Background: Smoking during pregnancy is a public health problem worldwide and the leading preventable cause of fetal morbidity and mortality and obstetric disease. Although the risk of tobacco-related harm can be substantially reduced if mothers stop smoking in the first trimester, the proportion of women who do so remains modest; therefore, the treatment of smoking in pregnant women will be the first therapeutic measure that health professionals should adopt when providing care to pregnant women. The recommendation of nicotine replacement therapy during pregnancy remains controversial due to the potential effects on the health of the fetus. Purpose: The aim of this review was to provide an overview of human studies about the use of nicotine replacement therapy during pregnancy, evaluating the efficacy and safety of the different formulations. Methods: The electronic databases PubMed and EMBASE were searched from May 2012 to May 2022. A total of 95 articles were identified through database searching using a combination of keywords. Out of 79 screened articles and after the removal of duplicates, 28 full-text articles were assessed for eligibility and 12 articles were finally included for review. Results: Although demonstrated to be effective in adult smokers, evidence in support of NRT in pregnant women is limited. The results of the apparent safety of the use of NRT during pregnancy contradict the FDA classification of the different NRT formulations. Faster-acting formulations seem to be the safest and even most beneficial forms for the offspring. Conclusions: NRT is not completely harmless for the fetus or for the mother; however, if an adequate assessment of the risk-benefit binomial is made, its use during pregnancy to aid in quitting smoking does seem appropriate. It is necessary to establish individual recommendations on the formulation and dose to be used during pregnancy based on individual nicotinic needs. Smoking during pregnancy is associated with different serious adverse obstetric and neonatal outcomes ,2. TheseMany women are unable to quit smoking despite receiving behavioral interventions ,10. It iOn the one hand, the use of NRT to avoid smoking during pregnancy reduces the number of toxins , but on the other hand, NRT exposes the nicotine  so its uIt should be noted that the pharmacokinetic characteristics of nicotine in the fetus are different from those in the mother. Most of the nicotine that reaches the fetus returns to the maternal circulation, so the mother is responsible for its elimination. However, the fetus excretes a certain amount of nicotine into the amniotic fluid through urine. This will contribute to the amniotic fluid of pregnant smokers having high concentrations of nicotine and cotinine. This fact causes the fetus to be exposed to high concentrations of nicotine even after concentrations in maternal blood have decreased ,16. AnimDespite several systematic reviews and recommendations on the benefit-risk ratio of NRT use during pregnancy, current knowledge is insufficient about the different types of NRT and the efficacy and safety of each of them for smoking cessation in pregnancy ,23,24,25This review was performed according to PRISMA guidelines ,27. The No restrictions on language and publication status were applied. Abstracts were included if there was sufficient information to assess the study’s quality. Original studies that explored NRT during pregnancy in humans and review articles that aimed to determine the efficacy and safety of pharmacotherapy for smoking cessation when used during pregnancy were eligible for inclusion. The exclusion criteria were studies that did not mention pharmacotherapy or without mention of metabolism in pregnant women, those that did not study the use of different formulations of NRT among smokers and non-human research.Two authors conducted data extraction independently and reached a consensus. The first selection was made based on title and abstract. Eligible publication full texts were assessed. Variables of interest extracted were authors’ names, the year of publication, the type of study, the sample size, the period of inclusion, the country of the study, and the article’s main outcomes.The different selected studies that met the inclusion criteria were classified according to their pharmaceutical form: chewing gum; inhalers; patches; combination of different NRT formulations. The information obtained for each of the different NRT formulations was assessed: efficacy and safety.A total of 95 articles were identified through database searching using a combination of keywords. Out of 79 screened articles and after duplicates were removed, 28 articles were assessed for eligibility. Finally, nine original articles were found and included in this review, along with three review articles. In all of the studies, the degree of smoking of the mothers is established either through questionnaires or through the determination of biological markers (cotinine and CO). In some of them, the degree of dependency (FTND and HSI) is also determined.p-value (p) = 0.45; at 32–34 weeks of gestation: 18% compared to 14.9%, p = 0.56). NRT, compared to the placebo group, showed significantly greater reductions in cigarettes smoked per day. Birth outcomes showed that there were clinically important and statistically significant differences in favor of NRT compared to placebo in birth weight  and gestational age . Nine times higher incidence of low-birth-weight infants and twice the incidence of preterm birth in the placebo group compared to the NRT group. In summary, nicotine gum therapy was associated with a lower risk of preterm birth and higher neonatal birth weight.In relation to NRT gum or lozenge, specifically on the use of nicotine gum, there is a study by Oncken et al., 2008 , which ap > 0.99). Even the dropout rate was higher at 32 weeks’ gestation for the placebo group  than for the nicotine group  (p = 0.220). A difference in initial motivation to quit smoking could explain this difference in quit rates at 32 weeks gestation between the two groups. However, it should be noted that although abstinence was not achieved in most of the pregnant women who participated in the study, a reduction in the number of cigarettes smoked per day was observed from the beginning of the trial to the end in the group randomized with nicotine. With regard to safety in nicotine oral inhalers, more women in the placebo group had a preterm birth compared to the nicotine group (15% (10 of 67) vs. 4% (3 of 67), respectively, p = 0.030) or a low-birth-weight baby (15% (10 of 67) vs. 6% (4 of 67), respectively, p = 0.035). On the other hand, a group of participants who had been randomized to NRT reported moderate adverse reactions, all associated with the use of oral nicotine inhalers during treatment, including throat irritation, bad taste, and increased mucus in the upper respiratory airways, which are well known. Throat irritation likely arises from attempts to inhale like a cigarette rather than holding the dose in the mouth to absorb through oral mucosae. These findings suggest that oral nicotine inhaler has a favorable safety profile.Concerning oral nicotine inhaler, it is a form of NRT that provides some of the sensory and ritualized components of smoking, such as handling and inhalation, which may be particularly important for women smokers and thus increase adherence to treatment in women. Absorption is through oral mucosae with this device, with an onset of action similar to NRT gum/lozenge. The study by Oncken et al., 2019  is the oNicotine patches are the most studied presentation of NRT in recent times, Coleman et al. 2012  in a ranIn the trial conducted by Berlin et al., 2014,  402 pregp = 0.023). However, no difference in frequency was observed with respect to respiratory problems.The trial by Coleman et al., 2012 , did notFive years later Iyen et al., 2019  investign = 1143) reported having been abstinent for at least two weeks and had an expired-air CO measurement of less than 10 ppm. In the trial, it describes that 29.4% of pregnant women who did not have medication continued to smoke, 31.6% of those who used only NRT and 21.2% of those who used combined NRT. Consistent with findings from previous RCTs in pregnancy, NRT alone is not associated with better abstinence rates; however, combined NRT was strongly associated with greater odds of abstinence at four-week follow-up , while NRT alone showed no benefit . The trial by Brose et al., 2013 [The combined use of NRTs  is evaluated in the study by Brose et al., 2013 . Nicotinl., 2013 , is the As can be seen in the studies by Coleman et al., 2015 , Claire In Cooper et al. of 2014 , the offThe study by Zhu et al., 2014  used datThe second study is that of Dhalwani et al., 2015 ; it doesIn the reviews found with these characteristics, no differentiation is made between faster-acting or long-acting NRT, so when the concept is used in these articles, reference is made to all possible presentations of NRT that have been used in published studies without distinctions. The first two studies, Coleman et al., 2015 , and Clap = 0.08).In the trial by Claire et al., 2020 , a furthIn all three studies, Coleman et al., 2015 , Claire Coleman et al. 2015  and ClaiNRT is available as transdermal patches, lozenges, gum, sprays and inhalers. Patches provide long-acting nicotine exposure, while gum, lozenges, inhalers and sprays act faster with a shorter duration of action. Treatment may involve the use of a single formulation or multiple formulations simultaneously, usually a patch and a faster-acting product . NicotinAmong the different presentations of NRT, whether they are faster-acting or long-acting, there is no significant evidence in favor of NRT in achieving abstinence among pregnant women ,30,31,32The results of the apparent safety of the use of NRT during pregnancy, as determined in the trials and reviews studied , contraAfter analyzing the results, we observe that NRT is not completely harmless for the fetus or for the mother; however, if an adequate assessment of the risk-benefit binomial is made, it does seem appropriate to use it to quit smoking during pregnancy, but it is necessary to establish recommendations on its use during this period.While it would be preferable for pregnant women to stop smoking without the need for NRT, if it is needed, it does not expose the fetus to a new drug that it would not already be exposed to otherwise and its use in place of cigarettes likely decreases the exposure to the other toxins and carbon monoxide present in cigarettes. This reduced exposure to carbon monoxide in the fetus could be the mechanism for some of the improved outcomes observed, such as birth weight, in NRT users.Pregnancy is well known to affect the metabolism of some drugs and may result in higher or lower clearances compared to the non-pregnant state. If the metabolism of nicotine were slower during pregnancy, with the usual doses of NRT for adults, the plasma levels of nicotine could increase to toxic levels in the pregnant woman and potentially be more toxic to the fetus; however, the scientific literature affirms that in pregnancy the metabolism of this organic compound is accelerated ,21,39,40The exact causes of increased metabolism during pregnancy are unknown, but more recent studies suggest the hypothesis that it may be due to increased progesterone levels during pregnancy. Non-pregnant women using progesterone-containing contraceptives metabolize nicotine more rapidly than women not using contraceptives; during pregnancy, these hormones begin to increase, so it is hypothesized that they may be responsible for the increased activity of CYP2A6 during pregnancy ,43.The hepatic enzyme cytochrome P450 2A6 (CYP2A6) is primarily responsible for converting nicotine to cotinine and cotinine to its close metabolite trans-3’-hydroxycotinine (3HC) ,41,44. TRegarding the weaknesses of the study, we found that all the included studies were carried out in countries with a high economic level. Therefore, these results may not be applicable to lower-middle-income countries if women’s smoking patterns or beliefs about medication use in pregnancy differ.In the reviewed studies, there is heterogeneity in the approach; hence, the lack of certainty regarding the efficacy of the therapy may have been the result of certain limitations in the way in which the studies presented have been developed. For example, while in some studies an individualization of the therapy doses is carried out based on the smoking status of each of the patients, in others, it is not, which could explain the lack of efficacy and low compliance by the participants. Moreover, during pregnancy, many women tend to reduce the number of cigarettes smoked per day , which lThis review provides an overview of studies on the use of NRT during pregnancy. Despite the fact that there is an increase in studies that aim to evaluate the use of NRT during pregnancy, the number of studies continues to be very low. Although the studies have certain weaknesses, the information they provide on the subject is essential to be able to establish guidelines and protocols for the management of smoking cessation during pregnancy. The combination of faster-acting and long-acting NRT has been the only strategy that has achieved higher rates of abstinence among pregnant women. Faster-acting formulations seem to be the safest and even most beneficial forms for the offspring. Further, well-designed controlled clinical trials evaluating safety based on other parameters that are not exclusively perinatal results are suggested. The use of NRT during pregnancy must involve the active participation of health personnel to guarantee its correct use as an individualization of the formulation. Moreover, doses must be carried out for each patient based on their individual nicotinic needs, taking into account both psychosocial factors and the increased metabolism of nicotine during pregnancy before starting treatment.


The coronavirus disease 2019 (COVID-19) time exacerbated some of the conditions already considered critical in pediatric health assistance before the pandemic. A new form of pediatric social abandonment has arisen leading to diagnostic delays in surgical disorders and a lack of support for the chronic ones. Health services were interrupted and ministerial appointments for pediatric surgical healthcare reprogramming were postponed. As a result, any determination to regulate the term “pediatric” specificity was lost. The aim is, while facing the critical issues exacerbated by the COVID-19 pandemic, to rebuild future perspectives of pediatric surgical care in Italy.Each Pediatric Society, including the Italian Society of Pediatric Surgery (SICP), was asked by the Italian Federation of Pediatric Associations and Scientific Societies to fill a questionnaire, including the following the main issues: evaluation of pre-pandemic criticalities, pediatric care during the pandemic and recovery, and current criticalities. The future care model of our specialty was analyzed in the second part of the questionnaire.Children are seriously penalized both for surgical treatment as well as for the diagnostic component. In most centers, the pediatric surgical teams have been integrated with the adult ones and the specificity of training the pediatric operating nursing is in danger of survival. “Emotional” management of the child is not considered by the general management and the child has become again an adults patient of reduced size.A new functional pediatric surgical model needs to be established in general hospitals, including activities for day surgery and outpatient surgery. To support the care of the fragile child, a national health plan for the pediatric surgery is required. The Italian Society of Pediatric Surgery (SICP) is one of the oldest in Europe, having been founded in Livorno on the 24 February 1963. It aims to promote the progress of surgical art and science in the pediatric field, to promote and maintain the highest standard in the quality of surgical treatment provided to children in Italy, to protect the prestige and interests of pediatric surgery and its practitioners, and to facilitate the relationships of association and the exchange of ideas between pediatric surgeons. Since those early days, pediatric surgery has enormously evolved and is today one of the most vigorously growing fields in surgery. Pediatric surgery is unique in many instances. It is one of the last true general surgeries. The pediatric surgeon deals with a completely distinctive set of disorders, namely, congenital malformations that are largely unknown to the general adult surgeon. Finally, the pediatric surgeon operates on a future, as most of patients have a long life expectancy in front of them. This brings with it the greatest responsibility for the caring surgeon. Despite, or maybe due to these peculiarities, pediatric surgery has long faced several critical issues. Diagnosis Related Groups (DRG) dedicated to the child are largely lacking, leading to the application of DRG created based on adult surgery necessities that do not take into account the peculiar aspects of the pediatric patient. Additionally, a clear definition of the pediatric patient is missing, which may change from region to region. As a consequence, pediatric patients may be treated in pediatric or general surgical units, depending on the region where they are located. This leads to treatment disparities due to the lack of specific pediatric expertise for patients admitted to general surgical units. In addition to the confusion on the definition of the pediatric patient, there are no projects involving the whole of Italy on the number of centers necessary to cover the needs of the population. The regions work without general coordination, which should give behavioral guidelines to the identification and authorization to open centers that should respond to clear and precise criteria. Finally, there is a shortage of pediatric surgeons in part due to mistakes made in the past regarding the forecast of future needs and in part to the fact that trainees in pediatric surgery have strict limitations on their clinical and surgical activity.These critical issues were further exacerbated during the COVID-19 pandemic. Management of patients with COVID-19 became a priority. For all other patients, the pandemic modified and slowed down hospital admittance and disarrayed the daily routine programs of diagnosis and treatment. From a healthcare point of view, there was no determination to regulate the term “pediatric” specificity. Pediatricians and pediatric surgeons were moved to adult medicine, either directly to adult patients with COVID-19 or to “free” adult colleagues to be employed in COVID-19 units or hospitals . The “stAs result, the COVID-19 time exacerbated some of the conditions already considered critical in pediatric health assistance before the pandemic. All elective health services were interrupted and ministerial appointments for pediatric healthcare reprogramming were postponed with the consequence that restrictions placed pediatric needs in the last position on the social ladder.The aim of this report is, while facing the critical issues exacerbated by the COVID-19 pandemic, to rebuild future perspectives of pediatric surgical care in Italy. To propose a perspective of the surgical children's care, a collection of data from before and during the pandemic period, as well as the current situation, was considered.The Italian Society of Pediatric Surgery is institutionally included in the Italian Federation of Pediatric Associations and Scientific Societies (FIARPED). Each pediatric society was asked by the FIARPED to describe how their field was impacted by the COVID-19 pandemic following predefined questions  operate in exclusively pediatric hospitals, whereas, 21 units (31%) operate in institutions offering both adult and pediatric surgery services and belong to university centers.The type of pediatric care is completely different from that of adults with completely peculiar implications related to age, fragility, and complexity. Specific and updated DRGs are missing. The current ones are obsolete and most of the time derive from those of adults very far from the needs and complexity of pediatric ones. Although about 10 years ago, a special ministerial commission, including pediatricians and pediatric surgeons, studied and drafted a hypothesis, this hypothesis has never been supported as a project, nor applied to clinical practice.The age of admittance in pediatric wards ranges between 0–14 and 0–18 years and they are strictly related to decisions established by local authorities or regions in almost all cases. As a consequence, the lack of shared indications creates confusion that finds its maximum expression in adolescent patients who are treated in both pediatric and adult centers, causing inequality in treatment and a lack of acquisition of correct expertise.sic and simpliciter from adulthood without taking into account the objective limitations related to age and particular to the fragile pediatric patients. Not without greater importance, it should be emphasized that the uncontrolled proliferation of pediatric surgery units on the territory of the country due to a lack of national planning for the distribution. Currently, there are 56 pediatric surgery units in Italy and with about one million inhabitants per unit as a reference. The lack of a project involving the whole of Italy on the number of centers necessary to cover the needs of the population penalizes not only the existing ones but also the local new acquisitions. There is a formal and substantial disorder because the regions work without general coordination that should give behavioral guidelines to the identification and authorization to open new centers that should respond to clear and precise criteria. An adequate national plan with precise indications would facilitate the identification of existing references and real territorial needs.Moreover, there is a great deal of confusion between day surgery and outpatient surgery activities imposed by the regions, probably because they have been imported It is not always when children are hospitalized that they end up in the pediatric wards. In Italy, about 25% of children do not receive care in child-friendly pediatric wards. The little ones are frequently and willingly enticed together with the older patients, potentially causing psychological discomforts for the child, who would need a more protective environment. According to the National Agency for Regional Health Services, Agenas, in 2019 over 175,000 hospitalizations of patients between 0 and 17 years, accounting for over 25% out of 695,215 admissions, were carried out in adult departments, in particular when surgery was required. The most frequent admissions in adult surgical units are for orthopedics, ENT, testis disorders, and appendicitis.Last but not least, the problem of surgeons in training who, due to a reduction in number in the pediatric surgery area, do not help the necessary generational turnover. This point fits perfectly with the previous one. National central planning is needed to define the number of pediatric surgery units in the country.To deal with the COVID-19 pandemic, SICP has identified the following recommendations to avoid and contain the infection, guaranteeing the protection of children, surgeons, anesthetists, nursing staff, and personnel belonging to the “surgical team,” providing timely surgical treatments to children with pathologies of surgical interest, and optimize the resources needed for child care. SICP identified a list of surgical emergencies , 2 for wThe programming of the elective interventions has been taken, with everything that follows: instrumental examinations, anesthesiologic examinations, and expected date of intervention.The pediatric surgery units in non-pediatric hub hospitals resulted in being seriously penalized concerning the scheduled activities that were expunged due to the wide use of the operating rooms as intensive care rooms for COVID-19 admittance. Every center suffered from a dramatic reduction of ward spaces because some rooms were dedicated to surgical patients with COVID-19, operating rooms in general hospitals were used for adults and children, and some pediatric hospitals were converted to intensive care units (ICUs). Some pediatric hospitals accepted adult patients with positive COVID-19 for a period in intensive care  related multisystem inflammatory syndrome in children (MIS-C), a new nosological entity that has mainly affected small children and adolescents with serious consequences , 11. In The centers have slowly and gradually rescheduled their activities, reclassifying the disorders according to recommendations given by the SICP. Reclassification of patients on the waiting list by severity classes was made, trying to highlight that even “routine” disorders  must be operated on at certain times .Due to the COVID-19 pandemic, the “emotional” aspects of the admitted child have lost their central position in patients' management. A single-parent admittance is allowed during the whole hospital stay, surveillance in the recovery room has completely disappeared, and the reception paths dedicated to fragile and chronic children have been suppressed. In addition, in non-pediatric hub centers , the child is heavily penalized and is not prioritized in emergencies compared with other adult surgical specialties. Children are seriously penalized both for surgical treatment as well as for the diagnostic component. In the operating theaters, the COVID-19 time brought together nurses and scrub nurses of various surgical specialties. The result is that surgical teams have been integrated with the adult ones and pediatric nurses and scrub nurses have been shifted to adult operating theaters. In this way, the specificity of training the pediatric nursing staff to manage the premature and critically low weight children is affected.The child has become again as an adult patient of smaller size.The COVID-19 pandemic affected every phase of emergent and scheduled activity in pediatric surgery. Interactions with the territory, already critical in a pre-COVID-19 pandemic, indicated a lack of organization of the pediatric hub-spoke network.The goal of pediatric surgeons is to ensure specific care dedicated to the pediatric patient, in a devoted environment, and with dedicated methods. The pediatric surgery unit must be the “container” of specialists in the subject and related specialties and must offer expertise in the care of the child. Infections of COVID-19 are reported to be milder in children than in the adult population. However, COVID-19 infection in children may cause concerns both for the risk of contributing to the spread of the infection and for the appearance of the MIS-C, which is considered a serious complication . To dealA “functional pediatric surgical model” for the pediatric area can also be established within a general hospital .To achieve this fundamental objective, it is necessary to resort to some urgent measures. First, it is a formalization of the concept that pediatric patients should be operated on by pediatric surgeons. Second, the development of a collaborative relationship with other satellite pediatric surgical specialties  is urgently required to identify pediatric paths dedicated to children to give back the child the dignity of care that the COVID-19 has subtracted. The COVID-19 pandemic has increased the already high number of children admitted to adult wards while children should be admitted only in a dedicated pediatric environment. Considering the high number of pediatric patients hospitalized in adult wards, the time has come to reiterate the concept of pediatric age limits valid for all Italian hospitals. It must be recalled that the first article of the “Convention on the Rights of the child” defines a child as “every human being below the age of 18 years”.On the other hand, there is a complete lack of a project involving the whole of Italy on the number of centers necessary to cover the needs of the population. There is formal and substantial disarray because the regions work without general coordination that should give behavioral guidelines to the identification and authorization to open centers that should respond to clear and precise criteria. Pediatric surgery centers must be identified based on the needs of the population and the territory and divided into treatment areas (who is authorized to do what). Having, for example, 150 cases of kidney tumors operated in 56 different centers in Italy does not allow to develop and maintain the needed skills neither for surgeons nor for the whole structures.Needs are changing rapidly. Day surgery function is increasing in all units, which constitutes a very important percentage of pediatric surgical activity. Alongside this, outpatient surgery, which has helped to reduce hospitalization, especially in chronic patients, requires space and time and dedicated staff, as well as a reorganization of nursing activities. Day surgery, outpatient surgery, and day hospital, all require investment and adaptation as they offer a quick service to the territory by reducing hospitalization, related costs, and inconveniences for the family. Such important projects of quality childcare and cost reduction are not supported by national health projects for the requalification of personnel, spaces, and related regulations.Surgical technology is advancing rapidly. In recent years, we have witnessed technological innovations in pediatric surgery with the integration of minimally invasive, robotic, and virtual reality surgery even in young patients. The response that pediatric surgery has given to the reorganization required by the pandemic has reinforced the need to implement telemedicine in clinical practice, especially aimed at chronic and frail patients. According to data reported by the activity of social and health professionals, the use of telemedicine increased significantly during the COVID-19 pandemic, also in some pediatric surgery settings . PediatrFinally, there is a lack of specialists due to past mistakes and this creates enormous discomfort. In the current attributions to post-graduate training schools (therefore with a 5-year vision), old evaluations have been used that do not meet the criteria of receptive as well as didactic capacity. Regarding surgeons in training, the legislation is very restrictive in Italy. Absurdly, a recent graduate could, in theory, be hired in cardiac surgery and operate as the first heart operator, but a surgical trainee, for example, in pediatric surgery cannot do tutoring on call. The legislation is also lacking from the point of view of the responsibility of health professionals operating in the national pediatric field. Italian legislation is not the same as that enjoyed by other professionals , and in most cases, pediatric expertise is supported by adult professionals who have no experience in pediatric surgical pathology.New protocols of pediatric care could be taken into consideration as possible scenarios for each hospital. Surgical teams are asked to adhere to national and regional guidelines, to evidence their expertise, and the availability of resources dedicated to children.The COVID-19 pandemic has upset the assistance in the pediatric area. As a consequence, the pediatric surgical organization in general hospitals and pediatric hospitals has been completely subverted. The COVID-19 infection is still spreading and children are seriously penalized both for surgical treatment as well as for the diagnostic component. In most centers, the pediatric surgical teams are the adult ones and the specificity of training the pediatric operating nursing is in danger of survival. Moreover, the pandemic has removed the “emotional” aspects of the admitted child has lost its central position in patients' management and the risk is real that in general hospitals the child will once again be considered a small adult. Given all these criticalities, all efforts should be done to define guidelines on the management of surgical children, both in pandemic times and in normal ones to ensure the specificity of treatment and give back the child the dignity of care that the COVID-19 has subtracted.FM and GP contributed to the conception and design of the study and wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer FG declared a shared affiliation with the authors FM to the handling editor at the time of review.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.


How are words connected to the thoughts they help to express? Recent brain imaging studies suggest that word representations are embodied in different neural systems through which the words are experienced. Building on this idea, embodied approaches such as the Concept Attribute Representations (CAR) theory represents concepts as a set of semantic features (attributes) mapped to different brain systems. An intriguing challenge to this theory is that people weigh concept attributes differently based on context, i.e., they construct meaning dynamically according to the combination of concepts that occur in the sentence. This research addresses this challenge through the Context-dEpendent meaning REpresentations in the BRAin (CEREBRA) neural network model. Based on changes in the brain images, CEREBRA quantifies the effect of sentence context on word meanings. Computational experiments demonstrated that words in different contexts have different representations, the changes observed in the concept attributes reveal unique conceptual combinations, and that the new representations are more similar to the other words in the sentence than to the original representations. Behavioral analysis further confirmed that the changes produced by CEREBRA are actionable knowledge that can be used to predict human responses. These experiments constitute a comprehensive evaluation of CEREBRA's context-based representations, showing that CARs can be dynamic and change based on context. Thus, CEREBRA is a useful tool for understanding how word meanings are represented in the brain, providing a framework for future interdisciplinary research on the mental lexicon. Linguistic knowledge includes (spoken and/or written) words defined by their relations to other words in the sentence and in the context in which they are expressed. This knowledge provides individuals with the capacity to communicate about history, scientific terms, ideas, plans, emotions, objects, everything. For example, the word dog is defined as a domestic animal, carnivorous, subspecies of the gray wolf, etc.Many experimental studies suggest that there are two types of semantic knowledge: linguistic and experiential . Their linguistic interactions with users are therefore limited to simple responses. Given the ambiguity and flexibility of human language, modeling human conceptual representations is essential in building AI systems that effectively interact with humans. This is the practical motivation for the work described here.The work is based on two foundations. The first is a grounding in brain activations. Although early efforts of understanding word meanings were restricted to behavioral observations . This problem has driven researchers to develop new componential approaches, where concepts are represented by a set of basic features, integrating textual and visual inputs. , but such representations are still shallow and fall short from symbol grounding. In most cases, these models build semantic representations from text corpora, where words that appear in the same context are likely to have similar meanings Harris, . Howeverpiano depending on whether he will be playing in a concert or moving the piano. When thinking about a coming performance, the emphasis will be on the piano's function, including sound and fine hand movements. When moving the piano, the emphasis will be on shape, size, weight, and other larger limb movements  words in different contexts have different representations, (2) the changes observed in the concept attributes reveal unique conceptual combinations, and (3) the new representations are more similar to the other words in the sentence than to the original representations. Further, behavioral analysis confirms that the changes produced by CEREBRA are actionable knowledge that can be used to predict human responses.While there are many computational models of word meaning in the literature, most of them fall into two general classes: relation-based, i.e., those in which a word's meaning is represented through its relations to other words Harris, , and feaCAR theory  is an embodied approach supported by evidence on how humans acquire and learn concepts through sensory-motor, affective, social, and cognitive interactions with the world  receive high ratings on features representing auditory experience , relative to things that do not make a sound .In CAR theory, neurobiologically defined “experiential attributes” form a set of primitive features representing the basic components of meaning. This set of features  capture aspects of experience that are central to the acquisition of event and object concepts, both abstract and concrete. The main idea is that people weigh concept features differently based on context, i.e., they construct meaning dynamically according to the combination of words that occur in the sentence , states , mental “products” of cognition , social cognition , and affective states . These concepts are learned in large part by generalization across these cognitive experiences in exactly the same way as concrete concepts are learned through generalization across perceptual and motor experiences Binder, .red apple) and there are general principles that govern such combinations as part of people's world knowledge. Functional groupings known as ad hoc categories  unless additional sources provide it . These features are mutually enhanced, altering the similarity between the concepts, and resulting in functional groupings or categorizations. For instance, the difference in meanings for  Harris, , CARs caNext section discusses the processes and materials used to instantiate the CAR theory through interviews of human subjects. For a more detailed account of feature selection and definition see Binder et al. , 2016 anThe CEREBRA model is based on the following sets of data: A sentence collection prepared by Glasgow et al. , the semwww.iarpa.gov/index.php/researchprograms/krns), sponsored by the Intelligence Advanced Research Projects Activity (IARPA) under the White House BRAIN Initiative Program  project  in the sentences. A total of 240 sentences were composed from two to five of those words. Sentences are in active voice and consist of a noun phrase followed by a verb phrase in past tense, with no relative clauses. Two hundred of these sentences contain an action verb and the remaining 40 contain the verb chair as having a fixed location, as on a map?”). Participants responded by selecting a number where 0 indicates “not at all” and six indicates “very much”. A “Not Applicable” option was also available to cover cases in which the participant felt the question has no logical relation to the word; these responses were coded as 0. Approximately 30 ratings were collected for each word in this manner. After averaging all ratings and removing outliers by rejecting participant responses that had a Pearson‘s correlation coefficient of <0.5 against the mean for that particular word  to the corresponding neural processes and systems for which the CAR dimensions stand . Unfortunately, the neural data set does not include such images. Therefore, a technique developed by Anderson et al.  was adopmouse  containsThe technique of averaging sentence fMRI is commonly used in imaging studies for that reason . This SynthWord collection represents the third essential input to the CEREBRA model: These are the SyntWord representations introduced in System Design.CEREBRA uses sentence fMRI patterns  and the CAR semantic feature-based model of concept representations to characterize how word meanings are modulated within the context of a sentence. With CARs of words as input, the neural network is trained to generate initial approximations of fMRI patterns of subjects reading sentences. Then, the FGREPThe overall design of CEREBRA is shown in The following sections present a detailed description of the architecture at each stage of the system implementation. CEREBRA is built on several data sets described in detail in Section Data Collection and Processing. Briefly these are: the sentence collection of 237 sentences (Section Sentence Collection), the CAR ratings or semantic representations of 236 words , the fMRI images of 237 sentences , and the fMRI synthetic representations for the 236 words . The specific terms to the CEREBRA model are denoted by abbreviations throughout the paper . For reference, they are described in the The CEREBRA model is first trained to map the CARWord representations in each sentence to SynthWords  consists of training the BPNN to map CARWord representations  to SynthWord representations . After training is completed for each subject, it yields 20 different networks, plus 20 sets of 786 predicted SynthWord representations, that is, one word representation for each sentence where the word appears.The next segment of This process is performed until the prediction error is small (near zero) or cannot be modified , which is possible since FGREP is run separately for each sentence.As a result, each SynthWord encodes the average meaning of the word. Their combination encodes the expected meaning of the sentence (SynthSent), and the difference of this combination from the actual fMRI encodes the interactions between words. The FGREP modification of the CARs then makes the effects of those interactions explicit. Therefore, the SynthWords do not need to equal the exact fMRI patterns for words in isolation, as long as they carry that information consistently. This is why synthetic fMRI words work well in CEREBRA.These steps (7 to 14) are repeated 20 times for each subject. At the end, the average of the 20 representations is used to represent each of the 786 context-based words (CARWord Revised), for every single fMRI participant.Eventually, the Revised CARWord represents the word meaning for the current sentence such that, when combined with other Revised CARWords in the sentence, the estimate of sentence fMRI becomes correct.The original FGREP mechanism . That is, the goal is not simply to predict fMRI sentence patterns accurately and generally; instead, the prediction serves only as a starting point for modifying the CARs. Of course, its performance needs to be competent; the learning curves for each mapping task . Characterizing how these features change under the context of a sentence, this research will demonstrate that context-dependent meaning representations are embedded in the sentence fMRI, and CAR theory can be used as a foundation for modeling the neural representation of word meaning. The demonstration includes several computational experiments as well as a behavioral study. The computational experiments characterize how the CAR representation of a word changes in different sentences and demonstrates that the linear regression is not powerful enough to capture these changes – a nonlinear model like CEREBRA is needed. The experiments further quantify such changes by correlating them to the CAR representations of the other words in the sentence (OWS) both through individual examples and statistically throughout the dataset. The behavioral study compares CEREBRA's context-based changes to explicit human estimate of those changes, finding that indeed they constitute actionable knowledge.The Glasgow sentence collection is not fully balanced and systematic, but instead aims to be a natural sample. To investigate the effect of context, finding mutual similarities between words or sentences sounds like a good approach. However, similarity alone is not enough, because anything is similar to anything else to some degree. Contrasting words or sentences is a better mechanism to address such effect. Therefore, a collection of 77 such sentences, with different shades of meaning for verbs, nouns, and adjectives, as well as different contexts for nouns and adjectives was assembled manually .live mouse vs. dead mouse, good soldier vs. soldier fighting, built hospital vs. damaged hospital, and playing soccer vs. watching soccer. Such list allows the computational models to evaluate distinctive attribute representations and consequently adjust the baseline meaning of a word to convey the effects of context and conceptual combination.These sets include differences and similarities like flew in sentences 200, 204 and 207 appears in two different contexts: animate (as in bird and duck) vs. inanimate (as in plane). Such contrasting sentences illustrate the idea of conceptual combination and provides the basis for computational models that characterize the effect of context. For this collection, all content words are used as target words for the analyses on the 8 subjects with the most reliable fMRI data (as determined by the fMRI team).Multiple Linear Regression (LReg) can be used to measure how CARWord change across sentences. If the mapping of semantic representations to fMRI sentences is linear, then LReg will capture such changes. In this section, the LReg approach is described; it will be evaluated in Different Contexts for the Verb “listened”.Multiple regression is first used to learn the mapping between CARWord and SynthWord voxels at word level. The training set has attribute vectors of words as independent variables and the corresponding SynthWord vectors as the dependent variable, predicting one voxel at the time. Subsequently, at sentence level, the training contains assembled sentences (SynthSent) as the independent variable and the corresponding observed fMRISent as the dependent variable. Once the prediction error is calculated, LReg is inverted (which is possible because it is linear), to determine what the CARWord values should have been to make the error zero.fitml was used to run LReg to map the CARWord to the SynthWord and the inverted linear process to map the SynthWord-revised to produce the CARWord-revised. It uses least squares to predict more than one dependent variable (Y) for one or more independent variables (X).The Matlab function i is the number of observations , Yi represents the dependent variable, Xi represents the independent variable, β0 represents y-intercept (constant term), βp is the slope coefficient for each independent variable, and ε represents the error or residual.where Additional processes such as assembling the sentences  and calculating the predicted and proportional errors were implemented in Matlab scripts.The experiment in Section Different Contexts for the Verb “listened” tests if the LReg approach and the CEREBRA nonlinear neural network can discriminate between sentences based on feature weightings. The comparison will test whether CEREBRA is a better tool than LReg in bringing out significant changes in word representations.This section evaluates experimentally how word meaning changes across different sentence contexts. For conciseness, the experiments presented here analyze example cases where word attributes are weighted differently in various contexts for verbs, adjectives, and nouns  with salient activation for the central attribute Small and low activation for the non-central attribute Large. In contrast, small hospital) presents low activation on the non-central attribute Small but high activation on the central attribute Large.The size dimensions , demonstrated the centrality principle for these specific contexts. These findings suggest that these attributes are essential to small objects and big structures, respectively. However, the size dimension alone cannot represent the centrality effect completely. This type of conceptual combination requires additional world knowledge to determine the centrality for a particular object, and the relationships between the dimensions of various contexts.camera and hospital are inanimate objects, camera or hospital).Additionally, given that both small bird vs. small boy; small boy vs. small lake; bird flew vs. plane flew, kicked football vs. kicked door, etc.), producing comparable results.These observations are robust and general: analysis was done for all 8 subjects using other types of conceptual combinations .The aggregate verifies these conclusions through a statistical analysis: It measures how the CARs of a word change in different sentences and correlates these changes to the CARs of the other words in the sentence. Particularly, it quantifies the conceptual combination effect statistically across sentences and subjects.The aggregation study hypothesis is based on the idea that similar sentences have a similar effect, and this effect is consistent across all words in the sentence. This effect was verified in the following process .hospital, hotel, and embassy (within the same cluster of sentences). To that end, the differences between the modified and original CAR representations are measured separately for each CAR dimension in each word semantic role, and their significance estimated using Student's t-test.Each cluster of sentences is expected to reveal similar changes in some of the dimensions. To recognize such common patterns of changes, the next step is to calculate the average of the changes for words with similar roles, e.g., The modified CARs of the OWS were averaged.Pearson's correlations were then calculated between the modified CARs and the average CARs of the OWS across all the dimensions.Similarly, correlations were calculated for the original CARs.These two correlations were then compared. If the modified CARs correlate with the CARs of the OWS better than the original CARs, context effect based on conceptual combination is supported.Specifically, this process aims to demonstrate that changes in a target word CAR originate from the OWS. For example, if the OWS have high values in the CAR dimension for Music, then that dimension in the modified CAR should be higher than in the original CAR for such target word. The correlation analysis measures this effect across the entire corpus. It measures whether the word meaning changes toward the context meaning.p < 0.05) according to the Student's t-test. Interestingly, the AGENT role represents a large part of the context in both analyses. In other words, the average correlations of the original and modified CARs are most similar in the Agent panel suggesting that this role encodes most of the context. It is important to note that the clusters obtained for each subject's sentences in the aggregation analysis, dictates the way the correlation analysis is conducted for the modified and the original CARs. Each subject produced a different arrangement of sentence clusters that is why the average correlations of the original CARs are different within each role , even though the original CARs include a single set of 236 words compared to the modified CARs that include eight sets of 786 context-based words, or revised CARWords.The results are shown in Thus, the results indeed confirm that the conceptual combination effect occurs consistently across subjects and sentences, and it is possible to quantify it by analyzing the fMRI images using the CEREBRA model on the CARs. As a summary, the average correlation was 0.3201 (stdev 0.020) for original CARs and 0.3918 (stdev 0.034) for new CARs.While previous sections have shown that differences in the fMRI patterns in sentence reading can be explained by context-dependent changes in the semantic feature representations of the word, the goal of this section is to show that these changes are meaningful to humans. Therefore, human judgements were compared against CEREBRA predictions  were selected as the example sentences. They each represent a different context that should have a distinct effect on the words. Across the different subjects, 64 such sentences were found to result in at least 10 statistically significant attribute changes and used for the questionnaire. Second, words in each of the three possible roles of Agent, Verb, and POLE (Patient/Object/Location/Event) were included in each of these sentences, resulting in 38 Agents, 39 Verbs, and 46 POLE words to be tested.Third, from the 25 attributes with the largest statistically significant change, 10 were randomly selected for each sentence, for four reasons: (1) there is a large number of potentially meaningful attributes, i.e., 25 at least; (2) for simplicity, the survey must not contain many questions; (3) the differences among the top 25 are not considerably large; and (4) it is necessary to get a varied selection of attributes. Choosing the top 10 instead would have resulted in too many visual features for most sentences, either because they frequently changed more, or because visual attributes are more numerous . The statistically significant attribute changes thus selected represent meaningful differences between the new and the original CAR representations.politician (Agent), for 15 sentences such as The politician celebrated at the hotel. An example sentence questionnaire is shown in To make the questions more understandable for the participants, the original descriptions of the 66 attributes by Binder et al.  were rephttps://drive.google.com/drive/folders/1jDCqKMuH-SyTxcJ7oJRbr7mYV6WNNEWH.The entire set of questionnaires can be found at: Human judgements were crowdsourced using Google Forms in accordance with the University of Texas Institutional Review Board (2018-08-0114). The experiments were completed by 27 unpaid volunteers . The participants' ages ranged from 18 to 64 years, with the mean of 33. Nineteen of them were self-reported bilinguals (English as a second language) and eight English native speakers. Four subjects were affiliated with The University; the rest of the population consisted of working people residing in different parts of north and central America . The subjects had no background in linguistics, psychology, or neurosciences.The 24 questionnaires were designed using Google Forms. The respondents were asked to think how the meaning of a specific word changes within the context of a sentence compared to its generic meaning, by evaluating which word attributes change “more”, “less”, or stay the same.Subjects were recruited by sending emails or text messages directly along with the survey link to access their assigned questionnaire. The data collection was done online, and the participants responded using their cell phone or personal computer. Each questionnaire consisted of an Introduction, Description of the Experiment, Example, and the Survey. Each questionnaire takes about 15 min to complete.Three of the participants responded to all of the 24 questionnaires. The entire survey consisted of a total of 3,600 questions, so it took them 4–7 days to complete this task at a pace of approximately four questionnaires . Because this task was a lot of work, the fourth set of responses was obtained by distributing it among multiple raters: 24 additional participants were recruited to each respond to one of the 24 questionnaires.p < 0.05); indicating the agreement between raters is significantly better than chance.Human responses were first characterized through data distribution analysis. Although the inter-rater reliability was low, there were a lot of questions. Thus, it was possible to perform the analysis on those that were reliable enough. In the first such set there were 631 questions where all four participants agreed, or 18% of the total set of questions. In the second such set there were 1,966 questions where at least three of the four participants agreed, or about 55%.Three different approaches were designed to quantify the predictions of the CEREBRA model. In order to measure the level of agreement between humans and CEREBRA, a model fitting procedure was implemented.The survey directly asks for the direction of change of a specific word attribute in a particular sentence, compared to a generic meaning. Since the changes in the CEREBRA model range within , in principle that is exactly what the model produces. However, Aguirre-Celis and Miikkulainen  found thThe direction of change is therefore not a good predictor of human responses; instead, these changes need to be measured relative to changes in the other words. Thus, the problem was addressed by three different approaches:What is the effect of the rest of the sentence in the target word? This effect was measured by computing the average of the CEREBRA changes  of the other words in the sentence and subtracting that average change from the change of the target word.What is the effect of the entire sentence in the target word? This effect was measured by computing the average of the CEREBRA changes  of all the words in the sentence including the target word and subtracting that average change from the change of the target word.What is the effect of CARs used in context as opposed to CARs used in isolation? This effect was measured by computing the average of the CEREBRA changes  of the different representations of the same word in several contexts and subtracting that average change from the change of the target word.The first two approaches have the advantage of being simple. However, the third approach is motivated by neurological evidence suggesting that sentence comprehension involves a common core representation of multiple word meanings combined into a network of regions distributed across the brain . Responses for each model were thus obtained for the 631 questions where all four subjects agreed, and for the 1,966 questions where three out of four agreed. In order to demonstrate that the CEREBRA model has captured human performance, the agreements of the CEREBRA changes and human surveys need to be at least above chance. Therefore, a baseline model that generated random changes in the same range as the CEREBRA model was created. The chance model was queried 20 times for each of the 631 questions and for the 1,966 questions, for each of the eight subjects. In this manner, 20 means and variances for each of the eight subjects for both CEREBRA and chance were created.To estimate the level of agreement of CEREBRA and chance models with humans, a single parameter in each model was fit to human data: the boundary value above which the change was taken to be an increase  or decrease/no change . The “less” and “neutral” categories were combined because they were much smaller than the “more” category in human data. The optimal value for this parameter was found by sweeping through the range  and finding the value that resulted in the highest number of matching responses with the 631 and 1,966 questions. Further, a second boundary was introduced to capture the “neutral” responses .The three approaches to measuring the predictions of the CEREBRA model, i.e., the context effect of the rest of the sentence, the context effect of the entire sentence, and the context effect of the word in different contexts, were implemented and fit to human data using two-boundary model fitting. The three approaches produced remarkably similar results. Furthermore, the first two approaches achieved slightly better results than the third one (by 2%).p-values of the Student t-test, revealing that the differences are highly statistically significant for all of the 8 subjects for the three approaches shown. These results indicate that the changes in word meanings due to sentence context (observed in the fMRI and interpreted through semantic feature representations) are real and meaningful to the subjects.The match results for each set of questions are presented in Word meanings have long been known to change in the context of a sentence Harris, . HoweverThe yellow bird flew over the field vs. The yellow plane flew over the field) and contrasting contexts , could help characterize the effects in detail. The context-based changes should be even stronger, and it should be possible to uncover more refined effects.The CEREBRA model built on this theory generates good interpretations of word meanings especially considering that the dataset was limited and was not originally designed to address the dynamic effects of meaning. It would be interesting to replicate the studies on a more extensive data set. A fully balanced stimuli including sentences with identical contexts  would require new data to be collected. However, such data provides a grounding to neural processes and behavior that does not exist with statistical approaches. This difference becomes evident when the CAR semantic model is compared to approaches such as Conceptual Spaces . They reflect semantic knowledge acquired through a lifetime of linguistic experience, found in the corpus used for training the model, based on statistical co-occurrence, and do not provide precise information about the experienced features of the concept itself  context-dependent meaning representations are embedded in the fMRI sentences, (2) they can be characterized using CARs together with the CEREBRA model, and (3) the attribute weighting changes are real and meaningful to human subjects. Thus, CEREBRA opens the door for cognitive scientists to achieve better understanding and form new hypotheses about how semantic knowledge is represented in the brain. Overall, this research is expected to contribute to the development of a unified theory of concepts, the organization of the semantic space, and the processes involved in word meaning representation. CEREBRA promotes further research on issues such as how words can be related thematically, how concepts can be combined, how word meaning can be formed, and how different individuals perceive the world , thus advancing the understanding of grounded representations in the mental lexicon.naguirre@cs.utexas.edu. For the fRMI data, contact Jeffrey Binder at Medical College of Winsconsin.The data analyzed in this study is subject to the following licenses/restrictions. The original and new CAR collections are available. The fMRI data is not public. Requests to access the available datasets should be directed to NA-C, The studies involving human participants were reviewed and approved by University of Texas Institutional Review Board (2018-08-0114). The patients/participants provided their written informed consent to participate in this study.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.This work was supported in part by IARPA-FA8650-14-C-7357 and by NIH 1U01DC014922 grants.The authors declare 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.


American Journal of Preventive Cardiology (AJPC) marks our 10th issue which we are proud to present to you all. The success of the journal represents the tireless efforts of our associate editors and greater editorial board and the many reviewers which we will be forever grateful to. This month we in particular wish to thank Dr. Koos Admiraal who recently departed Elsevier as our publisher and was instrumental in his efforts to help us launch the AJPC and to provide guidance and help in our application last year to successfully obtain Pub Med and Scopus indexing. Since our first meeting in Summer 2019 at the European Society of Cardiology in Paris to propose the idea of the AJPC, he provided the greatest support to launch and sustain the journal. We now welcome our new Elsevier publisher, Diana Goetz who will help us take the journal into the future!This issue of the How well is the AJPC growing and getting exposure worldwide? We are happy to announce that the number of submissions grew from 108 to 149 from 2020 to 2021. While the great majority of the submissions were from the United States, we also had submissions from China, Finland, France, India, Iran, Japan, Sweden, and the United Arab Emirates. We particularly welcome submissions internationally and continue to encourage those from overseas to contact us if they are interested in being a reviewer and possibly editorial board members for the journal. Moreover, the current (2022) average time from submission to first decision is 4.8 weeks, to acceptance 11.1 weeks, and to first on-line publication 11.5 weeks. Very impressive, in particular, is the growth in usage of the journal – in 2020 there were 49,109 total downloads which increased to 163,330 in 2021. For the first 3 months of this year, there were 57,930 downloads, a 93% increase over the same period last year.Our June issue features a number of key articles of great value to the preventive cardiology community. Two ASPC clinical practice statements are featured in this issue, one on evidence-based nutritional modifications to reduce atherosclerotic cardiovascular disease (ASCVD) risk and another on strategies for ASCVD risk assessment. Following is a commentary on the need for increasing virtual cardiac rehabilitation availability and then state-of-the-art reviews, one being the annual Ten Things to Know about Cardiovascular Risk Factors and the other on evaluation of blood lipids throughout a woman's lifecycle. The issue is rounded out by original research contributions on an update on lipid treatment and goal attainment in US adults, effectiveness of community-based interventions, patient experiences with familial hypercholesterolemia, cascade testing for lipoprotein(a), and on area deprivation index and anticoagulation among atrial fibrillation patients.https://www.aspconline.org/2022congress/. Thank you for your readership and continuing support of our AJPC journal, which continues to grow in impact.Finally, we wish to thank our outgoing ASPC President Peter P. Toth, MD, PhD for his tireless efforts and accomplishments too many to be named here in this short message, taking ASPC to greater heights during the past two years. We also welcome Martha Gulati, MD, MS as our incoming ASPC president who will undoubtedly lead our organization to even greater heights. We hope you will consider attending our upcoming ASPC Congress on CVD Prevention to be held July 29–31, 2022 in Louisville, Kentucky. A great program has been planned and is featured on our website  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


In this article, we present a method to determine the influence of meteorology and air pollutants on ruptured aortic aneurysm (rAA). In contrast to previous studies, our work takes into account highly resolved seasonal relationships, a time-lagged effect relationship of up to two weeks, and furthermore, potential confounding influences between the meteorological and air-hygienic variables are considered and eliminated using a cross-over procedure. We demonstrate the application of the method using the cities of Augsburg and Munich in southern Germany as examples, where a total of 152 rAA can be analyzed for the years 2010–2019. With the help of a Wilcoxon rank-sum test and the analysis of the atmospheric circulation, typical weather situations could be identified that have an influence on the occurrence of rAA in the southern German region. These are a rainy northwest wind-type in spring, humid weather in summer and warm southwest wind-type weather in autumn and winter.  •Influence of meteorology and air pollutants on ruptured aortic aneurysm (rAA).•Consideration of time lags within flexible high temporal resolution analyses.•Case-crossover procedure ensures that only relevant variables influence the results.•Developed methodology can be applied to all regions of the world.•In southern Germany, specific weather conditions significantly influence rAA. Aortic aneurysm ruptures, rAA, Germany, Weather, Airborne substances, Atmospheric circulation. The aneurysm is at risk of rupture once the aortic wall stress reaches a certain extent, which could be a fatal threat. Aortic aneurysm most commonly affects individuals over the age of 65, with men developing the aneurysm approximately five times more often than women. The risk of aortic aneurysm increases with age. The reason is that the structure of the vessel wall changes over the years. It is less elastic and can no longer absorb the high pressure which is increasing with diameter enlargement of the aorta .In more than 50 percent of cases, atherosclerosis  is the cause of an aortic aneurysm. It also frequently develops in people with high blood pressure (hypertension). High blood pressure puts strain on the vessels and is also a risk factor for atherosclerosis.The risks for life-threatening rupture of the aorta are primarily hypertension, smoking, and male sex . AlthougBecause of the heterogeneity of the results obtained in recent years and the sometimes immature statistical methods that have been used, we have developed a statistical approach that takes into account as many potential sources of error as possible. In doing so, we do not limit ourselves to the meteorological variables mainly mentioned in the literature, such as air pressure and temperature, but extend the spectrum of investigation to include other important variables such as air humidity, precipitation, wind speed and wind direction. In addition, the influence of air pollutants such as ozone and particulate matter are also investigated. For this purpose, in addition to meteorological and air-hygienic measurement data, we retrospectively investigated patient data on rAA from two university hospitals in southern Germany (from the cities of Augsburg and Munich) for a ten-year period (2010–2019).Our results are based primarily on the use of Wilcoxon rank-sum tests (WRS) to distinguish meteorological and air-hygienic conditions on days followed by rAA from days not followed by aortic ruptures. In contrast to previous studies, our work takes into account highly resolved seasonal relationships with continuous, shifting 3-month analyses to find seasonal differences in the aortic rupture-weather relationship. A fixed division into annual periods  is avoided, because these have no causality in the aortic rupture-weather relationship. The addition of so-called lag days  allows, on the one hand, the investigation of time-lagged associations between weather events and aortic ruptures and, on the other hand, the sample can be enlarged in this way, leading to more robust statistical conclusions. Furthermore, potential influences of meteorological and air-hygienic variables on each other are considered and eliminated using a case-crossover procedure in advance of the WKS tests.Then, all variables of the significant results of the WRS tests occurring at the same time of year are considered together and are used to explain the results of the WRS tests from a climatological point of view. In this way, we identify seasonally different weather conditions that could have an influence on the occurrence of rAA in southern Germany.Section 22.1To be able to investigate potential influences of weather or air pollution on rAA the following data were used: Patient data with the date of rAA and indication of place of residence by postal codes from the University Hospital Augsburg and the University Hospital rechts der Isar in Munich from the years 2010–2019. Data include ruptures of abdominal aortic aneurysms (AAA), thoracoabdominal aortic aneurysms (TAAA) and thoracic aortic aneurysms (TAA), with the former accounting for by far the largest proportion.Daily weather data from the German Weather Service  for air temperature , atmospheric air pressure (slp), relative humidity (rhum), precipitation (prec), wind speed (windv), and wind direction (windd) for 2010–2019 at the DWD stations Augsburg-Mühlhausen and Munich-City .3), nitrogen monoxide (NO), nitrogen dioxide (NO2), PM2.5 , and PM10  as daily means and daily maxima for the monitoring stations Augsburg/LfU (suburban background), Munich/Lothstraße (urban background), and Munich/Johanneskirchen (suburban background) for 2010–2019 (Daily data on air constituents from the Bavarian State Office for the Environment (LfU), for ozone  from the ERA5 reanalysis  for the The daily measurement data of the DWD and the LfU are first de-trended (using the trend of a linear regression) to eliminate the influence of climate change, which is already evident in the 10-year data, and to eliminate potential biases at the beginning and end of the time series. Then daily anomalies are calculated using the 31-day moving long-term (2010–2019) averages of each calendar day. The anomalies now make it possible to assess whether the individual days deviate particularly strongly from the normal state, whether, for example, particularly warm or cold days or particularly high or low air pressure prevailed.In the following statistical analyses only patients are considered who live within a maximum distance of 20 km from the measuring sites of the DWD. This selection of the patient data is necessary because weather and air pollutants are local phenomena and therefore have a limited range of effects. The radius of 20 km is the result of a compromise: on the one hand, as many patients as possible should still be included in the survey, and on the other hand, it must be ensured that they are still exposed to the influence of the measured weather and air pollutants. The method we developed for analyzing rAA is shown in 2.2To determine if weather and/or air pollutants have an impact on the occurrence of rAA, we must first determine which days should be included as rAA-influencing and rAA-independent in the subsequent testing methodology. Since we want to examine not only the conditions on the day of the rAA itself, but also the preceding atmospheric conditions, the 13 days preceding an rAA were also included in the sample of rAA-influencing days.Since it is known that the meteorological variables and the air pollutants can be interdependent , it must be ensured that these influences are minimized in the selection of the samples. We have developed our own case-crossover procedure for this purpose, based on the approaches of We first check whether the meteorological and air quality data under study are correlated  with rAA differ significantly from periods without rAA. The analyses should have the highest temporal resolution possible to reveal seasonal relationships. The choice of temporal resolution depends on the amount of patient data available. In our case, a single-month analysis would have resulted in sample sizes that were too small, so we consider the rAA of three consecutive months together and then shift our analysis period by one month each time. Thus, WRS tests are performed for January to March, then February to April, March to May, and so on. In this way, we obtain a more realistic representation of the seasonal course that is not limited to predefined seasonal sections.Depending on the variables and month under consideration, a case-crossover analysis is applied beforehand. If case-crossover is necessary, which was determined via the correlation of the individual variables, the samples consist of the days on which rAA occurred together with the 13 days before, and the selected control sequences defined by the case-crossover methodology. If no case-crossover is necessary, the samples consist of the days on which rAA occurred together with the 13 days before, and all other days in the corresponding months that are not within the influence of an rAA.2.4In order to further analyze the results of the WRS in the context of the underlying meteorology, so-called air pressure composites are calculated using the ERA5 reanalysis data. First, mean values are calculated from the air pressure fields for the corresponding months that emerged as relevant from the WRS to determine the representative climatological condition. Next, those days are singled out that correspond to significant anomaly results before or during an rAA - for example, days with particularly high winter air temperatures before rAAs occurred. The air pressure fields on these days are also averaged and the mean state of the atmosphere prevailing during the days important for rAA is obtained. The difference between the climatology composite and the anomaly composite is formed, yielding a picture that shows the differences in atmospheric air pressure between rAA-relevant and non-relevant days.2.5In order to further verify the statements of the composite analysis, daily Jenkinson-Collison (JC) weather types  were cal3The suggestion that weather may have an influence on aortic ruptures has been investigated for many years. However, all publications to date on this topic show a very wide range of results. The most studied variables in relation to rAA are atmospheric pressure and air temperature.Two recent meta-studies  on the pIndividual studies very well come to significant results, such as that rAA are related to low air pressure  or to loThe pathophysiological mechanisms underlying the effect of meteorological influences on rAA remain equally uncertain. Although it is hypothesized that increased stress on an existing aneurysm may be caused by a reduction in extraluminal pressure (as a result of lower atmospheric pressure) to increase the pressure differential across the aortic wall, thereby increasing the risk of rupture . In addiThe studies to date on the influence of weather and air pollutants on rAA are methodologically very heterogeneous. The number of patients, the number of years for which data are available, the size of the study area, how many atmospheric or air-hygienic parameters and, if applicable, a combined influence were investigated, and the statistical methods used differ greatly.In the literature review, it is noticeable that no research has yet been done to determine whether the meteorological data show a trend in their study period. A climatic trend in the data can possibly lead to biases at the beginning and end of the time series. In many studies, it is also not apparent whether the patients were under the influence of the meteorological data used at the time of rupture. Exceptions to this are, for example, the studies by The most commonly used statistical methods to date to describe the characteristics of rAA and associations with weather are chi-square tests, Student t tests, the nonparametric U test, and linear and multiple logistic regressions . We are 4In the following chapter, the results of our methodology are explained using the data available to us from southern Germany.4.1In the investigated period from 2010-2019, 140 patients with rAA were admitted to the University hospital of Augsburg and 148 patients to the University hospital rechts der Isar in Munich. After narrowing down the patient data to a radius of 20 km around the DWD stations, 79 cases remain in Augsburg and 73 in Munich see . In Augs4.2Since it can be assumed that the study regions, which are relatively close in space (the distance between the two cities is about 50 km), should be subject to similar exposure-outcome mechanisms between weather/air constituents and rAA, the following analyses, based on the results of the WRS, focus on the similarities between the two cities.4.2.1The single-month correlation analyses between all meteorological variables and the air constituents in the case-crossover study have shown significant results (|r| > 0.7) for several combinations of variables. Therefore, for these variables, a case-crossover procedure was applied for the selection of the samples to be included in the WRS in the corresponding months. Thus, especially for the combination of air temperature and ozone in the summer months and for wind speed, ozone and nitrogen oxides, respectively, in the winter months, it became necessary to apply case-crossover. This can ensure that the samples used in the WRS tests are not perturbed by meteorological-air content correlations.4.2.2Because aortic ruptures from three consecutive months (of running three-month combinations within the year) are included in a WRS test, each sample contains a different number of cases. For the WRS tests containing only the days when rAA occurred  wind flow.•In mid and late summer (July–September) the days before an rAA are characterized by below-average air pressure and increased relative humidity.•In autumn and winter (October to January) higher than usual daily minimum, mean and maximum temperatures before rAA occurred.It is also striking that the significant differences mostly exist up to two weeks before the rupture occurred. The results of the WRS on air pollutants show basically no similarities for the two cities studied.4.3The three groups of variables identified by the WRS are now examined in more detail for their atmospheric circulation background. In the DWD data, the days before and during rAA are selected which correspond to the conditions of the variable groups. For these days a composite of the ERA5 air pressure data is formed and compared with the air pressure fields independent of rAA.4.3.1For the months of April through June and a maximum of twelve lag days before an rAA, days are selected that have above average rainfall, daily minimum temperature, and an above normal wind speed. 87% (27 out of 31 rAA) of all rAA from April to June of the years 2010–2019 are connected with these conditions. The air pressure fields matching these days from the ERA5 reanalysis data are now averaged and compared to the air pressure field shown by the April through June climatology see . The shi4.3.2For the months of July through September and a maximum of 13 lag days, days are selected that have below average atmospheric pressure and higher than normal relative humidity. 90% (36 out of 40 rAA) of all rAA from July to September are associated with these conditions. The corresponding air pressure fields in 4.3.3For the months of October through January and a maximum of eleven lag days, days are extracted that have above average minimum, mean and maximum daily air temperatures. 68% (36 out of 53 rAA) of all rAA from October to January are related with these conditions. The composite images in 4.4rainy northwest-type in spring. While anticyclonic (A), cyclonic (C), and the indifferent weather type (U) occur most frequently averaged over the months of April through June of 2010–2019, the frequencies of occurrence of weather types on rAA-inducing days change significantly. Almost all anticyclonic weather situations, i.e. determined by high pressure, decrease significantly, while cyclonic  and also westerly weather conditions  occur much more frequently in comparison. This frequency distribution of the weather situations consequently underlines the picture that has already emerged from the composite analysis.The top row of humid weather in summer, is associated with a strong decrease in anticyclonic weather types compared to the long-term average  when considering JC weather patterns, while mainly pure cyclonic (C), and north and east WTs  become less important. So, also in this case, the assumptions about the prevailing weather of the days important for the rAA are verified.The third identified weather type affecting aortic ruptures in autumn and winter, namely 5The accumulation of rAA in the winter half-year mentioned in the literature applies to only one of the cities we investigated (Augsburg). In Munich the two months with the highest number of ruptures were in summer. Also, the so far most mentioned claims that rAA occur more frequently at low air pressure and cold air temperatures and the related pathophysiological explanations cannot fully be confirmed by us. Only in the summer months a lower air pressure plays a significant role, for other months this is not the case. Moreover, the results of the WRS test show exclusively positive anomalies for the air temperatures. The underlying pathophysiological mechanisms that lead to the rupture of the aneurysm accompanied by the weather types we found need to be explored in further medical studies and are not the objective of our present work. Because we did not have complete data on the age and sex of the patients, it was not possible to analyze their influences on our study results.When investigating meteorological and air-hygienic influences on the patients, it is essential that these people were actually under the influence of the assumed environmental parameters at the time of the aortic rupture. Therefore, on the one hand, we had to assume that the patients were at least in the vicinity of their place of residence on the day of their admission to the hospital. And on the other hand, we had to estimate in which radius around the measurement sites the meteorological and air-hygienic measurement data still retain their validity. Therefore, we tested different residential radii of 10, 20 and 30 km around the measurement sites and analyzed how this affects the results. Only minor deviations in the results were found and they did not affect the conclusions of our study. As a compromise between decreasing measurement site-actual patient exposure relationships with increasing spatial distance and the reduction of sample size with smaller analysis radius, we decided to use a radius of 20 km in the results shown here.To further validate the results of our analyses, in addition to the WRS test, two other test procedures were used to check whether the frequency distributions of two different samples differ from each other. The Cramér-von Mises criterion and the Anderson-Darling test were used for this purpose. The two alternative test procedures underlined the results of the WRS test. Since the WRS test appears to be the most stringent of the three test procedures, our analysis results are based on its results.In our study, meteorological conditions as well as air pollutants were investigated. The results show that in our case the meteorological influences are more important than the air pollutants. However, if the investigated cities are considered separately, there are quite significant anomalies in the air constituents, which should be investigated in more detail in further studies. Since we have attached importance to evaluate only the similarities of both cities, in order to make the results consistent and meaningful, we do not make any statements about the influence of air pollutants on aortic ruptures in this paper.Furthermore, it should be noted that not all ruptures were associated with the weather conditions we mention, but that there are also several other conditions that can prevail. This can be seen for instance in the composite analysis for autumn and winter, where only just under 70 percent of the ruptures were accompanied by increased air temperatures.The very different study results reported in the literature on rAA in relation to meteorological factors (mainly air pressure and air temperature) and also the fact that our results show strong seasonal differences suggest that the risk of rAA due to weather phenomena may vary considerably from region to region and from season to season. It is also possible that regional extreme weather events like the alpine foehn play a crucial role in the rupture of an aortic aneurysm.We argue that the rAA-associated weather conditions identified in our study are not necessarily valid for other regions of the world. However, the developed methodology can be applied to other regions, and can advance the development of prediction and prevention strategies. This gains even more importance in the scope of climate change, where significant changes like increases of heat waves and a higher persistence of specific weather types occur in many parts of the world.6We have developed a methodology to test the influence of weather and air pollutants on rAA in a statistically correct and meaningful way. This allows for a very detailed seasonal analysis that also includes any period before the rupture occurred . Important here is the careful preparation of the data, such as a possible removal of the climatic trend or the calculation of the daily anomalies. In addition, it must be ensured that only patients who were spatially exposed to the weather or air pollutant influence are considered. We solved this using the known residence of the patients and a radius of 20 km around the weather measuring stations.A WRS test can then check whether days on or before an rAA differ from days without an rAA. However, it must first be checked whether the weather and air pollution data used influence each other and it must be ensured that only the relevant variables result in an influence on the result of the WRS. We solved this by a case-crossover procedure that checks the correlations of all variables and if a correlation is found, adjusts the samples to be used for the WRS test. Applying this test scheme to the rAA data from Augsburg and Munich have shown that at different times of the year specific anomaly groups occur in both southern German cities before rAA.For the months of April through June and a maximum of twelve lag days before an rAA, days with above average rainfall, high daily minimum temperature, and a greater than normal wind direction are found. For the months of July through September and a maximum of 13 lag days before an rAA, days are found with below average atmospheric pressure and higher than normal relative humidity. For the months of October through January and a maximum of eleven lag days, days with above average minimum, mean and also maximum daily air temperatures precede an rAA.In order to verify which atmospheric conditions and circulation dynamic backgrounds led to these significant anomalies before rAA, the matching air pressure fields over an extended European area were considered. These then reveal typical large-scale weather patterns that appear to have an influence on rAA in southern Germany.Irena Kaspar-Ott: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.Patrick Olschewski: Conceived and designed the experiments; Contributed reagents, materials, analysis tools or data.Stephanie Koller: Conceived and designed the experiments.Alexander Hyhlik-Duerr, Elena Streck, Hans-Henning Eckstein & Oksana Radu: Contributed reagents, materials, analysis tools or data.Elke Hertig: Conceived and designed the experiments; Analyzed and interpreted the data.Deutsche Forschungsgemeinschaft (408057478).This work was supported by The authors do not have permission to share data.The authors declare no conflict of interest.No additional information is available for this paper.