show whitish tumor areas in the tunica albuginea. Endometriosis foci (with a hemorrhagic or cystic aspect) can be present.

When the ovary presents a solid lesion or an area of adherence to the uterine serosa, this transition area should be evaluated histologically to discard invasion of the uterus (serosa, myometrium).

The opening of the ovary should start from the free margin towards the hilum (largest diameter). The evaluation of the internal surface is an important stage, where we needed to describe: cystic lesions and type of content (serous, mucinous, chocolate, and hemorrhagic) [2]. If there is more than one cavity, the diameter of the largest cavity, specimen collection: it should be 1 section from the largest dimension of the tumor. A whole slice can be achieved along the larger axis and included in its entirety, the transition area between the ovary and the tube should be included [1-3]. (Figure 5)

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Figure 5.

In the intraoperative examination: weigh, measure, open and empty the cyst(s). Assess the content of the cysts and the internal surface. Sample solid areas, when presents and cut the material in the cryostat to prepare a slide. In mucinous tumors, the surgeon should always be alerted about the possibility of finding a neoplasm in the subsequent examination in paraffin. The imprint exam can be used.

Generalities of the macroscopy of the ovaries

Ovarian teratomas-presence of hair, cartilage, fatty tissue, teeth, pasty and yellowish contents. The wall is fibrous, The collection of specimens should be satisfactory and comprehensive due to the possibility of detecting an immature component.

Mucinous cysts multilocular, bulky cystic masses, with gelatinous content. Malignant forms present solid areas, necrosis and nodules in the capsule.

Unilocular or multilocular serous cysts: the internal surface is flat and the content is serous. Malignant forms contain internal or external whitish papillary outgrowths, with necrosis areas and hemorrhage. The wall thickness is irregular, containing solid areas. Firm whitish nodules can be observed in the capsule.

Cystoadenofibroma-tumors with a cystic internal surface and usually serous content. The internal surface shows light brown papillary outgrowths.

Macroscopy of the Vagina

The primary carcinoma of the vagina is rare. More frequently, we find in macroscopy lesions due to invasion of uterine cervix tumors, or relapses of uterine cervix tumors as yolk sac tumors; or also red nodular lesions that correspond to pyogenic granulomas, or papillomatous lesions of viral origin [3-5]

Resection specimens can be sent and, therefore, we should paint the section (opposed to the mucous membrane) surface with ink. If the piece is marked with a suture by the surgeon, demarcating its margins, its sections should be individualized, included in cassettes separately and identified.

Conclusion

People have been increasingly talking about interdisciplinary and multidisciplinary. Teamwork and good communication are key points for patient management. The surgeon, gynecologist, pathologist, oncologist, radiotherapists and depending on the type of neoplasm, other specialists, such as nutritionists, speech therapists, physiotherapists, nurses, psychologists, among others, meet the full set of requirements for a good performance and maintenance of the quality of life of cancer patients.

In this sense, we deemed important to describe the macroscopic examination of the female internal genital system so that the final report can be better understood by readers. All microscopy items refer to the slides prepared in agreement with the findings of the macroscopic examination, and staging will depend on these procedures.

References

  1. Bacchi CE, Mello Cra, Franco M, Neto RA (Ed.)manual de padronização de laudos Histopatológicos. Sociedade Brasileira de Patologia, 4 ed. Editora Manole Ltda, são Paulo.
  2. Becker, P. Manual de patologia cirúrgica. Guanabara Koogan, Rio de Janeiro, 1977.
  3. Rosai, J. Ackermans Surgical Pathology, 10th ed. Mosby, St. Louis, 2011.
  4. Fletcher CD. Diagnostic Histopathology of Tumors. Churchill Livingstone, London, 2007.
  5. Kumar, Vinay;ABBAS, Abulk.;Aster, Jon C.Robbins Patologia Básica.9ed.Rio de Janeiro:Elsevier, 2013.910p.Tradução de Robbins basic Pathology.ISBN 9788535262940
  6. Sobotta, Atlas de Anatomia Humana. Vol. 1 e 2. 22ª Ed. Rio de Janeiro. Guanabara Koogan, 2002.

The Reg`Activ Cholesterol Positive Effects in Asymptomatic Volunteers with Borderline Values of Cardio-Metabolic Risk Factors are Sustainable in Long-Term Run

DOI: 10.31038/EDMJ.2019324

Abstract

Previous part of clinical trial (ISRCTN55339917) highlighted several beneficial effects of RAC (Reg’ Activ Cholesterol™) comprising also antioxidative and antiatherogenic probiotic Lactobacillus fermentum ME-3[1]. Cardiovascular diseases are number one cause of death globally. Beneficial modifying of the cardio-metabolic profile has major impact for long-term success. Our previous open-label pilot study showed a complex positive influence of a food supplement Reg’Activ Cholesterol (RAC) on Cardio-Metabolic Parameters (CMP).

To test in very long-term run both sustainability of these effects and safety of RAC we now aimed to investigate RAC effects during 3 years. Main randomizing sign was prediabetic level of glycated haemoglobin (HbA1c between 5.7–6.4%) in clinically asymptomatic volunteers who had elevated level of low density lipoprotein cholesterol (LDL-chl) and oxidized LDL (oxLDL).

The level of Cholesterol, LDL-cholesterol and oxLDL and HbA1c% decreased significantly and HDL-cholesterol increased significantly.

RAC has shown a complex positive effect on cardiovascular risk profile. Still investigations are needed to evaluate its long-term effects on clinical outcomes. Trial registration: ISRCTN55339917 http://www.isrctn.com/ISRCTN55339917

Keywords

Reg’ Activ Cholesterol™, Lactobacillus fermentum ME-3, pre-diabetes, nutriceuticals

Introduction

The study presented here is a sub study from a larger set of investigations to evaluate the effect of a food supplement Reg’Activ Cholesterol (RAC) produced by VF Bioscience Company to cardio-metabolic risk profile. Our previous open-label pilot study [1] showed a complex positive influence of RAC on Cardio-Metabolic Parameters (CMP). Cardiovascular Diseases (CVD) and its complications still hold primacy of health care for societies despite decades of investigations, guidelines of primary and secondary prevention and a long list of medicines used to fight them. Managing atherosclerosis, the patho-physiological process underlying CVD, still needs a lot of improvement starting from finding a good set of diagnostic markers until blocking the process that culminates in total vascular obstruction. For decades we have known that dyslipidemia and especially an elevated LDL-cholesterol are linked to the pathogenesis of CVD. The acknowledgement of the role of LDL oxidation, tightly associated with inflammation,   is not new either [2]. Diabetes often co-exists with CVD and if present it complicates the course of CVD. The pathophysiological phenomena oxidative stress (OxS), chronic inflammation and glycation cause cardio-metabolic changes that are common in the development of metabolic syndrome, diabetes and CVD [3].The ATTICA study showed that a permanent low-grade/ high-normal inflammation (LGI) and an advanced glycation both may enhance the development of CVD thus linking LGI and diabetes  [4].  It is accepted that the ratio of blood triglycerides to HDL cholesterol (HDL-cholesterol) (TG/HDL-cholesterol) describes the insulin receptor resistance [5]. A possible role of a poor or unbalanced intestinal microbiota in atherosclerosis pathogenesis has also been described [6].  Thus interventions that favorably modify the cardio-metabolic profile may find a place in a comprehensive long-term strategy both in CVD and prediabetes /diabetes management.

RAC is a complex designed of components that theoretically could positively affect OxS and LDL oxidation and/or glycation and/or other CMP and inflammatory markers.

The components of RAC are:  red yeast rice, ubiquinol, vitamin E, vitamins B6, B9, B12 and Lactobacillus fermentum ME-3[1].

Lactobacillus fermentum ME-3 (DSM 14241) (LFME-3), a component in RAC     is a strain isolated from a healthy 1-year old child [7]. The strain has both antimicrobial and antioxidative functional properties [8–10]. Several clinical studies [11–14] have shown health benefits of fermented products containing LFME-3. Our previous open-label pilot study [1] showed a complex positive influence of a new innovative food supplement RAC on CMP.

The aim of the study was to find out if a compiled probiotic containing formula RAC (VF Bioscience) could have a clinically significant positive effect on cardiovascular disease risk factor profiles in clinically asymptomatic volunteers with borderline-high values of CMPs (alike) (primary targets were LDL-cholesterol, oxLDL and HbA1c%). Thus, targeted supplemental intervention that favorably modifies the cardio-metabolic profile may have impact for adjuvant long-term strategy both in CVD and pre-diabetes/diabetes management.

Patients and Methods

After finishing the first phase of clinical trial (ISRCTN55339917) [1] five clinically healthy volunteers with borderline values of risk factors for CVD and pre-diabetes sign were asked to continue this open label trial for 3 years, from May 2014 to May 2017. The inclusion criteria were age 50–75 years, BMI 24–30, being clinically healthy (asymptomatic). The exclusion criteria were the following: a history of gastrointestinal disease, diabetes, food allergy, use of any antimicrobial agent or probiotics or an acute infection within the preceding 2 months; use of any regular concomitant medication including any non-steroidal anti-inflammatory drugs and antioxidant products or probiotics within at least the preceding 2 weeks; pregnancy or breastfeeding; any serious organ or systemic disease, eating disorder, extensive exercise, genetic hyperlipidemia, drug or alcohol abuse, smoking, active weight loss > 5 kg in prior 3 months; participation in other studies within the last 30 days/ during the study and no wish to participate. The blood samples were collected at Tartu University Clinics.

From all the inclusion criteria we primarily targeted on the possible influence of RAC on blood sugar metabolism (HbA1c %) and thus it was needed to keep this parameter equal in groups at the beginning of the study. After establishing that the inclusion/exclusion criteria were fulfilled the HbA1c was measured (2 weeks before the actual intervention/test period started) and the five participants with pre-diabetes diagnostic criteria HbA1c value 5.7–6.4 were included into the study. According to literature, the screening to detect pre-diabetes and diabetes enables early prevention and intervention in asymptomatic, undiagnosed adults in the USA who could be detected with pre-diabetes using the ADA guidelines. HbA1c% is accepted as a good predictor for developing diabetes and according to the guidelines diabetes was defined as HbA1c% ≥6.5 and pre-diabetes was defined as HbA1c% ≥5.7 [15].The participants (5 persons) were asked not to change diet habits during the investigation period (it was also checked repeatedly) and continue the previous study protocol[1]for 3 years. This study was carried out in accordance with the Declaration of Helsinki of the World Medical Association.

Innovative RAC [1] has been designed to promote cardio-metabolic health (Table 1). This formulation combines pleiotropic Lactobacillus fermentum ME-3 (LFME3, deposited in the Deutsche Sammlung von Mikroorganismen und Zellkulturen, GMBH; the registration number DSM 14241) with other functional ingredients that have been used in food supplements due to different protective cardio-metabolic effects [16].

Table 1. The composition of the RAC capsule

Ingredients

Quantity per recommended daily dose (2 capsules)

% of RDA

Red Yeast rice

666mg

(10 mg monacolin K)

Lactobacillus fermentum ME-3

60 mg

(equals 6 × 109 LAB)

Ubiquinol (Kaneka QHTM)

30 mg

L-cysteine

30 mg

Vitamin E

10 mg

83%

Vitamin B1

0.66 mg

60%

Vitamin B6

1 mg

72%

Vitamin B9

100 µg

50%

Vitamin B12

1.5 µg

60%

Other ingredients: maltodextrin (filling agent), magnesium salts of fatty acids (anti-caking agent), silica dioxide (anti-aggregating agent), vegetable capsule (hydroxyl-propyl-methyl-cellulose), soy lecithin

To measure oxLDL the immunoassay ELISA kit (Mercodia AB, Uppsala, Sweden) was used. Analyses of metabolic indices (plasma glucose and lipids: total cholesterol Tcholesterol, LDL-cholesterol, HDL-cholesterol, TG), HbA1c and homocysteine (Hcy) were performed with standard laboratory methods using certified assays in the United Laboratories of the Tartu University Hospital, Estonia. Intervals for routine laboratory tests proposed by the Nordic Reference Interval Project [17] were used as references.

Statistical Analysis

Calculations were performed using commercially available statistical software packages (Statistics for Windows and Graph Pad PRISM Version 2.0). All values are given as mean and standard deviation (mean  ±  SD). Statistically significant differences between the different values of each asymptomatic patient during the period of 3 years of consumption of LFME-3 containing capsules were determined by using Student’s t-test. In all analyses, p-values < 0.05 were considered to be statistically significant.

Results

During consumption of RAC capsules for 3 years (two capsules per day) participants did not have any complaints and had statistically significant positive cardio-metabolic shifts (Table 2). The most impressive change appeared in the decrease of LDL-chlesterol level. HbA1c, oxLDL, TG/HDL-chlesterol ratio and Hcy also declined significantly whereas HDL-chlesterol level increased. Administration of LFME-3 containing RAC leads to significant decline of the level of HbA1c% after 3 year consumption (Table 2). The use of RAC also declined the insulin resistance marker the TG/HDL-chlesterol ratio (Table 2) which correlates inversely with the plasma level of small dense LDL particles. The ratio TG/HDL-chlesterol shows promise as an index of the atherogenic properties of the plasma lipid profile and reflects the INS resistance (Table 2) [5, 16].

Table 2. Markers for cholesterol fractions, triglycerides, prediabetes, inflammation, oxLDL at 0 week (baseline) and after consumption of probiotic LFME-3 containing RAC (2 capsules/per day, 3 years)

Baseline values

12 months

24 months

36 months

HbA1c%

6.27 ± 0.09

5.81 ± 0.17

5.75 ± 0.10
p=0.0001

5.68 ± 0.08
p*=0.0025

Cholesterol mmol/l

6.86 ± 0.09

6.16 ± 1.07

5.68 ± 1.02
p=0,0009

5.8 ± 1.17
p*=0.0029

LDL-cholesterol mmol/l

4.97 ± 0.86

4.22 ± 0.93
p=0.006

3.98 ± 0.088
p=0.003

4.21 ± 1.09
p*=0.0054

HDL-cholesterol mmol/l

1.49 ± 0.23

1.54 ± 0.24

1.61 ± 0.3
p=0.029

1.62 ± 0.19
p*=0.036

Triglycerids mmol/l

1.77 ± 0.14

1.47 ± 0.13

1.38 ± 0.06
p=0.0039

1.62 ± 0.19

Hcy

12.88 ± 2.6

12.22 ± 3.13

10.74 ± 2.01
p=0.012

9.95 ± 1.39
p*=0.024

oxLDL U/l

100.0 ± 22.6

83.6 ± 16.8

72.8 ± 15.2
p=0.0085

70.9 ± 8.9
p*=0.028

Ratio TG/HDL-cholesterol

1.22 ± 0.23

1.01 ± 0.27

0.91 ± 0.21
p=0.0015

1.03 ± 0.28
p*=0.021

p = baseline values/24 months; p*= baseline values/36 months.

Discussion

The pathogenesis of diabetes and CVD has several overlapping cardiometabolic signs. Within the framework of a double-blond, placebo controlled study clinical trial (ISRCTN55339917) we aimed to do a very long clinical sub-trial. During such a long-term study extremely important is careful fulfilment all rules (no do change typical diet habits, etc). To be convinced that such complicated options were actually followed during such long period the number of participants was limited, so it was possible to check very frequently real following of all needed options by participants. The special accent was focused on HbA1c. One of the reasons was the information that despite positive treatment effects of so called “aggressive statins” there are several side-effects concerns, including problems with blood sugar-related aspects. The RAC contains monacolin K (so called “mild statin”), which mechanism of action is similar to statins, however the level of HbA1c decreased during the period of 3 years. Innovative composition of RAC showed also some other beneficial effects, as a decline of levels of LDL-chlesterol, oxLDL, Hcy and TG/HDL-chlesterol ratio. It should be mentioned that Hcy is also one of the risk factor of cardio-metabolic diseases [18]. Obviously, one of components in RAC, a pleiotropic probiotic LFME3 has an independent substantial role regarding mentioned beneficial effects.

Human health is closely linked to and dependent on the quality and variety of gut microbiota. The complex ecosystem inside the gut consists of complex interrelations between the host, nutrients, microbiological and environmental factors – and we are just beginning to understand the mechanisms [6, 19–21]. It has been established in several settings by different investigators that the effect of probiotics on lipid metabolism parameters of the host can be quite strain and host specific [22–23]. The anti-oxidative and anti-atherogenic effects of LFME-3 have been tested for in several previous experiments in vitro, in animal models and human trials. The tested media containing the strain have been goat milk, cheese, yoghurt, kefir and capsules [8, 11, 12, 14].

In our previous studies all subjects in the LFME-3 enriched kefir group harbored lactobacilli during the trial [14].

It has been established that probiotics may bind bile acids and thus remove them from the enterohepatic circulation thus favoring the decline of Cholesterol level [24]. There may exist other possible mechanisms: from previous studies it is known that LFME-3 has good activity of glycosyl-hydrolases like alpha-galactosidase, beta-galactosidase, alpha-glycosidase, beta-glycosidase and beta-glycoronidase [1, 24]. Glycosyl-hydrolases are mucin degrading enzymes and the mucin degradation by intestinal bacteria and its use as a carbon source stimulate goblet cells to increase mucus production [24–25]. The effects of decrease of LDL level with normal and borderline high values may be associated with the assimilation of Cholesterol during bacterial multiplication or binding Cholesterol to the surface of the cell wall of bacteria, and this way preventing the absorption of Cholesterol from the intestine into the bloodstream [26].

The production of Short Chain Fatty Acids (SCFA) in the gut could lead to suppression of the synthesis of fatty acids in the liver, thus decreasing the TG and VLDL-cholesterol levels secretion rate, also stimulate carbohydrate oxidation, improved glucose tolerance and reduce the levels of some pro-inflammatory cytokines  [27–28].

Elevated OxS increases the production of oxLDL particles that are less likely to be recognizable to LDL receptors. The higher the LDL content the greater the possibility of production of oxLDL. Uptake of oxLDL particles by arterial wall macrophages leads to the formation of foam cells under the endothelium and atherosclerosis.  The consumption of RAC capsules for 3 years decreased both the amounts of LDL and oxLDL, while the amount of HDL-Cholesterol increased. The effect of monacolin K and LFME-3 may be the reasons for that [29–30].

The possible mechanisms of action of homocystein (Hcy) in contribution to vascular risk include endothelial dysfunction, inflammatory response, oxidation of LDL-cholesterol, and platelet activation [18].  The level of Hcy declined in RAC users.

The type 2 diabetes is a disease with multi-factorial etiology that is characterized by hyperglycemia due to resistance to insulin signal and insufficient compensatory response in secretion of this hormone. Insulin resistance is associated with cardiovascular disease pathogenesis [27]. Colonization with LFME-3 was negatively associated with blood glucose level thus showing its possible potential for carbohydrate metabolism modification in the gut or limiting their absorbance into the blood. In recent scientific papers it is shown that gastrointestinal OxS is associated with the non-specific glycation, which in turn may influence the long term level of blood sugar.  The ability of LFME-3 to decrease the level of HbA1c% was demonstrated in our study. The up-regulation of pro-inflammatory cytokines associated with OxS and inflammation as well as non-specific glycation may reduce glucose transporter type 4 (GLUT4) expressions and translocation to the plasma membrane in human adipocytes and muscle cells, resulting in decreased insulin-stimulated glucose uptake [28–29]. The same may happen to GLUT2, characterized with low affinity and high capacity for glucose.  This isoform of glucose transporter is involved in glucose-sensing in pancreatic β-cells, liver, and the hypothalamus as well as triggering the glucose mediated INS secretion cascade and/or INS synthesis. GLUT2 ensures that the glucose flux is proportional to blood glucose concentrations [30]. The RAC formula contains monacolin K that inhibits HMG-CoA-reductase, the key enzyme of cholesterol synthesis. This formula also contains powerful antioxidants vitamin E and ubiquinol (vitamin Q). A study by Macchi and colleagues [31] also demonstrated the beneficial effects of a probiotic, red yeast rice extract, niacin and coenzyme Q10 targeting dyslipidemia (high LDL-cholesterol) in two different mechanisms, by inhibition of cholesterol synthesis and by reabsorption.

Targeting hyperglycemia and OxS simultaneously may work in cooperation in correcting the lipid profile abnormalities (e.g. elevated LDL levels) and improve OxS which increases the susceptibility of LDL particles to oxidation and glycation [32]. In turn this is an option to prevent endothelial dysfunction and atherosclerosis.  Intake of cysteine is the rate-limiting factor in human glutathione (GSH) biosynthesis.  GSH is a regulator of many body functions and the principal cellular antioxidant. RAC contains L-cysteine and LFME-3 can transport and synthesize glutathione and has the ability of redox cycling of glutathione [10, 14, 33]. Vitamins B1, B6, B9 and B12 in the RAC composition have several cardio-metabolic effects including the control of Hcy level. Probably the simultaneous targeting of hyperglycemia and OxS could be at least as effective as intensive treatment of hyperglycemia in prevention of T2DM complications [33]. As CVD and T2DM are chronic conditions needing an (almost) life-long attention and management there is a place for food supplements and functional foods in the complex management of them [34–35].

Conclusion

In recent through meta-analysis was concluded that probiotics may cause beneficial shift in blood lipid profile and fast blood glucose in patients with T2DM. We have repeatedly showed that anti-oxidative LFME3 as several beneficial cardio-metabolic effects. Now we established that the RAC, comprising also LFME3, has positive effects in asymptomatic volunteers with borderline values of risk factors in very long run. A reduction in OxS status and simultaneous control of other cardio-metabolic risk factors seems to be a good option to improve prevention and treatment strategies. As CVD and T2DM are chronic conditions requiring a life-long attention and management an implementation of some adjuvant components (eg. nutraceuticals), with verified effects, and deserved attention regarding more comprehensive management.

Acknowledgement

The author would like to thank the participants who participated in the present study. The author wish to express appreciation to professor Mihkel Zilmer for the valuble theoretical advices and associated professor Dr. Aune Rehema for critical editing of English grammar and syntax of the manuscript. We thank the VF Bioscience Company for donating the RAC capsules used in this work.

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A Pilot Oral Health Continuing Education Program in In-Hospital Medicine

DOI: 10.31038/JDMR.2019214

Abstract

Objectives: The purpose of the project is to initiate an educational opportunity for hospital based physicians on their understanding of the relationship between oral health and systemic health. The project investigated the current level of oral health knowledge among medical health professionals.

Methods: Harvard School of Dental Medicine (HSDM) and Mount Auburn Hospital (MAH) offered an oral health session for in-patient clinicians (Hospitalists, Medicine Residents, and Physician Assistants) to investigate the current level of oral health knowledge among medical health professionals and introduce them to the concept of oral health. In-patient clinicians at MAH were asked to fill out a pre-session survey online, regarding their familiarity with basic oral health concepts and their comfort level with performing oral examinations, and a post-session survey on paper that repeated the pre-session questions.

Results: Fifty-three in-patient clinicians participated in the pre-session surveys, of which fourteen attended the educational information session and completed the post-session survey. Results showed that the session aided clinicians’ understanding of the relevance of oral health in overall patient care.

Conclusion: The oral health education session can be a useful tool in contributing to awareness of oral health and understanding the link between oral diseases with systemic issues for in-patient clinicians.

Introduction

A greater integration of dental and medical education and practice provides options for prevention, diagnosis and therapy that can produce improvement for a team based, comprehensive approach to care. To deliver patient services in a more inter-professional and cost-conscious environment, oral health providers will require a more extensive preparation in basic biologic science and will engage in more extensive collaboration and interaction with other health providers, especially physicians. Conversely, physicians will need a greater understanding of oral health and its implications for overall health. The integration of oral health into overall medical care is essential especially for patients with chronic diseases, as oral health has been shown to be closely associated with cardiovascular disease, diabetes, and pregnancy outcomes [1–3]. It is important to engage clinicians across the health care professions in the prevention and detection of oral conditions. Oral health is integral to systemic health and our approach to patient care should reflect the need for collaboration among health care professionals for health promotion and maintenance. It is widely established that dental and oral diseases are closely connected to associated systemic health conditions and disease prevention [4–6]. Therefore, it is imperative that primary care medical professionals contribute in the treatment of oral diseases and the maintenance of good oral health. The Harvard School of Dental Medicine (HSDM) in conjunction with Mount Auburn Hospital (MAH) offered an oral-health program to attending in-hospital physicians at MAH. This pilot program sought to introduce medical professions to the intraoral and extraoral examination as performed by dental professionals, and raise the physicians’ awareness of the evident links between oral health and systemic health. The purpose of this study was to evaluate our pilot program by evaluating the physicians’ perspectives on oral health and disease before and after the continuing education session on oral health.

Methods

Educational contents and setting

Harvard School of Dental Medicine (HSDM) and Mount Auburn Hospital (MAH) presented the first Oral Health Session for in-hospital clinicians at MAH. Clinicians included Hospitalists, Medicine Physician Assistants, and Internal Medicine Residents. A ten-question pre-session survey was distributed electronically to participants. Upon completion of the oral health lecture, participants received a post-participation survey at the end of the session. It took approximately five minutes to complete the survey. The inclusion criterion for participation was attending the oral health education seminar series. All post-participation surveys were completed using paper forms. The Oral Health Session was designed to give an overview of general oral anatomy and the experience of performing an oral examination. HSDM faculty presented topics on basic oral anatomy and oral health’s relationship to systemic health and clinical oral health and dental treatment. Following the lectures, HSDM faculty supervised small group exercises (10 participants per group), which included a tutorial case study and hands-on oral examinations by the medical and dental students. Students were also given toothbrushes, toothpaste and dental floss as part of oral hygiene instructions upon completion of the session.

Study design and data collection

The survey-based quantitative study used the survey questionnaires based on a survey design from a previous study [7]. The final survey instrument included 10 questions measuring the perception of participating in-hospital physicians using a 5-point-Likert scale. Participants were asked to rate their perceived understanding of oral health topics, awareness of oral health’s link to system health, and oral health’s usefulness in overall patient care. Participation was voluntary and survey responses were collected anonymously through the online survey tool, Survey Monkey (CA, USA). The study was approved by the institutional review board (IRB) at all participating institutions including at Harvard Medical School (HMS)/ HSDM and MAH.

Statistical analysis

All analyses were performed using SPSS software version 15.0 (SPSS Inc., Chicago, IL, USA). For the 5-point-Likert scale, data contain the outcomes of a nonparametric Chi square to determine the association, if any, between pre-session and post-session reporting for each item. Likert Scale score for each survey question was noted for their significant difference at p<0.05.

Results

Fifty-three clinicians completed the pre-session survey, of which 14 attended the oral health education session and completed the post-session survey. Pre-session survey results showed that in-patient clinicians who participated in the study had clinical experiences in the range of less than one to more than 15 years. Based on the post-session survey results, respondents generally found the session to be helpful in raising both their awareness of basic oral health issues and their comfort level with performing oral examinations. Table 1 shows the responses for questions on basic oral health issues and oral examinations on the pre-session and post-session surveys. Major findings from the pre-session data included that 40% of the participants were very or somewhat comfortable providing basic oral health information to patients before the session, which increased to 86% after the session. 45% of participants were very aware of the importance of oral health screenings before the oral health session, which increased to 71% after attending the education session. Also, 45% of participants were not very or not at all comfortable performing an oral examination before the session, and only 7% after the session. All participants (100%) reported oral health is important to overall health and well-being, and they all agreed that it is important for primary care health professionals to collaborate with dentists after the oral health session.

The data showed statistically significant results at a p-value of < 0.05 for five of the ten questions: awareness of the causes and prevention of periodontal disease, recognition of risks for oral disease, comfort with conducting an oral examination, provision of basic oral health information to patients, and whether it is important for health professionals to collaborate with dentists (Table 1).

Table 1. Pre- and post-oral health session survey results of in-hospital physicians.

Question

Category

Pre-Survey

Post-Survey

SD

Are you familiar with the causes, prevention, and signs of dental caries?

Very

7%

36%

6.6959

p = .153

Somewhat

64%

57%

Neutral

11%

0

Not Very

13%

7%

Not at All

4%

0

Are you familiar with the causes and prevention of periodontal disease?

Very

2%

29%

10.5971

p = .031

Somewhat

60%

50%

Neutral

9%

7%

Not Very

21%

14%

Not at All

7%

0

Are you aware of links between tobacco use and oral cancer?

Very

68%

93%

4.607

p = .330

Somewhat

28%

7%

Neutral

4%

0

Not Very

0

0

Not at All

0

0

Are you aware of the importance of oral health screening?

Very

45%

71%

2.2563

p = .689

Somewhat

34%

29%

Neutral

6%

0

Not Very

13%

0

Not at All

2%

0

Can you recognize risks for oral disease?

Always

4%

43%

14.5452

p = .006

Sometimes

60%

50%

Neutral

17%

7%

Not Often

15%

0

Never

4%

0

Are you comfortable conducting an oral examination?

Very

2%

21%

10.9733

p = .027

Sometimes

40%

43%

Neutral

13%

29%

Not Very

26%

7%

Not at All

19%

0

Are you comfortable providing basic oral health information to patients?

Very

6%

36%

10.8381

p = .028

Somewhat

34%

50%

Neutral

19%

14%

Not Very

32%

0

Not at All

9%

0

How important is oral health to overall health and well-being?

Very

62%

93%

5.3535

p = .253

Somewhat

32%

7%

Neutral

6%

0

Not Very

0

0

Not at All

0

0

How important is it for primary care health professionals to collaborate with dentists?

Very

42%

93%

9.599

p = .048

Somewhat

40%

7%

Neutral

15%

0

Not Very

4%

0

Not at All

0

0

Discussion

The findings in this study suggest that the oral health education session positively influenced how in-patient clinicians perceived the relationship between oral condition and overall systemic health. It is well established that oral health plays a significant role in one’s morbidity and mortality [8]. The World Health Organization (WHO) emphasized the extent of this connection when their Global Oral Health Programme released the Oral Health Report of 2003. As outlined in this report, prevention of oral disease must be integrated with that of chronic disease as these conditions are tightly linked [9]. With over half of the US population over the age of 30 suffering from periodontitis or gingivitis, [10] it is critical to continue to find ways of expanding oral health promotion and disease prevention into patient care. One such method would be to expand the scope of care of physicians to include the prevention of oral disease.

In 2001, 7.0% of the patients seeking dental-related care received treatment from a physician, with 2.7% receiving said care in the emergency department [6, 11]. This is reflected in that 110 million dollars is spent yearly for services provided in the ED directly related to dental caries [6, 12]. This care is palliative in nature, as patients usually receive prescription for antibiotics and pain medications without any treatment of the underlying active disease or without receiving an appropriate dental referral [6, 13–15]. Although dental-related care in the ED is often less than ideal, many patients, especially those of the lower socio-economic status, are left with the ED as their only option because Medicaid does not cover care from a dental provider for most adults [6, 16–19]. Physicians encountering these patients lack the knowledge and comfort in discussing oral health, losing opportunities to counsel patients on the topic [6].

Fortunately, some medical schools are now trying to incorporate oral-health related topics into their curriculum as these subjects are now tested on Step 2 and Step 3 of the United States Medical Licensure Examination [20]. However, in 2009, the deans of education at over 69 U.S. medical schools admitted that they offer less than five hours of oral health curriculum or none at all [20]. In addition, in 2012, family medicine residency directors of US programs were surveyed, and only a third of respondents reported themselves as being satisfied with their residents’ competency on the subject of oral health [21].

It is essential that physicians have an understanding of oral disease and its prevention, as collaboration between medical and dental providers is effective, especially in lower socio-economic groups [1, 22]. In addition, the interest among medical providers for training in oral health and disease is well established, [6, 23, 24] and those who receive such training are proven to be equipped in diagnosing oral disease and making the appropriate dental referrals [6, 25, 26]. In addition, most states reimburse physicians for certain preventative measures of oral disease, such as the application of fluoride varnish, [27, 28] but 95% of medical professionals in the US have never applied varnish [29]. This may be attributed to a lack of comfort and knowledge, obstacles which may be overcome with physician-targeted training sessions. The future direction for this program involves further developing the oral health topics and measuring evidence of impact in the overall patient care experience. This project could have a significant effect on patient care outcomes. A medical professional who is aware of oral health conditions and cognizant of the link between oral and systemic health and can provide a higher level of care to patients, and projects that could measure the effect of this level of care on patient care outcomes are being designed.

Conclusion

An initial project to provide an educational opportunity for in-patient clinicians on oral health increased their understanding of the relationship between oral health and systemic health. Understanding of oral health knowledge among medical health professionals can play a positive role in overall patient care in linking oral diseases with systemic issues.

References

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The Effect of Eruption Level and Angulation of Third Molars on Interdental Root Proximity: A Case-Control Study

DOI: 10.31038/JDMR.2019213

Abstract

This study was designed to assess the possible relationship between the level of eruption or impaction status and angulation of third molars (TMs) and the interdental root proximity (RP) in this quadrant, in adults with healthy periodontium and in patients with history of periodontitis. Root proximity was studied in the interdental spaces of 250 patients with periodontitis and 80 subjects with healthy and intact periodontium. Linear measurements were performed in digital radiographs. Root proximity was detected when the distance at the closest proximity level between the roots of adjacent teeth was < 0.8 mm. Eruption level was classified as full or partial, based on occlusal plane. Impaction status was assessed as semi or complete, based on coverage by soft tissues or alveolar bone. The Z-test, X2, Fisher’s exact test and Mann-Whitney test were used for the statistical analysis. In total, 718 TMs and 4,308 interdental spaces were studied in 330 subjects. In subjects with healthy periodontium, the angulation of mandibular TMs statistically significantly influenced the presence of root proximity in the interdental space between first and second molars. In periodontitis subjects, TM angulation statistically significantly affected the presence of root proximity in the interdental space between first and second molars in the maxillary left and mandibular right quadrants as well as in the interdental space between the mandibular right premolars. The eruption level or impaction status of TMs statistically significantly affected the presence of root proximity only between the first and second mandibular right molars both for subjects with healthy periodontium and for periodontitis patients. Within its limits, this study found that the angulation and eruption level or impaction status of third molars seem to be related to root proximity among the adjacent teeth, especially between lower first and second molars, irrespective of the presence or absence of periodontitis.

Key words

Angulation, Digital Radiography, Eruption, Interdental Root Proximity, Periodontitis, Periodontal Health, Third Molar, Third Molar Positioning

Introduction

Third molars (TMs) are the last in the tooth eruption sequence. The calcification of the TMs starts at 7 to 10 years of age and the calcification of the TM crown is completed at 12 to 16 years of age. Their eruption begins at the age of 17 to 21 years. The time of their formation varies widely due mainly to variations in crown and root morphology. TMs have the highest rate of development abnormalities. More than 20% of humans fail to develop at least one TM [1, 2], whereas TM agenesis accounts for about 75% of all affected teeth [3]. They are often impacted, with higher impaction rate for the mandible than the maxilla. The incidence of TM impaction may increase up to 50% in patients who have been orthodontically treated [4].

TMs are associated with a reduced amount of growth and with a more downward than forward direction of tooth eruption. The eruption status of TMs depends on the dimensions of the retromolar area. If there is sufficient space in the retromolar area, the TMs may completely or partially erupt depending on their axial positioning. The full or semi impaction of TM is often the result of a tooth/tissue disharmony or crowding. The retromolar area is the only significant variable associated with lateral asymmetry in the eruption or impact status of TMs. Hattab and Alhaija [5] assessed radiographically 213 mandibular TMs in 134 subjects and found that there was a strong positive relationship between the frequency of TM impaction and the degree of TM angulation and that the former was inversely associated with the retromolar area width. Inadequate retromolar area space was the most significant factor associated with TM impaction. Most impacted TMs had retromolar space/crown ratios of less than 1.

The position or angulation of TMs might change, mainly when they are visible clinically or partially impacted [6]. Such changes might occur even after completion of the jaw growth and TMs might erupt to the occlusal plane, yet at one third of vertically positioned impacted teeth during the third decade of life [7–9] or especially by the time the individual reached 24 [10] or 26 years of age [11]. It still remains unanswered whether the changes in position or angulation influence the root proximity of adjacent teeth, especially the interdental spaces between second and first molars. The extraction of impacted third molars (ITMs) seems a rather prophylactic surgical procedure for young adults, especially for orthodontic patients. The ideal orthodontic treatment plan should include rationale and recommendations for TMs extractions, whenever indicated [12, 13]. The purpose of the present study was to evaluate the relationship between the level of eruption or impaction status and angulation of TMs and the root proximity (RP), in adult individuals with healthy periodontium and in adult patients with history of periodontitis.

Materials and Methods

Study sample

The study sample was taken from 330 full mouth sets of conventional periapical radiographs belonging to 330 patients originating from the pool of the patients of the Department of Periodontology, School of Dentistry, National and Kapodistrian University of Athens and from private dental practices. Each subject signed an informed consent form prior to enrollment to the study. The study protocol was approved by the Ethics and Research Committee of the School of Dentistry, National and Kapodistrian University of Athens. Two groups of subjects were studied. Specifically, there were 80 subjects (31 men and 49 women; mean age 27.5 ± 0.6 years) with healthy and intact periodontium, who were classified in group A (control group) and 250 subjects (82 men and 168 women; mean age 44 ± 0.5 years) with moderate to advanced periodontitis, who were classified in group B (test group). The diagnosis of periodontitis was based on the clinical attachment level measurements [14]. The patient inclusion criteria were: presence of at least 28 teeth, presence of 26 interdental spaces, presence of full-mouth periapical radiographs and absence of third molar extraction and/or surgical intervention in the posterior jaw sextants for the last 5 years. The patient exclusion criteria were: orthodontic treatment, periodontal treatment (either non-surgical or surgical) for the last six months, medical condition or medication affecting the periodontium and presence of supernumerary or impacted teeth, except for third molars.

All radiographs were taken with the long-cone paralleling technique with the central beam directed to the alveolar crest and then assessed for sings of RP between adjacent teeth. Radiographic images with possible RP were transformed into digital images, to a resolution of 300 dpi with 8 bits of gray level resolution per pixel. RP was defined as an interdental distance of less than 0.8 mm (<0.8 mm) at the closest proximity level [15–17], as assessed from the digitized image in pixels (10 pixels = 1 mm). All interdental spaces were evaluated for RP (M2-M1: interdental space between second and first molar, M1-P2: interdental space between first molar and second premolar, P2-P1: interdental space between second and first premolar, P1-C: interdental space between first premolar and canine, C-I2: interdental space between canine and lateral incisor, I2-I1: interdental space between lateral and central incisor).

In total, 718 TMs were studied, of which 238 belonged to group A and 480 to group B. For each TM, the level of eruption or status of impaction and the angulation were recorded, as assessed from conventional periapical radiographs. Erupted TMs were classified in relation to the level of eruption into fully erupted (FETMs), when erupted to the level or above the occlusal plane, and partially erupted (PETMs), when erupted below the occlusal plane. Impacted TMs were classified in relation to the status of impaction into semi impacted (SITMs), when partially covered by soft tissues or alveolar bone, and completely impacted (CITMs), when completely covered by soft tissues and alveolar bone [18, 19]. TM angulation was assessed relative to the long axis of the adjacent second molar [20], specifically the angle (in angle degrees) formed by the long axis of the TM and the long axis of the adjacent second molar [6] was recorded. All radiographic measurements, linear or angular, were performed by one investigator (A-M. L.) with the Emago/Advanced dental image archiving software (3 EXE, Oral Diagnostic System, Amsterdam, The Nederlands). Each measurement was assessed twice (3 weeks apart) and the average value was taken for further analyses. The intra-examiner agreement was very high, with the weighted k between 0.92 and 0.94.

Statistical methods

Descriptive statistics for eruption status and angulation of TM were calculated as mean ± standard deviation (SD) for both groups (A and B). The Z-test was used for the comparison of two percentages on the incidence of RP per group, jaw or quadrant. The Z-test was used for the comparison of the two percentages of TM quadrant distribution between the two subject groups (A and B). The X2 was used for the comparison of the distribution of TMs between the two subject groups and between interdental spaces with or without RPs. Fisher’s exact test was performed for the comparison of the presence of RP in the interdental spaces in relation to the TM eruption level or impaction status. Mann-Whitney test was performed for the comparison of the mean angulation values between interdental spaces with or without RP for both groups (A and B). The level of statistical significance was set at 5% (p = 0.05). Statistical analysis was conducted using the STATA 0.9 software package.

Results

In total, 718 TMs were studied, of which 238 belonged to group A subjects and 480 to group B subjects. TM distribution did not statistically significantly differ between subject groups (A and B) both in total (X2 = 5.79 and p>0.05) and in quadrants (upper right-URTMs: Z = 1.775, p = 0.076, upper left-ULTMs: Z = 1.091, p = 0.275, lower left-LLTMs: Z = 1.421, p = 0.151, lower right-LRTMs: Z = 1.312, p = 0.192) (Table 1). The quadrant distribution of TMs in response to eruption level, impaction status and angulation for groups A and B is presented in tables 2 and 3, respectively. For group A, mean TM angulation was greatest for LRTMs (21.6ο ± 23.7ο) and least for URTMs and ULTMs (11.4ο ± 8.6ο and 11.7ο ± 8.7ο, respectively) (Table 2). For group B, mean TM angulation was greatest for LRTMs (16.2ο ± 16.7ο) and least for URTMs (11.4ο ± 8.8ο) (Table 3).

Table 1. Comparison of the distribution of third molars in total and in quadrants between the subject groups (A and B).

Groups

URTMs Number (%)

ULTMs Number

(%)

LLTMs Number

(%)

LRTMs Number

(%)

TMs in total Number

(%)

Total

171

(23.82%

164

(22.84)

199

(27.71%)

184

(25.63%)

718

(100.00%)

Group A

66

(9.19%)

60

(8.36%)

58

(8.07%)

54

(7.52%)

238

(33.14%)

Group B

105

(14.63%)

104

(14.48%)

141

(19.64%)

130

(18.11%)

480

(66.86%)

Z-testa

1.775

1.091

1.421

1.312

8.378

p-value

0.076

0.275

0.151

0.192

0.00

TMs: third molars, URTMs: upper right third molars, ULTMs: upper left third molars, LLTMs: lower left third molars, LRTMs: lower right third molars.
a:Comparison of the two percentages of TM quadrant distribution between the groups.

Table 2. Quadrant distribution of third molars (URTMs, ULTMs, LLTMs, LRTMs) in response to eruption level (FETMs, PETMs) or impaction status (SITMs, CITMs) and angulation for group A.

Parameters

FETMs

(147)

PETMs

(30)

SITMs

(50)

CITMs

(11)

Total
 (238)

URTMs

Number

(%)

46

(57.5%)

6

(7.5%)

13

(16.25%)

1

(1.25%)

66

(82.5%)

Angle (º)

x ± SD*

10.2 ± 6.6

20.8 ± 16.3

12.5 ± 8.0

 4**

11.4 ± 8.6

ULTMs

Number

(%)

37

(46.25%)

8

(10%)

10

(12.5%)

5

(6.25%)

60

(75.0%)

Angle (º)

x ± SD*

9.5 ± 5.1

9.3 ± 5.8

15.1 ± 13.0

24.6 ± 11.7

11.7 ± 8.7

LLTMs

Number

(%)

33

(41.25%)

11

(13.75%)

11

(13.75%)

3

(3.75%)

58

(72.5%)

Angle (ο)

x ± SD*

6.6 ± 4.9

9.1 ± 8.0

36.9 ± 2.3

46 ± 40.1

14.9 ± 18.8

LRTMs

Number

(%)

31

(38.75%)

5

(6.25%)

16

(20.0%)

2

(2.5%)

54

(67.5%)

Angle (ο)

x ± SD*

8.1 ± 5.9

16.8 ± 13.4

45.3 ± 26.1

52 ± 33.9

21.6 ± 23.7

URTMs: upper right third molars, ULTMs: upper left third molars, LLTMs: lower left third molars, LRTMs: lower right third molars, FETMs: fully erupted third molars, PETMs: partially erupted third molars, SITMs = semi impacted third molars, CITMs = completely impacted third molars.
* mean value ± standard deviation
** only one observation

Table 3. Quadrant distribution of third molars (URTMs, ULTMs, LLTMs, LRTMs) in response to eruption level (FETMs, PETMs) or impaction status (SITMs, CITMs) and angulation for group B.

Parameters

FETMs a

(373)

PETMs a

(34)

SITMs a

(58)

CITMs a

(15)

Total

(480)

URTMs

Number

(%)

77

(30.8%)

6

(2.4%)

18

(7.2%)

4

(1.6%)

105

(42%)

Angle (ο)

x ± SD*

8.2 ± 4.8

12.7 ± 7.5

21.6 ± 10.9

29.0 ± 7.5

11.6 ± 8.8

ULTMs

Number

(%)

80

(32%)

8

(3.2%)

11

(4.4%)

5

(2%)

104

(41.6%)

Angle (ο)

x ± SD*

8.3 ± 4.6

13.4 ± 3.9

30.3 ± 17.7

35.8 ± 11.7

12.3 ± 11.3

LLTMs

Number

(%)

112

(44.8%)

13

(5.2%)

13

(5.2%)

3

(1.2%)

141

(56.4%)

Angle (ο)

x ± SD*

10.2 ± 6.2

18.2 ± 11.5

38.3 ± 14.9

37.7 ± 31.9

14.1 ± 12.5

LRTMs

Number

(%)

104

(41.6%)

7

(2.8%)

16

(6.4%)

3

(1.2%)

130

(52%)

Angle (ο)

x ± SD*

10.7 ± 6.9

22.4 ± 23.5

37.5 ± 19.7

77.3 ± 10.7

16.2 ± 16.7

URTMs: upper right third molars, ULTMs: upper left third molars, LLTMs: lower left third molars, LRTMs: lower right third molars, FETMs: fully erupted third molars, PETMs: partially erupted third molars, SITMs = semi impacted third molars, CITMs = completely impacted third molars.
* mean value ± standard deviation
** only one observation

In total, 4,308 interdental spaces were studied for RP, of which 1,428 belonged to group A subjects and 2,880 to group Β subjects. RP was detected in 505 interdental spaces (11.72%), specifically in 167 group A interdental spaces (11.69%) and in 338 group B spaces (11.73%). The distribution of RP did not statistically significantly differ between the two subject groups (A and B) both in total (Z = 0.038, p = 0.976) and in quadrants (URTMs: Z = 0.007, p = 0.99, ULTMs: Z = 0.916, p = 0.93, LLTMs: Z = 0.364, p = 0.72, LRTMs: Z = 0.791, p = 0.43) (Figure 1).

JDMR-19-113- Eudoxie Pepelassi_Greece_F1

Figure 1. Distribution of root proximities (RP) in quadrants by subject group (A and B).

For group A, the highest frequency of RP for all four quadrants was found for the I2-I1 interdental space. In descending order, the second most frequent interdental space presenting RP was the M2-M1 space for both maxillary quadrants, the P1-C space for the mandibular left quadrant and the M2-M1 , P1-C spaces for the mandibular right quadrant (Figure 2). For group B, the highest frequency of RP for both maxillary quadrants was found for the M2-M1 interdental space, whereas the highest frequency of RP for both mandibular quadrants was found for the I2-I1 interdental space. In descending order, the second most frequent interdental space presenting RP was the P2-P1 space for the maxillary right quadrant, the M1-P2 space for the maxillary left quadrant and the M2-M1 space for both mandibular quadrants (Figure 3).

JDMR-19-113- Eudoxie Pepelassi_Greece_F2

Figure 2. Distribution of root proximities (RP) in interdental spaces for group A.

JDMR-19-113- Eudoxie Pepelassi_Greece_F3

Figure 3. Distribution of root proximities (RP) in interdental spaces for group B.

The relation between factors concerning the TM, specifically the eruption level, impaction status and angulation, and the presence of RP in the same quadrant was studied for each subject group. For group A, there were statistically significant differences in TM eruption or impaction status and angulation between the mandibular right M2-M1 interdental spaces presenting RP and those non-presenting RP as well as there were statistically significant differences in TM angulation between the mandibular left M2-M1 spaces presenting RP and those non-presenting RP (Table 4). For group B, there were statistically significant differences in TM angulation between the maxillary left M2-M1 spaces presenting RP and those non-presenting RP as well as there were statistically significant differences in TM eruption or impaction level between the mandibular right M2-M1 spaces presenting RP and those non-presenting RP and the mandibular right P2-P1 spaces presenting RP and those non-presenting RP (Table 5).

Table 4. Comparison of the presence of root proximity in the inetrdental spaces (M2-M1, M1-P2, P1-C, C-I2, I2-I1) in relation to the third molar eruption or impaction status (Fisher’s exact test) and comparison of the mean third molar angulation values between interdental spaces with or without root proximity (Mann-Whitney test) for group A.

Interdental spaces

M2M1

M1-P2

P2-P1

P1-C

C-I2

I2-I1

URTMs

Eruption or impaction status, p-value*

1.00

0.24

1.00

1.00

0.94

Angle, p-value**

0.10

0.11

0.61

ULTMs

Eruption or impaction status, p-value*

0.21

0.71

2.24

0.33

0.42

0.14

Angle, p-value**

0.39

0.48

0.12

0.92

0.08

LLTMs

Eruption or impaction status, p-value*

0.09

1.00

0.67

0.85

0.29

Angle, p-value**

0.02

0.32

0.69

0.62

LRTMs

Eruption or impaction status, p-value*

0.03

1.00

1.00

0.06

0.33

0.77

Angle, p-value**

0.03

0.33

0.09

URTMs: upper right third molars, ULTMs: upper left third molars, LLTMs: lower left third molars, LRTMs: lower right third molars, M2-M1: interdental space between second and first molars, M1-P2: interdental space between first molar and second premolar, P2-P1: interdental space between second and first premolars, P1-C: interdental space between first premolar and canine, C-I2: interdental space between canine and lateral incisor, I2-I1: interdental space between lateral and central incisors.
*Fisher’s exact test, **Mann-Whitney test, Bold indicates statistical significance.

Table 5.Comparison of the presence of root proximity in the inetrdental spaces (M2-M1, M1-P2, P1-C, C-I2, I2-I1) in relation to the third molar eruption or impaction status (Fisher’s exact test) and comparison of the mean third molar angulation values between interdental spaces with or without root proximity (Mann-Whitney test) for group B.

Interdental spaces

M2-M1

M1-P2

P2-P1

P1-C

C-I2

I2-I1

URTMs

Eruption or impaction status, p-value*

0.07

0.72

0.71

1.00

0.78

Angle, p-value**

0.07

0.97

0.94

0.08

0.57

ULTMs

Eruption or impaction status, p-value*

0.14

1.00

0.08

1.00

1.00

0.06

Angle, p-value**

0.005

0.46

0.05

0.59

0.30

0.63

LLTMs

Eruption or impaction status, p-value*

0.08

0.49

1.00

0.61

1.00

0.82

Angle, p-value**

0.58

0.66

0.81

0.76

0.86

LRTMs

Eruption or impaction status, p-value*

0.01

1.00

1.00

0.68

1.00

0.48

Angle, p-value**

0.47

0.10

0.02

0.74

0.33

0.47

URTMs: upper right third molars, ULTMs: upper left third molars, LLTMs: lower left third molars, LRTMs: lower right third molars, M2-M1: interdental space between second and first molars, M1-P2: interdental space between first molar and second premolar, P2-P1: interdental space between second and first premolars, P1-C: interdental space between first premolar and canine, C-I2: interdental space between canine and lateral incisor, I2-I1: interdental space between lateral and central incisors.
*Fisher’s exact test, **Mann-Whitney test, Bold indicates statistical significance.

Concerning group A, for both right and left mandibular M2-M1 spaces, the mean value of TM angulation was greater for sites with RP than without RP (LLTMs: 38.6ο ± 12.8ο and 12.6ο ± 2.2ο, respectively, LRTMs: 26.8ο ± 9.2ο, 13.7ο ± 2.5ο) (Figure 4). For group B, whenever there was statistical significance in the TM angulation between sites with or without RP, the mean value of TM angulation was greater for sites with RP than without RP (M2-M1 space/ ULTMs: 19.3ο ± 14.8ο versus 10.3ο ± 9.1ο, P2-P1 space/ LRTMs: 16.4ο ± 16.8ο versus 4.0ο ± 1.0ο) (Figure 4).

JDMR-19-113- Eudoxie Pepelassi_Greece_F4

Figure 4. Mean third molar (TM) angulation by root proximity (RP) for interdental spaces where TM angulation was statistically significantly different between the spaces with RP and those without RP.

Discussion

The present retrospective study was designed to assess the effect of the eruption level or impaction status and angulation of third molars (TMs) on the presence of interdental root proximity (RP) in this quadrant, both in adults with healthy periodontium and in patients with history of periodontitis. In total, 718 TMs and 4,308 interdental spaces were studied in 330 subjects. The results of this study demonstrated that in subjects with healthy periodontium, the angulation of mandibular TMs significantly influenced the presence of root proximity in the interdental space between first and second molars. In periodontitis subjects, TM angulation significantly affected the presence of root proximity in the interdental space between first and second molars in the maxillary left and mandibular right quadrants as well as in the interdental space between the mandibular right premolars. The eruption level or impaction status of TMs significantly affected the presence of root proximity only between the first and second mandibular right molars both for subjects with healthy periodontium and for periodontitis patients.

Comparing the results of the present study to previous findings is not feasible, since the role of TMs on the presence of RP in the neighboring interdental spaces has not been addressed in the literature yet. However, there are well-documented studies on RP, in which the importance of RP in the presence and progression of periodontitis is investigated [13, 16, 17]. Moreover, there are studies reporting root resorption of second molars in proximity to non-erupted third molars and suggesting the early extraction of impacted third molars, especially in cases with a mesial TM angulation of 60o or more and an apical TM location in proximity to the distal root of the second molar [21, 22]. It is widely accepted that one of the main causes for TM impaction, especially for the mandible, is the absence of adequate retromolar space for TM eruption. A limited retromolar space that prevents TM eruption might be implicated in the development of root proximity in the neighboring interdental space. Several factors have been reported to enhance, to a greater or lesser extent, the development of the limited retromolar space. Most of them are related to the time period of development, such as the distal eruption pattern of the teeth, the vertical direction of the condyloid growth which is associated with a decrease in bone resorption of the anterior border of the mandibular ramus, changes in the longitudinal growth of the mandible and delays in the development of facial structures [23, 24]. However, TMs might get erupted later in adult life, after completion of the jaw growth. In such case they often remain partially erupted. It has been claimed that in certain cases TM angulation tends to get reduced with time mainly between 10 and 21 years of age, whereas in other cases TM mesial inclination is increased with time. Orthodontic treatment might increase the retromolar space hoping that this might increase the chances for TM eruption, depending on the initial TM positioning. This seems to have a more favorable effect for the maxillary than the mandibular TMs. The present association between increased TM angulation and RP in the neighboring mandibular molar interdental space in subjects with healthy periodontium might be explained by the forces exerted by the inclined TM in the attempt to erupt.

There are well-established indications for the surgical extraction of impacted TMs [25]. Prophylactic surgical extraction of impacted TMs, which are free of any pathology, has been justified on the basis that TMs do not have important role in the function of the oral cavity, the need to minimize the risk of further disease as cysts and tumors [26] and the risk of mandibular angle fracture [27, 28] as well as the increased difficulty of TM surgical extraction with age [26].

Early literature data reported that second molars adjacent to partially or completely erupted TMs, especially in the mandible, were more frequently affected by periodontal disease and were at highest risk to develop periodontitis [29]. Later, it was demonstrated that in case of a visible TM the odds of finding at least one site with periodontal probing depth of 5 mm or deeper at the adjacent second molar becomes double [30]. Then, it was found that young adults with visible asymptomatic TMs were more likely (almost twice) to have periodontal disease around the adjacent first and second molars than subjects without visible TMs [31]. Moreover, periodontal probing of at least 4 mm deep was significantly more frequent at proximal molar sites [32] and in case of a visible TM, significantly more sites with clinical attachment loss of at least 3 mm were detected at the adjacent first and second molars [33]. These finding may partly be explained by the difficulty in successfully removing the dental plaque from the TM area. Plaque accumulation around the TM results in periodontal involvement at the distal surface of the adjacent second molar and may serve as a potential reservoir for oral pathogens colonizing more anteriorly located dental sites [34–36]. It has been suggested that orthodontically-aided extraction of impacted TMs might improve the periodontal condition of the adjacent tooth, though such a treatment plan should be considered only when TM extraction is associated with a high risk of postoperative complications [37]. The presence of root proximity between the third and second molars has been documented as well as the difficulties to control periodontal inflammation at that site [6, 38]. The present study showed that 25.63% of the subjects presented agenesis of at least one TM, which was more frequent for the maxilla than the mandible in group A. The prevalence of partially or completely impacted TMs was 19.06%. These findings of TM agenesis are similar to those by Hattab et al. [39] and Rozkovcona et al. [40] but greater than those by Sandhu and Kaur [23] and Celikoglu et al. [2]. These differences might be partly attributed to differences in the age of the subject populations studied, since TM angulation might slightly improve with time up to the age of 24 or 26 years, especially when the initial angulation is 35o or more [10].

Concluding, within its limits this study found that, the angulation and eruption level or impaction status of third molars seem to be related to interdental root proximity among the adjacent teeth, especially between lower first and second molars, irrespective of the presence or absence of periodontitis.

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