An increasing number of tobacco products are entering the market, offering a variety of options to attain desired nicotine intake. However, little is known about the effect of this diverse marketplace on the experiences and nicotine exposure among tobacco users. A mixed-methods study examined experiences with tobacco products among individuals with relatively lower or higher levels of biomarkers of nicotine exposure. Semi-structured interviews were conducted with younger and older adults to examine tobacco use behaviors, addiction to tobacco products, and nicotine effects. Younger and older adults provided similar narratives about addiction and nicotine effects, which were similar across age groups, product types , and having lower or higher nicotine exposure. Some individuals with higher nicotine exposure who switched from combustible cigarettes to another product  found similar or greater access and perceived addiction to nicotine. Adults with higher and lower levels of nicotine exposure provided narratives consistent with features of nicotine addiction, regardless of age and products used. Availability of multiple tobacco products may be associated with greater access and exposure to nicotine. Addiction may occur at low levels of use and with non-cigarette products. In recent years the tobacco product landscape has become more diverse, with new additions to the marketplace such as oral nicotine products , differTobacco product switching and co-use have been difficult to research due to the rapidly changing tobacco product landscape. It is necessary to assess the impact these products have on users, particularly motivations to use and associated experiences, to better understand the effects of new products on nicotine exposure, dependence, and disease risk. For example, individuals using or switching between multiple different types of products may achieve nicotine intake that is equal to or greater than single product use. Greater nicotine exposure could occur because different products can allow individuals to consume nicotine more discreetly in places where smoking is prohibited , or discAs the use of multiple tobacco products increases, it can be difficult to track and quantify nicotine intake among this population using self-report measures. This is because, with regards to nicotine exposure, there is not a standard equivalency for different types of tobacco products . A further difficulty arises with products like ENDS because there are often user-adjustable parameters  that can affect nicotine exposure . NicotinThe purpose of the current study was to utilize a mixed-methods approach to detail how younger and older adult tobacco users utilize different products in their daily routines. It was hypothesized that addiction narratives, perceptions of products, and motivations for product use would differ based on levels of nicotine exposure. It was also hypothesized that some products would be associated with differences in addiction narratives and that younger and older adults may differ in the types of tobacco products they use and their motivations for using these products.Semi-structured interviews were conducted on a sample of younger and older adult tobacco users from one wave of an ongoing longitudinal study on poly-tobacco users . Participants were asked about tobacco use behaviors, including product types, patterns of use, and motivations and perceptions of different products. Participants also provided urine samples that were tested for levels of nicotine and several of its metabolites to estimate recent exposure to nicotine.Participants in this study represent a sub-sample of two ongoing longitudinal mixed-method cohorts of poly-tobacco users in California. One cohort consisted of younger adults (18–29 years) recruited in 2017, and the other older adults (30 years and older) recruited in 2018. Eligibility criteria at the first visit included past 30-days use of at least two of the following products: combustible cigarettes, ENDS, and smokeless tobacco. Participant data included in this report are from the second (older adults) and third (younger adults) waves of each respective study, collected between 2019 and 2020. Participants completed an online screening questionnaire to confirm eligibility and were selected purposively at study onset to ensure a diversity of product use patterns and demographic characteristics. Specific recruitment details were previously published . InterviParticipants completed a baseline questionnaire with validated measures of tobacco product use, attitudes, sociodemographic characteristics, and custom measures of use of newer nicotine and cannabis products. Before each follow-up interview, participants also completed a questionnaire reporting their current frequency of tobacco use. Interviews aimed to capture participants’ experiences, perceptions, and routines of poly-tobacco product use. Interviews were conducted by an interdisciplinary and diverse research team in terms of race, age, gender, disciplinary backgrounds, and experience with qualitative research. The following authors were involved in conducting the majority of the interviews: AH , KK , HCK  SR , and PL . Two additional postdoctoral fellows also participated in data collection, and each was an intermediate-level interviewer. Team members with little to no prior experience interviewing received extensive training in didactic and experiential formats. For example, novice interviewers shadowed expert interviewers until they felt comfortable conducting interviews on their own. Since the younger adults were repeatedly interviewed, when possible, the same individual who had interviewed them during previous waves of data collection conducted the interview. During interviews, participants described, in a storytelling format, their tobacco product use over the course of a typical weekday. Interviewers prompted participants to describe when, where, how, and why they used a particular tobacco product and why they might prefer it to other products at a given moment of the day. Towards the end of the interview, interviewers asked participants to then quantify all tobacco and cannabis product use during the prior seven-day period using a validated timeline follow-back (TLFB) instrument . They weUrinary nicotine and metabolites were determined by LC–MS/MS modified for tandem mass spectrometry for improved sensitivity . Total nThe respective data sets were analyzed using an explanatory mixed methods design , wherebyt-tests for continuous variables and chi-squared tests for count variables. Due to their logarithmic distribution, TNE values were log-transformed for analysis. Quantitative analyses were performed using RStudio version 1.0.136 (Rstudio Team (2022). Rstudio: Integrated Development for R. Rstudio, PBC, Boston, MA, USA) and α < 0.05.Participant cases were divided into high and low nicotine exposure groups based on rank-ordered TNE levels to ensure substantial differences in nicotine exposure between groups. We selected five cases of the highest and five of the lowest TNE levels from both younger and older cohorts. Participant demographics, tobacco use behaviors, and levels of TNEs were compared between the younger and older adults, and the low and high nicotine exposure groups, using Salient information from these qualitative data was extracted and summarized in a template according to key topics of interest, including narratives about tobacco product use, nicotine effects, and perceptions of addiction, which were placed alongside the seven-day TLFB data. Cases were templated by four members of the research team , with each analyst reviewing 6–7 cases. During weekly meetings, high and low nicotine exposure cases were compared, and similarities and differences within and across cases were discussed and documented.Tobacco product use and subjective experiences from a template analysis of the qualitative interviews were compared to TNE levels for consistency. Data among these consistent cases were integrated, and the cases where the biomarker and interview data were discrepant were analyzed to identify possible explanations for the discrepancy. Presented below is an analysis in which equal emphasis was applied to TNE levels and qualitative interview data.t = (45)1.6, p = 0.114). Expectedly, there was a significant difference in TNE levels between low and high nicotine exposure groups (t(18) = 11.4, p < 0.001). Categories of products recently used by younger and older adults are shown in Demographics and tobacco use variables are reported in Initial analysis of the interview data examined younger and older adult groups separately. Results of this analysis indicated the reported nicotine effects and addiction narratives were similar between younger and older adults. Thus, subsequent analysis focused on comparing high and low nicotine exposure groups, combining younger and older adults.m = 12) and/or 5–60 (m = 30) puffs from an ENDS per day. The individual using nicotine-containing gum chewed 6–8 pieces of gum per day. Among the 10 participants in the high nicotine exposure group, 4 had used multiple products, 3 used only ENDS, 2 only combustible cigarettes, and 1 participant exclusively used a nicotine-containing gum in the 3 days prior to the urine sample according to the accompanying TLFB. Though nicotine-containing gum is technically not considered a tobacco product, this individual was included in the analysis because the intent of this study was to examine nicotine use from different sources. Although cannabis use was not examined in the biomarker analysis or a systematic focus of qualitative interviews, it is worth noting that five of these cases reported they had smoked or vaped cannabis in the past three days. When the quantity of nicotine used daily was examined, one participant reported smoking a pack of combustible cigarettes a day , two cases used one JUUL pod per day, and all others reported 4–20 cigarettes per day . However, despite a desire for continuous use, there were reports of relatively minimal nicotine effects. Instead, for many, nicotine effects were associated with the ritual and habit of tobacco use that would lead to relief from a nicotine craving, as exemplified by PT059, who said: “maybe it’s just routine since I’ve been smoking for, for so long”. Others in the high nicotine exposure group described nicotine effects as “satisfying”, as “a reward”, or offering a sense of relaxation or pleasure. For the majority, physical effects such as light-headedness or “head rush” sensations were perceived to have diminished over time. PT059 explains:Or someone who has like never smoked before, you smoke a cigarette and you get a little dizzy. Some kind of like little head high or something. I could still do that with the chewing tobacco if I chew enough of it. Um, if I chew enough of it. I, I don’t, but, yeah, you can.PT068 echoes this sentiment: It used to be was, like, a head rush and sort of, like, the—that woozy feeling. Now for me it’s, um, I’m not sure it’s anything more than just, like, this dopamine trigger… for me it’s like, oh, I’ve accomplished what I want, that goal of wanting to hit the JUUL almost is, like, what it is.Relative to each other, participants in the low nicotine exposure group reported similar quantity and frequency of tobacco use on the TLFB, with a few outliers. Two individuals reported using multiple tobacco products in the past three days. Two cases used a tobacco product on an intermittent basis (one ENDS user and another smokeless tobacco user), while all others were daily users of either combustible cigarettes, ENDS, or an oral tobacco product. Note, two of the cases  in the low nicotine exposure group were identified as “discrepant” in that their biomarker data  did not align with the subjective reporting of use . Because most cases were daily nicotine users, their use patterns could be described as regularly accessing nicotine throughout the day, though less frequently within each day compared to those in the high case category. Nicotine effects among low cases were sometimes described as calming or stress relieving or, similar to those in the high nicotine exposure group, described nicotine as having an energizing effect: “it stimulates my mind a bit” or “it helps me focus a little more, wakes me up a little bit”. Similar to several cases in the high nicotine exposure group, when asked about subjective effects of nicotine, low nicotine exposure group cases also had difficulty conjuring language to depict the physiological sensations and instead explained a lack of effect and more as a routine or habit. This was exemplified by PT104, a 35-year-old Filipino man who stated:So, like, I—I—for me, it’s not—I don’t feel—I don’t think it’s, like, the chemical high—the fizz, uh, physiologic. I think it’s more just like the habit of, like, smoking—like taking that deep breath and, like, puffing it out. I think that’s more of my, um, addiction, not necessarily [nicotine].It was expected participants in this group would mention prototypical nicotine effects such as light-headedness due to a lower tolerance from less use, but some in the low nicotine exposure group reported no longer experiencing these effects—“I don’t buzz hard anymore”. This is consistent with tolerance to the effects of nicotine, which is interesting given the relatively low levels of nicotine exposure among individuals in this group. This mimicked what was reported by participants in the high nicotine exposure group. Conversely, some cases in this group reported experiencing undesirable nicotine effects “vaping doesn’t make me feel good anymore”, which may partially account for low use in this group.The level of nicotine dependence was based on participant descriptions of withdrawal experiences as well as attitudes related to quitting, including quit attempts. Addiction narratives among cases in the high nicotine exposure group, regardless of product or products used, were comparable. That is, regardless of whether participants used ENDS, nicotine replacement therapy, combustible cigarettes, or some combination of these products, they all appeared to experience similar nicotine effects and withdrawal symptoms. Likewise, individuals in the high nicotine exposure group described similar strategies to help offset or cope with nicotine withdrawal. While patterns of products used differed by age group, descriptions of subjective effects of nicotine were similar across ages. Below are exemplary cases from each age group. PT123 is a 44-year-old White female who reported successfully quitting cigarettes by transitioning to an ENDS. Her stated intention was to quit all nicotine use within 12 months. However, upon reflecting on her stated intention to quit, she stated, “… I might be more addicted to nicotine now. I don’t know whether I am or not, but—than I was before”. Her feeling that she might be more addicted to nicotine after having quit cigarettes was related to her easy access to vaping—she said vaping was more accessible and socially acceptable than smoking cigarettes. She added that she was unaware of just how much nicotine she was using. Her ENDS was refillable, which she reported made tracking her use difficult. She mentioned the nicotine exposure measurement (simply referred to as “biomarker testing” in interviews) as one way to learn about just how much nicotine she was ingesting. She explained: I would be really curious about [biomarker results] that. Because I would hate to think that I’m—and I don’t know. I mean, is there really such a thing as more addicted? I don’t know. I mean, I smoke, you know, or vape, rather, you know, quite often during the day. I don’t think about it. I don’t set it down and then leave it in a room and go get it when I want one; whereas, cigarettes, I just left them by the back door. And when I went out to have a cigarette, I had to get up and go do that.The question raised by PT123, “is there really such a thing as more addicted?” indicated her reluctance to acknowledge that she could be more addicted now to an ENDS than she was to cigarettes. Participants explicitly and implicitly identified the unforeseen risk of increasing one’s nicotine dependence in the process of replacing smoking with ENDS. Another example was given by PT108, who describes having greater access to nicotine by having initiated ENDS use following combustible cigarette use: “I was going somewhere where you couldn’t smoke at all. So, I thought this would be a perfect—in combination, this [cigarette and ENDS] would be a perfect tool to—in that department”. Reflecting on her use behavior in the interview, PT123 described her use of her ENDS as “nonstop”. She further reflected on how much nicotine was actually entering her system and whether she was more addicted because she “hit” her vape all the time but only took in a little at a time. She wondered whether taking small hits nonstop was better or worse than using a JUUL or smoking an entire American Spirit brand cigarette. Another interesting case was PT127, who unsuccessfully attempted to replace cigarettes with a pod vape and ended up using both products. He smoked a pack of cigarettes a day in addition to using two different types of ENDS. His selection of which product to use was context-dependent. Below is an excerpt explaining the consequence of his attempting to use a pod vape to quit smoking: I wanted to try the JUUL. It wasn’t doing it for me. I just thought it would do it. I wanted to honestly quit smoking cigarettes and alternately get my nicotine in other ways. I didn’t want to stop consuming nicotine, I just wanted to not smoke cigarettes due to the smell, everything. And if this has like four ingredients in it versus this who we don’t even know what’s in it, at least the ingredients are on the bottle of e-juice. So, I wanted to quit smoking and to me all these devices did was increase my chances of smoking tenfold. …In the case of a younger adult (PT064), he stated that while ENDS are good for people who were “looking to get away from cigarettes” as it was for him, he simultaneously labeled this process as one where he “just transferred addictions from cigarettes to JUUL”. Unlike PT123, PT064 had a distinct vision in mind in terms of quitting vaping altogether. He did not question whether he was more or less addicted to nicotine as an ENDS user; he hypothesized that he would be able to give up JUUL more easily than cigarettes because he was successful in quitting cigarettes. To move from using JUUL to fully quitting nicotine without some sort of replacement may or may not be more difficult than quitting cigarettes in the context of JUUL. PT064 explains: While I think that JUUL does a great job of doing that, I do think that it can also be just a … a transfer of addiction from one thing to another. Whether it be cigarettes or smokeless tobacco to JUULing, you know. But I think it can be a very useful tool for people that are looking to get away from cigarettes because I know it—it certainly helped me. And once again, I’m one of those people who just transferred addictions from cigarettes to JUUL. But it did, you know, completely cut cigarettes out in the long run. So, were there to come a time when I actually do stop JUULing, I think it would be easier to get off of this than it would have been cigarettes because I’ve done that before. Just nicotine satisfaction is, I guess, achieved using JUUL, and getting away from cigarettes.Across the high nicotine exposure group, whether users were strictly using ENDS, combustible cigarettes, or some combination of the two, their reflections on addiction suggested equal dependence on the different types of products.The majority of cases in the low nicotine exposure group either denied having withdrawal symptoms or simply stated they did not perceive themselves to be addicted to nicotine. This was the case for PT143, a 34-year-old male who used smokeless tobacco as a way to relax or out of boredom, spontaneously offered that he was “not addicted”: It’s more just something that I do from time to time, and I really don’t even know why, it’s just something that I’ve done for years and years and years. But, I’ve—I don’t—I don’t have that addictive personality, I am not addicted to it. I told my wife, when we had our second child five and a half years ago, that I would quit, and I did. It was literally just one day, I just—I had half a can and just threw it in the trashcan and never even thought about it again and it didn’t bother me to not do it.Signs of addiction were noted in other interviews, though these were not typically as pronounced or severe as those in the high nicotine exposure group. For example, in the low nicotine exposure group, PT104 reported very consistent pod ENDS use throughout the day, initiating use about 50–60 min after waking. He perceived his addiction was to the habit of tobacco use rather than the nicotine itself. Two of the low nicotine exposure cases were labeled as discrepant, meaning their biomarker data did not align with their reported use. In each of these cases, indications of nicotine addiction similar to those expressed by participants in the high nicotine exposure category appeared in the narratives of participants with low levels of nicotine exposure. PT021, a younger adult, exemplified this scenario:The withdrawal symptoms, so, yeah, like the—there’s like, I don’t know how prominent this is in the vape culture…but like, uh, in Southern California and here, like I know it’s a thing in California, like we call it like fiending for it…In the past year I’d say I’ve had days like over the summer where like I’ll run out of a bottle of juice and like I’ll run out of like everything in my vape, and I’ll just start to get—I’ll tell myself like, oh this is okay. … I’ll wait until next week to buy a bottle of juice and then end up buying it two hours later, yeah.In the low nicotine exposure group, both an absence and a presence of behaviors commonly associated with nicotine dependence were reported in interviews.This study represents a uniquely detailed examination of younger and older adults recalling their experiences using multiple types of tobacco products in the natural environment, with the addition of quantitative biomarker data to classify and compare qualitative interview results. One important finding from this study was that younger and older adults, though having somewhat different product use profiles , did notThis study was initially designed to compare and contrast younger and older adults’ reports of nicotine effects and addiction narratives. However, qualitative results from this study indicated that younger and older adults’ narratives were similar, and therefore the qualitative data were subsequently combined for analysis and presented together. Similarly, another qualitative study found ENDS provided comparable nicotine effects and were perceived as equally addictive among younger (defined as 29 years of age or less) and older adults (defined as 30 years of age or older) . One difNew tobacco products may be an alternative to combustible cigarettes, which had long been the primary form of nicotine consumption. While there are no long-term studies to definitively address whether these new products are effective at reducing harm, at least with regards to ENDS, research indicates lower short-term exposure to many toxicants associated with the negative health effects of combustible cigarette smoking among exclusive ENDS users versus exclusive combustible cigarette users . HoweverIt was surprising to note that similar addiction narratives and descriptions of nicotine effects as found in the high nicotine exposure group were also present, though less pronounced, in the low nicotine exposure group. Prior to the analysis of these data, it was speculated that individuals in the low nicotine exposure group might use tobacco products for desirable subjective effects  or social reasons but not for withdrawal symptom relief, which is consistent with data from light and intermittent cigarette smokers . HoweverA significant concern with non-combustible tobacco products is that they can be used more discreetly than combustible tobacco products. Past research has indicated that approximately two-thirds of adult ENDS users engage in some form of stealth vaping (the act of discreetly using ENDS where they are prohibited ). SimilaThe strengths of this study include having a sample of younger and older adult tobacco users using a diverse array of products, having biological verification of nicotine exposure, and collecting detailed information on tobacco product use using a semi-structured interview format. Despite these strengths, there are several limitations the reader should consider when interpreting this research. First, there was an unexpectedly high percentage of recent (past 3-day) cannabis use among participants in this study. Because this study focused on tobacco use, interviews did not focus on cannabis use, and biomarkers of cannabis use were not collected. Second, though adults were categorized as younger or older based on age, the older adult group encompassed individuals ranging from 32 years of age and older, and differences among older adults may exist within individuals in this wide-ranging age group.This study combined qualitative narratives and biomarkers of nicotine exposure, finding that both high and low levels of nicotine exposure are reflected in narratives consistent with features of nicotine addiction, regardless of age and specific products used. This suggests that a diverse market of tobacco products provides many options to access nicotine and that dependence on nicotine may persist as a greater variety of tobacco products are offered. Addiction may occur even with low levels of use and non-cigarette products and with both single product and multiple product use.


Since learners’ academic achievement is the ultimate goal of any system of education, multitudes of studies have been conducted on this variable and its determinants. That is, several scholars have explored the effects of student-related and teacher-related factors on learners’ academic achievement. Notwithstanding, a few researchers have investigated the effects of teachers’ self-efficacy and creativity on learners’ academic achievement. Furthermore, no study has reviewed the role of these teacher-related factors in learners’ achievement. Therefore, the present study seeks to bridge the lacunas by delving into the influence of teachers’ self-efficacy and creativity on English as a Foreign Language (EFL) learners’ academic achievement. The beneficial effects of self-efficacy beliefs and creative teaching were outlined through the existing evidence. This seems to be illuminative for EFL teachers. Given the positive consequences of teachers’ self-efficacy for students’ achievement, EFL teachers should believe in themselves and their abilities to lead their students to academic success. Additionally, with regard to the positive impact of teachers’ creativity on learners’ achievement, EFL teachers are expected to teach the course content creatively. In any instructional-learning context, learners’ academic achievement is the primary focus of policymakers, educational administrators, and instructors, and English as a Foreign Language (EFL) contexts are not an exception by any means. Academic achievement is “the outcome of learning, which is typically measured by classroom grades, classroom assessments, and external achievement tests” , p. 270.The term “self-efficacy” generally refers to an individual’s belief in his or her own ability to successfully carry out a given action . AppliedTeacher creativity as another influential factor in learners’ academic achievement pertains to “the utilization of imaginative approaches to make learning more interesting” , p. 78. Despite the prominence of teachers’ self-efficacy and creativity in improving learners’ academic achievement , the effefficacy for instructional strategies,” “efficacy for classroom management,” and “efficacy for student engagement.” Accordingly, teachers with strong self-efficacy beliefs are able to engage students in learning tasks, utilize effective teaching techniques, and control the classroom atmosphere (The construct of self-efficacy generally pertains to one’s beliefs, thoughts, and perceptions about his/her personal abilities and capabilities . Likewismosphere .The concept of creativity has been theoretically defined as “the interaction among aptitude, process, and environment by which an individual or group produces a perceptual product that is both novel and useful” , p. 91. To explain the value of teachers’ personal traits in promoting English language learners’ academic achievement, As mentioned earlier, despite the value of teacher self-efficacy and creativity in learners’ academic achievement, few investigations have been performed to explore the effects of these teacher-related factors on EFL learners’ academic achievement . MojavezSo far, the variables of teacher creativity, self-efficacy, and learner academic achievement were described. Moreover, in light of available evidence, the effects of teacher self-efficacy and creativity on EFL learners’ academic achievement were illustrated. Taking the theoretical and empirical evidence into consideration, one can logically infer that both self-efficacy beliefs and creative teaching positively influence EFL learners’ academic achievement. This finding seems to be beneficial and enlightening for EFL teachers. With respect to the positive consequences of teachers’ self-efficacy for students’ achievement, EFL teachers need to believe in themselves and their abilities to lead their students to academic success. Further, considering the positive impact of teachers’ creativity on learners’ achievement, EFL teachers are required to make use of creative teaching in their classes. Due to the scarcity of research on the role of teachers’ creativity and self-efficacy in learners’ academic achievement, further empirical studies are thus needed.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


We argue that this is a misunderstanding and misuse of history.How should we refer to the diverse group of professionals who provide health care? This is a long debate, which has now taken on new form, as recent articles have disingenuously connected the contested term “provider” with the history of Nazi horrors.New York Times, bemoaning the “double speak” of insurance, and lamenting that on insurance forms physicians are referred to as “providers” and the patients as “consumers,” noting it imbued medicine with a “supermarket touch.”3 In 1993, conservative columnist William Safire torched the term “managed competition,” at the base of the proposed Clinton health reforms, while criticizing the term provider. The column opened with a quote from a concerned physician who noted he was “distressed” at being called a “health care provider” and tellingly added that it was “easy to regulate providers but more difficult to regulate doctors.”4Many physicians do not like the term provider, and they have made this publicly clear over the past four decades. In 1986, Connecticut physician Lee Sataline wrote the 3The term provider, which first appeared in the mid-1960s with the passage of Title XIX of the Social Security Act and the creation of Medicare and Medicaid, reflected the realities of third-party insurance and its regulation. A service is provided, and the provider of services, initially referring to “hospital, extended care facility, or home health agency,” and only later expanded to include health care professionals, received payment by a third party.9 Others suggest that replacing the term holds the stakes for the future of medicine, in terms of bolstering “trust in physicians” and helping “rebuild the resilience” needed during the pandemic.5 This is not a new argument, but rather one that harkens to over a century of physicians’ concerns about regulating their profession and the perceived risks of third-party payors that may reduce physician autonomy of practice.10 Yet it ignores an important historical context.In the past decade, multiple perspective pieces on the term “provider” have been published in top journals. These generally argue that the word diminishes the physician-patient relationship, blurs distinctions between various health care professionals, and enshrines a transactional, rather than healing, relationship.11 Patient activism was subsumed into a form of consumer activism, which brought about a realignment of forces in the practice of medicine. These activities included women demanding doctors abandon radical mastectomies in favor of lumpectomies, patients advocating for lower-cost medications, and advocacy groups working to articulate various forms of “patient bills of rights.”14 As critiques have rightfully argued, these small-scale reforms, while important, also served to hinder larger calls for an overhaul of the health care system.14 The patient as a consumer, and the physician as a provider, was a result of sustained pressure of patient activists. Ignoring this history means ignoring the advocacy of the very people we serve.In fact, the “patient as consumer” movement was fueled by patient activists, who were eager to reclaim power, autonomy, and independence. As historian Nancy Tomes has shown, the 1970s patient-consumer movement was a response to medical paternalism, and an unresponsive medical establishment.15 For this claim, the author relied on the unfortunate mistranslation in a single essay from a decade and a half prior that focused on the plight of Jewish pediatricians under the Nazi regime.16 This erroneous argument was uncritically amplified by a number of other online publications and social media posts, and made its way to the mainstream in 2021, appearing in academic articles.2 The reference to the supposed Nazi origin of the term “provider” is now used as an argument not only against the use of the term, but also to highlight what some see as an erosion in the status and independence of the physician.In 2019, in a polemic blog post with the egregious title “If You Call Me a Provider, I Will Assume You are a Nazi,” the author argued that the term provider has Nazi roots.Krankenbehandler, which the Nazi authorities introduced for Jewish physicians in 1938. It was a newly coined concept which had no echoes in contemporary Nazi nor in post–World War II economic contexts, and had no economic parallels or overtones. As such, there is no adequate English translation. A literal translation of the term’s components might be “sick-treater,”—a term devoid of any transactional nature.17 This is in stark contrast to the German term Anbieter which is in use today as the equivalent to the English “provider” in German debates on health care provision since the 1970s.18 Similar to the US context, this term originated in the sphere of economics and consumer rights, and was transferred from this context to the sphere of health care—it has no semantic or historical connections whatsoever to the term Krankenbehandler. This history would be readily evident to any student of the Holocaust, or any practitioner familiar with the current German health care system.This argument is factually baseless and morally flawed. First, it builds on an erroneous and misleading translation of the German term Krankenbehandler and “provider” is morally problematic as it completely ignores the context of its introduction in 1938. The intention by the Nazi authorities was not to identify or analogize Jewish physicians with a broader group of health professionals, or any other individual providing services or commodities. Rather, this term helped enshrine a racialized health care system in which the newly created subgroup of Jewish Krankenbehandler, or “sick-treaters” was only allowed to care for Jewish patients.Second, this equation of 1 The Nazi category of Krankenbehandler resulted in a massive restriction of their immediate legal capacity to act as a physician, resulting in delicensure for the vast majority of Jewish physicians.17 These things are not the same. The mistaken translation and equation of Krankenbehandler to “provider” falsely equates physician concerns over perceived professional devaluation with the systematic persecution and mass murder of Jewish physicians. In a time of rising anti-Semitism and unfortunate politicization of studying the Holocaust, instrumentalizing the history of the Holocaust to revisit this debate over the term provider is harmful.Some physicians in the USA worry that the term “provider” devalues their unique professional skill and expertise in comparison to other colleagues, such as nurse practitioners, certified registered nurse anesthetists (CRNAs), and physician assistants.5 They have argued for a concerted effort involving professional societies, engaging government entities, and even private electronic medical efforts, suggesting that such a profound effort is necessary, and absent such “could potentially increase the likelihood of greater dissatisfaction, confusion and expense in the long run.”5 After over four decades of physicians’ writing about their concerns over the term provider, perhaps these energies would be better spent elsewhere.Physicians who have argued for replacing the term provider acknowledge that this will be an onerous process, requiring “rewording of regulations, policies and electronic health record interfaces.”For those physicians who are worried about engendering trust, perhaps they should join forces with other members of the medical community and continue to work on rebuilding trust, particularly with marginalized populations, and to demonstrate that the medical community is worthy of their trust. Trust is lost when physicians use their powerful platform to perpetuate false historical arguments. This is particularly ironic when physicians argue for the unique nature of their profession and expertise, by making erroneous claims outside of their area of professional expertise. Physicians who are worried about resilience, rather than agitating to replace terminology at multiple societal levels, should come together to advocate for better working conditions for trainees, all health care workers, and for our colleagues in underserved and understaffed hospitals. And finally, if physicians are genuinely appalled by the transactional nature of medical care as evidenced by a “market-based” term, perhaps it is time for physicians to actively work to expand and democratize access to high-quality care for our patients, rather than making ahistorical arguments about the origin of the word provider.


Gattaca has emerged as a canonical pop culture reference used to discuss modern controversies in genetics and bioethics. It appeared in theaters a few years prior to the announcement of the “completion” of the human genome (2000), as the science of human genetics was developing a renewed sense of its social implications. The story is set in a near-future world in which parents can, with technological assistance, influence the genetic composition of their offspring on the basis of predicted life outcomes. The current moment—25 years after the film’s release—offers an opportunity to reflect on where society currently stands with respect to the ideas explored in Gattaca. Here, we review and discuss several active areas of genetic research—genetic prediction, embryo selection, forensic genetics, and others—that interface directly with scenes and concepts in the film. On its silver anniversary, we argue that Gattaca remains an important reflection of society’s expectations and fears with respect to the ways that genetic science has manifested in the real world. In accompanying The 1997 film  Gattaca, using the moment as an opportunity to examine contemporary issues—both technical and ethical—in modern human genetics.In this article, Ogbunugafor and Edge commemorate the 25th anniversary of the release of the film  Gattaca, written and directed by Andrew Niccol, envisions a “not-too-distant” future in which predictions made on the basis of genotypes play a central role in structuring society. Despite positive reviews from critics, Gattaca underperformed at the box office in its initial theatrical run. Since then, however, Gattaca has become a cult classic, and its title is a stand-in for the idea of genetic dystopia in popular parlance (e.g. The 1997 film nce e.g. .Gattaca’s protagonist is Vincent Anton Freeman (Ethan Hawke), who was conceived the old-fashioned way, without the aid of modern technology. So-called “faith births” have become taboo in Gattaca’s society—such people are labeled as “in-valids,” “uteros,” or “God children” and barred from opportunities and status. Based on what is in his genome, Vincent is predicted at birth to be at risk for several conditions, including a heart disorder foretold to lead to early death, which precludes his participation in educational and social institutions and in most employment opportunities.Gattaca’s world—doors are closed to Vincent that would allow him to pursue his lifelong dream of becoming an astronaut at the Gattaca Aerospace Corporation. This goal is unreachable until he takes bold and desperate action, adopting the genetic identity of another person: an illegal, underground process called a “borrowed ladder.” Vincent pays to adopt the genetic persona of a cooperating “valid”—that is, a person born under genetic supervision and assistance—Jerome (Jude Law), a former elite swimmer whose paraplegia prevents him from competing.Because of this genetic discrimination—outlawed in principle but common in practice in Gattaca remains as relevant as ever, a lens on modern uses of genetics. A quarter century later, we look back on the film, considering it from our perspective as geneticists. We organize our discussion around major scenes in the movie, taking up its depiction of genetic discrimination, genetic prediction, embryo selection, genetic investigations of crime, gene-by-environment interactions, and related topics. Along the way, we briefly review some technical aspects of contemporary genetics work related to Gattaca. For clarity, we have provided a brief definition of these concepts , with genetics the instrument of discrimination in this fictional world. The science of genetics has already been a close partner of discrimination in its history, including via the eugenics movement  can propagate their privilege by ensuring that their children are born with genetic assistance. Privilege also becomes naturalized, justified by scientific prediction. Economic barriers to genetic assistance undercut Vincent’s narrative claim that class is “no longer determined by social status.” Through his experiences, Vincent realizes that though genetic variation matters, the social force of genetic prediction can be at least as powerful. Uncertainty about whether Vincent will continue to outwit the genetically defined elite, in part by capitalizing on their misplaced faith in an overstated genetic determinism, is an important driver of tension in the film’s plot.The world of Gattaca despite their uneven performance. Some commentators have taken the overly precise predictions in Gattaca at face value. For example, futurist Ramez Naam wrote , as well as about the correlations of genetic liability for the diseases considered.One question raised by the probabilities recited at Vincent’s birth  who have an identical twin, the twin has bipolar I disorder only about 40% of the time  manifest, as they can be modified environmentally .Box 1.“the time .The potential to predict a trait from genetic information is limited by the trait’s heritability, the proportion of trait variance explained by genetic variation in a given population and range of environments. Heritability can be estimated in many ways , in which the associations between genotypes at genome-wide loci and a phenotype are estimated in a large sample of individuals.P-value (thresholding). Once m loci are selected, the polygenic score A widely applied method for estimating a polygenic score is clumping and thresholding, in which the goal is to select loci for inclusion in the polygenic score that are not strongly correlated (clumping) and that each pass a threshold for evidence of association with the phenotype, based on a j and jX is the number of effect alleles carried by the individual at locus j. The thresholds for P-value and for correlation among sites can be chosen empirically to maximize predictive accuracy , they are told, “this child is still you, simply the best of you.” This line and others, as well as the image of 4 candidate embryos on a screen in the geneticist’s office, strongly suggest that “genetic assistance” is some form of embryo or gamete selection rather than CRISPR-like editing of parental genetic material.The geneticist details the features available in the candidate embryos for consideration. The parents opt for a boy and confirm their preference for some cosmetic features—hazel eyes, dark hair, fair skin.  As the geneticist continues through a list of traits he has “eliminated,” Vincent’s parents appear uncomfortable and protest, saying that although they are comfortable preventing diseases, “we were wondering if it’s good to just leave a few things to chance.” The geneticist replies, “You want to give your child the best possible start. Believe me, we have enough imperfection built in already.”Gattaca was released, beginning in 1989 Box 3.“You could conceive naturally a thousand times and never get such a result”Gattaca takes the form of embryo selection from a large number of embryos, what might the results be? How different from a couple’s average child (produced the old-fashioned way) might we expect the “assisted” child to be? Several recent papers have taken up the related question of how embryo selection on the basis of polygenic scores might perform  would tend to lower risk for several other diseases , rendering moot the need for parents to carry the desired alleles . But whiGattaca’s original ending, cut for the theatrical release but included in an advance screening for scientists  straight out of noir, complete with fedora and trenchcoat, and his younger, valid colleague (Loren Dean), who outranks him. Much of the tension in Vincent is not the murderer, but the investigation nonetheless threatens to uncover his genetic impersonation of Jerome. Though Vincent is fastidious in his effort to keep his identity secret, he nonetheless sheds an eyelash near the crime scene, which ultimately alerts police to the presence of an in-valid in the facility.Vincent’s illicit presence makes him a prime suspect, leading to a genetic manhunt. When Vincent’s eyelash is analyzed, detectives learn he is an “unregistered” in-valid—i.e. one who is not included in an implied central database—and they see a picture of Vincent, complete with his preimpersonation hairstyle and eyeglasses. They do not receive a name, but they do learn that he used to work as a janitor at the facility, perhaps by questioning his former supervisor (Ernest Borgnine).Gattaca’s release, following its origin in the United Kingdom in the mid-1980s  has opened large segments of the population to de facto genetic search. In an IGG search, genetic genealogists upload genome-wide genotypes—not the handful of markers included in CODIS—to platforms typically used for recreational genealogy.pulation . At the Gattaca raises a puzzle: If Vincent is unregistered, how do the detectives get his picture? And further, how do they have access to his picture but no name attached? One possibility is that the film wants us to assume that the detectives predict his phenotype, generating the picture from the genetic information in the eyelash. The detectives do make reference to other phenotype predictions, including Vincent’s short predicted lifespan and a “violent temperament,” which, in the eyes of the older detective, replaces the need for a plausible motive.Speaking of universal databases, the genetic investigation in Phenotype predictions in forensic contexts, termed forensic DNA phenotyping, have been explored in the academic literature . ForensiGattaca’s use of phenotype prediction specifically to investigate a crime is more than a plot device used to explore the ways in which forensic genetics would work in this fictional world. Debates about innateness have been central in conversations around criminal behavior and its social consequences. For example, the search for criminal “types” based in and recognizable in terms of biology has a long history with deep connections to the eugenics movement  has several roles: she is Vincent’s love interest and a staff member at the Gattaca Corporation who is assigned to assist the murder investigation. The interactions between Vincent and Irene generate windows onto the interpretation of genetic “imperfections” in Gattaca’s world. Early in the film, Irene takes a nonconsensual look at Vincent’s genetic identity by taking a hair from his desk drawer to a corner genomic sequencing service.  When Irene confesses her clandestine genetic monitoring, she also shares her insecurity about a heart defect that prevents her from going to space.Gattaca-world doctrine of biological determinism—some people are born with the equipment to play certain tunes.One especially critical moment involving Irene takes place on her first date with Vincent. They attend a performance, and we see a pianist playing an impressive serenade. At the end of the concert, Vincent (posing as Jerome) and Irene stand near a poster advertising the event that highlights the pianist’s 12 fingers. Vincent says, “One finger or twelve, it’s how you play,” to which Irene responds “that piece can only be played with twelve”.Gattaca: should we interpret the presumptive celebration of the 6-fingered pianist as a symbol of acceptance or of exoticism? Perhaps the scene highlights that certain conditions are tolerated insofar as they entertain and do not threaten the valid class.The film is not clear about whether the 12-fingered pianist was the product of genetic assistance  or was a “God child” from a natural birth. Whatever the mechanism, the 12-fingered pianist was born with some version of polydactyly, in which vertebrates have additional digits on their extremities (more than 5 digits in humans).Gattaca’s world of physical conformity. But they also let him play a transcendent piece of music that few others can manage. One lesson is that fixed notions of impairment are imprecise. This is not only an ethical message but also a technical one: gene-by-environment interactions are a central concept in modern genetics, defined by how the phenotypic manifestation of genotypic information is dependent on context.In many settings, conversations around abnormalities, impairments, and disability have become more sophisticated, as scientists, scholars, and advocates have challenged scientific fields to rethink normative definitions of fitness, health, and disability , and broader questions regarding how new technologies (e.g. gene editing via CRISPR) should be used . And unfA recurring problem at the interface of the science and ethics of genetics, participated in by both scientists and users of science, is a kind of giddiness—an unjustified optimism that genetic research will imminently solve the most relevant questions surrounding human nature and society. For example, Charles Davenport once wrote with exhilaration about the potential for tying all sorts of human traits to the Procrustean bed of Mendelism, including “nomadism,” “shiftlessness,” and love of the sea (Gattaca’s world are based on science advanced beyond our own, but they mirror ones in our own history. Reflecting on Gattaca implores us to look ahead, toward creating a world different from the one it portrays, where science is no longer misused to reinforce social inequality, to limit possibilities, and to transform hopes into dreams deferred.The abuses of science in iyac142_Supplementary_DataClick here for additional data file.


The politics of children’s literature and the actors surrounding it have never been more visible than they are now, in the digital age. As one of the first children’s series to gain widespread popularity concurrently with the spread of the internet, the Harry Potter septet arrived on the global stage at the perfect moment to develop an avid, connected fandom. But the fandom has laid bare the many conflicting ideologies of the fans themselves and of the actors surrounding the texts. This article examines the contentious issue of gender nonnormativity and its relation to the Harry Potter texts, the queer/trans reading practices and political resistance common to the fandom, and the ongoing disagreements over gender, made visible on social media, between Rowling and the fans of her series. The article discusses the Harry Potter novels’ varied and conflicting ideologies; queer/trans readings of the Potter septet, including both invitations and resistances to queer/trans reading by Rowling herself; how gender is queered and queried in and through fan fiction; and finally, the recent hostilities between Rowling and her fans. It concludes by discussing the worsening relationship between Rowling and her fans and highlighting how fans are using their collective power to undermine Rowling’s gender politics through fan fiction. By doing so, the article traces the complex politics of the reception of books for young people in the digital age, demonstrating that authors’ powerful voices continue to shape readers’ responses to texts long after their publication but showing, too, that readers often resist authors’ attempts to influence not only their textual interpretations but their politics. The Deathly Hallows (Fantastic Beasts (2016–) film franchise is ongoing, and Harry Potter and the Cursed Child (2016) has been a hit—but there is more happening in the fandom than meets the eye.The internet and social media have escalated a shift in reading practices toward participatory, networked communities of interpretation Jenkins, . As one  Hallows , p. 163,The politics of children’s literature has never been more visible. The Harry Potter fandom, in particular, has been a political battlefield. Many fans feel they are fighting for inclusion and against discrimination, including against a conservative children’s publishing industry, against exclusionary political movements, and against author J. K. Rowling herself . However, the ways in which ideologies are written into children’s texts differ; some are explicit and didactic, while others are more covert, encoded within the language and imaginative premises of the narrative worlds presented to readers. Stephens identifies three kinds of ideology that are usually present in children’s texts: the first are explicit ideologies, which usually aim to “openly advocate for ‘progressive’ or ‘enlightened’ ideas” . He and Robyn McCallum later refer to these ideologies as “topicalized.” Topicalized ideologies are those that appear “as … overt or explicit element[s] in the text, expressing the writer’s social, political, or moral beliefs”  subject matter not typically seen as appropriate for child readers. As Tison Pugh argues, Rowling regularly “slyly introduce[s] numerous topics typically considered taboo for children – vulgarity, bestiality, alcoholism, excrementality,” and homosexuality 2011, p. 86). The careful occlusion of transgressive topics allows Rowling to introduce them even while they remain absent from the text and to use humor to deflect criticism. Rowling’s tongue-in-cheek, often euphemistic depictions of sexuality, while usually focused on heteronormative entanglements, include cross-species and homosexual hints . She emphasizes that the wizarding population in the novels is regularly portrayed as abnormal precisely because of its nonhegemonic gendered behaviors and dress: wizards are often depicted wearing bright or feminine colors, robes that appear dress-like, or unconventional clothing for their apparent genders. Moreover, they are often shown to be more physically and emotionally affectionate than traditional gender roles would allow, for example by hugging strangers on the street. Wannamaker argues that these “abject” depictions of gender:Half-Blood Prince (2005) and Deathly Hallows  and Fleur (one-quarter Veela); the material transformations made possible by glamors (spells that can change one’s appearance) and potions like the Polyjuice Potion ; and the bodily fluidity of Animagi , Metamorphmagi (born shapeshifters who can change their appearance at will), and magical creatures such as werewolves and Veela (who transform under specific stimuli). Although the characters in the novels usually limit their transformations to the gender they were assigned at birth, mishaps such as Hermione’s accidental use of a cat hair in her Polyjuice in the second novel and jokes made by the characters suggest early in the series that the barriers between the genders are just as permeable as those between species. This is confirmed in the two final books in the series,  Hallows : in the d Prince  and DeatThe Harry Potter fan community is extraordinarily large, varied, and productive . For Fish, then, “an interpretive community... constitute[s] the objects upon which its members  can then agree” . The act of reading, in this view, is deeply entangled with the act of self-building, and neither texts nor readers can be disentangled from the social, political, and historical contexts in which they find themselves. However, reading communities can work together to open up and explore the multiple, at times disavowed, identificatory possibilities latent within texts  characters as trans” Rose, , p. 107.trans-) [and destabilize] existing categories for sexuality and gender” . She argues that through slash, “the body is experienced – felt – differently…. [This] allows us to change our embodiments (the bodies we feel ourselves to have) without changing our physical or corporeal bodies, although some slash fans may (and do) go on to do this” . Willis’s focus on cis women in her piece does not diminish the importance of her argument when it is considered in conjunction with a number of recent articles exploring the importance of slash to gender minority fans  films, as a private matter . He linked this impetus in the text to the “loving, passionate,” and accepting Harry Potter fan community, “a community that continues to foster that same safe space for every queer or trans person who needs it, and which commits itself intentionally toward growth and learning in its inclusion” (2019a). Moreover, Bird argues, “While I was nervous about coming out to some relatives and acquaintances, I never doubted that the Harry Potter fan community would accept me for who I was” (2019a), a sentiment which echoes his earlier writings on the importance of Harry Potter to his personal journey (2019b).Rowling’s commentary has justifiably been received with horror by many Harry Potter fans, who have learned through her books and the fandom not only to privilege inclusivity but quite specifically to consider gender as expansive and fluid Bird, . A greatThe ongoing conflict between Rowling and many of her fans emphasizes that children’s culture is neither limited by “top-down forces of ideological and institutional control, nor … a free space of individual expression” but is rather “a site of conflicting values, goals, and expectations” Jenkins, , p. 4. GGender minority individuals report that a key factor that increases acts of discrimination and violence in their day-to-day lives is “behavior by politicians, public figures, [and] community leaders” FRA, , p. 3. ARowling’s attempts to silence and dismiss her critics demonstrate the uneven balance of power between authors and readers. As is shown above, Rowling has spent considerable time and effort cultivating a specific type of fandom—one that bows to her interpretive whims—and quashing dissenting voices and movements. The fallout of her most recent “feminist” rants on Twitter and her blog demonstrate just how slippery, contradictory, and contingent readers’ interpretations of the ideologies within and surrounding texts can be. As Busse argues, “Contemporary readers may dismiss authorial intentions but nevertheless rely on authorial identity in their readings and public utterances” . Rowling’s carefully cultivated persona as a fan-positive, progressive author is beginning to crack. This is not only because she is receiving justifiable criticism for “apparently wanting credit for things she failed to actually do in her books” (Salter and Stanfill, Nonetheless, in a world in which gender minority individuals are feeling increasingly discriminated against FRA, , fan fic


Fibromyalgia is a chronic condition, with a high degree of psychiatric comorbidity and an insufficiently explained pathogenesis. Therefore, its therapeutic management is challenging, with both pharmacological and non-pharmacological approaches being suggested as treatment options.To analyze the current level of evidence in favour of pharmacological treatment for fibromyalgia.A literature review was performed through the main medical databases using the search paradigm “fibromyalgia” AND “pharmacological therapy” OR “antidepressants” OR “moodstabilizers” OR “anxiolytics”. All papers published between January 2000 and August 2020 were included in the primary analysis.A gradually increasing interest for the treatment of fibromyalgia has been observed in the last decade, and the number of clinical trials for this indications has almost doubled in this period, when compared to the previous decade. Pregabalin, duloxetine, and milnacipran are the most supported by evidence pharmacological treatments for fibromyalgia, especially for the pain component. Amitriptyline, gabapentin, cyclobenzaprine, and tramadol have also been studied in various clinical trials, but tehre are less evidence to support their use. Cognitive dysfunctions, sleep disorders, and mood disturbances benefit from far less investigation in clinical trials, therefore no clear recommendation can be made regarding the superiority of an agent over another.The pain component of fibromyalgia benefits from treatment with pregabalin, duloxetine, and milnacipran, while the affective component and the cognitive dimension still need more research from the psychopharmacological perspective.


Communication between cells enables the coordination that drives structural and functional complexity in biological systems. Both single and multicellular organisms have evolved diverse communication systems for a range of purposes, including synchronization of behavior, division of labor, and spatial organization. Synthetic systems are also increasingly being engineered to utilize cell–cell communication. While research has elucidated the form and function of cell–cell communication in many biological systems, our knowledge is still limited by the confounding effects of other biological phenomena at play and the bias of the evolutionary background. In this work, our goal is to push forward the context-free understanding of what impact cell–cell communication can have on cellular and population behavior to more fully understand the extent to which cell–cell communication systems can be utilized, modified, and engineered. We use an in silico model of 3D multiscale cellular populations, with dynamic intracellular networks interacting via diffusible signals. We focus on two key communication parameters: the effective interaction distance at which cells are able to interact and the receptor activation threshold. We found that cell–cell communication can be divided into six different forms along the parameter axes, three asocial and three social. We also show that cellular behavior, tissue composition, and tissue diversity are all highly sensitive to both the general form and specific parameters of communication even when the cellular network has not been biased towards that behavior. Communication between cells is a key property of living systems, from unicellular microbes to multicellular organisms. By signaling to each other, cells are able to coordinate their activity, thereby attaining structural and functional complexity. Fundamentally, these complexities are achieved by regulating which cellular behaviors occur within a population and how those behaviors are organized. To achieve this, organisms have evolved communication systems that are diverse in both mechanism and function.V. cholera and P. aeruginosa relying on quorum sensing to collectively express virulence factors when pathogenicity will be maximized [E. coli secreting a chemical trail to collectively migrate toward food sources [B. subtilis collectively sporulating in response to quorum signals when there is not enough food for colony survival [B. subtilis colonies during colony expansion [In microbial populations, cell–cell communication systems are pervasive and utilized for a variety of population functions. For example, signaling is used to propagate information through a population to provide long range coordination, as in the use of ion channels to regulate metabolic states during growth cycles in biofilms ,2. It caaximized ,4; motil sources ; and sposurvival . Cell–cexpansion ,8; and txpansion ,10. Furtxpansion ,12,13.In multicellular organisms, cell–cell communication is so vital that it is recognized as a defining feature of multicellularity . Indeed,In addition to naturally occurring systems, cell–cell communication is increasingly being utilized as a tool in synthetic systems. Many of the communication mechanisms used in living systems can be adapted for synthetic systems. Current research areas include the synthesis of populations capable of swarming behavior , reliablWhile research has elucidated the form and function of cell–cell communication in many biological systems across both unicellular and multicellular organisms, there are often other phenomena at play that confound the effects of communication. For example, the architecture of the genetic network, stochasticity in gene expression, asymmetric cell division, and cell cycle heterogeneity can all contribute to behavioral heterogeneity within a population ,36,37,38Given that cell–cell communication is such a vital aspect across many diverse systems, understanding the extent of its effects can provide widely-applicable insights. Thus, with the work reported here, we strive to push forward the general understanding of what impact cell–cell communication can have on cellular and population behavior. We can apply this understanding to learning how current systems might have evolved, including the transition from unicellular to multicellular life. We can also more fully understand how extant systems operate and how modifications to communication can affect population dynamics. Such knowledge extends to the role of communication in disease-altered states and how disease effects might be remediated by cell–cell communication-based intervention. Lastly, for synthetic systems, it is necessary to understand the role of communication so that systems can be designed accurately and efficiently, and undesirable collateral effects can be avoided.In order to isolate the effects of communication so that we may understand the general principles relating cell–cell communication to cellular and collective behavior, we use an abstract in silico model of cellular populations. Specifically, we use a 3D multiscale cellular population model, with dynamic intracellular networks interacting via diffusible signals to form intercellular connections . By inclWe find that cellular populations are characterized by different forms of communication as a function of the effective interaction distance and receptor threshold. These include the disruption of communication altogether and various degrees of dependence between cells within a population. Cellular and population behavior is highly sensitive to both the general form and specific parameters of communication present even when the cellular network has no bias towards that behavior. Tissue diversity, both behavioral and spatial, is also broadly impacted by communication. Overall, this work shows that communication between cells has a strong and tunable effect on biological behavior across a general cellular background that did not evolve a communication system.Our in silico framework consists of a population of individual cells, organized on a 3D grid, which send signals through diffusible molecules a. Each cEach cell in our simulation framework is modeled as a Boolean network. BNs have a long history of being used as biological models, especially as gene regulatory networks . Importai is a network defined on a set of n binary-valued variables,j. The nodes in the cellular networks are divided into two categories: regulatory nodes and signaling nodes. Signaling nodes come in pairs of a signal node, which secretes a diffusible molecule, and a receptor node, which is activated by that molecule. Over time, the state of the cell, The BN of cell j, is determined by applying a corresponding Boolean update function with k inputs, The value of each regulatory node, k is constant for all nodes; the k input nodes for each regulatory node are randomly chosen uniformly from the regulatory and receptor nodes. The signal node is never used as an input in order to keep communication distinct from internal regulation. For the truth tables, elements are assigned values of 0 or 1 with a bias k and p can be varied to tune the network’s response to perturbations, ranging between ordered dynamics (insensitive to perturbations) and chaotic dynamics (highly sensitive to perturbations).The function k scheme . For theThe two types of signaling nodes, signals and receptors, each behave differently. The signal node follows the same rules as the regulatory nodes. The receptor node updates using a threshold function on the local concentration of its corresponding signal—described in N cells in a tissue is described by the same BN  and occupies a grid point on a 3D structured lattice. Specifically, cells are located in the center of voxels, which have a volume of H is the lattice size. We set In our simulations, each of the m. A cell i releases molecule m with a secretion rate of C, of molecule m changes in space and time according to a diffusion degradation equation. For cells arranged in a rectangular lattice, this is approximated by:i of the lattice containing cell i. D is the diffusion coefficient and R is the radius of the cell [R so that the value of m, cell i checks the local concentration of the signal at its grid point. If the local concentration of m is above a threshold value, m at the position of cell i. We will vary We include signaling between cells by modeling the secretion and sensing of a single diffusible molecule, the cell ,49. λ ist of the simulation, the concentration of signalling molecule m is updated by numerically solving diffusion Equation  and asocial  categories =xSi(t) b. Even weither itself or neighbors; in region S3, a cell must receive signal from both itself and neighbors for its receptor to be activated. For each of these regions, the configuration of signaling states within the population affects receptor response and more neighbor signal is required as Signaling becomes communication and cells’ receptor responses are affected by their social environment in regions S1, S2, and S3 of the  θ space a. In the θ space b. A cellWhile these results were obtained from experimental simulations, one can also analytically derive the four boundary curves necessary to define the regions in the signaling parameter space using an approximation of the steady state equation for molecule concentration see . This anHere, we have only considered the extreme case in which every neighbor cell is either signaling or not. However, the switch in social behavior occurs exactly at these extremes. Within each parameter region, the particular response of a cell is dependent on the fraction of signaling neighbors, their spatial configuration, and the signaling parameter values; nevertheless, the particular response will fall under the category determined by the parameter region. The granular effects of signaling state configuration were explored by Maire et al.  in a simHaving identified six distinct signaling regions, we then investigated how cellular and tissue behavior can change between and within them. For this, we simulated tissues with different ng cells ,52. ThouWe simulated each tissue with 108  1 in A3 . The iniAll simulations were run for 2000 time steps, at which point all tissue samples had reached steady state behavior (attractor). A tissue sample reaches an attractor once all cells collectively revisit the same cell states, i.e., the set of all nodes in the tissue sample revisits the same state. Formally, this occurs when there exists a t:i. Note that, typically, attractors are fully ordered sets under circular permutation; however, we do not consider state order. In practice, we have observed that the state order is never the sole discerning feature between two cellular attractors.The tissue attractor is defined as the vector of all cell states that occurred between time For each tissue, there exists a set of unique CAs, a is true and zero if a is false. First, we simply considered whether a cell behaves differently when cell–cell communication is present (S parameter regions) versus absent (A parameter regions). To quantify this question, we measured the likelihood that a cell’s behavior would change as a function of the signaling parameters. For a given tissue sample, we identified which cellular attractor each of its 4096 cells occupied, representing the tissue sample by its tissue attractor, ncreases a. Surprincreases b. In allIn the other 64% of tissues, some fraction of cells in the social tissue samples entered different CAs compared to the ones occupied in the asocial references. Here, we found that the magnitude of the cells affected is not only different between tissues but within tissues (across tissue samples) as well c–e. Thusθ values c, have a θ space d, or hav θ space e. Additi θ space . For eac tissues . Interes (λ = 3) a. OveralFor those tissues in which cellular behavior is affected by cell–cell communication, we also considered whether it can alter the range of possible behaviors cells can exhibit. In other words, is cellular behavior limited or expanded by communication? For each tissue, we counted the number of all cellular attractors observed across either asocial tissue samples  or social tissue samples  and found a significant difference between the two a. In rouGiven the discrepancy between the number of cellular attractors available to cells in social versus in asocial tissue samples, the set of CAs in each category must be distinct, i.e., cells that communicate are capable of different behavior compared to cells that do not. By directly comparing CAs between the asocial and social parameter regions, we found that cellular BNs can both lose or gain CAs when communicating . A celluWhile missing CAs are missing from the entire social signaling parameter space, the expression of novel CAs is not evenly distributed across interaction distances and receptor threshold values. Some novel CAs are only observed at particular at λ=1.5 c. Additintil λ=3 d. Thus, X will only occur once and will always have the same following cell state In order to understand how novel CAs can arise in cells in social tissue samples, we considered how they are related to other CAs. Per the definition of a cellular attractor, a CA consists of a set of cellular states. In the case of cells in asocial tissue samples, when cells are essentially closed systems, a cell state  tissues a and usu tissues b. ModifiDoes the composition of a tissue change as communication is added?M is the number of unique CAs for that tissue across all interaction distances, M, regardless of the CAs observed at a particular value of P and Q is given by:P and Q are identical distributions, then the symmetric KL divergence will be 0 and will increase as P and Q diverge. In practice, a small value P and Q to avoid calculations involving a value of 0.Next, we examined the relationship between communication and population behavior. Since changes in lower cellular-level properties are not perfectly correlated with changes in higher tissue-level properties, we began by testing whether a tissue has any change to its behavior in response to changes in communication. Specifically, we measured the macroscopic property of CA distributions within the tissue samples. To construct a CA distribution for a given tissue sample, we calculate the fraction of cells in the tissue with each CA, which gives:P and Q) that we compare are the CA distribution of a tissue sample, In our calculations, the two distributions , some displayed distinctive patterning  resembliCommunication is a key component of living systems, providing a means by which cells can coordinate their activities to achieve collective goals and accomplish complex functions. Understanding the range and magnitude of the effects of communication within populations advances our understanding of how communication systems have evolved and how they function in extant organisms. It also advances our ability to modify, manipulate, and repair existing or synthetic systems. In this work, we have used an in silico model of three-dimensional cellular populations to explore the effects communication can have on cellular and population behavior. In order to capture the interplay between intercellular communication and intracellular systems capable of diverse behavior, we modeled cellular dynamics using random Boolean networks. Boolean networks have been successfully utilized to capture cellular dynamics with multiple stable behaviors, including the transition into or between behaviors upon external perturbation ,54,55,56We focused on two signaling parameters, the effective interaction distance between cells, en cells ,44. In aen cells ,59,60. TUsing our model, we have shown that signaling by cells does not guarantee communication, in which a signal sent by one cell can alter the receptor response of another a. Moreove et al.  who explWhen biological cells do communicate, they coordinate by regulating cellular behavior within the population. Thus, cells utilize external signals as cues for changing their behavior. We found that the fraction of cells within our simulated populations that change behavior due to communication is highly variable with λ and θ a. It is One consequence of the external influence from other cells is that the set of behaviors that cells can exhibit is not consistent between cells within asocial and social signaling environments. Cellular behaviors can be lost or gained due to cell–cell communication a,b. InteWhile the behavior of individual cells is regulated by intercellular signals, cell–cell communication is ultimately a population phenomenon. As such, population-level properties are also regulated by communication as a culmination of cellular level changes. In this work, we focused on the distribution and diversity of cellular behaviors within a tissue  as population properties that are often important in achieving collective behavior, especially division of labor. We have shown that both tissue composition and diversity can be tuned by changing the effective interaction distance and receptor activation threshold f,k. InteFor each of the cellular and tissue properties we have discussed, we have found that not only do different tissues have different responses to changing cell–cell communication parameters, but that a single tissue is capable of distinct responses within the social regions of the Overall, there is a clear difference between the cellular and population behavior of communicating and non-communicating populations. Due to the small sample size of tissue BNs that were simulated (100 of


To perform a bibliometric analysis of scientific production related to gut microbiota and Parkinson's disease between 2011 and 2020.  A descriptive, retrospective, cross-sectional, and bibliometric study was carried out. The Scopus database was used as a source to evaluate the worldwide scientific production on intestinal microbiota and its relationship with Parkinson's disease. Data were extracted from Scopus using a formula developed with thesaurus terms MeSH (Medline) and Emtree (Embase).  A total of 591 documents were found. The retrieved manuscripts received an average of 41.9 citations per document. Four of the 10 most productive authors were Italian. The University of Helsinki (Finland) was the institution with the highest scientific production (19 papers) and the highest impact (5921 citations). In terms of productivity and impact, Movement Disorders ranked first with 38 papers and 2782 citations, and those papers published in Q1 quartile journals exceeded the sum of the remaining quartiles. Papers with international collaboration were the most cited. Keyword analysis showed that the terms Parkinson Disease, Disease, and Intestine Flora were the most frequent.  The number of papers on Parkinson's disease and gut microbiota has been increasing; however, high-quality journals maintain the same high publication rate. International collaboration from high-income countries played an important role in the impact generated by the publications. Parkinson's disease (PD) is a common neurodegenerative disorder that is age-related. It has an approximate prevalence of more than 6 million people worldwide . Due to PD is expressed by a decrease in dopamine levels which in turn triggers motor disturbances such as tremor, loss of balance, and rigidity . It has In addition to the report of intestinal dysbiosis present in PD patients , 10, theBibliometrics is the use of different statistical methods to analyze scientific publications through different indicators of production, impact, and collaboration. In addition, authors, institutions, keywords, etc. are evaluated. Bibliometric analyses have been used to explore the scientific production of researchers, institutions, and regions in certain areas –17. ThisTherefore, the aim of this research was to analyze the status and characteristics of current trends in worldwide publications on gut microbiota and Parkinson's disease through a bibliometric analysis.https://www.scopus.com/) was used to access the metadata of the manuscripts. It was decided to work with this database because of its scope since it condenses international data and has a wide range of scientific journals compared to other databases [The Scopus database  was used to increase the scope of the search for words that share the same root. The search was performed in Medicine, and a cut-off period of 2011-2020 was established in SciVal.The MeSH and Emtree terms from PubMed and Embase were used, respectively. The “AND” and “OR” operators were used to elaborate the final search strategy. In addition, the truncator  AND TITLE-ABS-KEY (“lactobacill∗” OR “bifidobacter∗” OR “enterococ∗” OR “saccharom∗” OR “streptoc∗” OR “escheric∗” OR “probiot∗” OR “Prebiot∗” OR “Dietary Fiber∗” OR “Wheat Bran∗” OR “Roughage∗” OR “Dietary Carbohydrate∗” OR “Synbiot∗” OR “dysbios∗” OR “gut intestine∗ flora” OR “microbiota∗” OR “microbiome∗” OR “flora” OR “gut microflora”) AND ).The following strategy was established: TITLE-ABS-KEY , where some indicators of production, impact, and collaboration were identified.On September 19, 2021, the data corresponding to the period 2011-2020 were downloaded and exported from Scopus in .csv format. This was since the year 2021 was not yet in force in SciVal because it was still a current year. They were then analyzed with the SciVal tool  number of papers and most productive journals, universities, and authors publishing scientific papers on Parkinson's disease and gut microbiota; (b) collaboration in research related to the topic; (c) citation count; (d) document count; (e) citations per document; (f) CiteScore calculates the average number of citations received in a calendar year for all articles published in that journal in the previous 3 years ; and (g)The VOSviewer software (version 1.6.10) was used to analyze the most important collaborative networks . In addin = 219; 37.1%), general medicine , pharmacology , gastroenterology , and immunology and allergy .A total of 591 documents were retrieved from the Medicine Category, with 24750 citations, 3243 citations and, in addition, an average of 41.9 citations per document. Most of the retrieved documents were published in the following subcategories: neurology , followed by only institutional collaboration  and international collaboration . However, in terms of impact, international collaboration  exceeds both national  and institutional . The rest of the documents belong to the “single authorship” or “no collaboration” category .In recent years, an association between microbiota and neurological diseases has been found. Recent studies have demonstrated alterations in the intestinal microbiota in PD patients as well as a possible use of this microbiota as a therapeutic target, so that in the coming years the number of publications will increase significantly. The present research constitutes the first study that analyzes the worldwide scientific production on PD and gut microbiota, with emphasis on the category Medicine. This research assumes that the impact of a study is expressed in the citations it receives from the world literature once it is published.Bibliometric analyses are used to evaluate the characteristics of published scientific research, especially in specialized scientific fields . Scopus When evaluating the data for the period 2011-2020, Scheperjans (Finland) is the author with the largest number of papers and is the most influential in gut microbiota and PD research by far with respect to the other authors. One of his greatest contributions is the suggestion that the gut microbiome is altered in PD and is associated with the motor phenotype of PD such as postural instability and difficulty in walking . On the In terms of the 10 most prolific institutions, U.S. institutions were the most productive. University of Helsinki was the institution with the highest production and impact. It is also important to note that University College London is the institution with the highest citation per paper. This is consistent with a bibliometric study by Shafiei et al. who reported that this institution is the most productive in the field of movement disorders; so, this denotes intrainstitutional collaboration and a line of research directed to be at the forefront of global research in this field .Movement Disorders was the journal with the highest number of papers (38) and citations (2782). In addition, it has remained among the most productive journals among other bibliometric studies, ranking first in Deep Brain Stimulation Treatment for Dystonia  and in tIn our analysis, national collaborative papers predominated over international ones. These results are like those of a bibliometric analysis on multiple sclerosis . In addiFinally, our research has some limitations. First, only the last 10 years were analyzed; so, some studies on the subject were excluded, representing more than 80% of all available papers on the topic in Scopus. Second, like other bibliometric studies, some papers may have been omitted because they were published in journals not indexed in Scopus. However, this is the first study on Parkinson's disease and gut microbiota applying bibliometric indicators. Third, we only analyzed bibliometric information from the Scopus database, which does not reflect the totality of publications on the subject. However, Scopus only includes journals that met a strict peer review process and high standards .The number of papers on Parkinson's disease and gut microbiota has been increasing; however, high-quality journals have maintained the same high publication rate over the last decade. International collaboration from high-income countries plays an important role in the impact generated by publications. Joint efforts between institutions and researchers from different countries are needed to establish connections and future research to expand knowledge on this growing and novel topic.