There is growing policy emphasis on self‐management as an essential component of musculoskeletal chronic care models. Underpinning this drive is the assumption that with correct ‘informational’ framing people will better manage their condition's progression and thereby maintain quality of life.To assess associations between self‐management behaviours and health‐related quality of life for people with chronic musculoskeletal conditions.Using survey data from health census and follow‐up structured telephone interviews, linear regression  and logistic regression examined associations between use of specific self‐management behaviours and quality of life.A total of 885 respondents (2012) who indicated still having a musculoskeletal condition reported in a 2010 health census .Specific self‐management activities, age, sex, education, marital status, smoking, comorbidities and pain.EQ‐5D‐5L.Exercise (63%) and diet (19%) were the most commonly reported self‐management activities used to manage musculoskeletal conditions. About 24% reported not using any specific self‐management activities. Involvement in self‐management showed no association with quality of life, with and without adjustment for confounders. Diet had a negative association with quality of life as did use of formal support (self‐management course or community group support).Taking a real‐world perspective, these findings raise important questions about how people currently engage with self‐management activities and the kinds of outcomes that can be expected from undertaking these activities. The timing of people's uptake of self‐management within the musculoskeletal disease continuum is an issue requiring further attention in both research and practice. Thus, the condition had now persisted for 18 months or more (i.e. was chronic). Although CATI interviews collected information about affected site(s) on the body, and whether a diagnosis had been given, this study does not exclude respondents without a formal diagnosis or restrict analysis to only certain MSK conditions. This inclusive selection criterion was chosen because it is important to understand how people manage the full range of chronic MSK conditions in a community setting where 11% had not visited a health provider about their condition (unpublished data).The hypothesis being tested in this study is that people participating in self‐management activities for their chronic MSK condition are likely to have better quality of life than those who do not. In 2010, a health census of adults aged 15 years and over was conducted in Port Lincoln, a regional centre in South Australia . The census methodology is described in detail elsewhere.The exposure of interest was use of self‐management activities to manage their MSK condition (as assessed in the 2012 CATI). Respondents were asked five separate questions (with yes/no response options) as to whether they had used exercise, diet change, self‐management courses, community services/groups or other activities to manage the MSK condition reported in the 2010 health census. Where a response to ‘other self‐management activity’ was yes, the specific activity was described by the participant. As this question did not identify a cohesive group of self‐management activities, it was not analysed as a separate question but was included in the combined variable. Responses to these 5 separate questions were combined to create a dichotomous variable indicating whether they had undertaken at least one self‐management activity or none, to manage their MSK condition.The primary outcome, health‐related quality of life, was measured using the new version of the EuroQOL five dimension questionnaire (EQ‐5D‐5L)P‐value below 0.3 in the bivariate analysis or were identified from the literature as of potential importance .The proportion of respondents who undertook each of the nominated self‐management activities was determined. Descriptive analyses , the CATI survey respondents were more likely to be female, non‐smokers, have comorbidities and report at least moderate pain  14.9] [mean age of Census MSK population was 56.5 years (SD 17.7)]. Compared to the 2010 census MSK population  and moderate problems with usual activities . Regression models run separately for men and women found that the negative associations between dietary change and index scores remained , and moderate problems with usual activities . When models were run separately for males and females, similar negative associations were observed for each sex . People undertaking both dietary change and exercise to manage their MSK condition reported poorer quality of life relative to those who did not. When this combination was analysed, a negative association with health‐state index scores was observed (Table P = 0.028).People who used formal support to manage their MSK reported poorer quality of life relative to those who did not. That is, those who used formal support  were more likely to have a negative association with health‐state index scores Table . ProgresTaking a whole population perspective, this study demonstrates that the most commonly reported self‐management activity with persisting MSK condition/s was exercise, followed by diet. There were low levels of reported participation in formal self‐management programmes, community services or group support activities. Of particular note, almost one‐quarter of respondents reported that they had not used any specific self‐management activities and almost two‐thirds had not accessed information to assist them in the management of their condition. It has been argued in other studies that for many people with arthritis, there is a belief that arthritis is something to be tolerated and not managed.A key finding of this study is that within this community setting, where independent self‐management activities (such as exercise and diet change) were more commonly used than formal support programmes, there is no association between the use of self‐management activities for MSK conditions, and quality of life. This finding raises important questions about how, in real‐world settings, people currently engage with activities; whether self‐management in a general community setting can be effective; and what should be expected from undertaking self‐management activities. These questions require more focused research including longitudinal studies of populations in community settings to establish casual relationships and pathways.Given the growing policy emphasis on the provision of information and counselling about diet change and weight management for the management of arthritiset al.'sThe negative association between use of formal support programmes and quality of life corroborates Kroon This study has a number of important strengths, including the large population‐based data set, the range of variables covered and the administration of both surveys by trained personnel using a structured format. The cross‐sectional study design limits the analysis to associations: future population health studies which collect longitudinal data would be useful to examine issues of causality between MSK related self‐management activities and quality of life, including detailed measures of frequency, intensity and duration of self‐management activities. Study participants were potentially a heterogeneous group containing those who have a MSK lifelong diagnosis, such as OA, and those that have potentially resolvable MSK conditions. These groups may have responded differently to self‐management, but this study is unable to differentiate between them. Future research should consider potential differences in the response to self‐management between these groups. A further limitation of this study relates to the use of self‐reported data, including the respondents’ diagnoses of MSK conditions, and the potential response bias particularly in relation to those agreeing to be recontacted for the CATI survey. There may also be issues of generalizability given that the study site was a regional centre in Australia, particularly in relation to access to formal support and programmes.These findings do not sit comfortably with current policy discourse emphasizing the expectation that individuals undertake regular self‐management tasks to successfully manage chronic conditions to protect their quality of life. Given this current policy environment, the question becomes the following: What should we do to support people to manage their MSK condition? The inverse care law tells us that those with greatest need, as identified in this study, are less likely to act to address their care needs.In conclusion, self‐management relies on the ability of people to access, understand and interpret a wide range of information. Use of self‐management activities will be influenced by a person's understanding of what works for them given the particular challenges and experiences of their social, economic and practical situation.The LINKIN Health study is funded by an NHMRC Project grant 627240: The Physiology of Health Systems; Port Lincoln as a case study. Elizabeth Hoon is currently supported by Arthritis SA and the University of Adelaide's Florey Research Fund. Tiffany Gill is currently a National Health and Medical Research Council Early Career fellow.The authors declare that they have no competing interests.


To assess the relationship between developmental coordination disorder (DCD) and mental health outcomes in late adolescence.Data were analyzed from the Avon Longitudinal Study of Parents and Children. Moderate‐to‐severe DCD was defined at 7 to 8 years according to the DSM‐IV‐TR criteria. Mental health was assessed at 16 to 18 years using self‐reported questionnaires: Strengths and Difficulties Questionnaire, Short Moods and Feelings Questionnaire, and the Warwick–Edinburgh Mental Well‐being Scale. Logistic and linear regressions assessed the associations between DCD and mental health, using multiple imputation to account for missing data. Adjustments were made for socio‐economic status, IQ, and social communication difficulties.n=168) had an increased risk of mental health difficulties  than their peers (n=3750) . This was, in part, mediated through poor social communication skills. Adolescent females with DCD (n=59) were more prone to mental health difficulties than males. Greater mental well‐being was associated with better self‐esteem .Adolescents with DCD (Individuals with DCD, particularly females, had increased risk of mental health difficulties in late adolescence. Interventions that aim to promote resilience in DCD should involve improving social communication skills and self‐esteem. Mental health difficulties in developmental coordination disorder persist into late adolescence.Adolescent females with developmental coordination disorder may have greater risk of mental health difficulties.Social communication difficulties mediate the relationship between developmental coordination disorder and mental health.891–892 of this issue.This article is commented on by Wagner on pages This article's abstract has been translated into Spanish and Portuguese.abstract to view the translations.Follow the links from the  ALSPACAvon Longitudinal Study of Parents and ChildrenDCDDevelopmental coordination disorderSMFQShort Moods and Feelings QuestionnaireSDQStrengths and Difficulties QuestionnaireWEMWBSWarwick–Edinburgh Mental Well‐being ScaleDevelopmental coordination disorder (DCD) is a common neurodevelopmental condition which affects 2% to 6% of the population.The mechanisms for DCD leading to poor mental health outcomes are not well understood. A monozygotic twin study reported that twins with DCD demonstrated higher levels of depressive symptoms than their co‐twins without DCD, which suggests that mental health problems in DCD may be explained by unique environmental experiences.Previous work on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort has shown that poor mental health outcomes at 9 to 10 years in children with DCD were associated with poor social communication skills, increased bullying, and poor peer relationships.http://www.bris.ac.uk/alspac/researchers/data-access/data-dictionary/). Ethical approval was obtained from the ALSPAC Ethics and Law Committee and the local research ethics committees.ALSPAC is a large population‐based birth cohort that invited all pregnant females in the Avon area, south‐west England, with expected dates of delivery between 1 April 1991 and 31 December 1992 to take part.Children were defined as having DCD according to the adaption of the DSM‐IV‐TR criteria set out in the Leeds Consensus Statement 2006.Motor skills were assessed in a research clinic between 7 and 8 years of age using the ALSPAC coordination test, which consisted of three subtests of the Movement Assessment Battery for Children.A cohort of 6902 children had all the data required for full assessment. Those with a motor score below the fifteenth centile and who failed their National Curriculum writing test, or scored less than the fifteenth centile in the activities of daily living scale, were defined as having moderate‐to‐severe DCD.The Strengths and Difficulties Questionnaire (SDQ) was self‐reported at 16 years 6 months. The SDQ is a standardized questionnaire widely used to screen for mental health difficulties in young people and comprises 20 items relating to four different psychosocial scales (five items each): emotional symptoms; conduct; hyperactivity/inattention; and peer problems. Responses were scored using a three‐point Likert scale, and answers summed to give a ‘total difficulties’ score out of 40. In a large survey of UK children, those with a score in the worst decile have been shown to have a 15‐fold increase in the odds of having an independently diagnosed psychiatric disorder.The Short Mood and Feelings Questionnaire (SMFQ) was self‐reported at 17 years 6 months. The SMFQ is a 13‐point validated questionnaire used to identify depressive symptoms. It has good validity and reliability in determining the presence of depression when a young person scores 11 or more.The Warwick–Edinburgh Mental Well‐being Scale (WEMWBS) questionnaire was self‐reported at 17 years 6 months. The WEMWBS comprises 14 positively worded items and responses were scored using a five‐point Likert scale. Responses were summed to provide a single score out of 70, which indicates overall mental well‐being. WEMWBS score demonstrated good validity and reliability in adolescent populations in the UK.Potential confounding variables were selected based on previous literature and our own univariate analyses against both the exposure (DCD) and the outcome measures.Child‐related variables assessed were sex, gestation, and birthweight. In this follow‐up cohort, sex was associated with both exposure and outcomes.Parental mental health and socio‐economic status were associated with both DCD and child mental health in previous analyses.The following variables were considered as potential mediators, based on previous literature: IQ;IQ was measured using the short version of the Wechsler Intelligence Scale for Children III, applied in a research clinic at 8 years 6 months of age. IQ shows high stability over time when measured in school‐age children onwards.Difficulties with hyperactivity are incorporated in the total SDQ score as one of the subscales, and so were only adjusted for in the SMFQ analyses, using those in the worst decile of the SDQ hyperactivity/inattention subscale to denote significant hyperactivity.Social communication difficulties were measured using the Social and Communications Disorders Checklist,Self‐esteem was assessed at 17 years 6 months using the Bachman revision of the Rosenberg's Self‐esteem Scale, which comprises 10 statements relating to self‐esteem, each with four responses (strongly disagree/disagree/agree/strongly agree), which are summed to give a total score.Friendship support was assessed at 13 years 6 months using five questions from the Cambridge Hormones and Moods Project Friendship Questionnaire;Bullying was assessed at 15 to 16 years as part of a self‐reported questionnaire. Respondents were asked how often they were upset by name‐calling/exclusion or bullying in the last year, with four possible responses (never/rarely/sometimes/most days). Children were classified as being overt victims of bullying if they answered ‘sometimes’ or ‘most days’.χ2 tests were used to ensure satisfactory model fit. Linear regressions were used to examine the association between mental well‐being on the WEMWBS and each of the covariates. Tests were two‐tailed, with an a priori set alpha‐level of p<0.05.Logistic regressions were used to assess the associations between DCD and mental health difficulties on the SDQ and SMFQ. Multivariable models were created to adjust for the effect of the confounding and mediating variables sequentially. A ‘variable‐focused model’ of resilience was used to consider how different variables influenced the risk of psychopathology in children with DCD compared with controls.Multiple imputation using chained equations was used to impute missing data in the covariates only. Analysis of imputed data sets helps to minimize attrition bias and improve precision of estimates.n=6902), data for the SDQ at 16 years 6 months were available for 3918 children (168 [4.3%] with DCD), whereas data for the SMFQ and WEMWBS at 17 years 6 months were available for 3177 children (130 [4.1%] with DCD). Compared with those who were followed‐up, those with missing outcome data were more likely to be male, have lower IQ, have lower socio‐economic status, and have mothers who reported depression (Appendix S1). Characteristics of the children with DCD and controls who responded to the SDQ are compared in Table For those assessed for DCD at 7 to 8 years of age (The odds ratios (OR) and 95% confidence intervals (CI) of mental health difficulties measured by the SDQ using the imputed data sets are presented in Table n=25) of those with DCD were at risk of mental health difficulties versus 7.5% (n=282) of those without DCD. After adjusting for socio‐economic factors (Model 1) and IQ (Model 2), the odds of difficulty were attenuated but remained high. However, further adjustment for co‐existing social communication difficulties (Model 3) substantially attenuated the relationship. Using the SDQ subscales, children with DCD were more likely to have problems with hyperactivity and peer relationships, and these associations were similarly attenuated in the fully adjusted model.Cross‐tabulation for the total difficulties SDQ score showed that 14.9%  of DCD cases reported symptoms versus 17.8% (n=541) of those without DCD. After adjusting for socio‐economic factors, this association persisted but was attenuated after adjustment for IQ and social communication skills.A weak association was found between reported depressive symptoms on the SMFQ and DCD; 24.6% . Higher well‐being scores were positively associated with higher self‐esteem for both males and females with DCD. For females only, lower self‐esteem was associated with poor social communication skills.The linear associations between well‐being and psychosocial factors for those with DCD using the imputed data sets are presented in Table The results of this prospective study using a large UK cohort showed that children with DCD had a greater risk of mental health difficulties in late adolescence than their peers. They had particular difficulties with hyperactivity and peer relations and were also more likely to report depressive symptoms than their peers. When compared with same‐sex controls, females with DCD were more likely to report emotional difficulties and depressive symptoms, whereas males with DCD experienced greater peer problems. These mental health difficulties were mediated by poor social communication skills. In those with DCD, higher mental well‐being was associated with higher self‐esteem. These results add robust longitudinal data, using a strict definition of DCD, to the growing body of evidence linking motor coordination problems with mental health problems in later life, and highlight the important contributory role of poor social communication skills.The key strengths of this study are use of a large population‐based cohort, which avoids the bias inherent in clinical samples, and the prospective follow‐up over 10 years. We were able to adjust for multiple confounders and covariates and were also able to consider a positive outcome of well‐being, collected separately from the mental health difficulties.The main limitation is missing data. ALSPAC, in common with all cohorts, suffers from considerable attrition, which we have attempted to account for by using multiple imputation, an increasingly recognized method of dealing with missing data to minimize bias.Few studies have been large enough to assess sex differences in psychosocial outcomes in DCD. In our previous work on ALSPAC, no sex effect was found at 9 to 10 years.The Environmental Stress Hypothesis proposes that the primary stressor of poor motor coordination leads to a series of secondary stressors over time, which, in turn, lead to poor mental health.In light of mounting evidence that poor motor coordination and mental health are linked, clinicians need to manage not only the primary deficits in DCD, but also the secondary features that may influence the trajectory of mental health. The importance of social communication skills, self‐esteem and peer support in mediating psychosocial outcomes in DCD has been increasingly highlighted in numerous studies. Clinical, psychological, and social interventions targeted on these domains may represent the best opportunity to improve mental health and well‐being of children with DCD. This has been recognized in programmes such as the Partnering for Change initiative,In summary, the work on the ALSPAC cohort has demonstrated longitudinally that poor mental health is an important consequence of DCD, especially so for females in adolescence. Factors that consistently affect these relationships are social communication skills, peer support, bullying, and self‐esteem.Clinicians need to be aware of and screen for mental health difficulties in young people with DCD. Combining therapy for motor coordination difficulties with interventions that help promote social interaction, self‐esteem, and positive peer relationships may improve mental health outcomes in these individuals.Appendix S1: Missing data and multiple imputation.Table SI: Factors which predict missingness in the data (Strengths and Difficulties Questionnaire at 16y 6mo) for the whole cohortTable SII: Mental health difficulties measured using the Strengths and Difficulties Questionnaire (SDQ) and the Short Moods and Feelings Questionnaire (SMFQ) at 16 to 18 years in adolescents with developmental coordination disorder (DCD) compared to controls, using all available dataTable SIII: Mental health difficulties measured using the Strengths and Difficulties Questionnaire (SDQ) and Short Mood and Feelings Questionnaire (SMFQ) in males and females with developmental coordination disorder (DCD), compared to same‐sex controls, using all available dataTable SIV: Linear associations between mental well‐being score on the Warwick–Edinburgh Mental Well‐being Scale (WEMWBS) and psychosocial factors for adolescents with developmental coordination disorder (DCD), using all available data and stratified by sexClick here for additional data file.


The issue of over‐ and underdose at the interfaces that is observed when symmetric MLC apertures are used is reduced from more than ±4% to less than ±1.5% with asymmetric MLC apertures. Lungs are shielded by 20%, 30%, and 40% of the prescribed dose by adjusting the MLC apertures. Dose‐volume histogram analysis confirms that the revised technique provides effective lung shielding, as well as a homogeneous dose coverage to the whole body. The asymmetric technique also reduces hot and cold spots at lung‐tissue interfaces compared to previous symmetric MLC‐based TBI technique. MLC‐based shielding of OARs eliminates the need to fabricate and setup cumbersome patient‐specific physical blocks.A revised translating bed total body irradiation (TBI) technique is developed for shielding organs at risk (lungs) to tolerance dose limits, and optimizing dose distribution in three dimensions (3D) using an asymmetrically‐adjusted, dynamic multileaf collimator. We present a dosimetric comparison of this technique with a previously developed symmetric MLC‐based TBI technique. An anthropomorphic RANDO phantom is CT scanned with 3 mm slice thickness. Radiological depths (RD) are calculated on individual CT slices along the divergent ray lines. Asymmetric MLC apertures are defined every 9 mm over the phantom length in the craniocaudal direction. Individual asymmetric MLC leaf positions are optimized based on RD values of all slices for uniform dose distributions. Dose calculations are performed in the Eclipse treatment planning system over these optimized MLC apertures. Dose uniformity along midline of the RANDO phantom is within the confidence limit (CL) of 2.1% (with a confidence probability PACS number(s): 87.55.‐x, 87.55.de, 87.55.D‐ Unlike conventional radiotherapy where part of the body is irradiated, total body irradiation (TBI) is a specialized radiotherapy technique where the patient is exposed to high whole‐body doses of radiation. TBI is usually prescribed for: a) suppressing the immune system of the patient prior to stem cell transplant, or b) treating various hematological diseases .Several groups have developed dynamic TBI techniques for irradiating the entire patient by moving either the patient or the radiation source. Constant and variable bed velocity TBI, aperture modulated TBI, and radiological depth‐based TBI are a few examples of dynamic TBI techniques.∼±4% of the prescribed dose. This method results in improved overall dose uniformity and accuracy compared to static TBI techniques, but nevertheless produces regions of over‐ and underdose in parts of the body with sharp changes in RD .One of the complications in the implementation of dynamic TBI techniques is that commercially available treatment planning systems (TPS) are designed to perform dose calculations for relatively small volumes, at nominal source‐to‐axis distance (SAD). In TBI however, the beam arrangements and patient positioning are significantly different from this standard. Recently a novel radiological depth (RD)‐based TBI technique (RD‐TBI) has been designed for improving dose distribution uniformity by translating the patient under a radiation beam while dynamically optimizing MLC apertures.In SMT‐TBI, the MLC leaf positions are defined using radiological depth (RD) values from the CT slice at the level of the beam central axis.The current study presents a modified SMT‐TBI technique that uses asymmetrically defined MLC apertures to account for the sharp RD changes and is referred to as Asymmetric MLC‐based Technique (AMT‐TBI). We investigate the feasibility and accuracy of lung shielding with this revised technique, aiming to avoid the use of heavy physical shielding blocks, which are time‐consuming and labor‐intensive to design and fabricate.di denotes the physical thickness of the tissue segment with a uniform electron density (ρi), and n is the total number of such tissue segments along the ray line, incorporating the beam divergence.A whole body CT scan of a 99 cm long anthropomorphic RANDO phantom  is performed with a 3 mm slice thickness. CT images are imported into MATLAB version R2013a , for radiological depth (RD) calculation  lung shielding. The RD values for the lung region, as expected, are lower than the surrounding values. This region is contoured in MATLAB and the RD values are scaled by the scaling factor F calculated for the desired lung shielding. The study is performed for 20%, 30%, and 40% lung shielding with the corresponding ‘F’ scaling factors of 0.784, 0.676, and 0.568, respectively.The aperture optimization is carried out using the same method as described above; however, the beam apertures over the lungs are further adjusted per shielding requirements. Desired percentage shielding, or in other words, the reduction in lung dose as compared to the prescription is termed as shielding fraction S. The apertures are modified by a shielding scale factor F. This (F) is defined as the ratio of MLC aperture values for shielding fraction S and the MLC aperture values for zero shielding. The MLC aperture values for shielding fraction S are derived from In the AMT‐TBI technique, the leading and trailing MLC leaf positions are optimized such that each point along the craniocaudal axis remains in the radiation field for a time period that results in a desired uniform dose to all these points. This means that the previous and subsequent beam apertures around the central axis are adjusted such that the CT slice at the central axis is exposed to the beam for a time period that is optimized for this slice. The entire aperture optimization process is performed using an in‐house MATLAB code. (The authors can be contacted by email for obtaining code files.) The optimization algorithm looks to the nearest neighbor planning CT slices relative to the slice of interest and asymmetrically optimizes the MLC positions of the neighboring apertures. In this way, the MLC aperture value is optimized for all the planning CT slices being irradiated. In the symmetric MLC technique, the MLC aperture values are symmetrically shaped according to the RD value of the slice at the central axis only.119 (10+99+10) fields are defined to cover the entire RANDO phantom. In order for the leading and trailing MLCs to reach the intended positions and cover the entire phantom, treatment fields are extended 10 cm beyond RANDO on either side. Individual static MLC files, with a craniocaudal step size of 9 mm are created for dose calculation purposes. The complete procedure is automated in MATLAB. For treatment delivery, a single dynamic MLC file is created, which is to be delivered with the translating bed under the radiation field.A total of ∼4 cGy/min) with heterogeneity corrections turned on. This along with the incorporation of scatter corrections within the RD calculations inherently takes into account the lung dose correction factors, as reported earlier.±3% was observed.The optimized individual static MLC files are imported into the Eclipse treatment planning system for dose calculation with a 9 mm interval in between two consecutive apertures along the craniocaudal direction. Dose calculations are performed by the analytical anisotropic algorithm (AAA) version 10.1 in Eclipse, using photon energy of 6 MV at extended source‐to‐table distance (STD) of 200 cm and machine dose rate of 300 MU/min (effective dose rate at the patient body p=0.065). The results are significantly better as compared to SMT‐TBI, where a 3.0% confidence limit is observed. Dose distributions in color shades are presented in The 3D dose distribution is analyzed by drawing line dose profiles through various body sections, as well as using color wash to visualize dose discrepancies. Dose‐volume histograms are also presented. The concept of confidence limit (CL) is employed to represent a true picture of midline dose uniformity, by incorporating the mean and standard deviation (SD) of dose distribution. The confidence limit, as defined by Venselaar et al.,±4% with SMT‐TBI, whereas the deviation is significantly reduced to ±1.5% with the AMT‐TBI methodology. Dose profiles in the transverse dimension through the lungs are presented in VD: percent volume receiving dose D, and DV: dose received by percent volume) are presented in The over‐ and underdose at the lung‐tissue interface is graphically shown in The results , 4, 5 deIt has also been established in the literature that in order to achieve improved dose sparing for lungs, it is more important to reduce the lower doses to larger lung volume than to reduce the higher doses to lesser volume.For the first few centimeters towards the head of the phantom, midline dose is considerably lower due to the presence of an air cavity inherent to the construction of the RANDO phantom. On logical grounds, the remaining dose perturbation observed with AMT‐TBI may be attributed to three factors, namely: internal inhomogeneities, contour variations, and difference in scatter distributions. Sharp contour variations in the head and neck region lead to sharp RD changes in those regions. However, AMT‐TBI has shown better dose homogeneity in these regions than that achievable with SMT‐TBI . A decreIn the thoracic region, the midline dose is lowered due to the presence of lungs.in vivo positional accuracy — a possibility worthy of future study. Finally, it is worth noting that overall treatment planning and delivery time is a bit longer for this technique.The results obtained with this revised technique are promising and superior to the SMT‐TBI translating bed technique in terms of lung shielding and dose homogeneity.With the revised AMT‐TBI technique, effective lung shielding to a specified dose limit can be achieved without compromising the 3D dose homogeneity (midline dose within confidence limit of 2.1%) in a RANDO phantom. Furthermore, the time‐consuming and laborious procedure of designing and fabrication of heavy, patient‐specific shielding blocks for translational TBI may be avoided.The authors acknowledge the financial and infrastructural support provided by Pakistan Institute of Engineering & Applied Sciences (PIEAS), Islamabad and Aga Khan University Hospital (AKUH), Karachi during the course of this research project.Creative Commons Attribution 4.0 International License.This work is licensed under a Supplementary Material FilesClick here for additional data file.Supplementary Material FilesClick here for additional data file.Supplementary Material FilesClick here for additional data file.Supplementary Material FilesClick here for additional data file.


The purpose of this study was to introduce and describe the development of RadShield, a Java‐based graphical user interface (GUI), which provides a base design that uniquely performs thorough, spatially distributed calculations at many points and reports the maximum air‐kerma rate and barrier thickness for each barrier pursuant to NCRP Report 147 methodology. Semiautomated shielding design calculations are validated by two approaches: a geometry‐based approach and a manual approach. A series of geometry‐based equations were derived giving the maximum air‐kerma rate magnitude and location through a first derivative root finding approach. The second approach consisted of comparing RadShield results with those found by manual shielding design by an American Board of Radiology (ABR)‐certified medical physicist for two clinical room situations: two adjacent catheterization labs, and a radiographic and fluoroscopic (R&F) exam room. RadShield's efficacy in finding the maximum air‐kerma rate was compared against the geometry‐based approach and the overall shielding recommendations by RadShield were compared against the medical physicist's shielding results. Percentage errors between the geometry‐based approach and RadShield's approach in finding the magnitude and location of the maximum air‐kerma rate was within 0.00124% and 14 mm. RadShield's barrier thickness calculations were found to be within 0.156 mm lead (Pb) and 0.150 mm lead (Pb) for the adjacent catheterization labs and R&F room examples, respectively. However, within the R&F room example, differences in locating the most sensitive calculation point on the floor plan for one of the barriers was not considered in the medical physicist's calculation and was revealed by the RadShield calculations. RadShield is shown to accurately find the maximum values of air‐kerma rate and barrier thickness using NCRP Report 147 methodology. Visual inspection alone of the 2D X‐ray exam distribution by a medical physicist may not be sufficient to accurately select the point of maximum air‐kerma rate or barrier thickness.PACS number(s): 87.55.N, 87.52.‐g, 87.59.Bh, 87.57.‐s Diagnostic medical X‐ray exams produce ionizing radiation which must be shielded to protect radiation workers and the general population. The National Council on Radiation Protection (NCRP) has provided guidelines to the medical physics community for shielding radiographic and fluoroscopic rooms (R&F rooms) contained in NCRP Report 147.In this work, a graphical user interface was developed to accurately perform radiation shielding design pursuant to NCRP Report 147. The software, RadShield, is a Java‐based drawing program designed to both accurately compute barrier thickness and give aesthetic presentation of results. This software package now provides an opportunity to perform shielding calculations for more than one calculation point at a time. RadShield produces more thorough and rigorous shielding designs than a physicist doing calculations by hand or spreadsheet because it computes required barrier thicknesses using an iterative method for hundreds or thousands of points and reports the maximum values for each barrier.Example calculations in NCRP Report 147 encourage overconservative shielding for the sake of increased safety and simplicity.The workload distribution and transmission curves for diagnostic range primary and secondary radiation, found by Archer et al.A review of the literature suggests that only XRAYBARR, a shareware program by Doug Simpkin,a priori. The medical physicist will round to the next thickest commercially available lead sheet . Differences of a few percent may not matter in some cases, but calculating barrier thickness as precisely as possible is the ideal starting point for recommending final thickness.In shielding design, one must account for a variety of diagnostic exams taking place in a typical radiographic and fluoroscopic room (R&F room) . For exaRadShield is a Java‐based GUI that is designed to be used through a series of ordered steps . The GUIWhen all required information has been entered, the user presses a final button to run the calculations. Air‐kerma rate and barrier thickness are calculated at multiple points beyond barriers and within nonadjacent regions of interest. Once the results are generated, the design and shielding variables may be saved in .xml format to disk and loaded at a later time for modification.For each sample point, a black circle appears showing that it is a point for which barrier thickness was calculated. The points at which the maximum value for air‐kerma rate and barrier thickness are found are displayed on the workspace as large red and blue circles respectively. The maximum found numerical values for air‐kerma rate and barrier thickness are displayed on a separate window below the canvas which updates if the user makes a change and recalculates.The air‐kerma rate contributions from all X‐ray tubes and patient locations are summed at each sample point. The total air‐kerma rate at each sample point is stored in a wall‐specific array and the maximum value for each wall is reported to the user once the calculation is completed. NCRP 147 contains example calculations which use the total air‐kerma rate and the most penetrating workload distribution to obtain final barrier thickness. RadShield finds the barrier thickness required to attenuate the user specified workload distributions to the occupancy adjusted design goal (P/T).P is the design goal (mGy cm−1), T is the room‐specific occupancy factor, K1 is the air‐kerma rate at one meter (mGy), N is the number of exams per week (wk−1) for a particular exam, and d is the distance (m) from the X‐ray source or scattering body to the calculation point.RadShield calculates barrier thickness using an iterative method which employs the barrier transmission factor for each X‐ray source, as described by Simpkin.When taking radiation line of sight path length through the material into account , NCRP Report 147 Eq. 4.6 becomes:The transmission factor of the ith X‐ray exam as a function of barrier thickness can be found by rearranging the above equation.Care must be taken when using this path length correction for scatter generating materials such as concrete.The transmitted air‐kerma rates are summed and compared to (P/T). Ideally, the transmitted air kerma rate is equal to P/T so that the exact amount of material is calculated to meet the design goal. RadShield adjusts the barrier thickness using a bisection method,θ=0∘, in accordance with NCRP Report 147 assumptions.In practice, this takes approximately 50 iterations or less. The same methodology is used to calculate unshielded air‐kerma rate and barrier thickness for the floor and ceiling. Instead of sampling across a line 0.3 m away from the barrier, RadShield samples a plane located at a user‐specified distance from the floor or ceiling. The unshielded air‐kerma rate for each exam is summed at each sampled point, and the barrier thickness is calculated iteratively as described above.In order to validate the results of RadShield, a second separate approach for finding the values and locations of maximum air‐kerma rates was developed. The geometry‐based method was designed to independently validate the locations of maximum air‐kerma rate found by RadShield. A series of equations was derived to yield the location of the point of maximum air‐kerma rate with respect to a reference location. Three general cases were considered: two point sources with two degrees of freedom, three point sources with two degrees of freedom, and three point sources with three degrees of freedom shielded by one barrier. The first two cases are analogous to shielding wall barriers and the last case is analogous to shielding floor and ceiling barriers.S1 and S2 are located at distances h1 and h2, respectively, from a line parallel to 0.3 m away (the sampled line) from a barrier  from a barrier. Let S1 and S2 be separated by a distance w1,2, and S1 and S3 be separated by a distance w1,3 in the dimension parallel to the sampled line , general orientation  and distances from each other  are varied between 2 and 10 m. Each combination of constants is entered into both RadShield and the geometry‐based program and their percentage errors were found.In testing these three cases, source strengths  and wall 6 (10.62% and 0.040 mm). The medical physicist overshielded these walls in both cases if results are compared with RadShield. The large percentage error is a result of the physicist only considering distance in one dimension, per the exemples provided by NCRP Report 147. RadShield automatically uses the triangulated distance based on the floor plan dimensions and user‐entered scale. There fore, RadShield's measurement reflects the more accurate expected distances from each source to the calculation point given the nonperpendicular geometry.This work presents an improved methodology to radiation shielding design which performs many calculations beyond each barrier and reports the maximum calculated value of barrier thickness. RadShield's accuracy in finding the location of maximum air‐kerma rate was validated using a set of mathematical equations describing a finite number of isotropic X‐ray sources and scattering bodies. RadShield's accuracy in determining barrier thickness was tested against the thickness values found by an ABR‐certified medical physicist.Air‐kerma rates and maximum air‐kerma rate locations obtained by RadShield agree with the geometry‐based equations to within 0.01% error and 1.4 cm. This is compelling empirical evidence that the geometry‐based equations and RadShield's methodology are correct and fundamentally valid. From the data, RadShield performs best when the air‐kerma rate is slowly varying because RadShield calculates across sampled lines beyond barriers. When the underlying distribution of sources and distances becomes more complicated, the point‐to‐point change in air‐kerma rate tends to increase and maximum point accuracy decreases. This variation increases when greater degrees of freedom are allowed such that falloff can occur in a second dimension. Nevertheless, the greatest deviation in the location of maximum air‐kerma rates between RadShield and the geometry‐based method is 14 mm and is certainly unlikely to be significant for clinical diagnostic radiology shielding calculations.The adjacent catheterization labs example performed by RadShield and the medical physicist shows that RadShield handles relatively straightforward calculations without issue. The maximum thickness points occur in locations geometrically closest to the X‐ray sources, which is to be expected for uniform design goals and occupancy factors along the length of each wall. An important feature of RadShield is that it determines the orientation of X‐ray sources and barriers and generates lines 0.3 m beyond barriers, opposite from the X‐ray source. In this case, the middle wall is between two X‐ray sources and is simultaneously shielding two rooms. The air‐kerma rate contributions are not mixed; the calculation points on the left side of the middle wall only shield the X‐rays incident from the right and vice versa. Both RadShield and the medical physicist calculated the shielding requirements for both sides of the middle wall and shielded to and reported the maximum with good agreement.The R&F room example shows that the medical physicist can miss the maximum thickness point. a priori in order to guarantee all rooms meet their design goals, a difficult task for complicated geometries. RadShield might also be used to spot‐check manual calculations if needed.Testing as many points as possible is most prudent no matter which computer program is used and was the basis for RadShield's design. RadShield's approach is a major improvement over current methods because its algorithm calculates at many points beyond each barrier and within nonadjacent rooms of interest. It has been shown that using a program like XRAYBARR and spreadsheets may not be sufficient for shielding design because the physicist has to know the most stringent point to shield The Java framework allows for other practical and convenient features beyond accuracy and thorough consideration of shielding design. The locations, colors, and properties of each drawn object may be saved in .xml format and loaded from disk. This gives the user the ability to change or modify shielding designs, either by entering new values or dragging objects to different locations, if the institution or hospital decides to repurpose a room in the floor plan or make adjustments to workload or exam geometry. Java library add‐ons allow the user to generate plots of air‐kerma rate across barriers and heat maps of air‐kerma rate on floor and ceiling barriers. Another library creates an automatically generated shielding report in a Microsoft Word document which summarizes the results and rounds lead thickness to the next highest 0.079 cm increment.RadShield, as a stand‐alone program, brings greater possibility for current and future development. RadShield uniquely allows for easy inclusion of computerized tomography and positron related imaging incident on the same barriers because each X‐ray source and workload distribution is considered simultaneously in a priori by integrating a point‐by‐point calculation approach. This semiautomated approach reduces the likelihood of the medical physicist missing the maximum thickness point while also calculating thickness to a greater degree of accuracy than what would be found by following the examples contained in NCRP 147. It is understood that the medical physicist rounds to the nearest 0.079 cm increments of lead thickness; however, accurate calculation and consideration of all areas of interest is the appropriate starting point upon which to base more conservative shielding recommendations.Visual inspection of the 2D X‐ray exam distribution is not sufficient to accurately select the point of maximum air‐kerma rate or barrier thickness. RadShield can also eliminate the need for the physicist to select the most stringent point RadShield was tested for its ability to determine the maximum air‐kerma rate point and the maximum shielding point. A comparison was made between two separate methods for independent validation. RadShield's point‐by‐point approach was shown to be effective in locating maximum points for a variety of exam distributions. A physicist will benefit from RadShield's approach to radiation shielding design because it reduces the possibility of missing the correct point to calculate required material thickness. This has been shown to be a problem when the physicist must consider regions of interest nonadjacent to the X‐ray room and when line of sight geometry becomes a factor. RadShield forms a core method as a stand‐alone program advancing the practical art of shielding, making it potentially more accurate and time‐efficient.This work is licensed under a Creative Commons Attribution 3.0 Unported License.


Big Breakfast Study therefore is to investigate the mechanistic basis of this amplified morning thermogenesis leading to enhanced weight loss, by exploring behavioural and physiological adaptations in energy expenditure alongside the underlying circadian biology. This report briefly discusses the current research linking meal timing, circadian rhythms and metabolism; highlights the research gaps; and provides an overview of the studies being undertaken as part of the Medical Research Council‐funded Big Breakfast Study.A growing body of evidence highlights the importance of the biological clock as a modulator of energy balance and metabolism. Recent studies in humans have shown that ingested calories are apparently utilised more efficiently in the morning than in the evening and this is manifest through improved weight loss, even under iso‐energetic calorie intake. The mechanisms behind this enhanced morning energy metabolism are not yet clear, although it may result from behavioural adaptations or circadian driven variations in physiology and energy metabolism. A major objective of the newly funded  The UK has been reported to have one of the highest evening energy intakes, with the proportion of daily energy intake increasing gradually across the day and dinner providing on average 40% of daily calories . Over the last 15 years, there has been increased recognition of how chronobiology impacts on health and disease. Chrono‐nutrition extends chronobiology research and defines the emerging discipline of science surrounding the complex interactions between circadian biology, nutrition and metabolism. Clock genes are now recognised for their indisputable role in coordinating nearly all biological and physiological processes of the body. The suprachiasmatic nucleus (SCN) of the hypothalamus, the ‘master clock’, is primarily regulated by light/dark cycles in order to synchronise the body to the light cycle or solar day 1). Impor. et al.  studied . et al. . Therefoet al. et al. et al. et al. et al. et al. Diurnal variations are evident in gastrointestinal absorption rate and expression of gastrointestinal genes involved in nutrient transport, which are both typically higher during the active phase and following fasting  are influenced by meal timing, circadian and behavioural effects. The aim is to understand the underlying mechanisms (i.e. hormones/metabolites/gastric emptying), that determine time of day differences in energy expenditure and thereby make consuming the largest meal of the day at breakfast , important in influencing daily energy balance. The project will combine specialised techniques  and protocols with complete dietary control to assess the physiological and behavioural factors influencing the relationship between external clock time, internal circadian rhythms, energy expenditure and energy balance (body mass).Growing evidence suggests some truth to the adage ‘Breakfast like a king and dine like a pauper’, with meal timing appearing to influence energy balance and bodyweight . The  to assess the impact of timing of eating on mechanisms associated with energy expenditure and substrate utilisation; to test the contribution of biological circadian influence on energy expenditure and related endocrine pathways during a fixed feeding phase shift protocol.Two studies will explore potential behavioural and circadian/diurnal influences on energy expenditure and energy balance. Specifically, the project will address two overriding objectives:These studies will extend current knowledge about the interaction of diet and the body's circadian rhythms (‘chrono‐nutrition’) and help to inform future development of nutritional guidelines for weight control, based on optimising the timing of energy consumption. An overview of the current literature, research gaps and aims of the current project are reviewed in Figure Mealtime Study aims to answer the questions: ‘Does morning‐loaded energy consumption significantly influence energy balance and therefore weight loss compared to evening‐loaded energy consumption?’ and ‘What are the underlying mechanisms leading to differential weight loss due to meal timing?’ The study will implement a 10‐week randomised, crossover energy restrictive dietary intervention study designed for weight loss in overweight or obese, but otherwise healthy, adults comparing morning‐ and evening‐loaded feeding. The dietary intervention will involve two 4‐week weight loss phases with calories distributed predominantly in the morning  or the evening  with 1‐week weight maintenance diets at baseline and mid‐study between the two weight loss phases (washout). All diets will be prepared at the Rowett Institute for participants to collect and consume outside the Institute. The primary outcome measure, bodyweight, will be measured three times per week throughout the 10‐week protocol, when participants attend the Institute's human nutrition unit for measurement and food collection. All other outcome measures will be assessed at the end of each study phase .The i.e. weight maintenance 1 or 2, big breakfast or small breakfast energy restriction diet)]. This will enable us to determine whether differences in energy expenditure and energy balance in relation to timing of energy intake are due to behavioural changes  or changes in physiological energy expenditure (RMR and TEF). Breakfast skipping has been correlated to lower levels of physical activity . Doubly‐labelled water, which remains the gold standard for assessing total energy expenditure (Buchowski 13C Octanoic Acid) at the same time as assessing TEF and postprandial changes in glucose, insulin and gut hormones. While previous studies have indicated a greater morning TEF . It has previously been shown that morning feeding resulted in significantly greater reductions in fasting glucose, insulin, homeostatic model assessment‐insulin resistance and serum triglyceride, and significantly greater improvements in high‐density lipoprotein (HDL)‐cholesterol, compared to evening feeding . Daily energy intake for participants will be set at 1.1 times RMR, which is used as the energy intake required to meet weight maintenance requirements under test conditions. Energy intake will be consumed as three iso‐caloric meals at breakfast, lunch and dinner . By analysing participants over the 5 days following the phase shift, we will be able to follow the realignment of each participant's internal rhythms of energy expenditure, metabolism and related endocrine pathways with the newly imposed light/dark cycle.Participants will attend the research facility for a 7‐day in‐house stay, including 2 baseline days and 5 days following an acute 5‐hour phase shift. The 5‐hour phase shift will involve a 5‐hour delay in timing of light and dark exposure, sleep and wake times and all meal times so that during baseline, sleep will be permitted from 23:00 to 07:00, while following the phase shift, sleep will be permitted from 04:00 to 12:00. Breakfast will be 1 hour after waking, lunch 5 hours later and dinner 5 hours after lunch. This will permit the retaining of an 8‐hour sleep opportunity and thereby minimising any possible effect of acute sleep deprivation. Outcome measures will be assessed on day 2, prior to the phase delay, and on days 3, 5 and 7 , which will allow us to investigate whether metabolic rhythms realign to the new behavioural and light/dark rhythms over the 5 days following the phase delay. The study design allows postprandial responses to be assessed at the same clock time immediately before and after the phase shift (e.g. between 16:00 and 06:00). Data will be analysed by calculating the timing of melatonin signal onset, according to validated methodologies  will be controlled on all days with participants blinded to time of day so as not to interfere with their natural circadian rhythm. The gold standard marker of human circadian phase, plasma melatonin concentration, will be measured every hour for up to 15 consecutive samples  at the breakfast meals, we will be able to identify whether there are differences in the rate or magnitude of the TEF response in relation to the phase shift and whether these are attributable to differences in gastric emptying, substrate uptake and utilisation. This phase shift study will enable us to assess the influence of the endogenous circadian clock in the regulation of these digestive and metabolic processes and on the individual components of energy expenditure .Our current work aimed to investigate whether the typical meal consumption pattern in the UK, of having a small breakfast and large evening meal, is working against internal biological rhythms and exacerbating difficulties in successful weight management. Complementary research supported by the Scottish government's Rural and Environmental Science and Analytical Services is currently being undertaken at the Rowett Institute to examine how breakfast meal composition  may also affect energy balance and assist in weight management in a similar 10‐week weight loss crossover study. Currently, there are no dietary guidelines specific to meal timing and particularly, no guidelines in relation to shift workers. Together these studies will provide evidence‐based data for translation to improve dietary guidelines directed at meal timing as an alternative strategy to promote bodyweight control.Big Breakfast Study will be disseminated to an extensive audience including the scientific community, industry, public and independent bodies and the general public. Specifically, we will produce infographics, short video summaries, press release statements, and written guidelines and media for presentation and distribution to industries (e.g. Scottish Food and Drink Federation), health bodies (e.g. NHS) and independent bodies, as well as presenting information at local and UK‐wide public events (e.g. Aberdeen's Café Med and Food Matters Live). These broadcasts will be used to highlight the study findings, educate important stakeholders and provide evidence for development of health policy and support opportunities for future studies.Findings from the Big Breakfast Study aims to explore the mechanistic basis for such findings and determine the contribution of the endogenous circadian system to energy expenditure and energy balance. This under‐researched area of nutritional science may lead to innovative knowledge, which could pave new ways of addressing metabolic health and obesity via implementing dietary guidelines directed at meal timing.Early evidence supports morning‐loaded energy distribution as a beneficial strategy for weight control. The The study is funded by the Medical Research Council.Alex Johnstone, Leonie Ruddick‐Collins, Peter Morgan and Jonathon Johnston all contributed to the writing and preparation of the manuscript.JDJ has performed consultancy work for Kellogg Marketing and Sales Company (UK) Limited and has a research collaboration with Nestlé Research Centre. No conflict of interest has been declared by any other author.


CCS) experience higher hospitalization rates compared to the general population for neoplasms, circulatory diseases, endocrine/nutritional/metabolic diseases and eye disorders. We studied trends in hospitalization rates and associated patient and treatment‐specific risk factors for diagnosis subgroups among these four diseases. We performed medical record linkage of a ≥5‐year CCS cohort with national registers, and obtained a random reference sample matched on age, gender and calendar year per CCS. For each diagnosis subgroup we compared hospitalization rates and trends over time in CCS and the reference population. Further, we analyzed risk factors for hospitalizations within the four CCS diagnosis groups. We used multivariate Poisson regression for all models. We retrieved hospitalization data from 1382 CCS and 26,583 reference persons. CCS had increased hospitalization rates for almost all diagnosis subgroups examined. Hospitalization rates for endocrine/nutritional/metabolic diseases appeared to increase with longer time since primary cancer diagnosis up to 30 years after primary cancer diagnosis. Survivors initially treated with radiotherapy had increased hospitalization rates for neoplasms (P < 0.001), those initially treated with anthracyclines (2.5 [1.1–5.5]) and radiotherapy to thorax and/or abdomen (9.3 [2.4–36.6]) had increased hospitalization rates for diseases of the circulatory system, and those initially treated with radiotherapy to head and/or neck had increased hospitalization rates for endocrine/nutritional/metabolic diseases (6.7 [3.5–12.7]) and diseases of the eye (3.6 [1.5–8.9]). Our study highlights that long‐term health problems resulting in hospitalizations are still clinically relevant later in life of CCS. The identified treatment‐related risk factors associated with hospitalizations support targeted follow‐up care for these risk groups of CCS.Childhood cancer survivors ( Five‐year survival rates for childhood cancer survivors (CCS) have considerably improved in the last 25 years A better understanding of the specific long‐term health problems in CCS that require hospitalization can help prioritization of follow‐up by further refining high risk groups. In a previous study we performed medical record linkage between a study cohort of CCS and Dutch administrative registers to report the burden of disease of CCS. We analyzed all hospitalizations within an individual longitudinally and we found the highest average hospitalization rates among CCS in the following groups: neoplasms, diseases of the circulatory system, endocrine/nutritional/metabolic diseases and diseases of the eye. These four disease groups together accounted for a quarter of the total number of hospitalizations in CCS As in our previous study we were not able to study in detail these four specific hospital diagnoses, in this study our aim was to determine the hospitalization rates and trends of hospitalization over time for neoplasms, diseases of the circulatory system, endocrine/nutritional/metabolic diseases and diseases of the eye in comparison with a random sample of the general population, and to examine the associated risk factors within the survivors group.N = 1564).Our eligible population included all CCS within our survivors cohort at the Emma Children's Hospital/Academic Medical Center (Dutch acronym: EKZ/AMC) primarily treated at EKZ/AMC between 1st January 1966 and 1st January 1999, with a primary diagnosis before the age of 18 years, who survived at least 5 years after diagnosis and were still alive at 1st January 1995  by linking them to the Hospital Discharge Register (Dutch acronym: LMR) We used a two‐step medical record linkage that has been shown to be feasible and valid within the Dutch CCS context We obtained a random sample of reference persons from the Dutch general population in GBA. We sampled 20 reference persons at maximum with corresponding year of birth and gender per CCS retrieved in GBA. To these reference persons, we assigned the starting date of follow‐up of the corresponding cancer CCS, namely 5 years after the date of primary cancer diagnosis of the corresponding CCS.In order to avoid overestimation of hospitalizations due to the likelihood of increased treatment‐related hospitalizations at recurrence, we censored late primary cancer recurrences. Full censoring applied to 90 CCS and partial censoring applied to 35 CCS We obtained hospitalization‐related health problems by retrieving the primary diagnosis code at hospital discharge according to the International Classification of Diseases version 9‐clinical modification (ICD9‐CM) In our previous study we used multivariable Poisson regression models to quantify all hospitalization rates in CCS compared to a random sample of the general population, and to determine the risk factors for hospitalization within our study cohort of CCS P‐values for the overall effect of the variables. For the other models , we provided the estimates and confidence intervals. For all the models we chose different risk factors models for each disease group based on clinical experience and known associations previously described in the literature.In a second stage of the analysis within CCS, we explored which treatment‐ and patient‐related factors influenced hospitalization rates in each of the four selected disease groups. We used the same Poisson model, correcting for recurrent hospitalizations via GEE, and we included follow‐up time since primary cancer diagnosis, cancer treatments before 5‐year survival, calendar year of primary diagnosis and age at primary diagnosis. The relatively small sample size per disease group and the inclusion of additional covariables forced us to restrict to a linear trend for the time since primary cancer diagnosis, except for the outcome of hospitalizations for neoplasms. In that case we modeled the continuous covariables including follow‐up time, calendar year of primary cancer diagnosis and age at primary cancer diagnosis via natural splines (using four knots). In addition, as the parameter estimates of the individual spline components are hard to interpret, we presented P‐values <0.05 were considered statistically significant. As per Statistics Netherlands (CBS) confidentiality regulations, we do not present frequency tables with <10 units.We followed the Strengthening the Reporting of Observational Studies in Epidemiology guidelines for reporting of cohort studies Table . We perfAfter record linkage to LMR, the study population that contributed to unique follow‐up time consisted of 1382 CCS and of 26,583 reference persons (both 94% of the persons retrieved from GBA). We censored late primary cancer recurrences and this resulted in 1292 CCS and 23,567 reference persons (88% and 84% respectively of the persons retrieved from GBA). In particular, after censoring 5‐year CCS (and corresponding reference persons) at the incidence date of first primary cancer recurrence after the date of 5‐year survival, or at the date of 5‐year survival if there was on‐going primary cancer recurrence treatment for a primary cancer recurrence at that moment. Characteristics of the total group of hospitalized CCS and reference persons were comparable  and 38 per 1000 person‐years at risk, respectively. Total average RHRs and AERs were increased in CCS compared to the general population for all four disease groups , followed by hospitalizations for malignant neoplasm of bone, connective tissue, skin and breast .Within diseases of the circulatory system, the following disease groups had an increased RHR: “other form of heart diseases” ; heart failure, myocarditis, pericarditis, valve, arrhythmia and other form of heart disease ; and the combined group “diseases of arteries, arterioles, and capillaries” together with “diseases of veins, lymphatic vessels, and lymph nodes not elsewhere specified” .Within hospitalizations for endocrine/nutritional/metabolic diseases, the highest average RHR concerned diseases of the thryoid gland , followed by the group comprising diabetes mellitus and pituitary gland disorders . Hospitalizations under “other metabolic disorders and immunity disorders” also presented an increased hospitalization rate in CCS compared to the general population .The highest average RHR within hospitalizations for diseases of the eye concerned “disorders of eyelid, lacrimal system and orbit” together with “disorders of conjunctiva” . This was followed by “disorders of sclera, cornea, iris and ciliary body, lens, choroid and retina” . Hospitalizations concerning “disorders of optic nerve and visual pathways, disorders of ocular muscles, binocular movement, accommodation and refraction” and “other disorders of eye and adnexa” were also higher than for the general population .When we examined trends in hospitalization rates over time since childhood cancer diagnosis in each disease group, we found that hospitalization rates in CCS for neoplasms were highest right after the 5 year survival and (to a much lesser extent) between 20 years and 30 years after primary cancer diagnosis Fig. A, for diP < 0.001). For diseases of the circulatory system, hospitalization rates were higher after anthracyclines  and radiotherapy to thorax and/or abdomen . Hospitalizations for endocrine/nutritional/metabolic diseases were increased after radiotherapy to head and/or neck . For diseases of the eye, radiotherapy to head and/or neck  increased, while higher age at primary cancer diagnosis  decreased the risk of hospitalization.The four multivariate models of risk factors for hospitalizations of neoplasms, diseases of the circulatory system, endocrine/metabolic/nutritional diseases and diseases of the eye are presented in Table In this study we were able to show a detailed report on the type of diseases and related risk factors for longitudinal hospitalization rates in CCS. We found that 5‐year CCS had significantly increased average hospitalization rates for almost all diagnosis subgroups of neoplasms, diseases of the circulatory system, endocrine/nutritional/metabolic diseases and diseases of the eye in comparison with the general population. Hospitalization rates for endocrine/nutritional/metabolic diseases seem to increase with longer time since primary cancer diagnosis up to 30 years after primary cancer diagnosis. CCS originally treated with radiotherapy had increased hospitalization rates for neoplasms, CCS originally treated with anthracyclines and radiotherapy to thorax and/or abdomen had increased hospitalization rates for diseases of the circulatory system and CCS originally treated with radiotherapy to head and/or neck had increased hospitalization rates for endocrine/nutritional/metabolic diseases and diseases of the eye.This study adds important information to the current knowledge of chronic health conditions in CCS. The strengths of our study are that we compared hospitalization rates to an appropriate reference group and the data presented no risk of selection bias and low risk of differential misclassification. We took into account the repeated hospitalizations within one individual as a way to comprehensively quantify the burden of chronic health conditions in CCS.Several studies have assessed hospitalization‐related health problems in CCS and they also found an increase in hospitalizations for neoplasms, diseases of the circulatory system, endocrine/nutritional/metabolic diseases and diseases of the eye Secondary primary malignancies are recognized in the literature as long‐term health problems experienced by CCS In line with our findings, reports that studied hospital admissions specifically for diseases of the circulatory system in CCS also presented increased hospitalization rates We showed increased average hospitalization rates for endocrine/nutritional/metabolic diseases, in concordance with previous studies In thisstudy our risk factor analysis was able to identify that radiotherapy to head and/or neck for childhood cancer increased the hospitalizations rate for endocrine/nutritional/metabolic diseases and diseases of the eye in CCS. This suggests that the known association between endocrinopathies and radiotherapy affects this patient group with disorders that require hospitalization To the best of our knowledge, hospitalizations for diseases of the eye in CCS are not presented separately in other studies As a limitation, our study did not have information on outpatient visits or general practitioner visits. This might have resulted in an underestimation of the healthcare consumption among CCS. However, we were able to study the long‐term morbidity that is severe enough to require hospitalization. Furthermore, the unavailability of reliable hospitalization data after 2005 means that we analyzed data with an outcome period of 11 years (1995–2005) In summary, this medical record linkage study shows that 5‐year CCS have higher average hospitalization rates for almost all diagnosis subgroups of neoplams, diseases of the circulatory system, endocrine/nutritional/metabolic diseases and diseases of the eye in comparison with the general population. Over time, hospitalization rates seem to increase with longer time since primary cancer diagnosis for endocrine/nutritional/metabolic diseases, even up to 30 years after primary cancer diagnosis. Survivors originally treated with radiotherapy had increased hospitalization rates for neoplasms, those originally treated with anthracyclines and radiotherapy to thorax and/or abdomen had increased hospitalization rates for diseases of the circulatory system and those originally treated with radiotherapy to head and/or neck had increased hospitalization rates for endocrine/nutritional/metabolic diseases and diseases of the eye.Our study emphazises that long‐term health problems resulting in hospitalizations are still clinically relevant later in life of CCS. In addition, our findings support the prioritization of further research and follow‐up care for the risk groups we identified, namely those originally treated with anthracyclines and radiotherapy to thorax and/or abdomen and head and/or neck.None.Figure S1. Hospitalization rate for neoplasms (excluding benign neoplasms) in CCS and matched reference persons over time, from 5 years after primary childhood cancer diagnosis.Figure S2. Hospitalization rate for malignant neoplasms of lymphatic and hematopoietic tissue in CCS and matched reference persons over follow‐up time since date of primary childhood cancer diagnosis.Figure S3. Hospitalization rate for solid tumors (excluding benign neoplasms) in CCS and matched reference persons over follow‐up time since date of primary childhood cancer diagnosis.Figure S4. Hospitalization rate for benign neoplasms in CCS and matched reference persons over follow‐up time since date of primary childhood cancer diagnosis.Click here for additional data file.Table S1. STROBE statement—checklist of items that should be included in reports of cohort studies.Click here for additional data file.


Xc− inhibitors) and class 2 ferroptosis inducers [glutathione peroxidase 4 (GPx4) inhibitors]. In addition to these small‐molecule substances, a number of drugs  can induce ferroptosis. Various factors, such as the mevalonate (MVA) and sulphur‐transfer pathways, play pivotal roles in the regulation of ferroptosis. Ferroptosis plays an unneglectable role in regulating the growth and proliferation of some types of tumour cells, such as lymphocytoma, ductal cell cancer of the pancreas, renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Here, we will first introduce the discovery of and research pertaining to ferroptosis; then summarize the induction mechanisms and regulatory pathways of ferroptosis; and finally, further elucidate the roles of ferroptosis in human tumourous diseases.Ferroptosis is a newly discovered type of cell death that differs from traditional apoptosis and necrosis and results from iron‐dependent lipid peroxide accumulation. Ferroptotic cell death is characterized by cytological changes, including cell volume shrinkage and increased mitochondrial membrane density. Ferroptosis can be induced by two classes of small‐molecule substances known as class 1 (system  C− and reduce the intracellular glutathione content, causing an oxidation‐reduction imbalance in cells. Class 2 ferroptosis inducers include Ras selective lethal 3 compound (RSL3), DPI7, DPI10, DPI12, DPI13, etc., which can directly inhibit glutathione peroxidase 4 (GPx4) A new form of cell death, ferroptosis, was recently discovered. Ferroptosis results from iron‐dependent lipid peroxide accumulation and is characterized mainly by cell volume shrinkage and increased mitochondrial membrane density without typical apoptotic and necrotic manifestations Iron (Fe) is the fourth most common element in the Earth's crust, and it plays a pivotal role in human bodies et al. identified a new chemical compound, erastin, that can cause RAS‐mutated tumour cells to die in a manner different from traditional apoptosis et al. discovered two new compounds, RSL3 and RSL5, that have the same effect as erastin. They also determined that the resulting cell death can be inhibited by an iron chelator, desferrioxamine B‐methane sulphonate (DFOM) and an antioxidant, vitamin E et al. used the term ‘ferroptosis’ to describe this type of cell death caused by the accumulation of iron‐dependent lipid peroxides C− and GPx4, in ferroptosis were partially revealed et al. published a relatively detailed summary of ferroptosis inducers, inhibitors and regulatory molecules In the history of ferroptosis, ferroptosis inducers were actually discovered before ferroptosis was named. In a 2003 study using a large‐scale screening experiment to explore the killing effect of various chemical compounds on tumour cells, Stockwell et al. defined a type of hepatatrophy‐associated ‘automatically programmed’ cell death as ‘apoptosis’ Cell death is the final stage of cells; it is caused by cytotoxicity from either exogenous or endogenous substances. There are various forms of cell death, which were originally defined and differentiated based on cellular morphology. In 1972, Kerr Ferroptosis can be induced by various types of small molecules, such as erastin, SAS and RSL3; however, it cannot be induced by the substances that induce apoptosis and necrosis , Boc‐Asp (OMe)‐fluoromethylketone (Boc‐D‐FMK), wortmannin and necrostatin‐1) RPL8, IREB2, ATP5G3, CS, TTC35 and ACSF2 are involved in the genetic regulation of ferroptosis. Research has confirmed that these six genes are closely associated with ferroptosis but are irrelevant to other forms of cell death, such as apoptosis, necrosis or autophagy Six mitochondrial genes, C− is a membrane Na+‐dependent cysteine‐glutamate exchange transporter, which is a disulphide‐linked heterodimer composed of a light‐chain subunit  and a heavy‐chain subunit  C− transports extracellular cystine into the cell C− inhibition leads to a compensatory transcriptional upregulation of SLC7A11 in cells. Similar to erastin, SAS, another system XC− inhibitor, can also act on HT‐1080 fibrosarcoma cells to induce an upregulation of SLC7A11 expression in cells C− in ferroptosis triggered by the above mentioned inducers. Cells with erastin‐ or SAS‐induced ferroptosis have a significantly lower GSH level System XC− by its competitive inhibitors et al. found that calcium chelators did not affect ferroptosis C− and ferroptosis.In the central nervous system (CNS), the neurotoxicity of glutamate is oxidative iron‐dependent C− to prevent extracellular cysteine from moving into cells and to reduce the intracellular GSH level, erastin results in iron‐dependent cell death mediated by the accumulation of lipid ROS. However, research has found that anti‐oxidants, including diethyldithiocarbamic acid , diamide  and 1‐chloro‐2, 4‐dinitrobenzene , cannon‐selectively kill human foreskin fibroblast (BJeLR) cells without depleting the intracellular GSH pool 2O2 and organic H2O2 into water or corresponding alcohols, and GSH is an essential cofactor in its activation By suppressing system XVoltage‐dependent anion channels (VDACs), also known as membrane porin protein, are the transmembrane channels for transporting ion and metabolites in eukaryotic cells The MVA pathway is an important contributor to selenoprotein synthesis, and GPx4 is a selenoprotein with selenocysteine in its active centre. However, because the genetic code of selenocysteine is UGA, which is identical to the termination codon, a specific transporter is required for the insertion of selenocysteine into GPx4 via GPx4; thus, it enables GPx4 to play a central regulatory role in ferroptosis Sulphur‐containing proteins are very important in mammal cells. Methionineis a sulphur‐containing amino acid that is essential for human bodies and can only be obtained from food. Through the sulphur‐transfer pathway in the body, methionine can be converted to S‐adenosyl homocysteine and cysteine. Under conditions of cysteine insufficiency, homocysteine is converted into cystathionine (a precursor of cysteine) to ultimately supplement the cysteine pool through the sulphur‐transfer pathway Heat‐shock proteins (HSPs) have been considered a molecular partner that regulates and controls the construction of the cellular skeleton via the glutamine decomposition pathway and the transferrin receptors on the surface of cells et al. found that the p62‐Keap1‐NRF2 pathway regulates the susceptibility of liver cancer cells to ferroptosis by regulating the expression of NRF2 et al. found that the MUC1‐C/xCT pathway could play a negative regulatory role and inhibit the erastin‐induced ferroptosis of triple‐negative breast cancer (TNBC) cells et al. confirmed its pivotal role in erastin‐induced ferroptotic cell death, as evidenced by its ability to induce the lipid peroxidation reaction and cause cellular ferroptosis Other pathways are also involved in the regulation of cellular ferroptosis. For example, glutamate and transferrin can regulate cell ferroptosis In recent years, an increasing number of studies has revealed the close relationships of ferroptosis with various human diseases, including Huntington's disease (HD), periventricular leukomalacia (PVL) and renal functional damage C− mediated cystine uptake of the cells from the extracellular space. As a result, DLBCL cells are much more susceptible than other tumours to erastin‐induced ferroptosis. Further experiments revealed that compared with other hematopoietic tumours, DLBCL cells are particularly susceptible to erastin‐induced ferroptosis C−) In a study investigating the effects of erastin on tumour cells of various tissues , the researchers found that DLBCL cells were remarkably more sensitive to erastin than any other types of tumour cells HCC is the most common type of liver cancer; it is ranked fifth in prevalence and third in mortality among males worldwide In vivo and in vitro experiments using HCC cell lines showed that the inhibition of NRF2 expression via genetic tools or drugs could significantly enhance the anti‐tumour effects of erastin and sorafenib, whereas the activation of NRF2 expression led to cellular resistance to ferroptosis During the ferroptosis of liver cancer cells, the p62‐Keap1‐NRF2 pathway plays a pivotal role. P62 inhibits the degradation of NRF2 by disrupting Keap1 and thus results in the accumulation of NRF2 in cells. NRF2 up regulates the expression of genes related to iron and ROS metabolism, including quinone oxidoreductase‐1 (NQO1), heme oxygenase‐1 (HO‐1), and ferritin heavy chain 1 (FTH1). Because all of these genes inhibit ferroptosis, NRF2 is a negative regulator of ferroptosis in liver cancer cells. Retinoblastoma (RB) protein, a member of the protein family that regulates the transcriptional function of various genes in eukaryotic cells Research on the effect of erastin in 60 tumour cell lines of eight tissues found that RCC cells were more susceptible than others to erastin‐induced cell death. Further research confirmed that erastin could induce the death of RCC cells in a manner that has the general characteristic features of ferroptosis  and can be inhibited with anti‐oxidants Pancreatic carcinoma is a highly fatal tumour, and even standardized pharmacotherapy can only prolong patients’ survival duration by less than 6 months Ovarian cancer is the most common fatal tumour in women. ART, a derivative of artemisinin, can suppress the proliferation of ovarian cancer cells. ART‐treated ovarian cancer cells have a higher ROS production level, and the amount of ROS produced is ART‐dependent, leading to ROS‐dependent DNA damage and cell death. Moreover, transferrin pretreatment of ovarian cancer cells increases the intracellular iron level and enhances the sensitivity of the cells to ART, suggesting that iron has an important role in ART‐regulated cell death in ovarian cancer. The ferroptosis inhibitor ferrostatin‐1 can remarkably suppress ART‐induced cell death in ovarian cancer et al. found that HSPB1 can affect the erastin‐induced ferroptosis of human cervical cancer cells, prostate cancer cells and osteosarcomacells Ferroptosis can occur in rhabdomyosarcoma cells, as demonstrated by an experimental observation that erastin and RSL3 treatments can induce ferroptosis in these cells Regarding ferroptosis, a newly discovered cell death form, a variety of questions remain despite increasing research progress in understanding its induction mechanism and signalling pathway. GPx4 is believed to be an important core molecule that regulates the ferroptosis process, but the role of iron and the mechanism underlying the effect of iron in ferroptosis remain unclarified. Clarification of the definitive role of iron in ferroptosis will be very helpful to our understanding of the occurrence and regulatory mechanisms of ferroptosis.Although research has revealed that ferroptosis is related to various diseases, the role of ferroptosis in human diseases remains a mystery. The susceptibility of cells to ferroptosis varies greatly among different tissues, and the sensitivity to ferroptosis inducers (e.g. sorafenib) differs significantly among individuals. Therefore, identifying an indicator that can reflect the susceptibility of cells and individuals is of great significance for improving our understanding, diagnosis, and treatment of ferroptosis‐related diseases. We believe that in the near future, ferroptosis will become a new strategy for treating tumourous diseases that currently have no successful treatments.The authors confirm that there are no conflicts of interest.