SD = 22.4 ± 4.5 years, 71 male). Wellbeing was assessed through the World Health Organization Quality of Life-BREF questionnaire evaluating two general measures, quality of life (QoL) and general health, and four specific dimensions: physical health, psychological health, social relationships, and environment. For both groups, respondents’ QoL was high on each measure: median scores were higher than 4 for the two general measures and higher than 70 for the four specific dimensions. Among the dimensions, respondents had the highest mean score for environment (75.0), then social relationships and physical health , and finally, psychological health (70.3). Differences between groups of musicians emerged in terms of overall QoL and general health, as well as the physical health dimension, where college music students scored lower than the amateur musicians; conversely, college music students scored higher than the amateurs on social relationships. Our overview of musicians’ wellbeing in Western Switzerland demonstrates that, while music making can offer some health protective effects, there is a need for greater health awareness and promotion among advanced music students. This research offers insight into musicians’ wellbeing and points to the importance of involving different actors  in facilitating healthy music making.Musical performance requires the ability to master a complex integration of highly specialized motor, cognitive, and perceptual skills developed over years of practice. It often means also being able to deal with considerable pressure within dynamic environments. Consequently, many musicians suffer from health-related problems and report a large number of physical and psychological complaints. Our research aimed to evaluate and analyze the wellbeing of two distinct groups of musicians, college music students and amateur performers in the French-speaking part of Switzerland. A total sample of 126 musicians was recruited for the study (mean age ± Health 2020 , as outlined in the policy program lth 2020 . Europealth 2020 , p. 732.Wellbeing is a multidimensional phenomenon and refers to emotional and cognitive dimensions of subjective experiences resulting from the individual evaluation of several facets of life. Research on wellbeing has revealed two fundamental perspectives : hedoniaIn the field of music, wellbeing has been investigated in two different ways, with music as a facilitator but also as a disruptor of wellbeing. In terms of facilitation, much research has pointed out its strong and positive impact on people’s lives . Boyce-THowever, research has also shown that making music can be a disruptor of wellbeing as it is linked with the many challenges that musicians face in their practice. Physical pain is one of the consequences in making music at a high level. Only 26.7% reported that they had never experienced performance-related pain . FurtherBeyond the fact that music can have an influence, positive and negative, on wellbeing, it has been argued that wellbeing can have an impact on facilitating good performance , and yetThe paradoxical bidirectional relationships between music and wellbeing as outlined above are puzzling and warrant further investigation. No doubt, there is large variation in the instruments and methods used when studying wellbeing, as well as cultural differences between countries and geographical regions. Indeed, many of the existing scales are based on morbidity, mortality, and the impact of disorders or disease on daily activities and behavior on perceived health, containing measures of disabilities . They arIn order to avoid these problems, the World Health Organization Quality of Life (WHOQOL) Group developed a multidimensional scale of QoL linked to their health policy program centered on a humanistic approach , 1998. TThe WHO has developed many alternative measurement tools from the original WHOQOL questionnaire, which was composed of 100 items. For example, the WHOQOL-BREF examines life satisfaction and general health, as well as four component scores of physical health, psychological health, social relationships and environment. This 26-item questionnaire has been used in many studies, some in the field of music . These sAs mentioned before, culture can influence the ways in which people define and characterize wellbeing, and cultural differences also affect the impact of health promotion interventions within a given country or geographical region. If we refer to Switzerland, there seems to be a growing interest in understanding and promoting musicians’ health. In 1997, the Swiss society for music medicine was founded in order to help musicians cope with performance-related physical problems. Recently, they initiated interdisciplinary consultations composed of musicians, doctors, psychologists, and diverse therapists in order to support musicians in their daily work . Such coOnly a few studies have been devoted to the understanding of health and QoL among musicians during their formative years in conservatoire training . TherefoSD = 22.4 ± 4.5 years, 71 male) of two groups: HEM participants  and non-HEM participants  serving as the comparison group, as detailed in t-tests with a medium effect size [ES = 0.5], a first error alpha of 0.05 and a power of 0.8, corresponding to 104 according to Gpower (version 3.1).One hundred and thirty instrumental and vocal musicians and singers took part in the study, recruited via different music schools and music colleges by contacting directors, teachers and, also, via personal contacts. Four musicians were excluded from analyses because they performed computer-assisted music but did not play an instrument such as those found in a symphony orchestra, leaving a final sample of 126 respondents  or amateur musicians , and whether or not they participate in judged performances or competitions (Yes or No).n = 117), but some completed the questionnaire online, with access provided by email. Information about the study was given to all participants and highlighted the confidentiality and anonymity of their participation. Musicians participated voluntarily and could stop answering the questionnaire at any time. Written informed consent was obtained from all participants.The majority of respondents completed the paper version (Very poor to 5 Very good) and general health (from 1 Very dissatisfied to 5 Very satisfied). It then progresses to a series of 24 items on four QoL dimensions: physical health (7 items), psychological health (6 items), social relationships (3 items), and environment (8 items). Each item is scored on a 5-point intensity scale , a 5-point evaluation scale (1 Very dissatisfied to 5 Very satisfied), a 5-point capacity scale (1 Very poor to 5 Very good), and a 5-point frequency scale (1 Never to 5 Always).The WHOQOL-BREF questionnaire, which consists of 26 items, was used to measure musicians’ QoL. This version of the original 100-item The physical health dimension includes questions on daily activities; dependence on medicinal substances and medical aids; energy and fatigue; mobility; pain and discomfort; sleep and rest; and work capacity. The psychological health dimension assesses knowledge of bodily image and appearance; negative feelings; positive feelings; self-esteem; spirituality/religion/personal beliefs; and thinking, learning, memory, and concentration. Social relationships are characterized through personal relationships; social support; and sexual activity. Finally, environment is captured through questions on financial resources; freedom, physical safety, and security; health and social care; accessibility and quality; home environment; opportunities for acquiring new information and skills; participation in and opportunities for recreation/leisure activities; physical environment (pollution/noise/traffic/climate); and transport.The dimension’s mean scores were calculated according to the procedure described by the Commission cantonale d’éthique de la recherche sur l’être humain (CER-VD). Authorization to use the WHOQOL-BREF was granted by the WHO through a standard user-agreement form.This study was led by the sport psychology laboratory at the Institute of Sport Sciences, University of Lausanne, and ethical approval was granted by the M-test and normality with the Shapiro–Wilk test. When the MANOVA was significant, we performed univariate F-tests with a significance correction. We also calculated effect sizes  among the four QoL dimensions, MANOVAs were used. For comparing HEM vs. non-HEM, we used sex and age group as covariates whereas for comparing participants vs. non-participants in judged performances, we used sex, age group and education as covariates. Homogeneity of the matrix of variance-covariance was assessed with Box’s ct sizes . FinallyWithin the sample, 56% of respondents were men and 43% women . In musiThe QoL of participants was high on each measure: median scores were higher than 4 for the first two measures and higher than 70 for the four QoL dimensions . Among tp = 0.227, and p = 0.904), nor for age groups .Quality of Life varied little among sociodemographic groups. There was no significant relationship between each of the two general measures and sex . Nevertheless, the Psychological health dimension differed significantly as a function of sex , where female musicians had lower scores, M(SD) = 67.4 (13.5), than male musicians, M(SD) = 72.6 (14.69). The four QoL dimensions did not differ according to age group .The four QoL dimensions did not differ according to sex , p = 0.006.The two general measures of QoL were each significantly related to education. For overall QoL, a lower percentage of HEM respondents answered “very good” compared with non-HEM respondents (26% vs. 54%), p = 0.001, 2Eta = 0.140, with the two covariates not reaching significance). The QoL dimensions showed few significant differences (p = 0.000 and 2Eta = 0.098): HEM respondents had a lower QoL physical score than non-HEM respondents (M = 69.46 vs. 76.31).The four QoL dimensions were also related to education, with sex and age group as covariates  and general health (p = 0.549). The four QoL dimensions were related to taking part in judged performances, with sex, age group and education as covariates . The QoL dimensions showed few significant differences. Psychological health varied significantly according to judged performance as did Environment  where respondents doing more judged performances had higher scores than those who did not.The two general measures of QoL were not related with participation in judged performances: overall QoL  of 0.42 and 77% of the respondents correctly classified. Overall, three factors were significant: age group , physical health , and social relationships z1 = 5.31, p = 0.021)  . What diThe QoL of music college students  and amateur performers who took part in this study was high, mirroring the positive wellbeing profiles reported by When comparing music college students with amateur musicians, our results showed that music college students evaluated their overall QoL more negatively than amateur musicians, but this was not related to participation in judged performances and competitions.As defined by the Our findings underline the results presented in However, the unique educational context of music colleges can also present opportunities . Indeed,Our results also show that music students evaluated their general health more negatively than amateur musicians, unrelated to participation in judged performances, and competitions.This matches findings among music students reported by Our results suggest that, as music college students’ lives are centered on music and performance, these musicians’ main focus may inhibit the importance they give to promoting their general health through physical activity, nutrition education or stress management training.Concerning the physical health dimension, our results show that amateur musicians report better physical health than college music students. This is not surprising, as it is well known that music students frequently report pain or discomfort linked to bad posture, excessive practice on their instrument, and performance anxiety . The phySleep and rest, energy, and fatigue are also evaluated through different items. As some studies have shown that musicians report high levels of exhaustion, stomachaches, headaches, sleep disturbances  and irreFinally, several studies have highlighted that musicians tend to use drugs or substances: drinking alcohol , using bPsychological factors may be involved in the genesis or maintenance of physical problems . One stuOur results do not specify which aspect  of physical health influences musicians the most. However, it clearly highlights the need for action to empower music college students in taking care of their physical health.Our results indicate higher psychological wellbeing among musicians who take part in judged performances and competitions and lower levels for female musicians when psychological health was examined as a function of sex.Numerous studies have highlighted the undue psychological pressures of working in music . TherefoAccording to our results, female musicians present lower psychological health scores. This result is in line with previous large-scale normative studies using the WHOQOL-BREF, which report significantly lower means for women compared with men . This psDuring the past two decades, a large number of studies have examined sex differences in self-esteem . ResearcBody image or physical appearance has been established as an important aspect of wellbeing. Physical appearance self-evaluation  is a specific domain of self-esteem, especially studied in female populations, showing that body esteem is a construct contained within the hierarchical framework of global self-esteem . This coFinally, findings from different studies have repeatedly shown a higher prevalence of anxiety and depression diagnoses in women compared with men . A studyFinally, our results highlight that social relationships and social support increase the chance of reaching a high level in the field of music.In a recent study conducted by In contrast to musical groups, solo-oriented musicians often face isolation and loneliness. Therefore, they have to find other ways of establishing and maintaining social relationships , for exaSeveral additional directions should be taken into account in future research. First, our sample was not representative of Switzerland’s musician population, nor wholly representative of the French-speaking part of Switzerland. The sample did not include students from all conservatories and music schools from the region. Regional culture is assumed to be similar across the French-speaking part of Switzerland; nevertheless, we could not determine the influence of musicians’ personal cultural backgrounds on their health and wellbeing evaluations . Second,This research offers important insight into musicians’ health and has implications for the future about the extent of health education programs in music education settings. Our overview of musicians’ wellbeing in the French-speaking part of Switzerland underlines the importance of helping musicians to be aware of their health in order to take care of themselves. As Worldwide, efforts are being made to propose health education programs for college music students. Some authors, such as The present study is only a beginning. As HEM: Haute École de Musique.WHO: World Health Organization.WHOQOL: World Health Organization Quality of Life.QoL: Quality of Life.RAP and CK contributed to the conception and design of the study. RAP, CK, NV, and FCvR organized the database. FCvR performed the statistical analysis. RAP, CK, NV, AW, and FCvR co-wrote the manuscript. All authors contributed to the manuscript revision, read, 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.


With the continuing growth of aged populations, it is imperative to find ways to maintain and improve the quality of life in old age. It has been documented that grandparents-grandchildren relationship is significantly contributed to quality of life of older adults. This study was conducted to identify the status and associated factors of grandparents-grandchildren relationship in a sample of Iran.This cross-sectional study was conducted on 377 community dwelling older adults 60 years and over living in Kashan, Iran. A multistage proportional random sampling technique was applied to obtain the sample. The grandparent -grandchildren relationship was measured by a researcher-developed 16-item scale. The data were analyzed using SPSS version 23 and AMOS 23. = 19.05, P < 0.001), where information communication technology of grandparents, geographical distance between grandparents and grandchildren, and the quality of relationship between grandparents and parents of grandchildren were the most important predictors of the grandparents-grandchildren relationship.The mean age of the respondents was 70.42(SD = 8.20) years. About 62% of the respondents were female and 60.7% were married. The average score of grandparents-grandchild relationship was 67.60(SD = 12.47). The multiple linear regression analysis revealed a significant model (F The findings from the current study showed that status of grandparents-grandchildren relationship is moderate to high and influenced by some factors. It is, therefore, suggested that policymakers pay more attention to strengthening grandparent-grandchild relationship by providing educational programs for families and encouraging the elderly to learn and use information communication technology. The eldPrevious reports have indicated that the world's aging population will increase from 200 million in 1950 to 1100 million in 2025 , 5. AccoOld age is a stage of life when an individual faces various problems, such as loneliness, diseases, and economic problems. These problems affect life satisfaction and quality of life of older adults . The preSeveral social and psychological theories of aging have been applied to conceptualize grandparents-grandchildren relationship. The solidarity theory is one of the most important theories, presented by Bengeston and colleagues. Six dimensions of “association”, “affection”, “consensus”, “resource sharing”, “strength of family norms”, and “opportunity structure for interaction”, are the essential aspects of intergenerational cohesion . AnotherIran, similar to many other countries around the world, is no exception to the process of modernization. It seems that the relationship between grandparents and grandchildren has deteriorated in Iranian families, which can lead to a generation gap in the Iranian society. According to the Madrid Operational Plan in 2002, the member states, including Iran, are responsible for identifying and strengthening intergenerational participation and relations with respect to intergenerational responsibilities .Considering the importance of aging population, it is imperative to find ways to maintain and improve the quality of life of older adults . In ligh2This cross-sectional study was conducted on a sample of older adults living in Kashan, Iran. Kashan is a historical city and part of Isfahan province. It is located in the center of Iran, 220 km south of Tehran. According to the census of 2016, the city population was 304 487, with the elderly comprising 10% of the population .A multistage proportional random sampling technique was employed to obtain a sample of 377 community-dwelling older adults 60 years and older. The sample size with 95% confidence interval, 85% power, and attrition of 15%, was calculated 377 older persons.At the first stage of the sampling procedure, the number of older adults covered by each health center was identified by health records. It is noteworthy to mention that community-dwelling older adults have health records at their respective health centers.In the second stage, the sample size per health center was proportionally determined based on the total number of the elderly population covered by each health center and the required sample size.At the last stage, health records were randomly selected from each center by the RAND function in Microsoft Excel. The selected numbers were being called until 385 responses were obtained. About 95% of the called numbers were agreed to participate. In case that selected number did not agree to participate in the study, another person would be randomly selected.1) shows the sampling process.Data collection was conducted using a face-to-face interview by trained enumerators in respondents' homes, with a response rate of 98 percent. Fig. ?”The associational solidarity dimension consisted of four questions. This dimension included questions such as, “How many times did your grandchildren come to visit you in the past year?” The affection dimension consisted of three questions such as, “How much do you love each other?” The functional dimension included nine questions. The extent of financial and social support of grandparents by grandchildren was measured by nine questions such as, “How many grandchildren help you move around the city , moderate (33.34 to 66.67) and high (66.68 to 100) levels.2.2.3To fulfill the study purposes, descriptive and inferential statistics using IBM SPSS version 23 and AMOS 23.0  were performed. First, univariate and bivariate analyses were conducted to identify variables distribution and potential statistical associations between independent and dependent variables. Second, a multiple linear regression analysis was employed to find out the most important predictors of the grandparents-grandchildren relationship. The assumptions for multiple linear regression analysis such as homoscedasticity, linearity, and collinearity were examined and the results showed that the assumptions were satisfied.1) and Variance Inflation Factors (VIF) were performed to determine multicollinearity. The results revealed no evidence of significant multicollinearity.The intercorrelations among study variables  illustrates the model.Construct validity was conducted by confirmed factor analysis using AMOS. The results from AMOS showed that model’s CMIN/df (2.51), GFI (.924), CFI (.921) and RMSEA (.063) fit statistics, indicated satisfactory model fit. Fig. , affection dimension (.60), and functional dimension (.85).32 presents sociodemographic characteristics and health status of the study respondents. As can be seen from Table 2 more than two-thirds of the respondents (65.3%) reported their level of income as adequate, and about 93% owned a house.The study sample consisted of 377 community-dwelling older adults 60 years and over, with the mean age of 70.42 ± 8.20 years. The majority of the respondents (68.4%) was 60-74 years old, and 71.6% were married. About half of the participants (42.2%) were no formal education. About two-thirds of the samples (60.5%), elderly pension and life partner were the most important sources of income. Moreover, 22.3% and 19.6% of the participants were pensioners and unemployed, respectively. Table P = 0.813) and marital status (P = 0.068). Based on the findings, grandparents-grandchildren relationship scores were significantly different (P < 0.001) with respect to grandparents' information communication technology. The scores of subjects who did not have any skills were lower than those with full (P < 0.001) or moderate (P < 0.001) knowledge.The mean score of grandparents-grandchildren relationship was found to be 67.60 (SD = 12.47). A series of independent t-tests revealed no significant association between grandparent-grandchild relationship and gender (P < 0.001) and those with a better relationship with parents , had a better relationship with their grandchildren (Table 1).The Pearson’s correlation test showed a significant negative relationship between the grandparents' age and grandparent-grandchild relationship, whereas a significant positive relationship was found between grandparent-grandchild and grandparent-parent relationships. Two groups, including younger people , while geographical distance showed a negative correlation with grandparent-grandchild relationship .However, Spearman’s correlation test showed a positive correlation between grandparent-grandchild relationship and grandparents’ income (P < 0.001). The results are presented in Table 3.A multiple linear regression analysis was conducted to identify the overall grandparent-parent relationship predictors and the relative importance of each predictor. The results of multiple linear regression analysis showed that the following variables were major predictors of grandparent-grandchild relationship: grandparent-parent relationship, distance between grandparents and grandchildren, and grandparents' information communication technology. The analyses showed that these variables could predict 37% of variance in grandparent-grandchild relationship  = 19.05, 4The purpose of the current study was to assess the status and related factors of grandparents-grandchildren relationship in a sample of Iranian older adults. The results showed grandparents-grandchildren relationship in Iran was found to be moderate to high. Around 45% of the respondents reported their relationship with their grandchildren as moderate. This finding is consistent with previous observations which found that the relationship between grandparents and grandchildren was moderate , 20, 21.Although some studies have shown that grandmothers have a better relationship with their grandchildren, as they are kind and form more intimate relationships with their family , 24-26, Results of the present study showed a significant association between the level of education and grandparent-grandchild relationship and supported previous studies documented higher level of education of older adults improve grandparent-grandchild relationship , 28.In the present study, the relationship between grandparents and grandchildren was not significantly different between married and unmarried grandparents. Contrary to the present findings, results from a study in China showed that married people tend to have more contact with their grandchildren .The findings from the current study showed that the income level of grandparents is significantly contributed to more grandparent-grandchild relationship and supported previous studies found that grandparents with a higher income are more likely to have more effective relations and receive more support from their grandchildren , 29. It Grandparents with good or excellent health reported better relations with their grandchildren since unhealthy people has limited abilities to spend time with their grandchildren. This finding is consistent with previous studies , 24.Our study showed that the use of information and communication technology among grandparents is significantly contributed to a high relationship with their grandchildren. In line with our findings, some other studies have underlined the importance of technology to maintain the relationship between grandparents and grandchildren , 31.The relation of grandparents with their grandchildren's parents was found to be a significant factor that is associated with grandparents-grandchildren relationship. This finding is consistent with previous studies that found the relation of grandparents with their adult children plays an important role in the grandparent-grandchild relationship , 24.The finding from the current study showed that geographical distance is significant and inversely associated with grandparent-grandchild relationship and supported previous studies reported a greater geographical distance reduces the relationship between grandparents and grandchildren , 28, 32.One of the limitations of this study is its cross-sectional design; therefore, longitudinal and interventional studies are suggested. In addition, this study only focused on the elderly population from Kashan. Therefore, the findings cannot be generalized to the entire Iranian population, and similar studies are recommended in other cities. Although psychometric properties of the grandparents-grandchildren relationship scale which developed by researchers were found to be valid, another limitation that should be addressed is related to the scale used to measure grandparents-grandchildren relationship which is a new scale.Despite the aforementioned limitations, to our knowledge, this is the first study to describe grandparents-grandchildren relationship in Iran. The results showed that the relationship between grandparents and grandchildren is moderate to high. The findings showed that information and communication technology skills, geographical distance, and the relation of grandparents with their grandchildren's parents (adult married children) are most important factors that are significantly associated with grandparents-grandchildren relationship. According to the findings from the present study, in order to enhance grandparents-grandchildren relationship, it is suggested that grandparents become acquainted with new technological and intellectual skills. In addition, families and adults children try to maintain their relationship with their parents.


The amalgam of noises inherent to the modern-day operating room has the potential of diluting surgeon concentration, which could affect surgeon performance and mood and have implications on quality of care and surgeon resilience.  Evaluate the impact of operating room environmental noises on surgeon performance including fine motor dexterity, cognition, and mood.  37 subjects were tested under three different environmental noise conditions including silence, a prerecorded soundtrack of a loud bustling operating room, and with background music of their choosing. We used the Motor Performance Series to test motor dexterity, neuropsychological tests to evaluate cognitive thinking, and Profile of Mood States to test mental well-being.  Our results showed that typical operating room noise had no impact on motor dexterity but music improved the speed and precision of movements and information processing skills. Neurocognitive testing showed a significant decrement from operating room noise on verbal learning and delayed memory, whereas music improved complex attention and mental flexibility. The Profile of Mood States found that music resulted in a significant decrease in feelings of anger, confusion, fatigue, and tension along with decreased total mood disturbance, which is a measure of psychological distress. Loud operating room noise had a negative impact on feelings of vigor but no increase in total mood disturbance.  Our results suggest that loud and unnecessary environmental noises can be distracting to a surgeon, so every effort should be taken to minimize these. Music of the surgeons' choosing does not negatively affect fine motor dexterity or cognition and has an overall positive impact on mood and can therefore be safely practiced if desired. All surgeons are familiar with the near constant din of the modern-day operating room. Ambient noise can become raucous with the myriad of intrinsic and extrinsic noises inherent to the typical operating room. Intrinsic noises include necessary conversations, alarms, surgical device noise including suction and cautery machines, shift changes, and surgical case counts. Extrinsic sources of noise include unnecessary conversations, phones and beepers, computers, doors slamming, traffic throughout the room, and hallway noise. Some surgeons even choose to alter the environmental noise in the operating room with background music. This amalgam of noises has the potential of diluting surgeon concentration from the task at hand, which could affect patient care. The relentless daily clamor could also influence surgeon mood, which could mount over a career and impact resilience and contribute to burnout. It is imperative to identify sources of potential surgeon distraction and mitigate these risks to patient safety and physician resilience. Therefore, we sought to investigate the impact of operating room environmental noises on surgeon performance including fine motor dexterity, cognition, and mood, as this could have implications on quality of care and surgeon resilience.We utilized the MLS Motor Performance Series of the Vienna Test Series by Schuhfried to assess fine motor dexterity. This is a modular test that utilizes Edwin Fleishman's factor analysis of manual dexterity. It consists of a panel with various contact surfaces, and the subject uses a stylus to perform static and dynamic tasks. We tested each subject's dominant and nondominant arm in the Steadiness, Aiming, Tapping, and Line Tracking tasks. These tests measure the accuracy and precision of movement, steadiness, finger dexterity, and speed of finger, wrist, and arm movements , 2.Cognitive thinking skills were evaluated using a battery of standardized paper-pencil neuropsychological tests that have undergone extensive validation studies. The battery consisted of Hopkins Verbal Learning Test-Revised , Brief Visuospatial Memory Test-Revised , Trail Making Test Form B , Symbol Digit Modalities Test , and the Stroop Test . Hopkins Verbal Learning Test was used to measure verbal learning and memory , 4. BrieTo evaluate for the effect on mental well-being, we utilized the Profile of Mood States created by McNair et al. in 1981. This is a self-reported inventory to assess transient and enduring mood changes. It consists of 65 items that describe emotional states, and the subjects grade each on a five-point Likert scale. The items are grouped into emotional states of anger and hostility, confusion and bewilderment, depression and dejection, tension and anxiety, vigor and activity, fatigue and inertia, and friendliness. This is a commonly used tool used by psychologists to measure psychological distress .We tested 37 subjects comprised of 10 undergraduate students, 22 medical students, and 5 neurosurgical residents. Each subject was tested in randomized order under three different environmental noise conditions: silence, a loud operating room, and background music of their choosing. Silence was utilized as a control for baseline performance and compared to the two other environmental sound conditions which were administered in alternating order to participants in order to randomize conditions. Subjects were tested while listening to a prerecorded soundtrack of a typical modern-day operating room and while listening to music of their own choosing. The subjects' fine motor dexterity, cognitive thinking abilities, and mood state were tested under each condition. We then analyzed the data for statistically significant changes in the cohort performance under each condition. The average age of subjects was 29 years of age. There were 45% female and 55% male subjects. This study was conducted under the review of and with the prior approval of the Carilion Clinic Institutional Review Board and consent of the participants.t-tests were used to assess for statistically significant differences in performances between silence and operating room noise and between silence and music of the subject's choosing. The cutoff value for statistical significance was chosen to be 0.05 to ensure at least a 95% confidence interval in the results.All participant responses were pooled and analyzed as a single group as there were not enough participants in each subgroup of medical students, residents, and undergraduate students to offer a statistically significant result. The scores for each subtest were reported numerically and statistically analyzed to assess for any significant effects on performance. Paired sample p=0.253) or nondominant arm (p=0.092) (see p=0.079) or nondominant arm (p=0.058). Statistically significant results are displayed in The steadiness subtest measured a subject's ability to position the arm and hand precisely and hold this position for a prolonged period , 2. It r092) see . There wp=0.186) or nondominant arm (p=0.055). There was also no difference in errors between silence and music of the subjects choosing for either dominant (p=0.446) or nondominant arm (p=0.057). There was no difference in the time it took to complete the task between silence and operating room noise for either dominant (p=0.057) or nondominant arm (p=0.475). There was a decrease in the amount of time to complete the task with music for both dominant (p=0.003) and nondominant arm (p=0.047).The aiming task is a measure of hand-eye coordination and precision of movements , 2. It rp=0.353) or nondominant arm (p=0.29). Music resulted in an improved speed of tapping with the nondominant arm (p=0.038), but no change with the dominant arm (p=0.345).The tapping subtest measures wrist-finger speed and the speed of untargeted movements , 2. The p=0.168) or nondominant arm (p=0.083) with operating room noise but there was a significant decrement in speed of both the dominant arm (p=0.036) and nondominant arm (p=0.004). Music of the subjects' choosing resulted in a decreased error rate of the dominant arm (p=0.043) and no change in the nondominant arm performance (p=0.478). There was no change in the speed of either arm with music .The line tracking subtest evaluated the precision of arm-hand movements and information processing , 2. Thisp=0.015) and retention (p=0.02) with operating room noise. Music had no significant impact on either immediate recall (p=0.112) or retention (p=0.213).The Hopkins Verbal Learning Test is a measure of verbal learning, immediate memory, and delayed memory , 4. Subjp=0.162) or music of the subjects' choosing (p=0.164).The Brief Visuospatial Memory Test is a measure of visuospatial memory , 5, 6. Ip=0.49) yet music resulted in improved performance (p=0.03).The Trail Making Test is a measure of complex attention, mental flexibility, and visual-motor speed , 8. The p=0.215) or music (p=0.175).The Symbol Digit Modality Test is a measure of psychomotor speed, short-term memory attention, and concentration –11. It ip=0.154) and music (p=0.27) had no significant impact on performance for this test.The Stroop Test is a test of cognitive flexibility and response inhibition –14. SubjThe Profile of Mood States was used to evaluate for changes in mood or psychological distress in response to the environmental noise conditions that the subjects were exposed to . The subp=0.312), confusion and bewilderment (p=0.404), depression and dejection (p=0.181), fatigue and inertia (p=0.121), or tension and anxiety (p=0.441). Operating room noise did decrease feelings of vigor and activity (p=0.044). Music of the subjects' choosing resulted in a significant decrease in feelings of anger and hostility (p=0.005), confusion and bewilderment (p=0.004), fatigue and inertia (p=0.005), and tension and anxiety (p=0.032). There were no changes in feelings of depression and dejection (p=0.064) or vigor and activity (p=0.382) with music. Total mood disturbance is calculated by adding the scores for tension, depression, anger, fatigue, and confusion and then subtracting the score for vigor. There was no significant change in the total mood disturbance with operating room noise (p=0.31) but there was an improvement in total mood disturbance with music of the subjects choosing (p=0.001).In comparison to silence, operating room noise resulted in no significant change in feelings of anger and hostility (t-test on the task improvement for each given participant in different environments between the residents (n=5) and the medical student/undergraduate (n=32) samples. There was no statistically significant change in task improvement at the 0.05 confidence level found between the two education level groups.We then tried to understand if the education and experience level of the participants impacted the motor and cognitive skills in different sound environment. For example, does a neurosurgical resident gain more improvement when listening to music versus OR noise compared to the improvement of an undergraduate student when listening to music versus OR noise. For the tests with statistical significance, we performed an unpaired, two-tail Student's Operating room noise can affect a surgeon's concentration, ability to discriminate speech, and memory . SurgeonThe present study demonstrated that operating room noise resulted in poorer performance on the Line Tracking Test, the Hopkins Verbal Learning Test, and the Profile of Mood. These scores can be translated to decrements in participants' arm-hand movement, information processing, immediate recall, retention, and decreases in feelings of vigor and activity. Music, however, resulted in improvements on the Aiming Task, Tapping Task, Line Tracking Test, Trail Making Test, and Profile of Mood. This correlates to improvements in hand-eye coordination, precision of movements, wrist-finger speed, speed of untargeted movements, arm-hand movement, information processing, complex attention, mental flexibility, visual-motor speed, and mood disturbance. Decreases in anger and hostility, confusion and bewilderment, fatigue and inertia, and tension and anxiety were also observed with music. The Hopkins Verbal Learning Test was not affected by music.The results from the present study indicate that the addition of music to the operating room can be beneficial to a surgeon's ability and mood. Music is known to have anxiolytic effects, and surgeons reported fewer feelings of anger, hostility, fatigue and anxiety with the addition of music of their choosing to the tasks presented. Better mood states may lead to better surgical performance and therefore better patient care and may lead to decreased rates of burnout . Better Limitations of this study include a small sample size composed of undergraduate students, medical students, and neurosurgical residents. Furthermore, the majority of our sample was not experienced in surgery. The present study required participants to complete tasks outside of the operating room with prerecorded operating room noise being played. For the few participants with operating room experience, this setting may not have simulated the state of an operating room that they would be conditioned to. Future directions of work of this nature may consider including the variables of music and operating room noise, operating room noise with white noise, and music not of the participants' choosing. The effects of music may vary if the music is not chosen by the participant; this is a common occurrence in operating rooms, as the lead surgeon would be the one to decide the music. Different types of music may be relaxing to one individual, but stressful to another. Data should also be collected from participants working on a virtual surgery or a more mentally taxing set of tasks.The inconclusive literature and varying opinions on music in the operating room has initiated a debate among surgeons. Through this study, we suggest that excessive and unnecessary noise can be distracting to surgeons and limit their ability to perform well. We conclude that operating room noise leads to decreased performance on tasks associated with fine motor dexterity and cognition and is disadvantageous to mood. We also conclude that listening to music is not detrimental to a surgeon's ability to perform tasks associated with fine motor dexterity and cognition and that music is beneficial to a surgeon's mood. Music, therefore, can be a positive addition to an operating room and can be beneficial to the surgeon and operating team if implemented safely and considerably.


Worldwide, over 500,000 people are diagnosed with head and neck cancer each year, a disease with major impact on life expectancy and quality of life. The purpose of the Netherlands Quality of life and Biomedical Cohort study (NET-QUBIC) is to advance interdisciplinary research that aims to optimize diagnosis, treatment, and supportive care for head and neck cancer patients and their informal caregivers.Using an extensive assessment protocol ), clinical data and data on quality of life, demographic and personal factors, psychosocial , physical , lifestyle , and social factors  are collected and stored in the data warehouse. A longitudinal biobank is built with tumor tissue, blood and blood components, saliva samples, and oral rinses. An infrastructure for fieldwork and laboratory protocols is established at all participating centers. All patients fill out patient reported outcome measures before treatment and at 3, 6, 12, 24, 36, 48, and 60 months follow-up. The interviews, physical tests and biological sample collection are at baseline and 6, 12, and 24 months follow-up. The protocol for caregivers includes blood sampling and oral rinses at baseline and a tailored list of questionnaires, administered at the same time points as the patients. In total, 739 HNC patients and 262 informal caregivers have been included in 5 out of the 8 HNC centers in the Netherlands.By granting access to researchers to the NET-QUBIC data warehouse and biobank, we enable new research lines in clinical (e.g. treatment optimization in elderly patients), biological , health related quality of life , and interrelated research . Worldwide, more than half a million people per year are diagnosed with head and neck cancer (HNC) , a diseaPrevious research over the past decades provided convincing evidence that cancer patients in general have to deal with various physical, psychological, and social side effects of cancer and cancer treatment, negatively affecting HRQOL. In HNC patients, specific stressors as oral dysfunction (e.g. xerostomia) and related swallowing and speech impairment and malnutrition often lead to emotional distress as depression and anxiety. This previous research also showed considerable variation between patients: some patients are at risk for poor HRQOL, while others are protected –18. CancIn HNC patients, associations between HRQOL and survival have been found. Factors influencing survival  have impact on HRQOL. Additionally, HRQOL has prognostic value for survival in HNC cancer patients, independently from known predictors as sociodemographic and clinical parameters –52. Howewww.kubusproject.nl). In this protocol paper, sociodemographic and clinical characteristics of the study sample of 739 patients and 262 informal caregivers are provided. Also, the key components of the NET-QUBIC project are described: the study population , the comprehensive electronic case report form (eCRF), the extensive outcome assessment protocol, biobanking protocols and quality controls, data management (collection and storage), and data and sample dissemination procedures . This paper thus also facilitates other consortia planning to set up a large prospective cohort study such as NET-QUBIC.Despite the existing body of evidence, there is also an unmet need for better understanding of all aspects of HRQOL in the context of increasing long-term survival and growing attention for cancer survivorship , 59–61. The purpose of the Netherlands Quality of life and Biomedical Cohort study in HNC (NET-QUBIC) is to advance interdisciplinary research that aims to optimize diagnosis, treatment, and supportive care targeting HNC patients and their informal caregivers. NET-QUBIC is designed as a longitudinal observational cohort study. In parallel to the data collection, is the establishment of a biobank.Inclusion criteria in NET-QUBIC are: newly diagnosed squamous cell carcinomas in the head and neck ; age > 18 years; treatment with curative intent; all treatment modalities ; able to write, read, and speak Dutch. Exclusion criteria are: other tumors in the head and neck ; patients unable to understand the questions or test instructions; and severe psychiatric co-morbidities , or unable to understand informed consent. Eligible patients are treated according to the current standard in the participating centers and that have been defined in national guidelines on diagnosis, treatment, and follow-up care. Via the patient, the spouse or another family member or lay caregiver  is asked to participate in this project.The sample size calculation is based on the primary research question, i.e. to describe the course of HRQOL over time. We aim to detect a difference over 60 months of 4 points change on the global HRQOL scale of the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire QLQ-C30 between categories of relevant variables (for example between patients with and without depression), using a residual standard deviation of 10 points within categories, and using an α of 0.05 and a power (β) of 0.80. For the dependency of the 5 repeated measures in the study, we assume an intraclass correlation coefficient of 0.50. This results in a total sample size of 462. Taking into account study attrition of 60% , we aim to include 739 HNC patients. In addition, informal caregivers when available during intake will be included. Based on our previous research indicating that 70% of HNC patients have a caregiver and 50% willing to participate, we expect to include 258 informal caregivers.An electronic Case Report Form has been built (OpenClinica) and information is retrieved from medical records. Consensus was reached on the data items to be collected, and changes during the study such as TNM8 impacted the data structure. General clinical information as well as tumor characteristics, detailed treatment information, and pathology data are collected by trained researchers. General information includes incidence date, age, sex, physical performance, performed diagnostics, ACE-27 comorbidity score and weight loss prior to treatment. Tumor characteristics include tumor subsite, lateralization, stage, and lymph node metastasis, according to the TNM7 and TNM8 classification, and in oropharyngeal tumors HPV status and type of HPV test. Information on treatment encompasses a question on type of treatment, followed by more detailed questions per treatment option.For surgery, information on type of resection, reconstruction, type of neck dissection (including details about removed levels and nonlymphatic structures), tumor-free margins, extended morphology of the tumor, grade of differentiation, number of nodes removed, number of tumor-positive nodes, extranodal spread.For radiotherapy, information on type of radiotherapy , technology use, boost methods, and start and end date of radiotherapy is collected. In addition, for patients treated with primary definitive radiotherapy, information on total dose, fraction dose and fractions per week delivered to primary tumor and N+ neck is collected, as well as total dose, fraction dose, number of fractions per week, and radiotherapy duration delivered to elective lymph nodes. For patients treated with postoperative radiotherapy, information on total dose, fraction dose, number of fractions per week and the overall treatment of radiation to the high and intermediate risk and elective target volumes is collected.For chemotherapy, information on type of chemotherapy , used cytostatic agents, chemotherapy scheme, completion of chemotherapy or reason for non-completion, start date, final dose (mg/m2), and information on adverse events is collected.Data are collected according to an assessment protocol (patient reported outcome measures (PROMs) and fieldwork) and subsequently stored in the data warehouse. PROMs target demographic , personal factors , HRQOL, psychological , physical , social , and lifestyle  factors. An overview of the PROMs is provided in Table The interviews target the presence of depression and anxiety -Composite International Diagnostic Interview version (CIDI), Nutritional status  and Dietary intake . Physical tests include assessment of body composition , and skinfolds), systolic and diastolic blood pressure, cardiorespiratory fitness (step test), upper (hand grip test) and lower (chair test) extremity muscle strength, and neurocognitive function . Objective levels of physical activity are assessed using an accelerometer (ActiTrainer). Oral function is assessed via the Functional Rehabilitation Outcome Scale (FROG), and assessment of trismus and dentures. Digital speech recordings are made via a standardized procedure enabling speech quality analyses. An overview is provided in Table In NET-QUBIC frozen tissue, blood components and oral rinses are collected at baseline, 6, 12, and 24 months. Formalin-fixed paraffin-embedded biopsies are routinely available from the pathology archives, but biobanking of frozen samples demands collection of extra biopsies. When patients are surgically treated, the resected specimen is sampled, but in all other cases additional biopsies are collected. Generally, 1 to 3 biopsies are taken, depending on the size of the tumor. These multiple biopsies increase available tissue amounts and allow studying intratumor heterogeneity. All oropharyngeal tumors are tested for HPV virus infection as routine using p16 immunostaining followed by an HPV DNA PCR for the p16-immunopositive cases. The tissue biopsies are snap frozen and stored in liquid nitrogen.Oral rinse sampling is performed and saliva sampling includes four saliva samples per assessment: at the time of awakening, 30 min post-awakening, 60 min post-awakening, and at 22:00 h. Afterwards, the subjects are asked to return the samples by postal mail to the coordinating research center. After receipt, salivettes are centrifuged at 2000 g for 10 minutes, aliquoted and stored at − 20 °C.Blood samples are obtained to assess parameters of cardiovascular, main organ function, immune function, and metabolic syndrome using routine assays. Additional blood samples are processed in components and stored at − 80 °C. An EDTA sample is sent to the coordinating center and DNA isolated and stored. A PaxGene tube of blood for RNA profiling is collected and stored at − 20. A serum sample is collected, centrifuged, the supernatant aliquoted and stored at − 20 °C. Four additional EDTA samples are collected and used for isolation and storage of plasma, blood platelets, cryopreserved Peripheral Blood Mononuclear Cells and pelleted Polymorphonuclear leukocytes. A Standard Operating Procedure (SOP) forms the basis to collect, isolate and store these components. The consented SOP was introduced to the participating centers and for quality control, samples were isolated at every center from healthy volunteers, and the sample performance tested at a central laboratory (Amsterdam UMC) in functional (Antibody-dependent cellular cytoxity of PBMCs) and molecular assays . Quality control was sparsely budgeted and thus limited, but revealed that all samples from all centers could be assayed well. Most variable was the quality and functional activity of cryopreserved PBMCs as expected, but with proper experimental controls also these samples are evaluable.All patients fill out PROMs before treatment and at 3, 6, 12, 24, 36, 48, and 60 months follow-up. Interviews, physical tests and biological sample collection are assessed at baseline and 6, 12, and 24 months follow-up only (because of budget restraints) . Participants are informed about the study progress by newsletters and the website (kubusproject.nl). There is prompt and adequate response to any question or letter from the participants. The patient and the general practitioner are informed on the home test results regarding e.g. body mass index, blood pressure or blood results, and in case of deviant test scores also the attending head and neck surgeon, radiation oncologist and/or medical oncologist .Data and sample collection take place at home visits or at the hospital, and consists of PROMs, an interview and functional tests, and collection of biological samples. PROMs are sent to the patients by postal mail. During home visits, neurocognitive tests, physical tests and a face to face interview take place, and blood samples are drawn. Tubes to collect saliva, and the accelerometer are given to the patients after the home visit. After completion of the measurements, patients send the tubes and accelerometer to the researcher by postal mail with the envelope provided. Patients are allowed not to complete all three components  if this is too much burden, or for logistic reasons (e.g. time too short between diagnosis and start of treatment).Research assistants conduct the field work, and manage the data collection. All data are coded directly after being collected and are entered into the NET-QUBIC data warehouse to ensure accuracy and completeness of the data. The field workers are extensively trained and supervised by a coordinating research nurse. Data management is coordinated at the Department of Otolaryngology / Head & Neck Surgery of Amsterdam UMC location VUmc, and GGZInGeest in Amsterdam. A special team of data managers takes care of data quality, data archiving and the creation of variables and scales. The NET-QUBIC Data Warehouse makes use of Open Clinica (collection of multisite case record forms) and Blaise (face to face data collection). This Data Warehouse is used to collect and store cancer and treatment data, outcome, PROMs, results of medical examination and function tests, and biobank data. Also, the logistics for project management are structured by means of this system.www.force11.org). Findable data: Data are described on the NET-QUBIC project website (www.kubusproject.nl). Accessible data: The collection and integration of large amounts of personal, biological, genetic and diagnostic information precludes open access to the NET-QUBIC research data. In the section Data and sample dissemination (below) is described how the data are made available for the research community. Interoperable data: All data is encoded by a single participant number that includes an institute code. This allows exchange of all collected data, but adding new clinical data requires that the codes at the participating institutes are broken. Re-usable data: Validated longitudinal data from the 739 patients and 262 caregivers, as fixed datasets will be available for re-use. The storage time is 15 years as the legal minimum for clinical data.Data and samples are stored via FAIR principles: Findable, Accessible, Interoperable, Re-usable (www.kubusproject.nl). Usage of NET-QUBIC data and/or biomaterials is regulated in the NET-QUBIC Data and Biomaterial Access Policy, and in the NET-QUBIC Publication policy (study procedures available via the website). In brief, access is provided as follows: A single-entry portal to all activities is provided on the NET-QUBIC website. The proposals can be submitted via an on-line application form. The NET-QUBIC team oversees the projects from evaluation, to experiment, to report after completion. Questionnaires are sent to users (i.e. 1 year following access provision) for feedback on the access service and to summarize the results (including patents and publications), enabling an evaluation of the outcome of the projects. An applicant will first choose the type of support and sample/data that they need for their proposed projects. The forms will be filled out by the applicant, and submitted to the NET-QUBIC Access Board for review. Transparency, fairness and impartiality are key objectives for the evaluation of the project ideas and project applications. Applications are judged on (i) scientific merit / excellence, and (ii) expected scientific, societal and economic impact, both carrying equal weight. While judging research protocols, there will also be emphasis on overlap between protocols (e.g. PhD-trajectories) and in case of overlap, researchers are encouraged to collaborate. Evaluation reports will be provided for all projects, including those that fail. These reports will provide constructive feedback from the evaluators that will help researchers to improve their projects. When a research protocol is granted, the data are made available by a fully automatic procedure by means of a protected website tool for researchers to download the requested data. For use of biobank samples, the research methods and requested amounts are critically reviewed and projects combined whenever possible. Before biobank samples are released, the research protocols are reviewed by the Institutional Review Board on Biobanking at the coordinating center. The participating centers agreed to this approach. Data and samples are accessible for external parties by collaboration with one of the Access Board members of the participating institutes.Data and sample releases will be organized 1 to 2 times a year and will be announced on the project website (A Data Transfer Agreement (DTA) or a Material and data Transfer Agreement (MTA), all according to national and European Law and Regulations as the European General Data Protection Regulation (GDPR) will be signed by the legal representative of the institute of the researcher and the PI. It also contains an Intellectual Property Strategy. The Technology Transfer Office in Amsterdam (IXA) and the legal representatives of the Board of Directors of all participating institutes have been actively involved in developing the Research Agreement, the data and biomaterial access and publication policies, and DTA/MTA. Research data obtained from new studies (e.g. new biomarkers) will be brought into the data warehouse for use in future studies.The flow diagram is shown in Fig. n = 539), not wanting to participate (n = 228), no time (n = 169) and feeling physically incapable to participate (n = 60); 71 patients provided no reason. In total, 262 informal caregivers agreed to participate. An overview of the sociodemographic and clinical characteristics of the 739 HNC patients and 262 informal caregivers is provided in Table Of the 1861 patients who were asked, 739 patients were willing to participate (40%). Reasons not to participate were: feeling psychologically incapable to participate  on the total Dutch HNC population in all eight HNC centers, treated from March 2014 to June 2018 in the Netherlands (the same study period as in the NET-QUBIC project) for newly diagnosed squamous cell carcinomas in the head and neck ; age > 18 years; all treatment modalities ; exclusion criteria were: other tumors in the head and neck . These are the same in- and exclusion criteria as in the NET-QUBIC project. The NCR does not have data on the NET-QUBIC inclusion criteria “treatment with curative intent; able to write, read, and speak Dutch” nor on the exclusion criteria “patients unable to understand the questions or test instructions; severe psychiatric co-morbidities ; unable to understand informed consent”. The NCR does not have information either on informal caregivers of HNC patients. In total, we obtained overall data  on 9802 Dutch HNC patients.n = 729 (739–10 patients who did not provide informed consent to combine their data with other registries)) was compared to the total Dutch HNC patient population (n = 9073 (9802–729)) regarding sex, age, tumor subsite and stage, and treatment modality   regarding sex, age, tumor stage, and treatment modality Table . The NETwww.eortc.be), and some other large longitudinal cohort studies in the United States [Literature suggests that the course of HRQOL and its association with survival is influenced by various cancer-related, personal, genetic, biological, psychobehavioural, physical, lifestyle-related, and social factors, which may also interact with each other. Many (molecular) mechanisms possibly influencing the course of HRQOL and the relation between HRQOL and survival are unknown. There is a strong unmet need for high quality data and biological sample resources to advance our knowledge. Besides NET-QUBIC, there are a few other large resources such as national registries , and the protocol also complies with the HNC toolbox as described by Ringash et al. [www.lasa.nl) and depression and anxiety (www.nesda.nl), (2) a pilot study among 15 HNC patients which proved that the outcome assessment protocol is feasible [www.cosmin.nl). Another strength is the large longitudinal biobank that can be applied for tumor-educated blood platelet profiling , circulating tumor DNA analysis , and immune profiling, and the data linked to outcome and HRQoL.A strength of NET-QUBIC is that the outcome assessment protocol was developed following the standardized assessment and evaluation of functioning based on the International Classification of Functioning, Disability and Health (ICF) Core Set for HNC  finAnother strength of NET-QUBIC is that data and samples are collected according to FAIR principles: Findable, Accessible, Interoperable, Re-usable. Legal issues are handled through a multicenter research agreement including MTA/DTA, taking into account the GDPR. There were several problems encountered before we achieved this agreement: the laboratory infrastructure had to be set-up at some centers, and storage of samples to local protocols required reorganization of the planned biobanking. Also the procedures on making data and biosamples available had to be centralized to prevent a huge administration for the researchers, and this was not in line with the standard policies at the participating institutes. A consensus could be reached between all centers, but this required extensive preparations. These problems caused a delay in starting recruitment of participants in some centers and took considerable time and efforts of the  principal investigators and legal advisors during the study. A limitation of NET-QUBIC is the response rate of 40%, which is slightly lower than the response rate as reported in the HN5000 cohort (49%) . The NETwww.kubusproject.nl.The NET-QUBIC Datawarehouse and Biobank are open for collaboration with (inter)national researchers. Already planned studies include 1) The course of HRQOL in HNC patients from baseline to 2 years follow-up, and to identify cancer-related, personal, genetic, biological, psychobehavioural, physical, lifestyle-related, and social determinants of HRQOL, 2) Whether the association between HRQOL and survival is direct or mediated by other variables, 3) The course of HRQOL in informal caregivers, 4) The course of symptoms of depression in HNC patients and the relation with survival, 5) Treatment optimization in elderly HNC patients, and 6) Predictive models for objectively and subjectively measured salivary, mastication, and swallowing function in relation to HRQOL. The first data release in 2017 granted access to 6 other studies making use of data of the first 254 included patients. The second data release in 2019 granted access to 7 new studies making use of all 739 included patients and 262 caregivers at baseline, and at 3 and 6 months follow-up. In the near future, new data releases will be organized and will be announced on the website In conclusion, by granting access to all interested researchers to the NET-QUBIC data, we enable new research lines in for example: clinical research (e.g. treatment optimization in elderly patients), biological research , molecular/digital pathology based predictive biomarker research, HRQOL research (e.g. the impact of toxicity on HRQOL), and interrelated research . Managing this access in an integrated (inter)national network is crucial to advance research with broad, multidisciplinary impact.


During the past decade, there has been a substantial rise in the knowledge about the effects of gut microbiota on host physiology and behavior, including depressive behavior. Initial studies determined that gut microbiota can regulate host tryptophan levels, which is a main serotonin precursor. A dysfunctional serotonergic system is considered to be one of the main factors contributing to the development of depression. Therefore, we hypothesized that regulation of brain tryptophan and serotonin can explain, at least partly, the effects of microbiota on depressive behavior. To test this hypothesis, we examined depressive-like behavior and brain levels of serotonin and tryptophan, of germ free (GF) and specific-pathogen free (SPF) mice under basal conditions, or after acute tryptophan depletion (ATD) procedure, which is a method to decrease tryptophan and serotonin levels in the brain. In basal conditions, GF mice exhibited less depressive-like behavior in sucrose preference, tail-suspension and forced swim tests, compared to SPF mice. In addition, in mice that were not subjected to ATD, GF mice displayed higher levels of tryptophan, serotonin and 5-hydroxyindoleacetic acid (the main degradation product of serotonin) in medial prefrontal cortex (mPFC) and hippocampus (HIPPO), compared to SPF mice. Interestingly, ATD increased depressive-like behavior of GF, but not of SPF mice. These behavioral changes were accompanied by a stronger reduction of tryptophan, serotonin and 5-hydroxyindoleacetic acid in mPFC and HIPPO in GF mice after ATD, when compared to SPF mice. Therefore, the serotonergic system of GF mice is more vulnerable to the acute challenge of tryptophan reduction, and GF mice after tryptophan reduction behave more similarly to SPF mice. These data provide functional evidence that microbiota affects depression-like behavior through influencing brain tryptophan accessibility and the serotonergic system. Depression is one of the most common psychiatric conditions, with lifetime prevalence ranging from 6 to 18% across different populations worldwide  is synthetized in serotonergic neurons originating from raphe nuclei, from amino acid tryptophan  mice exhibit less behavioral despair compared to their conventional counterparts  mice, to test if TRP reduction would attenuate the anti-depressive behavior of GF animals. Indeed, we determined that in basal conditions GF mice exhibit less depressive-like behavior compared to SPF mice. However, their serotonergic system is more vulnerable to the acute challenge of TRP reduction, leading to that GF mice act more similarly to SPF mice after TRP reduction. Therefore, these data provide direct functional evidence that microbial effects on depression-like behavior can be mediated through its effects on brain TRP accessibility and consequently serotonergic system.ad libitum. GF Swiss Webster male mice were housed in semi-solid GF isolators, also under a 12 h light/12 h dark cycle, at 22°C, with autoclaved food and water available ad libitum. Three to five mice were housed per cage and the experiment was carried out at 8–10 weeks of age. In the study of behavioral differences between GF and SPF animals, a total of 20 mice was used (10 mice per group). In the study of the effects of ATD on both GF and SPF animals, a total of 44 mice were used (11 mice per group). All experimental protocols were approved by the Animal Care and Use Committee of Bar-Ilan University.All animals used in the study were bred and maintained in animal facilities at our research institute. SPF Swiss Webster male mice were housed in SPF vivarium with 12 h light/12 h dark cycle, at 22°C, with food and water available Behavioral tests, except sucrose preference, were performed during the light phase of the diurnal cycle, between 12 a.m. and 16 p.m. On the day of behavioral testing, SPF as well as GF mice were brought to the behavioral room in the SPF facility, at least 1 h before the test, for acclimatization.Sucrose preference test (SPT) was used to assess anhedonic behavior in mice. The test was carried out in home cages, while mice were single-housed by dividers. Each of the mouse was presented with two pipettes to choose freely: one containing drinking water and the other 0.5% sucrose solution. The position of pippets was switched every 24 h to eliminate side preference as a confounder. The test lasted 5 days, with the 1st day considered as habituation, while the next 4 days were considered as the test. During that time consumption of water and sucrose solution was measured and sucrose preference was calculated as a percentage of the volume of sucrose solution intake divided by the volume of total fluid intake.Tail suspension test (TST) was performed by suspending mice by their tail for 6 mins, with the tape applied about 1 cm from the tip of their tail, under low light conditions (25 lux). Behavior other than trying vigorously to escape was scored as immobility, and considered as an indicator of depressive-like behavior  was performed using modified procedure with pre-test 24 h before the test day  gene expression. GF mice used for these analyses were sacrificed 1 h after being taken out from the isolator.+ group, 0.28% TRP of the total protein amount) or without TRP (TRP− group). The composition of the given protein-carbohydrate mixture is shown in Prior to TRP depletion procedure, mice were handled for 3 days and once gavaged with protein-carbohydrate mixture with TRP, in order to habituate to the procedure. On the experimental day, mice were food deprived for 5 h in order to avoid the effects of TRP available in regular chow. After starvation, mice were gavaged with protein-carbohydrate mixture containing TRP , the hippocampi (HIPPO) and dorsal rapeh nucleus (DRN) were isolated using brain matrix and gauge 13 (for mPFC and HIPPO) or 14 (for DRN). Brain tissues were immediately frozen on dry ice and stored at −80°C until further application.g, at 4°C and the supernatants were used for subsequent measurements according to Yamaguchi et al.  according to the manufacturer’s protocol. High Capacity cDNA Reverse Transcription kit  was used for the synthesis of cDNA, from 400 ng of total RNA from DRN extracts.Quantitative real-time PCR was performed using Fast Start Universal SYBR Green Master  and ViiA™7 Real-Time PCR System . Relative quantification by ddCt method was used for analyses of gene expression. Primer sequences of analyzed genes: TPH2, serotonin autoreceptor (5-HT1A) and SERT, as well as housekeeping gene  are listed in the t-test. The effects of mice microbiological status and TRP depletion were analyzed by two-way analysis of variance (ANOVA), followed by LSD post hoc test for evaluating differences between specific groups. Values that fell out of the range mean ± 2 SD were considered as outliers and excluded from the analyses. The level of significance was set at p < 0.05. As a measure of the effect size of ATD in GF and SPF mice, Cohen’s d was used.Statistical analyses were done by SPSS. Data from GF and SPF mice were compared using two-tailed t = 2.34, p < 0.05, First, we characterized the depressive-like behavior of GF mice compared to SPF. In the SPT, an established test of anhedonia, GF mice showed a greater preference for 0.5% sucrose compared to SPF  and microbial status  of mice. However, SPF mice that underwent ATD did not significantly differ from mice receiving full amino acid mixture , while the effect of microbial status was close to significant . Also, no significant differences were observed in SPF mice between TRP+ and TRP− groups  and GF state .In mPFC, the brain region involved in coordination and control of depressive behavior Drevets, , levels F = 14.09, p < 0.001; 5-HIAA: F = 12.74, p = 0.001) and microbiota status . In mice with no TRP depletion, GF mice had higher 5-HT and 5-HIAA levels compared to SPF . The interactions of ATD and GF status at the levels of 5-HT and 5-HIAA were also close to significance .The levels of 5-HT , as wellThe ratio of 5-HT/5-HIAA, as a measure of 5-HT turnover, was not affected by any of the treatments (data not shown).Therefore, GF mice had more 5-HT in the mPFC, but their 5-HT system showed higher vulnerability to ATD challenge, compared to SPF.F = 64.48, p < 0.001) and GF status .In HIPPO, a brain region also involved pathophysiology of depression  but not by the absence of microbiota. There was a tendency of increased 5-HT levels in SPF mice compared to GF control mice .Serotonin levels in HIPPO  were affF = 80.83, p < 0.001) and GF status . In mice not subjected to TRP depletion, GF had higher 5-HIAA levels compared to SPF .The levels of 5-HIAA  were affThere were no differences between groups in 5-HT turnover (data not shown).In conclusion, 5-HT system in HIPPO, as in mPFC, was affected more strongly in GF mice than in SPF.There is an increasing interest in dysbiosis of gut microbiota and its role in the development of various psychiatric problems, including depression. Our results show that GF mice exhibit less depressive-like phenotype, but they are more sensitive to acute TRP depletion challenge. These results give direct evidence that TRP availability to the brain and its subsequent regulation of serotonin levels is one mechanism through which gut microbiota may affect depression behavior.We first characterized the depressive-like behavior of GF animals, compared to their counterparts with normal nonpathogenic commensal microbiota. Indeed, it was already reported that GF mice exhibit different behavior compared to control mice: they are less anxious, with altered social behavior, and impaired memory. Our results are in concert with previous data showing that GF mice display reduced immobility in tests of behavioral despair, TST , which is also in line with previous data. For example, it was shown that GF mice, despite exhibiting anxiolytic and anti-depressive phenotype, have more exaggerated rise of corticosterone, in a response to restrained stress (Sudo et al., In conclusion, our data revealed anti-depressive effect of microbiota absence, but also higher sensitivity of GF mice in response to the challenge of TRP depletion. These results suggest that microbiota, through affecting brain TRP availability, affects the brain serotonergic system of the host, and can influence the vulnerability to depression.The study was carried out in accordance with the recommendations of the Institutional Animal Care and Use Committee of Bar Ilan University Faculty of Medicine and the protocol for this project was approved by the Institutional Animal Care and Use Committee of Bar Ilan University Faculty of Medicine.IL took part in designing the study, conducted experimental work, analyzed the data, and wrote the manuscript. DG helped in conducting the experimental work. OK took part in analyzing the results and revised the manuscript. EE designed the study, discussed results and revised the manuscript.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.


Environmental contaminants such as heavy metals are transported to the Arctic regions via atmospheric and ocean currents and enter the Arctic food web. Exposure is an important risk factor for health and can lead to increased risk of a variety of diseases. This study investigated the association between pregnant women’s levels of heavy and essential metals and the birth outcomes of the newborn child. This cross-sectional study is part of the ACCEPT birth cohort  and included 509 pregnant Inuit women ≥18 years of age. Data were collected in five Greenlandic regions during 2010–2015. Population characteristics and birth outcomes were obtained from medical records and midwives, respectively, and blood samples were analyzed for 13 metals. Statistical analysis included one-way ANOVA, Spearman’s rho, and multiple linear and logistic regression analyses. The proportion of current smokers was 35.8%. The levels of cadmium, chromium, and nickel were higher compared to reported normal ranges. Significant regional differences were observed for several metals, smoking, and parity. Cadmium and copper were significantly inversely related to birth outcomes. Heavy metals in maternal blood can adversely influence fetal development and growth in a dose–response relationship. Diet and lifestyle factors are important sources of toxic heavy metals and deviant levels of essential metals. The high frequency of smokers in early pregnancy is of concern, and prenatal exposure to heavy metals and other environmental contaminants in the Greenlandic Inuit needs further research. Environmental contaminants such as toxic heavy metals and persistent organic pollutants (POPs) are transported to the Arctic through long-range atmospheric and ocean currents ,5,6,7,8.Heavy metals is a general term that applies to metals and metalloids, which have a relatively high density and are considered to be toxic to living organisms and the environment in certain concentrations ,10,11.Metals and other elements occur naturally in the Earth’s crust. However, human and environmental exposure has increased with increasing use of heavy metals in industry, agriculture, technology, and medicine, as well as from domestic settings and workplaces ,10,11.Some metals and trace elements are essential nutrients for biochemical processes in the human organism. Insufficient or otherwise deviant blood concentrations of these essential metals and trace elements may result in various diseases ,11,16,17The severity of toxicity as well as organ systems affected depends on the heavy metal type, chemical form, whether it is single or mixtures of compounds, exposure dose and time, exposure route, physiologically based pharmacokinetic model, and the age of the exposed organisms, including humans ,20,21,22Exposure to heavy metals may lead to increased risks of cancer, allergies, neurological diseases, decreased cognition, and endocrine disorders ,25,26,27The developmental period of the fetus and the newborn is the most sensitive period in life, making them particularly vulnerable to exposure of heavy metals ,25,33. TThe traditional diet of the Greenlandic Inuit relies on marine food, such as seal, whale, and polar bears at the top of the food chain, and furthermore fish, and therefore, they are exposed to relatively higher levels of heavy metals ,12,28,34There are reports on a decreasing trend in blood levels of contaminants for some of the Arctic populations, indicating regulation through legislation as well as health interventions are working ,36,37. HThis cross-sectional study is nested in the birth cohort ACCEPT  . The oveData were collected from 2010–2015 in five regions of Greenland: North (RN), Disko Bay (DB), West (W), South (S), and East (E) .The criteria for inclusion were pregnant Inuit women ≥18 years of age who had lived more than 50% of their lives in Greenland.ACCEPT enrolled 614 pregnant women. Among them, 42 participants had not lived in Greenland for more than 50% of their lives, five participants were younger than 18 years of age, 33 women gave no information of life duration in Greenland, and 19 participants withdrew their consent to participate or had an early abortion and were excluded. Then, 509 women fulfilled the criteria for inclusion; however, of these, 12 participants had abortions or miscarriages, five participants had no birth outcome information, four twin pairs and two stillborn were excluded, and finally, 487 live born singletons were included in our study analysis .A Danish- and Greenlandic-speaking medical doctor recruited the participants in 2010–2011 and Greenlandic midwives and the study research team in 2013–2015. Enrolment and inclusion to the ACCEPT study have previously been reported ,27,28,34Samples of venous blood were collected from the pregnant women at inclusion to the study and stored at −80 °C until analysis.Prior to data collection, all participants received detailed descriptions of the objective of the project. Informed consent was obtained from all participants and data were anonymized after collection. In addition, participants were informed that participation was voluntary, and they could withdraw their consent at any time.This study was approved by the Ethical Committee for Scientific Investigations in Greenland (J.no. 011-0035-09/gope) as well as the Danish Data Protection Agency (J.no. 2011-41-6367) and conducted in accordance with the Helsinki II Declaration.Thirteen blood metals, including heavy metals mercury (Hg), lead (Pb), arsenic (As) and cadmium (Cd), chromium (Cr), manganese (Mn), and nickel (Ni), as well as essential metals, including selenium (Se), iron (Fe), copper (Cu), zinc (Zn), magnesium (Mg), and calcium (Ca), were measured using inductively coupled plasma mass spectrometry (ICP-MS) at the accredited element laboratory, Institute for Bioscience—Arctic Research Centre, Aarhus University, Denmark. The quality was ensured by repeated analyses and frequent analysis of certified reference material (Seronorm™), as well as by participation in the Quality Assurance of Information in Marine Environmental monitoring (QUASIMEME), an inter-laboratory comparison program . Unless Cotinine is a metabolite of nicotine and is therefore proportional to the amount of exposure to tobacco smoke and, thus, serves as a biomarker for recent exposure to tobacco smoke. The Calbiotech Cotinine Direct ELISA Kit from Calbiotech Inc., CA, USA was used to measure plasma cotinine at the Centre for Arctic Health and Molecular Epidemiology, Department of Public Health, Aarhus University, Denmark.The ratio between n-3 polyunsaturated fatty acids and n-6 fatty acids (n-3/n-6 ratio) is known to be a strong indicator for the consumption of marine food items vs. imported food items . Plasma The birth outcomes are basic measurements of the newborns : Birth wLow birth weight: Defined by the WHO as weight at birth less than 2500 g .Preterm birth: Defined by the WHO as babies born before 37 completed weeks of gestation .Low APGAR5: Defined as a score of less than 7 .Categorized outcomes have the following definitions:The APGAR score assesses the newborns and the need for intervention to establish breathing. The score is reported at one minute, five minutes and at five-minute intervals thereafter until 20 min for infants with scores below 7 . The metData were analyzed with IBM SPSS Statistics version 20.0  with a significance level of 5%, and 95% confidence intervals (95%CI) were calculated. Unless otherwise stated, only significant results are given in the text.Data distribution was checked by Q–Q plot and natural logarithmic transformed data made the distribution more symmetrical and improved the normality of data.One-way ANOVA was applied to compare the levels of metals in pregnant women from different Greenlandic regions. When ANOVA showed statistical significance, complementary multiple comparison post hoc tests were performed. A test for equal variances of variables was performed using Levene’s test. Fisher’s least-significant difference test was used if equal variance was observed; otherwise, Dunett’s T3 was used. One-way ANOVA was applied to compare birth outcomes for the quartiles of blood metals. Pearson’s chi-square was applied to check the regional difference of categorical variables. Student’s t-test was used to compare the levels of cotinine in smokers/nonsmokers, respectively. Spearman’s rho was applied to assess the bivariate correlation of the metals for all regions in total as well as stratified by region, and also to assess the correlation between metals and lifestyle factors.The association for the maternal levels of blood metals and the continuous birth outcome data was analyzed by multiple linear regression analysis and was stratified by gender. For the association between maternal blood metal concentrations and the categorical birth outcome data , logistic regression analysis was used. We built the models one element by one. The identification of potential confounders was based on literature knowledge and directed acyclic graphs (DAGs) supported by the “Change in estimate” method ,47. For 2. Primary school, secondary, and university education were 29.4%, 47.1%, and 23.5%, respectively, and 56.8% of the participants lived in the West region. More than a third (35.8%) of the women were current smokers at the beginning of their pregnancy. The proportions of smokers were statistically significant different among the regions with the highest frequency in East in the order: East (E) > South (S) > North (RN) > West (W) > Disko Bay (DB). No significant difference was found for plasma cotinine among the regions for smokers or nonsmokers; however, current smokers had significant higher plasma cotinine levels compared to nonsmokers .The study population included 509 pregnant women (18–43 years of age) with a median age of 27.0 years and median pre-pregnancy BMI of 24.3 kg/mp = 0.08) among the regions was found, possibly explained by only one person’s (from the North region) consumption of >2–3 times a month.A significant difference was found among the regions for parity, defined as a full-term pregnancy, with a higher median in the East region. No significant difference was found when parity was categorized into 0, 1–2 or ≥3 prior full-term pregnancies. The n-3/n-6 ratio was not significantly different among regions, although a slightly higher median value in the East region was observed.For alcohol consumption during pregnancy, a borderline significant difference  and cotinine , respectively. Smoking positively correlated with cotinine . Age positively correlated with the n-3/n-6 ratio  (not shown).Moreover, we found a negative correlation between age and smoking , Se , Pb , Cd , Cr , and Mn  in the order of Se > Cd > Hg > Pb > Mn > P-Se > Cr but negatively to Cu ; negative correlations were observed between plasma-Se and Cd , Cr  and Mn , and Cd and Cr . . The maternal blood level of Cd was negatively associated with birth weight both as raw data as well as upon adjustments. For Cu, the raw data were negatively associated with birth weight and upon core and region adjustment, whereas the inverse association for Ca disappeared upon further adjustments (ustments .p = 0.049), upon core adjustment , core adjustment plus gestational age at birth  and adjustment for core plus region   .p = 0.047) and Zn adjusted for core and gestation age   .p = 0.026), upon core adjustment  and adjustment for core plus region . Raw data Zn  and Mg  were weakly positive, while Ca were negatively associated with gestational age at birth , but upon adjustments, the associations disappeared  and lead (Pb) were relatively lower than in previously reported data for the Greenlandic population, indicating a decline over time ,39,50. MIn some regions, especially North and East, deviant levels of both essential metals and heavy metals and lifestyle factors were observed.Significant inverse relations were observed for birth weight and maternal levels of Pb, Cd, and Cu; birth length and maternal levels of Cd and Cu; head circumference and maternal levels of Pb and gestational age and maternal levels of Cu, As, and Cd.The population characteristics across regions were similar in general, but significant regional differences were found for smoking, alcohol consumption during pregnancy, and parity.A total of 35.8% of the participants were current smokers in their early pregnancy—we observed a decline compared to previous Greenlandic birth cohorts like the Disko Bay Birth Cohort (60%), INUENDO (56%), and IVAAQ (45%) ,34. HoweAlthough the smoking rate seems to have declined in some regions compared to previous reports, the high smoking rate is a major public health challenge in Greenland because of its high prevalence and related morbidity and mortality from a number of diseases. Lung cancer is the most common cancer in Greenland, amounting to 34% of cancer deaths during 2000–2014 .Smoking is a well-known source of heavy metals, affects growth and development of the fetus, and increases the risk of low birth weight and preterm birth and, thus, health risk in childhood and later in life ,53. Collp < 0.001) but not across the regions. Cotinine is a proportional marker for recent tobacco exposure and can support the smoking questionnaire that may be subject to reporting and/or recall bias [Significant differences in current smoking frequency were observed across the regions, being the highest in East (72.2%), followed by the South (40.9%), then the North (40.6%), then the West region (33.7%), and Disko Bay (32.2%). There was a significant difference in plasma cotinine level between smokers and nonsmokers  may mitigate the negative effects of some heavy metals in chronically exposed populations . FurtherNutrients and antioxidants such as Se and the n3/n6 ratio found in seafood are thought to be capable of attenuating the adverse effects of some environmental pollutants . FurtherA Canadian birth cohort study found that estimated Ca intake may be associated with lower maternal Cd, Pb, Mn, and Hg, as well as cord blood Pb . In suppSeveral metals correlated with lifestyle factors. Age was positively correlated with Pb, Se, and Fe but negatively with Cd and Ca . Cd and The fatty acids n-3/n-6 ratio correlated significantly positively with plasma-Se and whole blood selenium, respectively. This suggests that the traditional marine diet is an important source of this antioxidant. By contrast, the levels of Hg and Pb were also positively correlated with the n-3/n-6 ratio, suggesting the traditional marine diet was an important source of these heavy metals as well—a classic example of the so-called “Arctic dilemma”, describing the benefits and disadvantages of traditional food within the Arctic regions ,32,86.Metal-to-metal correlation analysis showed positive correlation between heavy metals such as Hg, Pb, As, and Cd, suggesting that the contamination from metals in the blood of the women may originate from the same exposure source . Cd may When stratified by region, these correlations showed some similarities and differences, suggesting different sources of exposure within the regions .No statistically significant differences were found for the birth outcome characteristics across regions, but a tendency for lower birth weight and shorter length was observed in the East. This might be explained by the higher frequency of smokers during pregnancy in the East . In the For the total study population, we found that Pb, Cd, and Cu levels were negatively related to birth outcomes. Moreover, the β estimates indicated that an increased level of Cu increases the risk of earlier delivery c. FurtheWhen stratified by gender, these associations showed clear differences in metal blood levels . For femGender differences were also reported for exposure to other environmental contaminants; e.g., the lipophilic POPs . The heap = 0.040) of Cd and low birth weight showed a higher risk of low birth weight upon exposure to Cd. Similar findings are previously described in the literature [The OR of 1.441   b, suggesAlthough weakly, the OR for preterm birth was positively associated with Cu c. This aThe strengths of the present study are the relatively large population compared to previous studies of the Arctic populations. Our results are the first to provide all included population data from the ACCEPT study. The relatively large number of measured metals of this study, compared to the typical analyses in the available literature, provides new insights into heavy metal effects on essential metals, e.g., Fe in the Greenlandic Inuit.This study has some limitations: Reference ranges of whole blood metal levels are nonexistent for Arctic populations. The reference population for normal ranges included in this study was non-Arctic, nonpregnant Nordic populations both male and female of various ages. No suitable whole blood references for Mg and Ca were found.Five newborns died within the first 24 hours; we reran the statistical analyses upon eliminating these five, and the statistically significant data given were not changed.Several non-expected estimates with APGAR5 were found, suggesting that the score improved with higher concentrations of toxic heavy metals, e.g., Cd and Cu, whereas increase in Cr lowered the APGAR5 scores. The effects of heavy metal exposure on the APGAR score is sparsely investigated in the literature, and the conclusions from the few studies that describe the matter differ on population, material, and statistical power and, thus, cannot be generalized to the present study ,93,94. OIn a quality control of the ACCEPT analyses, the number of samples eligible for analysis by ICP-MS was investigated. Some analyses of the metals did not exceed the detection limit and, thus, may influence the precision of the present study. Furthermore, 201 samples were not analyzed for Mg and Ca from 2013–2015 as well as 17 samples for Cu .Adjustments for POPs were not conducted in this study but should be considered for future studies. Adverse health effects associated with POPs in pregnant Inuit women, the fetus, and newborn are found in several studies ,99,100. When divided into five regions, the study population was relatively small. Consequently, some regions  had below 10% of the total study population included because of the relatively low proportion of residents in these regions, as reported in similar studies, and thus, the statistical power is low ,28,33,34Multiple hypothesis tests with an alpha error set to 0.05 were performed. In the present study, we measured 13 metals in maternal blood, analyzed, and estimated their association with birth outcomes. The ‘multiple testing problem’ should be addressed and chance findings cannot thus be ruled out ,102.The Greenlandic Inuit are exposed to high levels of heavy metals through a traditional diet. Previous ACCEPT studies reported a traditional food intake of 12–18% ,34, a deIt cannot be ruled out that socioeconomic status and food insecurity are factors for the consumption of heavy metal or POP-contaminated food items . In a poThe Arctic is an area of transition, both culturally with regards to lifestyle but also with respect to climate change and pollution. We believe this study elucidates important environmental issues to consider when assessing the human health of the Arctic.Our results may provide local governments and other stakeholders with information to base their decisions on regarding contaminants and public health. Elucidating the heavy metal effects on the Inuit population and their environment is essential for a complete health risk assessment and management of public health. Hence, continuous monitoring of changes in climate and culture is vital to interpret and understand the complex and synergistic effects between climate change, contaminants, and human health to reduce adverse health effects.This cross-sectional ACCEPT study investigated the association between blood metal concentration in Greenlandic pregnant Inuit women and their birth outcomes. High smoking frequency was observed, especially in the East region. For the East region, a tendency for lower birth weight and lower birth length were found compared to the other regions in Greenland. Maternal blood levels of Cd, Cr, and Ni were found to be higher than reported clinical references for nonpregnant, non-Inuit populations . Cd and