Participatory research, including self-assessment of exposure (SAE), can engage study participants and reduce costs. The objective of this study was to investigate the feasibility and reliability of a SAE regime among nail technicians. The study was nested in a larger study, which included exposure assessment supervised by experts, i.e., controlled assessment of exposure (CAE). In the SAE approach, ten formal and ten informal nail technicians were verbally instructed to use a passive sampler and complete an activity sheet. Each participant conducted measurements on three consecutive days, whereafter the expert collected the passive samplers. Sixty samples were, thus, analyzed for twenty-one volatile organic compounds (VOCs). The reported concentrations of 11 VOCs were converted into total VOC (TVOC) concentrations, adjusted for their respective emission rates (adj TVOC) to allow comparison within and between nail technician categories , as well as assessment regimes (SAE versus CAE), using the data from the main study. In total, 57 SAE and 58 CAE results were compared, using a linear mixed-effects model. There were variations in individual VOC concentrations, especially for the informal sector participants. The major contributors to the adj TVOC concentrations were acetone and 2-propanol for the formal category, whereas ethyl- and methyl methacrylate contributed most to the informal nail technicians’ total exposures. No significant differences in adj TVOC-concentrations were observed between the assessment regimes, but significantly higher exposures were recorded in the formal technicians. The results show that the SAE approach is feasible in the informal service sector and can extend an exposure dataset to enable reliable estimates for scenarios with substantial exposure variations. A second, randomly selected group of workers, performing the same tasks, was monitored under the supervision of an occupational hygienist. Although the reliability of SAE data varied between the studies, it was concluded that workers, if well instructed and motivated, can generate reliable exposure measurements. Silicone wristbands have recently been deployed as personal passive sampling devices to assess dermal and inhalation exposure to various VOCs, semi-volatile organic compounds (SVOCs), and pesticides [Citizen science, i.e., a voluntary collaboration among scientists and non-specialists to achieve both scientific and societal goals, is an emerging form of scientific inquiry that is growing in popularity in the environmental sciences ,2. Partisticides . The usesticides .To investigate the reliability of SAE, especially in the informal service sector, we report on the results of a self-assessment study in which nail technicians in both formal and informal nail salons measured inhalation exposure to VOCs using passive diffusion samplers. Therefore, we compared the central tendency of VOC exposure concentrations of a SAE nail technician group with a group of nail technicians for which exposures were measured under the conventional controlled assessment of exposure (CAE) regime.This comparative study had a cross-sectional design and was nested in a larger study in nail salons in the City of Johannesburg , hereaftAll nail salons in this study offered essential nail services, including manicures and pedicures, as well as nail polish, gel, and acrylic applications. Most nail applications began with an acetone soak-off process to remove old nail applications. The most common applications in the formal and informal nail salons were gel and acrylic nail applications, respectively. All the formal nail salons used similar products from known brands, procured through a structured company system. In the informal nail salons, such a central procurement system was lacking. In formal salons, four to six nail technicians usually offered nail treatment services simultaneously; in informal salons, only a single technician, or two nail technicians, worked simultaneously with a hairdresser, in most cases. Further details on the nail technicians and the nail salons are reported elsewhere .If a nail technician agreed to participate in the study, i.e., to self-assess their personal exposure on three consecutive workdays, oral instructions were given on how to open, attach, close, and store the passive samplers (diffusion tubes), as well as how to complete the worksheets. The worksheets facilitated the participant to record information, such as the time the passive sampler was opened and donned, the number and types of nail applications performed, and the duration of the nail applications. In most cases, the instructions were given on a Monday, and the sampling was conducted on Tuesday through Thursday afternoon, after which the samples were collected. Finally, the researcher checked and noted the sampling tubes’ status and the worksheets’ completeness. Where information was missing, attempts were made to retrieve this from the participants. Ten nail technicians from both formal and informal sectors were included in the self-assessment study, resulting in 30 measurements for each sector. Unfortunately, COVID-19 restrictions resulted in a time gap between the self-assessment and the controlled-assessment of the main study. The self-assessment of the informal sector was conducted in June 2021, whereas the other sampling campaigns were conducted in the last quarter of 2021. Consequently, it was difficult to recruit the same technicians from the main study (controlled assessment) into the self-assessment study due to business closures and dismissals. Only eight nail technicians, i.e., four from each sector, participated in both assessments. ® Passive sampler, Sigma Aldrich, Kempton Park, South Africa). Before sampling, the sorbent cartridge was removed from its glass storage tube and inserted into the diffusive body; whereafter, it was attached to the participant’s lapel. Sampling devices were deployed to measure exposures for at least 80% of the work shift over three consecutive days, for each nail technician. A total of 60 personal exposure measurements in the formal (n = 30) and informal (n = 30) nail salons were collected. Field blanks were also collected during the controlled assessment to check for contamination during transport. At the end of the sampling period, the participant detached the sampler from the lapel, placed it in the glass tube, capped and labelled it, and stored it at <5 °C until it could be analyzed. The same procedure was followed during the controlled assessment; however, the investigator attached and removed the sampler and recorded the nail applications, etc.Personal exposure measurements were collected using diffusion/passive samplers  for quantification, as well as a DB-WAX column  for verification, with a split injection of 3 μL and split flow of 20 mL/min. The carrier gas was nitrogen at a constant pressure of 5 psi. The injector temperature was 220 °C, and the detector temperature was 200 °C. The MSD ChemStation macro program extracted Peak areas, adjusted for internal standards, and transferred them to an Excel spreadsheet. The average concentration over the exposure period was calculated from the mass of the analyte found on the cartridge and the reported duration of sampling.Details of the chemical analysis have been published elsewhere by Keretetse et al. . In brieBased on a review of the literature and the information obtained from the labels of the products used, or the safety data sheets (SDS) or the ingredients list (if any), 21 VOCs were analyzed. The samples (batches) collected during the informal sector self-assessment were sent to the laboratory for analysis much earlier than the batches with other samples. Unfortunately, only 15 similar VOCs were common in both batches. To simplify the calculation, the analytical limit of detection (LoD) and limit of quantification  for all compounds were set to 0.50 µg/mL and 1.65 µg/mL, respectively. 3. Since measured exposure concentrations appeared to be lognormally distributed, all statistical analyses were conducted on ln-transformed concentrations. Eleven VOCs, with a detection frequency of ≥30%, were selected from the 21 reported VOCs for further statistical analysis. Data pre-processing, including data cleaning and visualisation, was conducted using Microsoft Excel 2016. Descriptive statistics were calculated using ExpoStats, a Bayesian toolkit . ImputatTM 2.0 mathematical model supporting files [3. Since both the number and the type of VOC varied within and between the sectors, the so-called adjusted total VOC concentration (TVOC) was calculated to enable comparison. The adjTVOC is defined as the total of the selected VOCs’ concentrations per subsector, each corrected by their respective evaporation rate relative to the lowest evaporation rate of the selected VOC, i.e., d-limonene  Table A1ng files . The equijrcdY = the ln-transformed TVOC concentration of the i-th worker, measured on the j-th day, under the assessment regime r in the category c; β0 denotes the intercept, whereas βr and βc represent the fixed effects of the assessment regime and the category, respectively. The random effects of the worker and the sampling day are represented by αi and α(j), respectively. εijrc denotes the random error. The nonparametric Wilcoxon signed-rank test was used to test differences between the two assessment regimes, based on the GSDs for the same VOC.JASP   was usedNearly all formal nail technicians completed data capture sheets. If any data were missing, such as the number of clients or type of treatments, this information was retrieved from the client registration system when the researcher collected the forms and the samplers. In contrast, since such a system was lacking for the informal nail technicians, 15 data sheets were missing from five nail technicians.Twenty-one VOCs were analyzed in total; however, only 15 VOCs from the SAE regime in the informal sector were analyzed. This included 1-butanol, which was not analyzed for all the other groups. From the 21 VOCs reported, 11 showed a detection frequency of >30% of the limit of detection (LoD) within the same sector. Methyl-isobutylene-ketone (MIBK) and trichloroethylene were not detected in any sample, whereas chloroform was detected only in the informal sector. Although benzene was detected in some samples, the concentrations were close to LoQ. Field blanks, which were collected and analyzed at each salon, showed negligible VOC levels, confirming that transport, storage, and handling activities did not contaminate the sampling badges. Based on the percentages detected, the 11 VOCs were selected for further analysis, i.e., acetone, n-butyl acetate, ethyl acetate, ethanol, ethyl methacrylate, d-limonene, methyl-methacrylate, 2-propanol, propyl acetate, toluene, and white spirits . For the3 for the SAE and CAE, respectively, with a much higher GSD (6.63) for the SAE compared to the CAE regimen (2.49). The GMs of the 2-propanol concentrations for the two assessment regimes were much closer, i.e., 46.7 versus 43.7, with a higher GSD for the SAE compared to the CAE, i.e., 2.21 versus 1.72. This demonstrates a general trend, wherein the GSDs of the VOC concentration distributions were slightly higher for the SAE regime, although they were not statistically significant (p = 0.064).p = 0.55).In the informal sector, acetone was also the VOC with the highest concentrations during both regimes. During the SAE regime, concentrations of ethyl-methacrylate and methyl-methacrylate showed the second-highest and third-highest GM, respectively, where the order was swopped during the CAE regime. The concentration distributions showed very large GSDs for both these VOCs. No statistically significant differences were observed in the GSD for all VOCs for both assessment regimes (p = 0.011); however, the effect of the assessment regime was not statistically significant (p = 0.37).The major contributors to the adjusted TVOC concentrations are depicted in Nail treatments require the use of various products, depending on the type of treatment. As was demonstrated by Keretetse et al. , the typ6–C16 [To enable comparison and to adjust for overweighting the results of the relatively higher volatile VOCs, we developed the concept of VOC–concentration, adjusted for the VOC-specific emission rate. Adding all adjusted VOC–concentrations resulted in an adjusted total VOC–concentration as a metric for cumulative exposure to the VOCs detected and included in our analysis. This differs from other approaches where TVOC was reported as the sum of the concentrations of compounds detected in the range of C6–C16 , or in t6–C16 . Our app6–C16 .This study aimed to investigate whether self-assessment of exposure could reliably estimate the true distribution for the nail technicians under investigation. Our results indicate that the different exposure assessment regimes did not significantly affect the exposure assessment results. Consequently, the results of both CAE and SAE could be pooled, revealing a significant difference in the adjusted TVOC concentrations between both categories. Whereas, based only on the CAE or SAE data, no statistically significant differences between the formal and informal nail technicians were observed. Our results, regarding the performance of SAE compared to CAE, are aligned with the results and conclusions of other quantitative studies of self-assessment exposure with similar designs.In the study reported by Hertsenberg et al., (2006), the authors found no significant differences in the sum score for VOCs. However, the exposure variability appeared to be significantly higher for the group that received written instructions. The comparison of the CAE and SAE within the group that received face-to-face instructions showed no differences in either the GM or the exposure variability. The study by Hedmer et al., (2017) revealed that there were no statistically significant differences in the mean exposures observed between the controlled and the self assessment groups. The authors concluded that, by employing SAE, more workers could be included in the study, especially under the harsh work environment conditions of the tunnel construction workers and limited accessibility to the (tunnel) workplace for experts to conduct the measurements . Since tSeveral limitations could have affected the results of our study. Environmental conditions, e.g., temperature and relative humidity, were not recorded during the SAE measurements. Since all CAE measurements and the SAE measurements in the formal sector were performed on three consecutive days in the early summer period (October 2021), the average temperature ranged only from 23 to 28 °C . As repoDespite the limitations, the results of the study demonstrate that, especially in cases with exposure scenarios where there are large concentration variances, an increase in the number of samples provides a better estimate of the central tendency, even though the SAE regime may generate ‘low-quality’ data compared to the CAE. Our findings support the conclusion by Nicas et al., (1991) that the analytical variability, or the quality of the measurement, contributes minimally to the total measurement variability, especially in scenarios with GSDs > 2 . Self-assessment of exposure in occupational settings, including informal workplaces, seems to be a feasible and economical method to contribute to the expansion of exposure data, which enables a more reliable interpretation of exposure variation. In principle, SAE can be a citizen science tool in occupational health; however, passive sampling, requiring analytical costs and experts’ feedback, is not the ideal method to assess exposure. However, exposure science approaches and expertise to identify the exposure pathway and determinants of exposure are still needed to develop effective exposure control strategies.


Cognitive reserve (CR) is the ability to maintain cognitive performance despite brain pathology. CR is built through lifecourse experiences  and is a key construct in promoting healthy aging. However, the operationalization of CR and its estimated association with late-life cognition varies. The purpose of this study was to systematically examine the operationalization of CR and the relationship between its operationalization and late-life cognition.We performed a comprehensive review of experiences (proxies) used to operationalize CR. The review informed quantitative analyses using data from 1366 participants of the Memory and Aging Project to examine 1) relationships between proxies and 2) the relationship between operationalization and late-life cognition. We also conducted a factor analysis with all identified CR experiences to create a composite lifecourse CR score. Generalized linear mixed models examined the relationship between operationalizations and global cognition, with secondary outcomes of five domains of cognition to examine consistency.IQR: 0.34 to 1.39). There was not strong consistency in the association between CR operationalizations and the five cognitive domains (mean consistency: 56.1%). The average estimate for the 28 operationalizations was 0.91 (SE = 0.48), compared to 2.48 (SE = 0.40) for the lifecourse score and it was associated with all five domains of cognition.Based on a review of 753 articles, we found the majority (92.3%) of the 28 commonly used proxies have weak to no correlation between one another. There was substantial variability in the association between operationalizations and late-life global cognition (median effect size: 0.99, Inconsistent methodology is theorized as a major limitation of CR research and barrier to identification of impactful experiences for healthy cognitive aging. Based on the weak associations, it is not surprising that the relationship between CR and late-life cognition is dependent on the experience used to operationalize CR. Scores using multiple experiences across the lifecourse may help overcome such limitations. Adherence to a lifecourse approach and collaborative movement towards a consensus operationalization of CR are imperative shifts in the study of CR that can better inform research on risk factors related to cognitive decline and ultimately aid in the promotion of healthy aging.The online version contains supplementary material available at 10.1186/s12877-023-04263-9. Cognitive decline that occurs with aging includes changes in multiple domains, such as memory and executive function, and can contribute to functional deficits . As the CR cannot be directly measured due to its theoretical nature and, therefore, the study of CR is open to threats to construct validity , 11. As Furthermore, the timing of proxies within a person’s life produce additional measurement challenges and alternatives. Many studies investigating the relationship between CR and late-life cognition rely on experiences from single life timepoints ; however, at its foundation, the CR hypothesis attributes the development of higher CR to experiences across the lifecourse , 22. In The purpose of the present study was to explore characteristics of CR proxies commonly used in the literature, investigate the relationship between different proxies, evaluate the impact of CR operationalization on its association with late-life cognition, and examine operationalizations of CR which incorporate multiple lifecourse experiences. We extracted proxies that have been used in the published literature to operationalize CR through a comprehensive review of the literature. Findings from the review were utilized to inform quantitative analysis using data from the Rush Memory and Aging Project (MAP) to investigate the operationalization of CR and how operationalization relates to understanding late-life cognition.We assessed articles published between January 1990 and December 2021 . All seaN = 280), with over three times that of the second-most common, occupation (N = 91). Education and occupation were used together most frequently of any pairing (N = 58). Leisure activities (N = 29), cognitive activities (N = 26), and premorbid intelligence quotient (IQ) (N = 24) were also frequently used with education. Additionally, several proxies were measured in different ways. Occupation was split almost equally in being categorized based on one’s level (54.76%) or based on qualities of the work (45.24%). On the other hand, IQ was divided among a larger variety of measures, with the National Adult Reading Test (NART) at 46.15%; verbal or vocabulary ability, including the Wide Range Achievement Test (WRAT), at 28.21%; literacy level at 20.51%; and formal IQ at 5.13%. Leisure activities and social activities often showed overlapping components or experiences.CR proxy use in the literature varied widely. Education was the most common proxy category by a large margin  the relationships between proxies through a correlation and multiphase confirmatory factor analysis and (2) the relationship between differing operationalization and late-life cognition.Data was obtained from the Rush Memory and Aging Project (MAP). MAP is an ongoing, hybrid cohort study that recruits participants ≥ 65 years of age, without known dementia, from retirement communities in Illinois, United States . At baseThe MAP dataset contained variables related to 18 of the 20 proxy categories from the literature search, with no reasonable equivalents for nutrition and novelty. Observed variables in MAP (life experiences) were used to create composite scores relating to the proxy category , we were able to base the composite score on the types of experiences that are included in each questionnaire. The CRIq-based score was a combination of education, job attainment level, children, frequency of participation in leisure activities at age 18, reading magazines and newspapers at the age with the highest frequency, and the following in late life: seeing relatives, participation in groups, going to church, going to restaurants and sporting events, traveling, and volunteering. The LEQ-based score was divided into three ages: ages 13–30 employed the variables of education, taking music lessons, and reading; ages 30–65 employed the variables of job attainment level and reading; and age 65 and older employed the variables of retirement, participation in groups and clubs, volunteering, going to restaurants and sporting events, visiting relatives, traveling, physical activities, and reading. Reading included books, newspapers, and magazines. Weights were applied to the variables based on the scoring guide for the CRI-q  and a vaA lifecourse CR score was assigned to each participant using variables from MAP. The score was developed through a multiphase confirmatory factor analysis (CFA). Observed variables were grouped and evaluated under six overarching dimensions based on prior uses of MAP variables: Leisure Activities, Social Characteristics/Activities, Physical Characteristics/Activities, Cognitive Activities, Socioeconomic Status (SES), and Demographics/Personality , 35, 36.A list of dimensions, factors within each dimension, and observed variables loaded to those factors is provided in Table Cognitive scores for each participant were used as outcomes in analyses examining the association between operationalization of CR and late-life cognition. As previously described , 38, parρ) and boundaries defined by Cohen (1988) ), based on their values on observed variables and standardized loadings of the factors of the CR construct.Using the final model, we computed predicted values for the CR factor, creating a unique score for each participant. The score ranged from -3.20 to 2.02 (IQR: 0.34 to 1.39). Detailed results are provided in Table SE = 0.18, p < 0.001), lifecourse CR score , education , LEQ-based score , and CRIq-based score .The point estimates and 95% CIs for the (standardized) CR predictors are illustrated in Fig. IQR: 0.40 to 1.37). The consistency of operationalization techniques for higher late-life cognition scores across the domains is provided in Fig. SE = 0.48), with the average estimate for IQ and education at 2.88 (SE = 0.49) and 2.39 (SE = 0.49), respectively. The average estimate for the lifecourse CR score was 2.48 (SE = 0.40) and the average estimate for the questionnaires was 2.21 (SE = 0.43). The lifecourse CR score was associated with all five domains (100% consistency) and had little variation in effect sizes .In addition to global cognition, we also evaluated five cognitive domains as outcomes: episodic memory, perceptual orientation, perceptual speed, semantic memory, and working memory. The point estimates and 95% confidence intervals for the cognitive domains are provided in Appendix The study explored the operationalization of CR in the published literature and examined the effect of this variability on the association between CR and late-life cognition. Our search of the literature resulted in 20 categories of proxies that have been used in studies related to CR and which show wide variability in their degree of use and, in some cases, the experiences that are classified into these categories. We employed quantitative analyses based on the comprehensive literature review. The results revealed three key considerations for research on CR. First, among the variety of experiences that have been used as proxies of CR, there was a lack of strong association between them. Second, the association between CR and late-life cognition was highly sensitive to the technique  used to operationalize CR. Third, operationalizations that include multiple experiences, including questionnaires and the lifecourse CR score developed in this study, are strongly associated with late-life cognition, demonstrating the utility of CR measures that incorporate experiences throughout the lifecourse. An awareness of qualities of operationalization and the impact of operationalization is imperative as the field of healthy aging continues to investigate the practical advantage of CR.The results of this study revealed problems that have been suspected within the practical use of CR in research , 56, 57.In an effort to overcome variability in CR operationalization and weakly associated proxies, the present study utilized the CFA to develop a composite lifecourse CR score as alternative operationalization. The CFA highlighted the weak associations between different life experiences, such that over half of the observed variables in the original factors were excluded from the final model for poor fit with the other variables. Based on the observed variables that were retained through multiple iterations, several experiences, through the lifecourse, may need to be considered for CR operationalization. Similar methods have been used to create composite scores for CR in past research , 24. OurThe findings have key implications for researchers. While the CR hypothesis is a commonly used explanation for the delay in symptoms of cognitive decline, the present results reinforce concerns by theorists that the research is in a state of disorder, failing to unanimously identify the most important life experiences largely due to methodological concerns . TherefoThe present study has several limitations. Our search of the literature, while comprehensive, does not meet criteria for a systematic review. As the goal was to examine the ways in which CR proxies have been utilized in the literature in order to inform quantitative analysis, the search can best be described as a scoping review . TherefoFinally, there is a limit to the generalizability of these results, based on the data. First, the data is from one region in the United States, Chicago, Illinois. Therefore, the population for this study was from an urbanized, metropolitan area and the data was comprised of a high percentage of individuals identifying as Non-Hispanic White and women. Second, the population was also highly educated, with an average of 15 years of education. This further limits generalizability as this population may be more protected against symptoms of cognitive decline than the general population, depending on the degree of importance that one puts on education for building CR. Lastly, our data also had some missing observations. While we do not expect the small amount of missingness to have biased the results, it is a possibility.Inconsistent methodology in the study of CR is a major limitation of current research in this area. Our study is the most comprehensive and conclusive study to date demonstrating the challenges associated with commonly used CR proxies. We found weak associations among the variables and proxies used to operationalize CR, as well as a relationship between CR and late-life cognition that is highly dependent on the CR operationalization technique. Lifecourse measures, including questionnaires and a score that was developed in this study from multiple experiences, were among the strongest and most consistent predictors of late-life cognition. Attention to qualities of predictors, reigning in of the use of a wide variety of CR operationalizations, adherence to a lifecourse approach, and collaborative movement towards a consensus operationalization and definition of CR are imperative shifts in the study of CR that are highlighted by this study. Through the recommendation of these methodological considerations, we hope to help improve the study of risk factors related to cognitive decline and aid in the prevention of this growing public health concern.Additional file 1:Appendix 1. Literature search procedures. Appendix 2. Occupational cognitive requirements score calculation. Appendix 3. Names and scoring for cognitive test in global cognition score. Appendix 4. Correlations. Appendix 5. Multiphase confirmatory factor analysis model fit indices. Appendix 6. Cognitive domain outcomes.


PurposeElderly trauma patients have a higher risk of severe disability and death, and this outcome burden in elderly trauma patients must be addressed in countries in which the population is aging. The clarification of the unique clinical features of elderly people who have experienced trauma is important. The purpose of this study is to evaluate the significance of the treatment for elderly severe trauma patients based on the prognosis and total hospital cost.MethodsTrauma patients transferred to our emergency department (ED) and admitted to our intensive care unit (ICU) directly or through emergency surgery between January 2013 and December 2019 were examined. We divided patients into three groups: <65 years old (Group Y); 65-79 years old (Group M); and ≥80 years old (Group E). We compared the pre- and post-trauma American Society of Anesthesiology Physical Status (ASA-PS) score and the Katz Activities of Daily Living (ADL) questionnaire at arrival among the three groups. In addition, the duration of ICU and hospital stays, hospital mortality, and total treatment costs were compared.ResultsThere were 1,652 patients admitted to ICU through the ED from January 2013 to December 2019. Of those patients, 197 trauma patients were analyzed. There was no significant difference in injury severity scores between the groups. Significant differences in both the ASA-PS and Katz-ADL scores in posttrauma status were observed among the three groups  in Group Y, 3.0  in Group M, 3.0  in Group E, p < 0.001*, posttrauma Katz-ADL, 10.0  in Group Y, 5.5  in Group M, 2.0  in Group E, p < 0.001). The duration of both ICU and hospital stay was significantly longer in Group E compared to the other groups  days in Group Y, 4.0  days in Group M, 6.5  days, p = 0.006, hospital stay, 16.9  days in Group Y, 26.7  days in Group M, 32.5  days in Group E, p = 0.005). ICU and hospital mortality were highest in Group E compared with the other groups, but the differences were not significant. Finally, the total hospital cost in Group E was significantly higher than the other groups.ConclusionsIn elderly trauma patients who required intensive care, PS and ADL in posttrauma status were worse, ICU and hospital stays were longer, and ICU and hospital mortality were higher compared with younger patients. In addition, medical costs were greater in elderly patients. It is supposed that the therapeutic effect observed in young trauma patients cannot be expected in elderly trauma patients. Traditionally, trauma has been viewed as a leading cause of disability and death in patients aged ≤45 years ,2. HowevWe hypothesized that the prognosis and post-trauma general states are more severe, and the total hospital cost is higher in elderly severe trauma patients. The aim of this study was to evaluate clinical features, including the pre- and post-trauma activity of daily life (ADL) and medical costs, in elderly trauma patients who required intensive care and compare the findings with those of younger trauma patients.The research ethics board of the Gunma University Hospital approved this retrospective study (HS2020-005) without the necessity for informed consent. The execution of this study was publicized on the homepage of Gunma University.Trauma patients transferred to our emergency department (ED) and admitted to the ICU of Gunma University Hospital directly or through emergency surgery between January 2013 and December 2019 were studied. We included trauma patients aged 18 and over. Exclusion criteria were patients with cardiac arrest on arrival, patients without positive requests from the family about active treatment, patients in the terminal stage of malignant diseases or liver cirrhosis, and patients moved from ICU to the normal ward within 24 hours. We divided patients into three groups based on their age: <65 years old (Group Y); 65-79 years old (Group M); and ≥80 years old (Group E). In general, elderly people are regarded as those aged ≥65 years . We compStatistical analysisThe distribution of normality was evaluated with the Shapiro-Wilk test. Those that fit the normal distribution were expressed as mean ± standard deviation, while those that did not fit were expressed as median and interquartile range. Categorical variables were expressed as values and/or percentages. The Kruskal-Wallis test was used for the comparisons of continuous variables among the three groups. Post-hoc analyses were subsequently conducted to evaluate the differences between the three groups. Comparisons of categorical variables were done with the chi-squared test. A p-value of less than 0.05 was considered statistically significant. The Statistical Product and Service Solutions (SPSS) Statistics ver. 26.0  software was used for the statistical analysis.From January 2013 to December 2019, 1,652 patients were admitted to ICU through the ED. Of those patients, 197 patients with trauma were analyzed in the study , tumble in 12, caught by machinery in eight, ski or snowboard injury in six, and other causes in five patients. Blunt and penetrating trauma were 184 and 13, respectively. The median age in all 197 patients  was 64 years (ranging from 18 to 92) years old. Pre- and post-trauma  activities, severities of trauma, duration of ICU and hospital stay, hospital mortality, and total costs in all 197 patients are shown in Table Table Figure There were no significant differences in the ICU and hospital mortalities among the three groups, however, those in Group E were the highest of the three groups Figure . The totIt has been already reported that the prognosis including mortality and disability in elderly trauma patients becomes worse compared with their younger counterparts -16, and Traffic accident was the most common cause of injury in all three patient groups in this study. Fall was the second most common cause in all groups, however, the rate of fall in Group E was higher than in Groups Y and M. In addition, the rate of tumble in the elderly group was higher than that of the other two groups. Elderly patients exhibit different injury patterns compared to their younger counterparts , and it In this study, the median of ISS in all three groups was more than 15 and similar. Severe trauma is generally defined as ISS>15 ,23, therThe physical status and ADL of the elderly patients in the pre-trauma status were poor, and, at discharge from our hospital, physical status and ADL have remarkably deteriorated in elderly trauma patients. The durations of ICU and hospital stay were longer in the elderly trauma patients and mortalities in ICU and hospital in the elderly trauma patients were worse than that of the younger trauma patients. In the elderly population, the decreased functional residual capacity and increase comorbidity may increase the risk of poor clinical outcomes. Antihypertensive medications, antiarrhythmic medications, and anticoagulant medications also impair the physiological presentation when injury occurs. In fact, the Eastern Association for the Surgery of Trauma published their guidelines for the management of elderly trauma patients in 2012, describing that pre-existing conditions and/or severe anatomic injuries dramatically increase the risk of poor outcomes in elderly patients, and concluding that evidence-based care of this population requires aggressive triage, correction of coagulopathy and limitation of care when clinical evidence suggests a clear likelihood of poor prognosis . Bonne eThe results of this study also showed that it costs more to treat elderly trauma patients compared to younger trauma patients. Rehabilitation after trauma might improve PS and ADL somewhat, however, it takes longer time and more resources to continue rehabilitation. It is difficult to predict who will or should receive quantitatively futile care, however, Fleischman et al. estimated that the costs associated with futile care in geriatric trauma patients have a median cost of $87,391 compared with non-futile care that had a median cost of $33,373 . In JapaLimitationsThis study was retrospectively performed at only one institution, and the number of patients analyzed in this study was not very large. Evaluation of long-term prognosis, including the post-rehabilitation status, such as PS and ADL, and all costs after discharge from our hospital should be performed. Multicenter studies are warranted to clarify further the appropriate treatment for elderly severe trauma patients.In elderly trauma patients requiring intensive care, PS and ADL in post-trauma status are remarkably worse, ICU and hospital stays are longer, ICU and hospital mortality are higher, and more medical costs are necessary compared with that in younger trauma patients. It is supposed that the therapeutic effect observed in young trauma patients cannot be expected in elderly trauma patients. The establishment of effective strategies to prevent elderly trauma is urgent in aging societies such as Japan.


Atopic dermatitis (AD) is one of the most common diseases worldwide. Severe AD has a major impact on the quality of life of patients. We performed a systematic literature review on the epidemiology of AD in Italian pre-school children (age 0–5 years) and we assessed the available data on the severity of AD. In August 2022, we performed a bibliographic search using PubMed/Medline and EMBASE. We identified 10 studies with Italian data on the prevalence and/or incidence of AD in pre-school children. The period (12 months) prevalence of AD varied widely across studies, ranging between 4.0% and 42.2%, with median estimates of 14.3% among all studies and 11.8% among studies from 2010 onwards. Applied to the Italian population, this leads to a prevalence of 309,000–375,000 pre-school AD cases. Only one study computed the incidence of AD, reporting rates of 9 cases per 100 person-years in children aged 0–1 year, and 2.5 cases per 100 person-years in children aged 1–4 years. Severity data from Italy were also reviewed, across three identified three studies. A point estimate found 8.4% of cases were considered severe in one study based on the Patient-Oriented Eczema Measure (POEM), with an overall range of 7.8–11% across different Italian studies and according to various severity score types. Atopic dermatitis (AD) ranks 15th among the most common non-fatal diseases according to a recent report from the Global Burden of Disease (GBD) study , with thThe same GBD study also reported that, among skin conditions, AD has the highest burden of disease measured through disability-adjusted life-years . While ADuring the last 25 years, several Italian investigations reporting epidemiological data on AD at the paediatric age have been published, derived from both prospective  studies and cross-sectional surveys ,11,12,13The aim of this study is, therefore, to review the available literature reporting epidemiological information on AD in pre-school children in Italy, as well as to review data on the severity of this disease in the same population.A systematic search for studies reporting data from Italy on the prevalence and/or incidence of AD in children aged 0–5 years was conducted in August 2022, using different scientific databases and search browsers. The selection process was performed by two independent reviewers. Initially, we examined the title and abstract of each identified paper and we excluded the publications that were evidently out of scope for this study’s aims. For example, we excluded studies of school children, adolescent or adult AD patients, those focused on other diseases, conducted outside Italy, that did not report original data, etc. The first step of the selection process led to the exclusion of 351 of the 367 articles identified in PubMed and of 769 of the 819 articles identified in EMBASE. In our second step, we checked the lists of publications selected in PubMed and EMBASE and we excluded duplicate ones . In our third step, 54 remaining papers were examined in-depth, on the basis of their full text, to assess the potential presence of epidemiological data on AD in pre-school children in Italy. A total of 44 publications were discarded in this step, mainly because they reported results on AD related to children >5 years or to countries other than Italy, or they did not report any new/original result on the prevalence and/or incidence of AD, and 10 publications were maintained. Additional cross-validation searches for scientific articles eventually missed by the main strategy were conducted as follows: (i) by exploring the references reported in relevant reviews and epidemiological studies  of AD; and (ii) by exploring Google Scholar, using various combinations of the main search keywords ; still, no further articles relevant to the research were identified. Therefore, a total of 10 publications were included in this review of the prevalence and incidence of AD.We extracted from each of these articles the main information on study features , patient characteristics  and epidemiological findings on lifetime prevalence, period prevalence  and incidence of AD, and we summarized these data in descriptive tables in order to improve the readability and interpretation of the results.A similar search strategy—though, in this case, not systematic—was used to identify Italian studies reporting information on the severity of AD at pre-school age, using PubMed/Medline and Google Scholar. Thus, in addition to the keywords “atopic dermatitis”, “Italy”, “children” and “infants”, we combined additional terms and scores used to address disease severity, including “severe”, “SCORAD”, “POEM” and “EASI”.The main results of the 10 studies reporting data on the prevalence of AD in pre-school children in Italy are summarized in This systematic review of national data on the epidemiology of AD in young children retrieved ten studies, mostly population-based, published between 2002 and 2021, although collecting information from the early 1990s to the late 2010s, with relevant data on this topic. The prevalence of AD measured over a 12-month period varied widely across studies, with a majority of analyses reporting disease in 10–15% of pre-school children. This is consistent with findings from international studies conducted in high-income countries , and highttp://dati.istat.it, accessed on 20 July 2023), the corresponding absolute number of pre-school children with any AD—i.e., including mild, moderate and severe cases—in Italy is estimated to range between about 309,000 and 375,000 cases.In an earlier review of Italian epidemiological data on AD in school children and adolescents, the period prevalence, synthesized through the central (median) estimate, was 8% in both groups . Using tAlthough the majority of epidemiological information on AD at the paediatric age is focused, following the International Study of Asthma and Allergies in Childhood (ISAAC) ,24, on cRecent international studies on the incidence of AD are scarce . As alreA few Italian studies reporting information on the percentage of severe AD cases in young children were identified. These used different measures and scores to classify severity of disease. This notwithstanding, their results were fairly consistent, indicating that 7.8% to 11% of Italian cases are severe at this age ,20,21. TReviews of epidemiological data on the prevalence and incidence of disease have several limitations. In our analysis, even though it was restricted to a national setting, findings on the prevalence of AD were highly heterogeneous across studies. This is likely explained by several factors including, among others, study type , period and geographic area of investigation, age considered  and, particularly, different sources and diagnostic criteria used to detect AD  . TherefoIn conclusion, our study confirmed and further quantified the proportion of AD cases in young children in Italy and provided an estimate of the burden of severe disease. This may be helpful to inform clinicians and health policy-makers, and thus help to plan adequate strategies to manage severe AD in pre-school children. Further data on the incidence of AD and on the percentage of young children with disease refractory to conventional treatment in Italy are needed.


Hare, D., Reeve, H.K. and Blossey, B. (2016) with their article.The authors apologise for missing the inclusion of the citation for a passage on page 4-5 for et al.Additionally, a recent theoretical model on the evolution of cooperation (which was modelled as respect for resource possession) found that cooperation was stabilised when resource holders  responded to ‘raiding’  with retaliation (i.e. punishment). Nevertheless, when the level of inequality between resource-holders and resource-seekers exceeds a critical threshold (which can be thought of as akin to variation in payoff differences among players in a laboratory game), then cooperation collapses and raiding strategies come to dominate the population until this inequality is reduced. This model, although not explicitly framed in terms of cooperation and punishment, illustrates the evolutionary logic of considering relative payoff differences in understanding the evolution of cooperation and punishment in nature. (Hare


Precision medicine is growing as an innovative approach in the neuroendocrine field, aiming to obtain a detailed understanding of the disease, including epigenetic and omics characterization, to ultimately improve patient care , 2. NeurNeuroendocrine tumors: the road to precision medicine”, in the Frontiers in Endocrinology Journal, is dedicated to collecting high-quality scientific contributions that mainly focus on recent advances in the context of the diagnosis, treatment, and prognosis of NETs.The current Research Topic, “Xu W et al. elaborates an easy-to-use web-based calculator to predict the overall survival of MCC patients. This tool is based on a nomogram including key prognostic variables. The study by Luo S et al. shows that F-PNETs incidence decreased over the study period (2000-2017). In addition, the statistical Cox proportional hazards model identifies tumor size, tumor stage, tumor type, and surgical resection as the main prognostic factors for F-PNETs.With these premises, two studies in the current Research Topic present an analysis of epidemiological data collected from the Surveillance, Epidemiology, and End Results (SEER) database in two challenging subtypes of NET; Merkel cell carcinoma (MCC), a highly aggressive neuroendocrine carcinoma, which correlates with poor prognosis; and functional pancreatic NET (F-PNETs), a heterogeneous group of pNET associated with the clinical diagnosis of hormonal hypersecretion and syndrome. In both cases, the main aim is to assess and further predict patients’ survival outcomes. Specifically, the work by Fanciulli G et al. summarize the available in vitro and in vivo data on the role of PrIn as monotherapy as well as in combination with other treatments for MTC. Their review highlights that despite the encouraging preclinical activity of PrIn in in vitro studies in human and murine MTC cell lines, evidence in the clinical setting is currently scarce. The authors advocate the launch of new clinical trials to establish the potential usefulness of these agents for MTC.One study in the current Research Topic, by Fanciulli, is focused on the assessment of a new potentially relevant class of drugs for medullary thyroid cancer (MTC), proteasome inhibitors (PrIn). Sira L et al. describe the case of a young woman with non-functioning advanced pNET associated with the mutation of JAK2V617F, which is an independent factor for thromboembolic events. The patient presented at first with massive portal and splenic vein thrombosis, requiring anticoagulation treatment. Three years later, she was diagnosed with a grade 2 (Ki-67 index of 6%) pNET, associated with unresectable liver metastases. In this case, the surgical removal of the pancreatic tumor was performed and systemic treatment with somatostatin analogs (SSA) was started. The treatment was stopped for the duration of the patient’s two pregnancies and then started again. Notably, after parturition, a complete remission of the liver lesions was achieved. Whole Exome Sequencing (WES) was performed but failed to demonstrate a mutation in MEN1, VHL, NF1, TSC1, TSC2, MUTYH, BRCA2, and CHEK2 genes. The second case report, by Tarris G et al., describes a giant (88 x 73 mm) F-PNET in a young woman. The diagnostic work-up was started due to the onset of hypoglycemia unresponsive to treatment with diazoxide. A CT scan detected the mass located in the pancreatic tail, which was surgically removed. At the histopathological evaluation, a grade 1 (Ki-67 < 2%) pNET with cytoplasmic expression of insulin in tumor cells was found, confirming the diagnosis of insulinoma. After a 16-month follow-up period after pancreatic surgery, the clinical symptoms were recovered and the patient was found to be free from disease recurrence.Finally, two case reports are published within this Research Topic. In conclusion, this Research Topic highlights recent advances in precision medicine in NET, including rare primaries such as MCC and MTC. The various contributions in this Research Topic demonstrate how the development of patient-tailored treatment approaches is evolving in the neuroendocrine field. This will likely result in better patient care and survival thanks to personalized treatments. We believe this Research Topic has the potential to support specialists involved in treating NEN.Neuroendocrine tumors: the road to precision medicine”. All authors contributed to the article and approved the submitted version.ALS, DG, and RM contributed to the development of this article by summarizing the results of all scientific manuscripts included in the Research Topic “


The current diagnostic modalities used during colorectal cancer follow-up appointments are known to have a limited sensitivity to detect recurrent disease. An electronic nose to detect volatile organic compounds (VOCs) in breath is shown to be a promising novel tool in the primary detection of lung cancer and colorectal cancer. To explore the potential role of an electronic nose in follow-up appointments for colorectal cancer patients, we evaluated the effects of surgery with curative intent on the exhaled VOC pattern. This pilot study showed that the VOC pattern changed shortly after surgery, paving the way for use in further clinical trials to address its added value during CRC follow-up appointments, and its ability to detect recurrent disease.TM. To evaluate the use of an electronic nose in the follow-up of CRC, we studied the effect of curative surgery on the VOC pattern recognition using AeonoseTM. A prospective cohort study was performed, in which 47 patients diagnosed with CRC were included, all of whom underwent curative surgical resection. Breath testing was performed before and after surgery using the AeonoseTM. A machine learning model was developed by discerning between the 94 pre-and postoperative breath samples. The training model differentiated between the pre-and postoperative CRC breath samples with a sensitivity and specificity of 0.78 (95%CI 0.61–0.90) and 0.73 (95%CI 0.56–0.86), respectively, with an accuracy of 0.76 (95%CI 0.66–0.85), and an area under the curve of 0.79 (95%CI 0.68–0.89). The internal validation of the test set resulted in an accuracy of 0.75 (95%CI 0.51–0.91) and AUC of 0.82 (95%CI 0.61–1). In conclusion, our results suggest that the VOC pattern of CRC patients is altered by curative surgery in a short period, indicating that the exhaled VOCs might be closely related to the presence of CRC. However, to use AeonoseTM as a potential diagnostic tool in the clinical follow-up of CRC patients, the performance of the models needs to be improved through further large-scale prospective research.As current follow-up modalities for colorectal carcinoma (CRC) have restricted sensitivity, novel diagnostic tools are needed. The presence of CRC changes the endogenous metabolism, resulting in the release of a specific volatile organic compounds (VOC) pattern that can be detected with an electronic nose or Aeonose Approximately 30% of patients with stage I–III colorectal cancer, and up to 65% of patients with stage IV colorectal cancer (CRC), develop recurrent disease after intentional curative treatment . The earThe presence of CRC changes the overall endogenous metabolism, resulting in the release of a specific composition of volatile organic compounds (VOCs) in the exhaled air ,8,9. TheTM”, which is also used in the present study, could discriminate between patients with CRC and advanced adenomas from healthy controls with an accuracy of 0.84 and 0.73, respectively [TM in the follow-up of CRC was first demonstrated by Steenhuis et al. In this pilot study, the AeonoseTM was able to distinguish between patients with recurrent and/or metastatic disease from patients without recurrent and/or metastatic disease, with a sensitivity and specificity of 0.88 (CI 0.69–0.97) and 0.75 (CI 0.57–0.87), respectively; the AeonoseTM exhibited an overall accuracy of 0.81 [Even though it is still in its infancy, breath analysis of volatile organic compounds (VOCs) could potentially be a minimally invasive and fast diagnostic tool to detect the first presentations of CRC, as well as recurrences during follow-ups ,14,15,16ectively . The potTM.Multiple studies indicate that a breath-derived analysis of VOCs might be helpful to detect first presentations of CRC and potentially recurrent/metastatic disease ,15,16,17A prospective observational cohort study with a pretest–posttest design was performed in which the VOC patterns of CRC patients, before and after curative surgery, were compared. All patients older than 18 years, diagnosed with CRC (AJCC stadium I–III), and eligible for curative surgical resection, were included. Exclusion criteria included patients with synchronous metastases, who were undergoing neoadjuvant treatment, or patients who had suffered any other type of malignancy  in the preceding 5 years. Patients that were not competent in the Dutch language or estimated to be physically incapable of performing the breath analysis were also excluded from the study.TM to discriminate between pre- and postoperative breath samples. Breath tests were performed at the time of diagnosis and subsequently during the first post-operative outpatient visit at the department of surgery. Patients were defined as curatively treated when the tumor was resected with histological tumor-free resection margins.Patients were included in two hospitals, as follows: Isala (Zwolle) and Bernhoven (Uden), The Netherlands. The primary outcome measure was the diagnostic accuracy of the AeonoseBefore breath samples were taken, exogenous factors that might influence the VOC composition, like smoking, medication, alcohol, or fasting time, as well as endogenous patient characteristics like the patient’s Body Mass Index (BMI) or specific comorbidities, were collected . PatientTM devices from The eNose Company . AeonoseTM technology has successfully been used and described for the diagnosis of lung cancer by Kort et al. [TM contains three micro hotplate metal-oxide sensors that behave like semiconductors. These sensors contain various types of metal and catalyzing agents. The present VOCs in the exhaled breath provoke a redox reaction on the surface of the sensors that subsequently changes the measured conductivity. The redox reactions are dependent on the present VOCs, types of sensors, reaction dynamics, and temperature. The AeonoseTM uses thermal cycling, in which the temperature varies between 260 and 320 °C [Breath tests were carried out with three CE-certified Aeonoset et al. ,19,20. Td 320 °C , thus ald 320 °C . Compresd 320 °C .n = 94). The train-test split method was used for model building, with a train-test split ratio of 80–20%. The model was developed using the training set, and its performance was evaluated using the test set. Due to the small sample size, training the model may encounter high variance and it might be more prone to overfitting. Therefore, ‘10-fold cross-validation’ was used to train our machine-learning model. After bootstrapping the performance of each model, they were evaluated and the optimal model was chosen, which was a model based upon an eXtreme Gradient Boosting (XGBoost) algorithm.  p-value < 0.05 was considered significant. Data analysis of the baseline characteristics was performed using the Statistical Program for the Social Sciences (SPSS) version 28.0 .Demographic data and baseline characteristics were summarized using means and standard deviations for normally distributed continuous data, or median and interquartile ranges for non-normal distributions. Patient and test characteristics between the correct and incorrectly predicted breath samples were compared using the Student’s The Medical Ethics Review Committee (METC) of Isala, Zwolle, has declared that the above study protocol is not subject to the Medical Research Involving Human Subjects Act (WMO) . Informed consent was obtained from all participants before sampling.In total, 78 patients were eligible for the study, and informed consent was obtained. Ten breath tests failed due to technical problems, mainly connection errors while transferring the data from the iPad to the server. Ten patients were excluded from the study because of a failed breath test due to patients’ discomfort. The most frequently mentioned symptoms, in this case, were excessive coughing and dyspnea. In addition, four patients did not meet the inclusion criteria. One of them appeared to have no malignancy after the pathological examination. Two patients were intraoperatively diagnosed with peritoneal metastases, and another patient received neo-adjuvant chemotherapy because of locally advanced colon cancer. Six patients did not perform a second breath test following surgery due to different reasons, and they were therefore classified as lost during the follow-up appointment. Finally, one patient was diagnosed with urothelial cancer during the study, and was therefore excluded from further analysis .n = 94). The model was developed using a training data set of 74 samples, and it was internally validated using a test set of 20 samples. Patients who were eligible between March 2021 and March 2022 were included. The baseline patient characteristics of the patient population are shown in This resulted in a total of 47 patients who were enlisted to provide samples to develop the model, which occurred by differentiating between the total pre-and postoperative breath samples  and post-operative breath tests (red), is shown in Pre- and post-operative paired comparisons are depicted in In total, nine out of forty-seven pre-operative samples were predicted incorrectly by the model, and therefore, they were not classified as positive for CRC. In addition to the finding that significantly more patients used a proton pump inhibitor (PPI) in the incorrectly predicted group, we found no other explanation for incorrect pre-operative prediction, such as limited depth of tumor invasion (T-stage).Fourteen out of forty-seven postoperative samples were incorrectly predicted as preoperative, and therefore, these results were false positives, resulting in a relatively low specificity. The median time between surgery and the second breath test was shorter in the incorrectly predicted group, however, this difference was not found to be significant . We founTM has demonstrated that the VOC pattern of patients with CRC was altered within 3 weeks after curative surgery, suggesting that the exhaled volatile organic compounds are related to the presence of CRC. However, as the performance of the model was not optimal, further research is needed to evaluate the added value of the AeonoseTM during the follow-up appointments of CRC patients.In this pilot study, the use of the AeonoseTo our knowledge, this is the first study in which pattern recognition is used to evaluate the effect of curative surgery on exhaled VOCs in CRC patients. Similarly, previous studies regarding CRC patients and other malignancies showed promising results, although these were all carried out using mass spectrometry ,28,29,30The timeframe for our endogenous metabolism to respond to cancer removal is still unrevealed, and therefore, the optimal timing for postoperative breath sampling was impossible to identify in advance. To minimalize the burden on our patients, we combined the postoperative breath test with the regular outpatient clinic visit at the surgery department. Although not significantly, the median time between surgery and the postoperative breath test was shorter in the incorrectly predicted postoperative breath samples, indicating that these breath tests may have been performed too soon to detect changes. Poli et al. compared VOCs from non-small cell lung cancer (NSCLC) patients before surgery (T0), and one month (T1) and 3 years (T2) after curative surgery using mass spectrometry . VOC levTM, we gathered considerably more failed breath tests due to patients’ discomfort [This study was limited by its small sample size and study design, and it lacked control groups. The discriminative performance of our model, and its relation to the presence of CRC, should therefore be interpreted with caution. The changes between the pre-and postoperative breath samples might not be solely due to the removal of the cancerous tissue, as other factors are also likely to play a role, such as physiological post-operative inflammatory reactions and perioperative medication. All patients received perioperative antibiotic prophylaxis, comprising a single dose of 500 mg metronidazole and 2000 mg cefazolin, which could have modified the intestinal microbiome, and therefore, the exhaled VOC patterns. Moreover, it is unknown to what extent a segmental colectomy influences the exhaled VOC pattern. Compared with other studies that were carried out with the Aeonosescomfort ,15. ThisTM.The use of PPI affects the gut microbiome ,32. The The results of this pilot study suggest that the exhaled VOC pattern of CRC patients is altered in a short period of time after curative surgery. This finding might indicate that the exhaled VOC pattern is related to the presence of colorectal cancer, justifying further clinical trials, addressing its added value during CRC follow-up appointments to detect recurrent disease. Although the detection of VOC patterns in exhaled breath using an electronic nose is still a novelty, it is a promising non-invasive low-cost technique. Before VOC pattern recognition can be incorporated in the follow-up of colorectal cancer in the future, further large-scale research is required to validate its performance.


During the COVID-19 pandemic, the absence of in-person teaching was partially compensated for through videoconferencing. However, lecturers complain that students do not participate actively in video-based online seminars. One reason cited for this is Zoom fatigue. Conferences in virtual reality (VR), accessible with and without head-mounted display, represent one potential remedy to this issue. The research to date does not shed any light on the (1.) teaching experience, (2.) student demand, (3.) learning experience , and (4.) learning performance  associated with VR conferences. The present work will compare these aspects for videoconferencing, independent study, and – in the case of teaching experience – with in-person teaching.A compulsory seminar in General Physiology was offered during the 2020/21 winter semester and the 2021 summer semester as part of the Human Medicine program at the Faculty of Medicine at Ulm University. The seminars were offered in three different formats with identical content: (a) VR conference, (b) video conference, and (c) independent study, with students selecting the format of their choice. In the VR conferences, the lecturer taught using a head-mounted display while students participated via PC, laptop, or tablet. The learning experience and learning performance were assessed using questionnaires and a knowledge test. A semi-structured interview was conducted to assess the VR teaching experience.The lecturer's teaching experience in the VR conferences was similar to in-person teaching. Students predominantly chose independent study and videoconferencing. The latter resulted in worse outcomes with regard to learning experience  and spatial learning performance than the VR conferences. Declarative learning performance differed only slightly between teaching formats.VR conferencing offers lecturers new didactic opportunities and a teaching experience similar to that of in-person teaching. Students prefer time-efficient videoconferencing and independent study, but rate participation and social presence, among other things, higher in VR conferencing. If faculty and students are open to the technology, VR conferencing can promote interactive exchange in online seminars. This subjective assessment is not associated with better declarative learning performance. Th. Th3]. Tpresence , i.e., tpresence , 6]. Lo. Losociapresence , 8], . Va. VaZoom er, Zoom , 11], , w, wZoom fcognitive load – is an important measure of the suitability of a teaching method and is differentiated into three cognitive processes . W. Wcognit fatigue , it does fatigue , 15], , w, w“I felh et al. . AnswersM), standard deviation (SD), and supplemental qualitative student feedback.In order to objectively validate the assessment of learning success, a voluntary single-choice knowledge test was administered in all teaching format groups during the 2021 summer semester. The test included eight questions, each with five answers to choose from . The solutions for the knowledge test, which was advertised as an opportunity for additional exam preparation, were made available to all students in the seminar after the questionnaire was completed. The learning experience was not re-surveyed. Data collected over the two semesters were adjusted and analyzed using SPSS (Version 27) and are presented using the arithmetic mean (“To what extent did teaching via head-mounted display (HMD) differ from in-person teaching?”) and identifying possible added values and obstacles of VR conferencing compared to videoconferencing . The interview was recorded and transcribed by hand. The statements collected were filtered based on their relevance to the two research questions on teaching experience, then sorted and summarized as continuous text including direct quotes.Data about the teaching experience of the lecturer who taught in the VR conferences was collected during a semi-structured interview in late February 2021. The interview questions in attachment 1 , table C1, were aimed at contrasting the VR teaching experience and behavior with those during in-person teaching  to 60% (nSS=158) across groups between semesters. While sex, age, and affinity for technology were similar across groups, the VR variant showed a descriptively higher interest in VR technology.Table 2 Due to the ability to move spatially and gesture freely with the HMD, the lecturer's teaching experience in VR was similar to that during in-person teaching:“The classic teaching situation […] is mirrored one-to-one in the VR conference. I was completely immersed in the world. Whether that was a virtual or real wall no longer made a difference to me.”“mannequins” to the lecturer, since their natural gestures and facial expressions could not be reproduced via conventional devices. However, this impression faded into the background in the course of the class. The lecturer estimated that active student participation was higher in VR than in videoconferencing. The generic, non-verbal expressions of the students  helped the lecturer to assess comprehension and attention, but was not equivalent to the real facial expressions and gestures in in-person teaching.At the beginning of the seminar, the students seemed like The lecturer stated that the greatest added value of VR was the possibility it afforded to teach almost as in-person despite social distancing requirements. Another advantage was the variety of didactic possibilities. In contrast to videoconferences, media  and tools  could be used and modified freely within the virtual space. This meant, for example, that students could spatially explore 3D models such as anatomical structures and chemical elements. However, users should be mindful of scaling the 3D models and lettering in the virtual space sufficiently large for smaller displays like tablets and smartphones. Although the initial effort required to prepare for VR conferences , represents a significant obstacle, this would be reduced in subsequent seminars, as with other teaching formats. In everyday practice, VR conferences therefore do not necessarily require more work than videoconferences and in-person teaching.NWS=174, NSS=159). In an optional query, the most frequently cited reasons for this decision were free time management (nWS=35), a preference for independent study (nWS=19), and less work (nWS=8). The second most common choice in both semesters was videoconferencing  due to social exchange (nWS=6) and the opportunity to ask questions (nWS=4). Significantly fewer students attended the VR conferences , but attendance increased by 61% between semesters (see figure 2 nWS=14) and a desire for change (nWS=3):In both semesters, the majority of students opted for independent study  than that in the videoconferences  and during independent study . However, the latter performed better with regard to germane load  than the VR conference  and the videoconference groups . In contrast to videoconferences, the VR conference format also induced a moderate sense of social presence  to 6 (“unsatisfactory”), and experienced enjoyment (E) in the VR conference group  than in the independent study  and videoconference groups :The winter semester seminar was rated higher with regard to both German school grades (SG), ranging from 1  according to the Technology Acceptance Model , 33]. V. V33]. VThe students who opted for the VR variant despite the extra work it entailed did so mostly out of curiosity and rated the seminar and their learning experience as better overall than their fellow students. The increase in the number of participants between surveys is thus possibly due to students recommending the VR variant. The high scores for motivation, attention, and interaction are consistent with previous research on non-immersive VR conferencing , 25], , , 38], , , 40], , , 42], , . By contIn contrast to VR conferencing, videoconferencing performed worst in all subjective aspects of the learning experience. This includes an unfavorable working memory load, which has already been identified by other authors as a possible cause of Zoom fatigue , 11], , . This isWhen interpreting the results, it must be taken into account that the students themselves chose their groups based on their personal preferences and that different lecturers taught in the various conferences. In addition, the ratings could have been influenced by the novelty effect . AccordiThe findings from curricular teaching show that VR conferencing can enrich synchronous distance teaching if lecturers and students are open to the technology. VR conferencing offers lecturers who invest the initial effort new didactic opportunities in a virtual 3D space and a teaching experience similar to in-person teaching. Most students prefer videoconferences and independent study, which require less preparation. However, interaction, participation, social presence, and the seminar, among other things, are rated higher in VR conferencing than in established teaching formats. Nevertheless, this subjective assessment does not result in better declarative learning performance.The field study was financially supported by the AG Lehrforschung  of the Faculty of Medicine at the University of Ulm. The authors declare that they have no competing interests.


Human milk (HM) is the ideal source of nutrients for infants. Its composition is highly variable according to the infant's needs. When not enough own mother's milk (OMM) is available, the administration of pasteurized donor human milk (DHM) is considered a suitable alternative for preterm infants. This study protocol describes the NUTRISHIELD clinical study. The main objective of this study is to compare the % weight gain/month in preterm and term infants exclusively receiving either OMM or DHM. Other secondary aims comprise the evaluation of the influence of diet, lifestyle habits, psychological stress, and pasteurization on the milk composition, and how it modulates infant's growth, health, and development.NUTRISHIELD is a prospective mother-infant birth cohort in the Spanish-Mediterranean area including three groups: preterm infants <32 weeks of gestation (i) exclusively receiving  OMM, and (ii) exclusively receiving DHM, and (iii) term infants exclusively receiving OMM, as well as their mothers. Biological samples and nutritional, clinical, and anthropometric characteristics are collected at six time points covering the period from birth and until six months of infant's age. The genotype, metabolome, and microbiota as well as the HM composition are characterized. Portable sensor prototypes for the analysis of HM and urine are benchmarked. Additionally, maternal psychosocial status is measured at the beginning of the study and at month six. Mother-infant postpartum bonding and parental stress are also examined. At six months, infant neurodevelopment scales are applied. Mother's concerns and attitudes to breastfeeding are registered through a specific questionnaire.ad-hoc designed sensor prototypes with a wide range of clinical outcome measures. Data obtained from this study will be used to train a machine-learning algorithm for providing dietary advice to lactating mothers and will be implemented in a user-friendly platform based on a combination of user-provided information and biomarker analysis. A better understanding of the factors affecting milk's composition, together with the health implications for infants plays an important role in developing improved strategies of nutraceutical management in infant care.NUTRISHIELD provides an in-depth longitudinal study of the mother-infant-microbiota triad combining multiple biological matrices, newly developed analytical methods, and https://register.clinicaltrials.gov, identifier: NCT05646940. The WorDuring the last decades, the incidence of preterm deliveries (<37 weeks of gestation) and survival rate of preterm infants (PI) have been steadily increasing , hand inIn situations where mothers are unable to produce sufficient milk quantities to exclusively or partially breastfeed, pasteurized donor human milk (DHM) is a viable option to avoid formula feeding, especially for low birth-weight children . DHM is Beyond the physiological adaptations, research has focused on the potential effects of the maternal diet on the HM composition. In an earlier report, HM composition was found rather different among mothers of diverse ethnic backgrounds, with different dietary habits . The fatTherefore, the main objective of this study is to compare the % weight gain/month in PI and TI exclusively receiving either OMM or DHM. In addition, secondary objectives are (i) to evaluate associations between the mother's diet, physical, and psychosocial status  and HM composition in PI and TI, (ii) to evaluate the effect of pasteurization/storage on DHM composition, (iii) to assess the interplay of microbiota and microbiota activity and HM composition, (iv) to assess the interplay of microbiota and microbiota activity detected in HM and PIs and TIs, (v) to evaluate the impact of microbiota and microbiota activity on the vitamin status of PIs and TIs, (vi) to test the performance of novel sensor devices developed within this project, and (vii) the development of a personalized nutrition algorithm for lactating mothers.2.2.1.The NUTRISHIELD study is a parallel group, non-randomized, observational study performed at the Division of Neonatology of the University & Polytechnic Hospital La Fe (HULAFE), including TI and PI and their mothers, covering the period from birth to 24 months of infant's age. In addition, mothers providing DHM to study participants are also included.The study protocol has been approved by the Scientific and Ethics Committee for Biomedical Research (CEIm) of the HULAFE (#2019-289-1). All methods have been performed in accordance with the relevant guidelines and regulations and written permission has been obtained from mothers or legal representatives by signing an informed consent form.Confidentiality of subjects is maintained during the study. All participants have been assigned a code and data allowing personal identification will not be shared at any time. Participants may withdraw consent for participating in the study at any time.2.2.Participants were recruited at the end of pregnancy (when admitted to the obstetric ward) or within one week after birth in case of hospitalized infants at HULAFE. Recruitment started in October 2020 and was completed in July 2022. Three mother-infant groups were enrolled, i.e., PI fed with OMM (PI-OMM), PI fed with pasteurized DHM (PI-DHM), and TI receiving OMM (TI-OMM), and their mothers.The inclusion criteria were (i) acceptance of the mother to participate and sign an informed consent form, (ii) a gestational age <32 weeks for the group of PI and >37 weeks for the group of TI, and (iii) exclusive consumption  of either OMM or DHM at time point CEN  for PI or RBW (recovery of birth weight) for TI. Although the type of feeding of PIs included in either group (PI-OMM or PI-DHM) may have changed at later time points, they remained in the same study group, so the effect of feeding of each type of milk at CEN and its long-term effects can be studied. Likewise, the use of infant formula and the initiation of weaning at later time points was recorded without affecting follow-up assessments. The exclusion criteria were (i) non-compliance with any of the inclusion criteria, (ii) the requirement of a special diet for the mother  or maternal consumption of probiotics, (iii) the need of intestinal surgery, severe congenital malformations, or chromosomopathies of the infant, (iv) mother's residence outside the Valencian Community and (v) severe language barriers hampering the collection of necessary data from mothers not speaking Spanish and/or English.Sample size estimation was performed for the primary outcome  and was based on result of a previous study . ConsideOn the other hand, HM donors were recruited during their regular visits at the hospital's HM Bank of the Valencian Community. All participants met ordinary criteria for HM donation  and accepted to sign an informed consent form and participate in the study.2.3.Samples from lactating mothers and their infants are collected at different timepoints, as shown in Samples collected at home are stored at 4°C during a maximum of 24 h before their transport to the hospital on ice, where they are registered, aliquoted, labelled, and stored at −80°C until analysis. A HM and faeces aliquot is directly stored in a tube containing a microbiome preservative solution. For DHM, collection times respective to delivery are heterogeneous, since from each donor several aliquots are collected over time, pooled, and then subjected to Holder pasteurization in batches . The lactation time was estimated as the mean  of time elapsed during the collection of different aliquots from one DHM batch, being 16 (SD 12) days.g for 10 min at 20°C) and the upper plasma layer is stored in opaque vials at −80°C until analysis. Mother's first morning urine is collected in a polypropylene container, and infant's urine is collected by placing sterile cotton pads in the diaper and, after urinating, squeezing them with a sterile plastic syringe into sterile tubes , and details regarding the extraction method , date, and extracted volume are registered. For DHM samples, aliquots of each pooled DHM sample are collected before and after Holder pasteurization.2.4.For all three study groups, information obtained from clinical records is collected. Anthropometric data , sociodemographic, dietary, other relevant information related to lifestyle , and psychosocial status are provided through questionnaires by participating mothers as summarized in Regarding the 24 h recall, trained researchers ask for all foods and beverages participants consumed during the previous day, using the multiple-pass method . Recall The FFQ is administered by trained personnel, and it comprises 142 questions on the consumption of foods that are commonly eaten by the Spanish population throughout a year, including dairy products, cereals, fruits, vegetables, meat, fish, legumes, added fats, alcoholic beverages, stimulants, and sweets. Using a 9-grade scale  participants are required to indicate the absolute frequency of consuming a certain amount of food, expressed in grams, milliliters or in other common measures, such as slice, tablespoon, or cup, depending on the food. The previous month is set as the timeframe. The FFQ is an easy-to-use questionnaire and is not expected to increase the burden of lactating mothers.Based on the FFQ-responses, adherence to the Mediterranean diet is evaluated by using the MedDietScore, a composite score calculated for each participant . For fooMaternal psychosocial status is measured at recruitment and at six months, including social support , familyAs for the infants, at six and twenty-four months (corrected age for PIs) assessment of neurodevelopment is conducted during a hospital visit by a trained psychologist and psychiatrist from the team. Parents complete the Ages & Stages Questionnaires, Third Edition (ASQ-3)  for psycMother's concerns and attitudes to breastfeeding are also registered through the Iowa Infant Feeding Attitude Scale (IIFAS)  at CEN/RMilk donors are asked to provide sociodemographic, medical, dietary, and other lifestyle data. PSS-10 is evaluated when entering the study in order to correlate with hormones and other compounds present in the milk. In particular, each time a batch of milk is prepared, a FFQ is administered (representing the period of time that the batch of milk covered) and the donors are asked to provide medical, anthropometric, and lifestyle data.2.5.A range of state-of-the-art as well as novel laboratory methods are employed for the analysis of the collected biological samples, as summarized in 2.5.1.For genome sequencing analysis, DNA extraction from buccal swab samples takes place according to the protocol developed by the sequencing provider facility. Polymerase chain reaction (PCR) quality control (QC) is performed before samples are shipped to the sequencing service provider, and again upon receival by the sequencing facility. QC and library preparation follow the Illumina NovaSeq protocol . Three polygenic risk scores (PRS) models are developed for body mass index (BMI), diabetes type 2, and lactose intolerance, calculated by Plink software , and theThis score can then be compared to the scores obtained from the UK Biobank set , to esti2.5.2.Advanced Testing for Genetic Composition (ATGC) is used for microbiota analysis of faeces and HM samples . It is aThe Bifidobacterium (Bb) assay used is specifically designed to analyze the main species and subspecies varieties in HM and newborn gut microbiomes. For sample processing, the HM lipid layer is solubilized using a detergent, while for faeces, a lysis step using a lysis buffer with bead beating for 20 s is required. Then, an in-house DNA extraction procedure and a PCR are carried out. Cycling temperature capillary electrophoresis (CTCE) is made for each primer on an independent capillary. It is performed on a MegaBace 1,000 instrument  as described earlier .2.5.3.(i)Short chain fatty acids (SCFAs) and branched chain amino acids (BCAAs) in faeces, urine and HM samplesSCFAs  and BCAAs  are determined by targeted gas chromatography coupled to mass spectrometry (GC-MS), as described elsewhere ((ii)Bile acids (BAs) in urine samplesIn total, 34 BAs  are determined in urine samples by liquid chromatography coupled to tandem MS (LC-MS/MS), as described elsewhere , respectively, related to nine food groups such as fruits, vegetables, meat, fish, dairy products, milk, seeds, coffee, and soft drinks is carried out , 67. Add2.5.5.Untargeted metabolomic analysis is carried out in urine samples by LC-MS/MS, employing an Agilent 1,290 Infinity HPLC system coupled to an Agilent 6,550 Spectrometer iFunnel quadrupole time-of-flight (QTOF) MS detector , as previously described .2.5.6.Direct measurement of HM macronutrients including fat, carbohydrates, crude and true proteins, total solids, and energy are determined using a Miris HM analyzer . Determinations, QC, and instrument calibration are performed following the SOP provided by the manufacturer .2.5.7.The targeted analysis of 36 fatty acids in HM samples is carried out by GC-MS as described elsewhere , 71, usi2.5.8.Quantification of water-soluble  and lipid-soluble vitamins  in HM and umbilical cord blood samples is carried out.The analysis of B, D and K vitamins are determined as described somewhere –76, usinThe retinol forms are analyzed as previously described , using aCarotenoids and vitamin E analysis is carried out as previously described , using a2.5.9.HMOs analysis is carried out by LC-MS in accordance with a previously described protocol , 79 with2.5.10.Steroid analysis of HM and urine samples is carried out on an Acquity UPLC system  coupled to a Waters Xevo TQ-S MS detector  as previously described , 81. A p2.6.Due to the special requirements of the study, three sensor prototypes enabling the determination of complementary parameters in HM and urine samples are being developed and benchmarked within the NUTRISHIELD study.2.6.1.α-lactalbumin, and lactoferrin) in HM milk is performed using quantum cascade laser-based mid-infrared (QCL-IR) spectroscopy  accessory  connected to a Tensor 37  FTIR spectrometer , 85.2.6.3.A custom-made portable system based on potentiometric measurements and screen-printed electrode technology is developed to measure pH in urine. The system works with small sample volumes  and no dilution is needed. An additive is spiked into samples prior to measurement in order to preserve and regenerate the sensor's surface, which extends sensor lifetime to multiple uses with no carry-over between urine samples.2.6.4.Quantification of phosphate and creatinine in urine samples is performed using a method based on FTIR transmission spectroscopy. Within the study, a dedicated QCL-based urine analyzer is developed. Reference values for phosphate are obtained by a colorimetric determination after reaction of inorganic phosphorus with ammonium molybdate, while creatinine reference values are obteined following the manufacturer's instructions of the modified Jaffe's method implemented in the DetectX® urinary creatinine detection kit from Arbor Assays .2.7.t-test, Wilcoxon ranksum test or Χ2 test with α = 0.05 will be used for between-group comparisons and fold changes (FC) will be calculated as the ratio of means or medians between groups in accordance to the underlying distribution of the data. Pearson's linear or Spearman rank correlation coefficients will be determined between continuous variables. If necessary, partial correlation coefficients adjusting for known confounding factors will be computed. The false discovery rate (FDR) from the p-values of multiple-hypothesis testing will be estimated using the Benjamini and Hochberg procedure . The CTA is a system intended for personalized medicine/nutrition, implementing the following main features: (i) data acquisition from questionnaires, (ii) data acquisition from laboratory biomarker analysis, (iii) processing data to train machine learning algorithms, and (iv) deploying trained algorithms to produce reports for final users.Using the CTA, all study data is consolidated in a structured database, of which an anonymized version can be later stored on public repositories for re-use in further research.3.n = 104), excluded (n = 49), lost to follow up (n = 10) and the number of PI that were finally included in the study (n = 45). In addition, a control group comprising 31 full term OMM infant-mother dyads was recruited, with five participants being lost during follow-up. Altogether, a total of 71 infant-mother dyads were included and completed the study , after losing 15 infant participants during follow-up. In total 662 urine, 594 faeces, 134 buccal swab, 33 venous and arterial cord blood, and 234 HM samples, as well as aliquots from 147 DHM batches before and after pasteurization have been collected. An ample array of laboratory methods for biomarker analysis and screening of biological samples and three ad-hoc designed sensors were developed. Currently, the analysis of all collected study samples is in progress at the different participating institutions.The results obtained from HM analysis will be used to study how macronutrients, proteins, vitamins, HMOs, steroids, fatty acids, and microbiota are affected by maternal nutrition, psychosocial status , other clinical variables , and pasteurization, in the case of DHM. Additionally, it is assessed how HM composition affects growth and other health parameters in TI and PI. The results obtained from urine samples analysis will also be used to study how urinary nutrition biomarkers and the metabolic profile are affected by nutrition, psychosocial status, the PRS obtained from genome sequencing and other clinical variables. In addition, HM and faeces microbiome analysis will be used to study its correlation with microbiota biomarker analysis . HM and urine samples will also be used to test the pH, protein, fatty acids, and phosphate and creatinine sensors developed within the study.This study presents several strengths and limitations. During the study design, special emphasis was put on the comfort of participants. Hence, the collected biological samples, including faeces, urine, HM, buccal swap, and umbilical cord blood samples, were obtained by non-invasive procedures that had been tested and employed in earlier studies carried out at HULAFE. SOPs for sample collection and handling were designed and reviewed by the study team ahead of time. Sample collection kits with detailed instructions and pictures were prepared for sample collection at home. Finally, all procedures were tested in a small pilot study conducted before the initiation of the main study, allowing for minor amendments in the protocols and leading to a homogeneous process conducted all through the main study. During follow-up, some visits were carried out at home avoiding the additional effort for participants to travel to the hospital. These efforts helped to encourage mothers to participate in the study and enhanced adherence during the follow-up period.One of the most outstanding strengths of this study is the rich array of information obtained from participants during the first six months of life, a pivotal period for health programming. Direct access to participants through trained staff of the research team at the hospital greatly aided to reduce the rate of missing data. The promotion of good relationships with participants could facilitate to further extending the life of the study cohort. Nevertheless, the follow-up period presented challenges. We would like to highlight the loss of some samples due to technical issues when collected at home as well as the temporary loss of some sampling time points, e.g., due to illness of participants or overburdening of lactating mothers. Our preliminary results need to be confirmed in a greater cohort of infants and in different European settings.This study will provide a better understanding of the impact of maternal nutrition in HM composition, and the interplay of HM composition, microbiota, and newborn physiology, especially in PI's development. More knowledge and a better understanding could allow for a personalized nutrition or even individualized care at an early stage of the neonatal period to improve the outcome of these vulnerable newborns. Additionally, data obtained from this study will be used to train a machine-learning algorithm for providing dietary advice to lactating mothers and will be implemented in a user-friendly platform based on a combination of user-provided information and biomarker analysis.4.A better understanding of the factors affecting the milk's composition, together with the health implications for infants plays an important role in developing improved strategies of nutraceutical management in infant care. The development of a user-friendly platform based on a combination of user-provided information and biomarker analysis for providing dietary advice would make latest scientific advances directly accessible to a wide range of lactating mothers. This development is anticipated to be of special importance for health, growth, and development of prematurely born infants.