Is there an association of the increase in cannabis minimum legal age (MLA) from 18 to 21 years in Quebec, Canada, with youth cannabis use?In this cross-sectional study with difference-in-differences analysis of 1005 youths aged 15 to 20 years, although youth cannabis use still increased after the policy change, the increase in past-3-month cannabis use among youths aged 18 to 20 years was 51% lower in Quebec than in other provinces. There was no change in cannabis use among youths aged 15 to 17 years.The lower increase in cannabis use among individuals aged 18 to 20 years alleviates concerns that youths would switch to illegal markets in response to a higher MLA; however, the increase in youth cannabis use despite the higher MLA highlights the need for additional policy measures to address rising youth cannabis use. This difference-in-differences study uses data from the National Cannabis Survey to evaluate changes in youth cannabis use after Quebec raised the minimum legal age from 18 to 21 years. In January 2020, Quebec raised the minimum legal age (MLA) for cannabis from 18 to 21 years. Evidence is needed to inform the ongoing debate on this policy. Although proponents believe that a higher MLA will protect youths from the harms of cannabis use, critics argue that it will push them back to the illegal market.To investigate changes in youth cannabis use after an increase in MLA for cannabis in Quebec.This cross-sectional study with difference-in-differences analysis compared changes in cannabis use among youths aged 15 to 20 years in Quebec vs all other Canadian provinces before and after Quebec’s increase in MLA. All estimates in descriptive and regression analyses were weighted. Nationally representative data from the National Cannabis Surveys 2018-2020 were used.Increase in MLA for cannabis in Quebec implemented in January 2020.Past-3-month cannabis use.P = .01), or 51%, lower in Quebec than in other provinces. Meanwhile, no significant change in cannabis use among youths aged 15 to 17 years was found. The results were robust to several checks, including accounting for possible confounding effects of the COVID-19 pandemic on cannabis use.The study sample included 1005 respondents . After policy implementation, the increase in past-3-month cannabis use among youths aged 18 to 20 was 16.4 percentage points (95% CI, −27.3 to −5.5 percentage points; In this study, an increase in the MLA from 18 to 21 years in Quebec was associated with a significantly lower increase in cannabis use among youths aged 18 to 20 years but no change in cannabis use among those aged 15 to 17 years. These findings can help to alleviate concerns that youths would switch to illegal markets in response to a higher MLA. The legalization was accompanied by a minimum legal age (MLA) law to prevent cannabis use among underaged youths. At the time of legalization, this MLA was set at 19 years in all provinces except Alberta and Quebec, which chose 18 years. Although the choice of a low MLA, such as 18 or 19 years, was supported by the need to divert youths from illegal to safer and regulated cannabis and to harmonize the MLA for cannabis with that for other substances,4 The policy also aligns with recommendations made by the Canadian Medical Association before the legalization on the basis of adverse cardiovascular, pulmonary, and neuropsychological effects of cannabis use.5 However, critics argue that this policy could undermine the purpose of cannabis legalization by inducing youths to go back to more harmful, illegal cannabis.4In January 2020, Quebec raised the MLA for cannabis from 18 to 21 years and thus extended the ban on recreational cannabis to youths aged 18 to 20 years. This policy change aims to protect youths from the adverse effects of cannabis on developing brains.6 It is also possible that a higher MLA sends a stronger message about the harms of cannabis use at young ages and hence further discourages its use among adolescents.Although the MLA increase from 18 to 21 years targets the 18- to 20-year age group, it may also affect those younger than 18. Evidence from Tobacco 21 laws in the US (which increased the MLA for cigarettes from 18 to 21 years) indicated that cigarette use declined among youths aged 16 to 17 years, who often realy on older peers to access tobacco products.7 However, that study examined only the association between different ages of first cannabis use and subsequent outcomes and used only prelegalization data.Despite the considerable policy interest and ongoing debate, evidence on the effects of raising the current MLA for cannabis is lacking. A previous study assessed the merits of alternative ages as the MLA by evaluating later-life outcomes of starting cannabis at different ages.In the current study, we provide the first evidence, to our knowledge, on the association between an increase in MLA for cannabis from 18 to 21 years and youth cannabis use by studying the experience of the Canadian province of Quebec and using the remaining 9 provinces that did not adopt a higher MLA as a reference group. We examine the changes among all youths aged 15 to 20 years and separately for ages 15 to 17 years and 18 to 20 years. Findings from our study will be useful not only to inform the ongoing debate on the optimal MLA for cannabis use in Canada but also to guide policy choices of MLA for cannabis use in other jurisdictions that are considering recreational cannabis legalization.STROBE) reporting guideline.Because this cross-sectional study with a difference-in-differences (DD) analysis used deidentified secondary data, ethics approval was not required based on Newfoundland and Labrador’s Health Research Ethics Board guidelines. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology .8 The survey uses a 2-stage stratified sampling design in which households are sampled for each province in the first stage and individuals are sampled in the second stage.8 The response rates for the survey waves included in our study ranged from 46% to 51%.8 The NCS is particularly suited for this analysis because it has collected data on cannabis use both before and after the MLA increase in Quebec.We used individual-level data from 6 waves of the National Cannabis Survey (NCS).The outcome of interest was an indicator of past-3-month cannabis use. This outcome captured whether a respondent used cannabis at least once in the past 3 months based on the following survey question: “During the past 3 months, how often did you use cannabis?: not in the past 3 months, once or twice, monthly, weekly, daily, almost daily.” In a robustness check, we also examined past-3-month cannabis initiation as an outcome. This outcome captured whether a respondent started using cannabis in the preceding 3 months and was based on the following survey question: “Did you start using cannabis in the past 3 months?: yes; no, I started more than 3 months ago.”We used NCS data for 1005 youths aged 15 to 20 years that spanned the period from quarter 4 of 2018 to quarter 4 of 2020. We chose quarter 4 of 2018 as the starting point because recreational cannabis was legalized in Canada in 2018 and all provinces first set 18 or 19 years as the MLA in this quarter. Quarter 4 of 2020 was the latest available NCS cycle. We note that although the NCS was conducted quarterly between quarter 4 of 2018 and quarter 4 of 2019, it was paused during quarter 1 of 2020 to quarter 3 of 2020 because of the COVID-19 pandemic. Thus, in this analysis, we used data from 5 survey cycles conducted in the 5 quarters immediately preceding Quebec’s MLA increase policy  and 1 survey cycle conducted approximately 1 year after the policy .13 to compare before-and-after changes in past-3-month cannabis use in Quebec (where the MLA was increased to 21 years) with similar changes in other Canadian provinces (where the MLA remained at 18 or 19 years). We estimated DD regressions using individual-level data. The covariate of interest was an indicator for the MLA increase policy, which was equal to 1 if the respondent resided in Quebec after January 2020 and 0 otherwise. The regression analyses controlled for respondent age (measured as a continuous variable), male sex , and household size (measured as a continuous variable). In addition, these regressions included province indicators to control for all time-invariant characteristics of provinces and quarter-year indicators to control for secular changes or shocks in outcomes that were common to Quebec and other provinces.We used the quasi-experimental DD method14 and for ease of interpreting the marginal effects.16 All estimates in descriptive and regression analyses were weighted. Standard errors were clustered at the province level to account for within-cluster correlation and serial correlation over time.17 Analyses were performed using Stata, version 16 software (StataCorp LLC).18 Tests were 2-sided, and a 5% significance level was used.We estimated the DD regressions for the full sample and separately for the samples of adolescents (ages 15-17 years) and young adults (ages 18-20 years). We modeled all outcomes using linear probability regressions to produce unbiased estimates in fixed-effects analyses19 Third, we reestimated the DD regressions by dropping different reference provinces one at a time. This analysis informed whether our findings were influenced by any individual reference province. Fourth, we examined the sensitivity of our results to the inclusion of respondents’ household income as a control; we did not control for respondents’ household income in the main analysis because more than 10% of respondents did not report this information. Finally, we examined changes in the likelihood of past-3-month cannabis initiation after Quebec increased the MLA. If the direction of any change in past-3-month initiation was the same as that of past-3-month cannabis use, our base case findings would be strengthened.We conducted several analyses to investigate the robustness of our results. First, we addressed the possibility that any observed changes in youth cannabis use after the MLA increase could be driven by differences in ease of access to cannabis over time between Quebec and the other provinces rather than by Quebec’s higher MLA policy. To do so, we controlled for the number of cannabis retail stores per 100 000 population at the province-quarter level. Second, because Quebec’s higher MLA was implemented just before the COVID-19 pandemic began, our estimate of the changes in cannabis use after the MLA increase may additionally capture differences in effects of the pandemic on cannabis use in Quebec vs the other provinces. To address this potential confounding, we reestimated the DD regressions but compared Quebec with only non-Atlantic provinces . These non-Atlantic provinces, which were relatively more affected by the COVID-19 pandemic than the Atlantic provinces , were more comparable with Quebec in terms of the pandemic experience.The study sample included 1005 respondents . In the full sample, the mean (SD) age of respondents was 17.5 (1.7) years; 50.2%  of the sample was male, and 49.8%  was nonmale ; and respondents had 4.1  household members on average . The NCSP = .047) lower than the corresponding increase in the reference provinces. Compared with the 20.4% prepolicy prevalence of cannabis use in Quebec, this decline means that the increase in youths’ cannabis use in Quebec was 30% lower than in other provinces after the increase in MLA in Quebec. Analyses by age group indicated that the relative decline in youths’ cannabis use was driven by the change in the 18 to 20 age group. Specifically, cannabis use among 18- to 20-year-olds in Quebec was 16.4 percentage points  lower relative to the corresponding change in the reference provinces . Meanwhile, we observed no significant change in cannabis use among those aged 15 to 17 years after the MLA increase .The regression results are shown in P = .01). The policy coefficients remained large and significant when we excluded the Atlantic provinces from the analysis  and when we excluded the other reference provinces, one at a time . Our results were also similar to the main analysis when we controlled for respondents’ household income . Furthermore, we found that the MLA increase in Quebec was associated with lower cannabis initiation in the past 3 months among youths aged 18 to 20 years  relative to those in the reference provinces. This finding lends additional support to that of a slower increase in cannabis use among youths aged 18 to 20 years after the MLA increase in Quebec.Our results were robust to several additional analyses . Our finOur finding of no change in cannabis use for the 15- to 17-year age group was also robust to the different checks. The changes in cannabis use remained insignificant even when we controlled for the number of cannabis retail stores, excluded subsets of reference provinces, and controlled for household income .This study provides, to our knowledge, the first evidence on the association between an increase in MLA for recreational cannabis from 18 to 21 years in Quebec, Canada, and youths’ cannabis use. We found that although cannabis use increased among youths in all provinces even after Quebec raised the MLA, the increase among youths aged 18 to 20 years was 16.4 percentage points, or 51%, lower in Quebec relative to the other provinces. Meanwhile, the higher MLA was not associated with changes in cannabis use among youths aged 15 to 17 years.20The smaller increase in cannabis use among youths aged 18 to 20 years after Quebec raised the MLA can help to address the concern that such a policy may cause youths to switch back to illegal markets. Although we were unable to directly evaluate changes in youths’ cannabis purchases from the illegal market, the NCS question captured all cannabis use . Thus, the large net reduction in cannabis use that we found suggests that any increase in illegal cannabis use was far exceeded by the reduction in legal cannabis use. From a public health perspective, the large reduction in cannabis use among youths aged 18 to 20 years suggests that the higher MLA policy could lead to substantial public health benefits, especially because prior to the increase in MLA in 2020, more than one-quarter of all cannabis users aged 15 to 20 years initiated cannabis between the ages of 18 and 20 years.21 In our analysis, we compared cannabis use from quarter 4 of 2020 after Quebec’s MLA increase with that in quarters before the MLA increase. It will be of interest to investigate whether the increases in cannabis use in Quebec are even smaller when data for more quarters after the MLA increase become available. However, we note that if the seasonality effects are similar between Quebec and the other provinces, they would likely be cancelled out in our DD analyses.Previous studies have documented seasonality in patterns of cannabis use. Specifically, cannabis use is lowest in the first quarter and highest in the last quarter of the year.22 Similarly, an increase in the MLA for alcohol is associated with a reduction in youths’ alcohol consumption.23Our results are consistent with evidence on raising the MLA for other substances to 21 years. Evidence from Tobacco 21 laws in the US suggests that raising the MLA for tobacco from 18 to 21 years reduces smoking and e-cigarette use among individuals aged 18 to 20 years.We note, however, that the higher MLA was only associated with a slower rate of increase in cannabis use in Quebec compared with the other provinces; there was no absolute decrease in cannabis use among youths in Quebec after the province implemented the higher MLA. This increase, therefore, calls for additional policy measures, such as raising youth awareness on cannabis harms and school- and community-based cannabis use prevention programs to be adopted alongside the higher MLA to further reduce cannabis use among youths.24 Thus, youths in Quebec could try to purchase recreational cannabis in the neighboring provinces of Ontario and New Brunswick, both of which have an MLA of 19. Although the available data did not allow us to test such evasion formally, our finding of a reduction in cannabis use in the 18 to 20 age group suggests that such evasion was low.Our study has several limitations. First, we looked at only the 1-year changes after the MLA increase. Future research should examine whether these changes can be sustained and lead to better physical and mental health outcomes. Second, the period after policy implementation coincides with the COVID-19 pandemic, which affected Quebec and other provinces differently. However, our findings continued to hold in the robustness check, where we used the subset of reference provinces that was most similar to Quebec in its pandemic experience. Third, it is possible that youths switched to using other substances, such as tobacco, e-cigarettes, or alcohol, after the increase in MLA. Although we were unable to evaluate these substitution effects because the NCS does not collect information on other substance use, it is an important direction for future research. Furthermore, even though cannabis initiation among never-users aged 18 to 20 years was lower after the MLA increase, it will be interesting to evaluate whether the MLA increase also encouraged existing cannabis users in this age group to reduce the amount of cannabis consumed. Finally, there is evidence that adolescents who reside close to jurisdictional borders evade the MLA laws by purchasing restricted substances from neighboring jurisdictions where the MLA is lower.In this study, the increase in Quebec’s cannabis MLA from 18 to 21 years was associated with a significantly lower increase in cannabis use among youths aged 18 to 20 years in Quebec than in other provinces. Although this finding helps to alleviate concerns that youths will switch to illegal markets in response to a higher MLA, the increase in youth cannabis use despite the higher MLA highlights the need for additional policy measures to address rising cannabis use among youths.


The late effects of treatments for childhood cancers may lead to severe and multiple health conditions requiring hospitalisation. We aimed to estimate the hospitalisation rate among childhood cancer survivors (CCS) in France, to compare them with the general population and to investigate the associated factors. We matched total of 5439 5-year solid CCS diagnosed before the age of 21 between 1945 and 2000 by sex, birth year and region of residence to 386,073 individuals of the French general population. After linkage with the national hospital discharge database, we estimated the relative hospitalisation rate (RHR), the absolute excess risks (AERs) and the relative bed-day ratio (RBDR) during 2006–2018. We used generalised linear models to estimate associations between hospitalisation and survivor characteristics. Overall, the RHR was 2.49  and the RBDR was 3.49 (95% CI 3.46–3.51). We found that neoplasm-related hospitalisations had the highest AER (105.8 per 1000 person-years), followed by genitourinary system diseases (34.4 per 1000 person-years) and cardiovascular diseases (19.2 per 1000 person-years). In adjusted analysis, CCS treated with chemotherapy , radiotherapy  or both  had a higher risk of hospitalisation than the ones who had not received any of these treatments. CCS treated during the past decades by chemotherapy and/or radiotherapy now had a higher hospitalisation risk for all main categories of diagnosis than the general population. Prevention strategies and medical surveillance programmes may promote a long-term decrease in the hospitalisation rate among CSS. Potential life-threatening or disabling late effects include second neoplasms, cardiovascular diseases, growth problems and mental health issues3. This increased morbidity may lead to the development of complex health conditions requiring hospitalisation4.Advances in cancer treatment, such as improvements in chemotherapy regimens, radiation techniques and surgery, have allowed achieving 5-year survival rates of more than 80% in patients with paediatric cancer. However, late effects from cancer therapies continue to be a challenge. It is estimated that two thirds of childhood cancer survivors (CCS) will experience at least one treatment-related adverse event and 40% will experience at least one severe or life-threatening or disabling event several years after the cancer diagnosis9. In addition, their average length of stay in the hospital was up to 35% longer than patients without a history of cancer10. A better understanding of the long-term hospitalisation of CCS is thus important to evaluate their health conditions and health care–related costs several years after cure.Some researchers have evaluated the long-term risk of hospitalisation among CCS and have reported an overall increased risk in survivors compared with the general population11. However, no studies have analysed and detailed the hospitalisation rate in long-term CCS. The aim of this paper was to estimate the hospitalisation rate among CCS residing in France compared those of the French general population. We have also described the hospitalisation-related clinical diagnoses and have investigated cancer-related factors associated with an increased probability of hospitalisation.In France, there are about 50,000 adult CCS, with a growing number of long-term survivors13. To study the FCCSS hospitalisation records, we selected survivors who were alive in January 2006, living in metropolitan France and who were linked to the National Health Data System (French acronym: SNDS). Of the 7670 5-years survivors from the FCCSS, 6,818 were still alive on 1 January 2006.The French Childhood Cancer Survivor Study (FCCSS) is a retrospective cohort of 7670 5-year CCS diagnosed for solid cancer or lymphoma  before the age of 21 years between 1945 and 2000 in five cancer centres in France. Cancer diagnoses were classified according to ICCC-3, with the exception of thyroid cancer, which was included in a separate group due to the specificity of iodine treatment and its consequences. Detailed information on the methods for data collection and patients has been already described in several articles14. It contains exhaustive data (beginning in 2006) on billing and reimbursement of beneficiaries, including private and public hospital data collected in the national hospital discharge database (French acronym: PMSI).The SNDS is the health care claims dataset in France; it covers around 99% of the population15.The PMSI is divided into four categories corresponding to hospitalisation in conventional hospital units (short stays), homecare units, rehabilitation and psychiatry institutions. It includes some demographic characteristics of patients  as well as clinical information of the hospitalisations such as the in-patient bed-days, primary and secondary diagnoses according to the 10th revision of the International Classification of Diseases (ICD-10), procedures performed, medications administered and the dates of death and cost information under the diagnosis‐related group systemLinkage and access of SNDS data of FCCSS cohort was provided by the national health insurance fund (French acronym: CNAM) by probabilistic matching using the survivor's family and first names, sex, date and place of birth and unique arbitrary number. The percentage of survivors linked to SNDS data after this procedure was 81.9% (n = 5583/6818), with data availability from 2006 to 2018.16. Health care claims including hospitalisation records (PMSI) are available in the EGB; however, information regarding hospitalisation in rehabilitation and psychiatric institutions has not yet been supplied. The reference sample was selected matched by sex, year of birth and the region (French administrative area) of residence and randomly assigned to each FCCSS survivors with the same characteristics.We obtained a reference sample from the General Sample of Beneficiaries (French acronym: EGB). The EGB is a 1/97th anonymised random permanent sample of all population included in the SNDS  which has been shown to be representative of the French general populationUsing the PMSI, we obtained hospitalisation records in conventional hospital units from January 2006 to December 2018 or death—whichever came first—for each CCS and individual of the reference population. Our endpoints of interest were (1) the total number of hospitalisations and (2) the total number of bed-days spent in hospital, which is the number of days in which the patient stays overnight in a hospital, excluding day hospital visits. We grouped hospitalisations according to the primary diagnosis into the 19 main groups of the ICD-10, excluding the following categories: pregnancy and childbirth (O00–O99), certain conditions originating in the perinatal period (P00–P96), external causes of morbidity and mortality (V01–Y98) and codes for special purposes (U00–U99), in order to focus on hospitalisation potentially linked to childhood cancer sequels.The study was approved by the French Data Protection Authority (French acronym: CNIL) (Authorization n°902287) and by the ethics committee of the French National Institute of Health and Medical Research (French acronym: INSERM). Informed consent was obtained for patients who could be contacted (n = 3312), and posters containing information about the study and how to decline participation were displayed in the French paediatric oncology departments. Finally, we obtained a specific act in law from the French ‘Conseil d’Etat’, the highest court in France (Order 2014-96 of 2014 February 3), that approved the cession of the SNDS data for all patients included in the FCCSS with or without informed consent. All methods were performed in accordance with the relevant guidelines and regulations.The hospitalisation and bed-day rates were calculated for both the FCCSS and reference populations as the total number of hospitalisations or bed-days divided by the number of person-years (PY) at risk and expressed as the rate per 1000 PY. Time during hospitalisation was not counted as time at risk when calculating the hospitalisation rate. To compare the FCCSS hospitalisation rate to the reference population, we calculated: (1) the absolute excess risk (AER) as the difference between the hospitalisation or bed-day rate of the FCCSS and reference populations expressed per 1000 PY, and (2) the relative hospitalisation rate (RHR) and the relative bed-day ratio (RBDR) with their corresponding 95% confidence intervals (CIs) as the division of the hospitalisation or bed-day rate of the FCCSS and reference populations based on the assumption that the observed number of hospitalisations and bed-days followed a Poisson distribution. We calculated the AER, RHR and RBDR for overall hospitalisations and for each ICD-10 main group.We used generalised linear models (GLMs) to model the number of hospitalisations and bed-days. We used the expected number of hospitalisations or bed-days as an offset to study the risk for FCCSS survivors relative to that for the reference population. We adjusted the models for sex, year of cancer diagnosis, age at cancer diagnosis, age in 2006, type of primary cancer, age and cancer treatment(s) received . We chose neuroblastoma as the reference primary cancer variable because it is one of the larger groups of cancer with the same histology. We have reported risk estimates as risk ratios (RRs) and 95% CIs. Finally, we executed separate models for each ICD main group to evaluate risk factors for the different types of hospitalisations. We performed statistical analyses by using SAS 9.4 software , considering p < 0.05 to be significant.We included 5439 FCCSS survivors and 386,073 reference persons. Each CCS was assigned an average of 71 (SD: 73.9) unique reference persons. Between 1 January 2006 and 31 December 2018, 3756 CCS (69%) and 208,217 reference persons (54%) had had at least one hospitalisation. By the end of the follow-up, 383 (7%) FCCSS survivors and 38,458 (10%) reference persons had died. About 28% of FCCSS patients were less than 20 years old at the start of the SNDS follow-up in 2006, 10% being 40 years old or more , followed by genitourinary system diseases (34.4 per 1000 PY), factors influencing health status and contact with health services (other factors) (26.6 per 1000 PY) and circulatory system diseases (19.2 per 1000 PY). There were the fewest hospitalisations for mental and behavioural disorders and auditory issues  , while CNS tumour survivors , kidney tumour survivors  and other primary cancer survivors  were at higher risk  Table . CompareWhen investigating the role of age in each hospitalisation category for the RHR  Table .In a cohort of 5439 5-year solid CCS, we found that individuals treated for childhood cancer in 1940–2000 in France were recently hospitalised more than twice as often as the general population during a 13-year follow-up (2006–2018). This increase in the hospitalisation rate occurred among cancer survivors who had been treated with chemotherapy and/or radiotherapy. The hospitalisation rate was elevated for all ICD-10 groups of hospitalisation-related pathologies, although the RHR was the highest for hospitalisation related to neoplasms, endocrine conditions and circulatory system diseases.9. In Europe, the RHR was generally higher: about two times higher in the Netherlands6 and the Nordic countries9, with a bed-day ratio of 5 in the Nordic countries, and an RHR of about 2.8 and a bed-day ratio of 3.7 in Scotland17, findings similar to our results. On the other hand, there was a lower hospitalisation rate in a small Utah cohort and in the large US Childhood Cancer Survivor Study (CCSS)5, probably because most of the children in those studies had been treated before the end of the 1970s. That time corresponds to the beginning of generalised use of combined chemotherapy18, which was more toxic than the previous single-agent chemotherapy.Our results are consistent with similar studies performed in the USA, Canada, the Nordic countries and the Netherlands in which CCS experienced a higher hospitalisation rate compared with the general population of their countries19. These results are similar to our findings in which both the AER and RHR were the highest in CCS. In two studies from North America, survivors were hospitalised more often because of blood disorders19. However, our results indicate that although blood disorders had a higher RHR, this category had a very low hospitalisation rate and AER. This outcome could be partially explained by the fact that our cohort did not include leukaemia survivors. One study from the UK reported that CCS had a four-fold risk of being hospitalised for cardiovascular disease compared to that expected from people of same age, sex and calendar year stratum20. Another study from the Netherlands7 showed a higher RHR but the lowest AER for endocrine conditions. These results are consistent with our findings but inconsistent with findings from the Nordic countries, where there was excessive hospitalisation mainly due to nervous system diseases9.Previous studies have shown that survivors are more at risk of hospitalisation due to neoplasms, recurrences and/or subsequent5, CNS tumours19 and bone tumours7 compared with other primary cancer types. However, our results showed few variations in the RHR according to the primary cancer type, except for thyroid and CNS tumours. A high hospitalisation rate for nervous system diseases and congenital malformations have been also reported in CNS tumour survivors17, but the reclassification of neurofibromatosis from a tumour of uncertain behaviour in ICD-9 to congenital malformation in ICD-10 partially explains this excessive hospitalisation. On the contrary, in one study renal tumour survivors were not at additional risk of hospitalisation4, and in another one they had among the lowest hospitalisation rate5, which disagrees with our findings. However, this could be explained by the fact that we accounted for day hospital admissions, which include dialysis. In fact, our results show that their excessive hospitalisation comes from genitourinary system diseases.Researchers have reported a significantly higher hospitalisation rate in survivors of Hodgkin’s lymphoma4, but not to another population-based cohort study performed in another US state, in which both the RHR and AER were higher for women8. Our findings are also different from the U.S. CCSS, in which women had a much lower RHR and AER than men5. In the Netherlands, two studies evidenced a higher hospitalisation rate but a lower RHR in women than in men7, whereas in the Scotland17 the standardised bed days ratio was almost the same in women and men.Among FCCSS survivors, women experienced slightly higher hospitalisation and bed-day rates than men . Compared with the reference population, women and men had a similar RHR and a higher AER for hospitalisation and bed-days, and women had a higher RBDR. These results are similar to a population-based cohort performed in Utah21. Another study in British Columbia, Canada, reported that hospital-related morbidity was elevated for all combinations of primary treatment and was highest for those who had received radiation, chemotherapy and surgery19. Our findings identified chemotherapy as a factor associated with hospitalisation especially for genitourinary system diseases, where cisplatin or ifosfamide have been established as treatment-related causes of chronic renal damage in CCS22.Our findings are consistent with those of earlier studies in the Netherlands in which survivors initially treated with radiotherapy had a particularly increased hospitalisation rate for neoplasms, endocrine diseases and circulatory system diseases21. Our results about the variations in RHR and RBDR according to year of childhood cancer diagnosis and the age at the start of SNDS follow-up have to be interpreted with caution because these two variables are linked—that is, survivors treated in later years are likely to be older at the start of the follow-up. As a general matter, the differences in results among studies are hardly explained by variations in demographic and clinical characteristics. A more thorough investigation would require performing a meta-analysis. Our results should be interpreted with caution because the SNDS data are only available for 2006–2018, a period of time after the FCCSS recruitment period (1945–2000). Thus, a selection bias could occur in older patients at the time of the SNDS follow-up. For example, patients treated before 1970 who survived until 2006 are not representative of all patients treated before 1970 and correspond to a different distribution of the treatment types.Unexpectedly, we did not observe a variation in the RHR and RBDR according to the age at childhood cancer onsetTo our knowledge, this is the first detailed study of the hospitalisation of long-term CCS compared with the general population in France. We used a national administrative database, which provided comprehensive information on hospitalisations over 13 years in both CCS and their reference population. An advantage of our study is that we have accounted for hospitalisation in day hospital units. Admissions to day hospital units are mainly for chemotherapy, radiotherapy and extracorporeal dialysis. By considering in-patient bed-days, we could focus on more severe hospitalisation that required more medical care.23. Moreover, given that the EGB includes a population that does not receive health care and the data are stored for a period of 20 years15, the EGB allows researchers to carry out longitudinal studies of hospitalisations24. Third, we could not address the association between specific types of hospitalisations with specific modalities of therapy (e.g. chemotherapy and radiation doses) because this requires special considerations. We will perform these investigations in separate publications. Lastly, the FCCSS included only patients from five non-profit private cancer treatment centres in France, which are not representative of all French childhood cancer treatment centres. Nevertheless, we have found that this did not impact the long-term survivor's medical expenditure25.Our study is subject to some limitations. First, we were not able to identify hospitalisations related to relapse or metastasis of childhood cancer to the ones related to secondary neoplasms. Second, we considered only hospitalisation in conventional hospital units because information regarding rehabilitation and psychiatric institution hospitalisation was not available in the EGB sample, which constitutes our reference. Thus, we have underestimated the hospitalisation rate, especially mental-related hospitalisation. Nevertheless, the conventional hospital units treat more than 90% of all patients hospitalised in FranceIn summary, we have shown that the hospitalisation and in-patient bed-day rates among CCS in France were more than twice higher than in the general population. The association of cancer treatment with the different types of hospitalisations suggests special attention should be paid to prevent long-term complications in all organ systems, especially among CCS treated with combined therapies.Supplementary Table 1.Supplementary Table 2.Supplementary Table 3.Supplementary Table 4.Supplementary Table 5.Supplementary Table 6.Supplementary Table 7.Supplementary Table 8.Supplementary Figure 1.


Visual functions of the dorsal stream are considered vulnerable in children with early brain damage. Considering the recognition of objects in suboptimal representations a dorsal stream dysfunction, we examined whether children with early brain damage and impaired object recognition had either general or selective dorsal stream dysfunctions.n = 48) we evaluated the dorsal stream functioning. To determine whether these patients had an increased risk of a dorsal stream dysfunction we compared the percentage of patients with impaired object recognition, assessed with the L94, with the estimated base rate. Then we evaluated the performance levels on motion perception, visual attention and visuomotor tasks in patients with (n = 18) and without (n = 11) object recognition abnormalities. A general dorsal stream dysfunction was considered present if a patient showed at least one abnormally low score in two out of three additional dorsal stream functions.In a group of children with early brain damage (p = 0.01). The difference of 24.1% between the patients with and without object recognition problems was not significant. Of the patients with object recognition problems 72.2% had at least 1 dorsal weakness, whereas this was only the case in 27.3% of patients without object recognition problems. Compared to patients with normal object recognition, patients with object recognition problems scored significantly more abnormally low on motion perception and visual attention (ps = 0.03) but did not differ on visuomotor skills.Six of the eighteen (33.3%) patients with object recognition problems scored abnormally low on at least two additional dorsal stream functions. This was significantly higher than the base rate (Children with object recognition problems seem at risk for other dorsal stream dysfunctions, but dysfunctions might be rather specific than general. Multiple functions/aspects should be evaluated in neuropsychological assessment of children at risk. Studies on visual perception in children with developmental disorders  and earlAlthough object recognition is primarily considered a ventral stream function, existing evidence indicates that it is not a ventral stream function alone: IPS , IPL Vu and SPL Studies on dorsal stream functions in children with early brain damage or developmental disorders indicate that different aspects of object recognition in suboptimal representations  and motiThe aim of the present study was to determine whether other dorsal stream dysfunctions are commonly present in children with an identified dorsal stream dysfunction. In this study, the L94 was used to detect children with a dorsal stream dysfunction in a group of children with (indications of) early brain damage. The L94 is a valid diagnostic test battery for object recognition in suboptimal representations. Abnormally low scores on the L94 are associated with parietal lobe damage . We hypon = 19) and through the Laboratory of Neuropsychology at the University Hospital in Leuven, Belgium (n = 29). Their chronological age ranged from 4 y1m to 14y7m .The patient group consisted of 48 children at risk for object recognition problems, because of brain damage, indications of brain damage, and/or reports of suspicion of visual perceptual impairments mentioned in their medical records. Patients were recruited through rehabilitation centers in the Rotterdam area  and the Catholic University of Leuven. Informed consent was obtained for all participants through their parents or guardians.Data on etiology of the brain damage and imaging results (CT and/or MRI), gestational age and recent orthoptic assessments were gathered from available medical records. The participant was invited for an orthoptic assessment, if no recent orthoptic assessment was done. Eye movements, visual acuity with up-to-date refractive corrections (lenses or glasses), visual field, and binocular vision were assessed by trained professionals (orthoptists) using  age-appropriate tests. Visual field was mainly assessed with the confrontation visual field exam (Donder’s test).Participants wore their prescribed glasses or lenses during the developmental age and dorsal stream assessment.IQ). We corrected for a time-lag between IQ assessment and dorsal stream function assessment using the following formula: DAdorsal = (DAIQ/CAIQ)*CAdorsal, where CA stands for chronological age.To control for cognitive impairments in the patient group, we estimated the participant’s developmental age (DA). The developmental age was defined as the median age-equivalent of multiple subtests measuring performance IQ (PIQ) : the patIQ estimation.To minimize the burden on the patients we decided to use recent intelligence results when available. If not available, we only studied non-verbal intelligence, because only non-verbal cognitive ability, and not verbal cognitive skill, is predictive of perceptual performance . AlthougThe following dorsal stream functions were studied in arbitrary order: object recognition in suboptimal representations; motion perception; visual attention; visuomotor skills. Published or preliminary reference data was used to classify performance levels. We used DA, instead of CA, as entry to the reference tables. In case PIQ ≥ 100, DA exceeded CA, we used the patient’s CA as entry to the reference tables.th percentile were defined as an abnormal performance. For other function tasks, a score below the 10th percentile was defined as abnormally low.If DA was out of range of the norm tables, we used the nearest age group. An object recognition score below the 5Testing was done by trained senior psychology students and neuropsychologists. All computerized tasks were run on a laptop connected to a 15-inch CRT monitor. Participants with refractive errors wore their prescribed glasses and were placed in front of the screen at approximately 40 cm.To assess object recognition in suboptimal representations we used five computerized subtasks of the L94 , 2001 thThis task consists of 1 example and 10 items: line drawings of everyday objects in prototypical view. Each item is presented for 1 s, followed by a screen with a semantically identical object and three distracters. The participant must point out the target object. Items scores are 1 (correct) or 0 (incorrect).This task consists of 1 example and 6 items. Each object is presented for 2 s and is partly occluded by noise. Participants must name or describe the presented object. Noise level decreases until the object is recognized correctly. There are 7 noise levels . 0% noise level is considered the control condition. Item score is (7-j)/(7-1), where j is the number of noise levels presented before the participant recognized the object.This task consists of 1 example and 6 items. Items are presented for 6 s and consist of two, three of four overlapping objects, followed by the target objects and two distracters, all presented separately. Participants must point out the target objects. The level of overlap decreases until all target objects are indicated correctly. There are four levels of overlap: full overlap, partially overlap, touching, and separate presentation. The last condition is considered the control condition. Item score is (4-j)/(4-1), where j is the number of overlap levels presented before a correct response is given.This task consists of 20 items. Items are presented for 3 s. Half of the items are presented in three conditions: Unconventional view, less unconventional view, and conventional view. For the other half of the pictures, the level of unconventional view decreases to the conventional view in four conditions. The level of conventional view decreases until the participants named or described the object correctly. The conventional view is considered the control condition. Items scores is (k—j)/(k—1), where k is the total number of conditions and j is the number of conditions presented before the participant recognized the object.This task consists of 43 items. There is no time constraint. Items are presented in a target condition and a control condition. In the target condition objects are less easy to recognize because they are embedded in context, they are partial drawn, only contours are presented, a typical part of the object is omitted, or they are presented in an unconventional view. Participants must name or describe the target object. Item score is 1 (recognized) or 0 (not recognized in target condition).Performance was expressed in a subtask score. The subtask score was the average item score, with exclusion of items not recognized in the control condition. Items with an incorrect response in the control condition were indicated as inconclusive and excluded, because an incorrect response could not only be the result of a recognition problem, but also of other problems (language etc.).We excluded the items rifle, bench, and alarm clock from the analysis of VIEW, because Dutch controls tended to name these objects differently, for example by their general category and often did not change their answer with changing views. This was considered no problem, because inconclusive items, items that are not named correctly in the control condition of the task, are excluded in the scoring procedure of the L94.To classify the scores we used the reference data published in a manual .th percentile . Participants were asked to indicate the location of the fastest car (presentation time 10 s). A decrease in the speed difference of the dots in the cars made the task more difficult  and the critical speed difference was the score for this task.The motion speed stimulus  consisteVisual attention was assessed by a computerized visual search task, developed at the department of Psychologic and Pedagogic Sciences of Leuven Catholic University. It consists of greyscale pictures (size 5 × 5 degrees at 40 cm distance) on a gray background . Reaction times for false alarms were excluded. Median reaction times were calculated for both reaction time tasks and for each visual search task. Because the presence of distracters in the search tasks made pop-out less likely, a serial search process  was assumed to be needed to detect the targets. In a serial search process, the reaction time is the sum of the motor response time and the visual search time. Visual search time was our primary outcome measure, so median reaction times of the reaction time tasks were distracted from median reaction times of the search tasks.M = 5y7m SD = 9 m). We divided the group in three age groups, equal to those for the motion perception tasks. Cut-off values for the 10th percentile can be found in We used the preliminary reference data of 60 typically developing children  without any signs of neurological or visual impairment and with a normal visual acuity. They were recruited through primary schools in Rotterdam, The Netherlands. Their chronological age ranged from 4y3 m to 7y4m   and the Each participant was asked to imitate and copy a maximum of 24 items of increasing complexity. The participant had one try per item. Tracing the pattern and erasing was not allowed. The scoring instructions in the manual were used to decide whether the copy was correct or incorrect. The test was discontinued after 3 consecutive failures .In Mosaics the participants must copy a maximum of 15 mosaic patterns in a frame. The difficulty level was determined by whether the examiner demonstrates the item, the number and color  of squares the participant must use and the scale of the printed pattern. After each item feedback was given whether the solution was correct or incorrect. In case an incorrect solution was given, the participant was engaged in correcting the solution, without explaining why the solution was incorrect. The subtest was discontinued after a total of three mistakes or two consecutive mistakes at the advanced level .Participants were included in the analysis if at least three out of five L94 tasks had been completed.th percentile, z = −1.645) on the battery of the five object recognition tasks. To estimate the base rate we used the correlations between the object recognition tasks in the reference group and then performed the Monte Carlo simulation method described by An assessment with 5 tasks, instead of 1, increases the chance of finding at least one abnormally low score. To be confident that our patient group is at risk for object recognition problems, the percentage abnormally low scores should exceed the base rate. The base rate is the expected percentage of the healthy population that would show 1 or more abnormally low test-scores  had an increased risk of a general dorsal stream dysfunction. A dysfunction or weak function was considered present if a patient showed a score below the 10th percentile (z = –1.282), in one of the other dorsal stream tasks. A patient was considered to have a general dorsal stream dysfunction if that patient showed at least two weak functions, i.e., had at least one abnormally low score in two out of three other dorsal stream functions: motion perception, visual attention and/or visuomotor skills. We therefore only included patients who completed at least one task per function. If only the group with object recognition problems was at risk for a general dorsal stream dysfunction, the percentage of at least 2 weak functions in this group had to be significantly higher than the base rate and the percentage of at least 2 weak functions in the patient group without object recognition problems (no score < 5th percentile on L94).Next, we studied whether children with object recognition problems   . AdditioM = 5y3 m, SD = 1y5 m). Nineteen patients (40%) had been born prematurely : 6 moderately to late premature , 12 very premature  and 1 extremely premature . In 31 patients (65%) a motor disorder was present. In another 3 patients (6%) some motor developmental problems were suspected, because a delay in motor development was mentioned in their medical record. More patient characteristics are presented in Eight patients out of 48 patients (17%) had low vision, a best corrected decimal visual acuity between 0.1 and 0.3 (US notation 20/200–20/63 or 1.0 logMAR–0.5 logMAR), but all patients should be able to perceive the detailed stimuli. Their developmental age, the median age equivalent of non-verbal intelligence subtests , probably due to the small sample sizes. A post hoc power-analysis  suggested that future samples should at least have 41 participants per group.The observed percentages of at least 2 weak dorsal stream functions in the group with and without object recognition problems did not differ significantly [difference 24.1%, Fischer’s exact one-sided p-value = 0.02). Most of the patient group with object recognition problems had other dorsal stream problems: 6 were considered to have a general dorsal stream dysfunction and an additional 7 were considered to have a specific dorsal stream dysfunction. In the patient group without object recognition problems 1 was considered to have a general dorsal stream dysfunction and 2 were considered to have a specific dorsal stream dysfunction.These results suggested that general dorsal stream dysfunctions might be more common in the group with object recognition, but our evidence is not strong enough. Additional analysis suggested that dorsal stream dysfunctions, specific and general, were more common in the patient group with object recognition problems: 13 out of 18 patients with object recognition problems (72.2%) had at least 1 weak function, while only 3 out of 11 patients without object recognition problems (27.3%) had at least 1 weak function (In p = 0.03) than the group without object recognition problems  and their coherence level was significantly higher than that in patients without object recognition problems . Although the percentage of abnormally low scores did not differ significantly on MDF, patients with object recognition problems were significantly less able to recognize the motion-defined forms . No significant differences were found for the motion speed task.The group with object recognition problems scored significantly more often abnormally low on GM (p = 0.03).The percentage of abnormally low scores on the visual attention task see  was signAbnormally low scores were mainly found on a single subtask: in 6 patients with and in 1 patient without object recognition problems. In the patient group with object recognition problems another 2 scored abnormally low on 2 subtasks and 1 on all three.p = 0.09). Additionally, patients with object recognition problems were significantly slower on each subtask and made significantly more mistakes than the group without object recognition problems (ps < 0.01), whereas the performance on the reaction time task seemed comparable.Although the observed percentages of abnormally low scores in the visual search subtasks did not differ significantly. the difference in the condition with four distracters was near-significant (No significant differences were found in the visuomotor skills see . Abnormath percentile) on one or multiple object recognition subtasks of the L94. This was significantly higher than the base rate of 12%, the expected percentage of abnormally low scores in the healthy population.In this study, we provided some evidence that children with early brain damage are at risk for dorsal stream dysfunctions. While controlling for the patient’s developmental age, 29 out of 46 patients with early brain damage (63%) scored abnormally low (score < 5n = 18) and compared their performance levels to that of children with early brain damage with unimpaired object recognition (n = 11). We defined a general dorsal stream dysfunction as abnormally low performance levels (score below 10th percentile) on at least 2 additional dorsal stream functions, such as motion perception, visual attention, and/or visuomotor skills. The results showed that a general dorsal stream dysfunction was present in 6 out of 18 patients with impaired object recognition (33.3%). Another 7 patients scored abnormally low on 1 additional dorsal stream function. Dorsal stream problems were uncommon in patients without object recognition problems: they were only found in 3 out of 11 patients (27.3%). Of these patients only 1 (9.1%) was considered to have a general dorsal stream dysfunction. This was as many as could we expected in the healthy population.We then studied whether general dorsal stream problems were present in children with impaired object recognition (p = 0.02) indicates that patients with object recognition problems are at risk of other dorsal stream dysfunctions, possibly rather specific than general. Motion perception and visual attention, but no visuomotor skills, were specifically affected.Although these results suggest that patients with object recognition problems are at risk for general, widespread dorsal stream dysfunctions, the difference of 24.1% between the patients with and without object recognition problems was not significant. The higher percentage of patients at least 1 dorsal weakness , whereas another aspect is impaired in another patient (group). The term generalized is used when impairments are widespread within and/or across various aspects of functioning. Although in some of our patients the dorsal stream dysfunctions seemed widespread, the dysfunctions within a single aspect, like motion perception seemed rather specific than generalized. Our estimation of a general dysfunction within aspects might be underestimated, because of missing data. The extent of generalized dysfunctions within aspects can only be reliably estimated if all patients were assessed with all subtasks.In current study we can only deduce that the dorsal stream is affected. We have no details on the exact locations and extent of the brain damage. Although the subtasks of the L94 are likely to activate both the ventral and the dorsal stream, the subtask profile of the L94 suggest that the ventral stream is mainly intact in our patient group. The performance level on VISM, a subtask with line drawings of everyday objects in prototypical view, probably mainly relies on the integrity of the ventral stream, as demonstrated in a fMRI study with passive object viewing  and patiPatients with object recognition problems performed worse on the global motion and motion-defined form task and were significantly slower on the visual search tasks. They also made more mistakes, which makes a speed-accuracy trade-off less likely. The available data are insufficient to study causal or interactional relationships between functions. One possibility is that a visual attention weakness leads to abnormally low motion and object perception scores, but performance levels on the assessed tasks could also be low because of difficulties in object discrimination, impulse control, and cognitive flexibility. Therefore, to test hierarchical models, not only a larger sample size but also assessment of additional indicators is necessary.The presence of object recognition and motion perception problems in combination with the normal visuomotor skill on the Beery VMI support the more fundamental idea that developmental age estimations based on PIQ subtests can be used to control for effects of motor impairments in addition to intellectual impairments. Because the Beery VMI  can provFurther, a more detailed analysis of inconclusive items, i.e., items that were not named correctly in the control conditions of the L94 and the motion-defined form task and were excluded from the calculation of perception scores, might help explain performance patterns in children at risk. Inconclusive items can indicate differences in experience or object knowledge, but also the presence of other problems such as problems in language development, naming, especially in relation to words (items) with lower word frequencies, memory and attention, or a combination of these problems. Differences in the number of inconclusive items between a group with unimpaired and impaired object recognition could provide indications for the reason why abnormal performers were unable to name or describe objects in the control items.We conclude that in children with early brain damage, dorsal stream functions and their aspects seem specifically and not generally affected, and that more extensive research is required for a better understanding of causal relationships and underlying mechanisms. For now, we recommend that in specialized clinical practice, multiple functions and their various aspects should be assessed in a neuropsychological assessment of at-risk children, using developmental age as reference level, i.e., entry of the reference table.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committees of the Erasmus Medical Centre MEC-2006-056) and the Catholic University of Leuven. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.PS and HE conceived the study. PS and YZ designed the study design and procedures, significantly contributed to procedures and execution, and interpreted the data. YZ, PS, and HE drafted, revised, and prepared the manuscript. All authors gave final approval for the submitted manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Can imaging data be used to derive a scoring system to estimate long-term risk of hemorrhage of unruptured brain arteriovenous malformations (AVMs)?In this prognostic study of 3962 patients with AVMs, 4 factors  were identified to build a scoring system to predict the rupture risk of AVMs. The scoring system had excellent performance in both the derivation and multicenter external validation cohorts and high discrimination in risk stratification of patients in the prospective follow-up cohort receiving conservative treatment management.These findings suggest that the scoring system is a reliable tool that can be used to reduce unnecessary interventions or unexpected AVM ruptures. The dilemma between natural rupture risk and adverse outcomes of intervention is of major concern for patients with unruptured arteriovenous malformations (AVMs). The existing risk score for AVM rupture includes factors that are controversial and lacks prospective validation.To develop and robustly validate a reliable scoring system to predict the rupture risk of AVMs.This prognostic study developed a prediction model derived from a single-center cohort (derivation cohort) and validated in a multicenter external cohort  and a cohort of patients receiving conservative treatment management . Patients were recruited from a nationwide multicenter prospective collaboration registry in China. A total of 4135 patients were enrolled in the registry between August 1, 2011, and September 1, 2021. Of those, 3962 patients were included in the study ; 1028 patients from the derivation cohort who had time-to-event data and prerupture imaging results were included in the conservative treatment validation cohort. Data were analyzed from March 10 to June 21, 2022.A scoring system was developed based on risk factors identified from a literature review and a robust selection process. Patients were stratified into different risk groups based on scores to calculate hemorrhage-free probability in future years, and Kaplan-Meier curves were plotted to visualize risk stratification. Receiver operating characteristic curves were used to assess the discrimination of models. Univariable analyses  were used to compare baseline information and assess bias.P < .001 for both comparisons).Among 3962 patients , 3585 patients  were included in the derivation cohort, and 377 patients  were included in the multicenter external validation cohort. Thirty-six hemorrhages occurred over a median (IQR) follow-up of 4.2 (0.3-6.0) years among 1028 patients in the conservative treatment validation cohort. Four risk factors were used to develop the scoring system: ventricular system involvement, venous aneurysm, deep location, and exclusively deep drainage (VALE). The VALE scoring system performed well in all 3 cohorts, with areas under the receiver operating characteristic curve of 0.77  in the derivation cohort, 0.85  in the multicenter external validation cohort, and 0.73  in the conservative treatment validation cohort. The 10-year hemorrhage-free rate was 95.5%  in the low-risk group, 92.8%  in the moderate-risk group, and 75.8%  in the high-risk group; the model discrimination was significant when comparing these rates between the high-risk group and the low- and moderate-risk groups (In this prognostic study, the VALE scoring system was developed to distinguish rupture risk among patients with AVMs. The stratification of unruptured AVMs may enable patients with low risk of rupture to avoid unnecessary interventions. These findings suggest that the scoring system is a reliable and applicable tool that can be used to facilitate patient and physician decision-making and reduce unnecessary interventions or unexpected AVM ruptures. This prognostic study uses data from a nationwide multicenter prospective registry in China to develop a scoring system that predicts the risk of hemorrhage among patients with brain arteriovenous malformations and validates the score in external multicenter and clinical practice cohorts. However, this scale should be applied and interpreted with caution due to its cross-sectional data–based selection of risk factors and its lack of prospective validation. Thus, clinicians and patients need a more reliable prediction and risk stratification tool for AVM rupture to inform expectations of hemorrhage-free outcomes and avoid unnecessary interventional treatment. Because the necessary imaging data were easily accessible for diagnosing AVMs, this study aimed to develop and validate a new scoring system combining evidence-based and statistically significant imaging features for the prediction of long-term hemorrhagic risk in patients with unruptured AVMs.The R16 nationwide multicenter prospective collaboration registry. The institutional review board of Beijing Tiantan Hospital approved this study, and patients who participated in the MATCH registry provided written informed consent at hospital admission. This study followed the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) reporting guideline for prognostic studies.17In this prognostic study, we developed a prediction model for AVM rupture risk using prospectively collected data from a single-center cohort (derivation cohort) between August 1, 2011, and September 1, 2021. Data were analyzed from March 10 to June 21, 2022. Patients in this study were recruited from the MATCH Validation of this model consisted of 2 steps. A multicenter cohort involving patients from 8 provinces in mainland China was used to validate the model externally . To further validate the generalizability of the model in a clinical practice scenario, we used data from patients with unruptured AVMs who were receiving conservative treatment management for more than 1 month . Only those with prerupture or pretreatment imaging data were eligible for inclusion in the study. The follow-up duration was censored at the date of hemorrhage or first treatment. The diagnosis of AVM was confirmed with digital subtraction angiography and/or magnetic resonance imaging (MRI). Those without essential imaging data for feature extraction and those diagnosed with dural AVMs, extracranial malformations, cavernous malformations, or hereditary hemorrhagic telangiectasia were excluded. The patient inclusion flowchart is shown in The comprehensive protocol for data quality management is available in eMethods 1 in visual cortex; hypothalamus or thalamus; internal capsule; brain stem; cerebellar peduncles ; and deep cerebellar nuclei) was based on the Spetzler-Martin Grading Scale.5 The size of AVMs was dichotomized into small and large based on whether the maximum nidal diameter was less than 3 cm or 3 cm or greater. Ventricular system involvement was determined via MRI based on whether the nidal border was adjacent to the cerebral ventricular system. Feeding arteries were considered dilated when their diameter was at least twice that of the same blood vessel segments. Venous aneurysm was defined as the focal aneurysmal dilation of the proximal drainage vein.18 Hemorrhagic presentation was defined as hemorrhage that could be ascribed to AVM rupture before or at admission.The nidus location was regarded as deep if the lesion exclusively involved the brain stem, cerebellum, basal ganglia, thalamus, corpus callosum, or insular lobe. The definition of eloquent regions . Parameters in the R2eD score (except for race and ethnicity because the study population included only Chinese patients) were used to fit the model in our training set (data from the derivation cohort), and the DeLong test14 was conducted to compare the ROCs between the R2eD-based model and our model. Data from the 3 cohorts were also used for external validation of the R2eD score to investigate its generalizability beyond its majority White population.We used receiver operating characteristic curves (ROCs) to assess the discrimination of models in the derivation cohort and the 2 validation cohorts. An area under the receiver operating characteristic curve (AUROC) higher than 0.70 indicated a good prediction of rupture. The new model derived from the derivation cohort was evaluated by performing ROC analyses separately in these 3 cohorts. A calibration curve was plotted to investigate the calibration ability of the new model. A perfect prediction was defined as a line with a slope of 1 and an intercept of 0 in the calibration plot. Kaplan-Meier curves were plotted for the conservative treatment validation cohort to visualize risk stratification according to score. Survival analyses were conducted using the rms, version 6.3.0,P < .05. All data were divided into 2 groups according to rupture presentation. For continuous values, means with SDs or medians with IQRs were reported for normal and nonnormal distribution data. The proportion of each categorical variable was also recorded. We compared the baseline information of the derivation cohort between groups using univariable analysis, with a t test or Mann-Whitney U test used for continuous data and a χ2 test used for categorical data, as appropriate. Missing data were assumed to be missing at random. Missing values were imputed using the missForest package for R software, version 1.5.21 All available data from the derivation database were used to meet the 20 events per variable rule to maximize the power of our results.We used R software, version 4.0.3 , to perform statistical data analyses. Statistical significance was set at 2-tailed 22 The number of predictors was limited to 4 to develop a scoring scale that could be easily applied in clinical practice. The predictors in the final model were the combination of 2 clinically acknowledged factors and 2 statistically significant and stable factors. Multicollinearity was evaluated using the variance inflation factor (with >3 indicating high collinearity). We also used β coefficients to assign points for these predictors to establish a scoring system that could be conveniently used in clinical practice. We plotted the predicted probabilities of rupture risk using the new model (y-axis) and the total scores from the new grading system (x-axis). A description of the probability calculation is provided in eMethods 2 in We identified potential predictors based on background knowledge and findings from systematically reviewed literature that investigated these factors using a prospective follow-up design. Odds ratios (ORs) and hazard ratios (HRs) and 95% CIs for these variables were calculated. The most frequently mentioned variables in the published studies were considered central predictors and were fixed in models during the variable selection. We first fitted a global model with all variables, then used backward stepwise regression with the Akaike information criterion as the stopping criterion. We repeated the process in 1000 bootstrap resamples to investigate the stability of selected variables.P < .001; ventricular system involvement: 1477 patients [67.5%] with rupture vs 468 patients [33.5%] without rupture; P < .001). Feeding and draining patterns were also associated with AVM rupture .A total of 4135 patients with AVMs were enrolled in the MATCH multicenter prospective registry. After careful screening, the final analysis included 3962 patients ; of those, 3585 patients  from Beijing Tiantan Hospital (the MATCH registry sponsor) were in the derivation cohort, and 377 patients  were in the multicenter external validation cohort. Hemorrhage occurred in 2189 patients (61.1%) in the derivation cohort and 225 patients (59.7%) in the multicenter external validation cohort. Missing values in the derivation cohort were less than 3%  were retrospectively chosen for inclusion , and 235 patients were prospectively followed up . Thirty-six hemorrhages occurred in the conservative treatment validation cohort (22.9%), with a median (IQR) follow-up duration of 4.2 (0.3-6.0) years. The annual hemorrhage rate for the total cohort was 0.84% (0.81% for the retrospective group and 0.87% for the prospective follow-up group). The overall and subgroup Kaplan-Meier curves are shown in eFigure 1 in 35 , with corresponding estimated β coefficients and SEs from the final regression model, is shown in P = .12), while the differences between these 2 groups and the high-risk group were significant . Hemorrhage-free probability among patients in the conservative treatment validation cohort at 3 years, 5 years, and 10 years is shown in The performance of the VALE score for predicting AVM rupture in the 3 data sets is shown in 2eD score) as the largest external validation set for our VALE score.14 The R2eD-based model fitted to the derivation cohort of the present study had good discrimination , but the VALE model performed better . The ROC of the R2eD score fitted to the 3 study cohorts, plotted separately, is shown in 2eD score performed well in the derivation and multicenter external validation cohorts, with AUROCs of 0.72  and 0.66 , respectively. However, in the conservative treatment validation cohort with survival data, the discrimination of the R2eD score was worse than that of the R2eD score in the other 2 cohorts . The VALE score better predicted AVM rupture in all cohorts, especially in the cohort simulating a clinical practice scenario . A description of how to use the VALE score in clinical practice, with detailed examples, is available in eFigure 3 in We also investigated the performance of a previously published risk score for AVM rupture  and established the first prospectively validated scoring system (the VALE score). The VALE score had good performance in the derivation cohort and was well validated in the multicenter external cohort and the conservative treatment cohort, with AUROCs of 0.85 and 0.73, respectively. Long-term follow-up of the conservative treatment validation cohort enabled the VALE scoring system to predict survival over different periods across risk groups, facilitating decision-making for both clinicians and patients.2eD scoring system includes 5 risk factors identified from statistical models .14 The VALE score shares similar purposes and 2 variables with the R2eD score: deep location and exclusively deep drainage. In our model, we selected these 2 acknowledged risk factors based on literature review,35 with the aim of avoiding results that may have been misleading because they were statistically significant but lacked clinical relevance. This issue is a limitation of other variables included in the R2eD score; for example, the risk associated with race may instead  be associated with socioeconomic status,14 and the inclusion of small AVM size in risk scores has long been debated, with the prevailing view in opposition to its inclusion.23 The discrepancies caused by selection bias are inevitable when using cross-sectional data. We conducted univariable analyses  in the 3 study cohorts to further investigate biases. Deep location and exclusively deep drainage remained significant in all 3 cohorts, which was consistent with the findings of previous studies.36 Among other predictors included in the VALE score, ventricular system involvement also had high predictive power in all groups, and venous aneurysm was nonsignificant in the prospective follow-up group within the conservative treatment validation cohort. The heterogeneity of the effect size suggested that selecting variables simply by using descriptive data analysis was unstable and unreliable. A study assessing the performance of AVM rupture prediction models in terms of methods used37 also found unstable results in models derived from data sets with different sample sizes and sampling times.The R29 which was limited by small sample size and low incidence of rupture, did not identify any angioarchitectural features. Therefore, the present study conducted a standardized variable selection procedure based on bootstrap resampling,22 combining evidence-based risk factors with statistically significant predictors to develop an easily applicable score that was then validated in a conservative treatment cohort with survival data. The good performance in the validation cohort enhanced the scoring system’s applicability in a clinical practice scenario.A better variable selection process can be derived by using prospective cohorts with time-to-event data. However, an international multicenter prospective study,38 One possible reason may be that the dilated cavity could serve as a buffer zone to reduce impedance of the outflow.When considering potential mechanisms of risk for the angioarchitectural features included in the VALE score, ventricular system involvement may lead to abnormal transmural pressure that makes it difficult to maintain the structural stability of the vessel wall due to lack of support from brain tissue. Venous aneurysms have been found to have a highly protective benefit for rupture despite the inconsistency of findings across studies.9 suggested that conservative treatment management was superior to intervention for the prevention of stroke. This conclusion has been controversial because of study design aspects.39 Treatment of AVMs is complicated, and individual differences in clinical decision-making should be considered. Many scoring scales have been developed in the AVM field, and they should be applied to different elements of the treatment process. In our study, the VALE score was developed for risk stratification of patients with different features of unruptured AVMs. Patients in different rupture risk groups are typically recommended to receive individualized therapeutic strategies based on assessment by different scales: the Spetzler-Martin and supplementary Spetzler-Martin grades for surgical operability,6 the Buffalo and Arteriovenous Malformation Embocure scores for endovascular treatment,40 and the Virginia Radiosurgery AVM Scale for radiosurgical procedures.7 For patients in different risk groups, the natural history of AVM rupture and the benefit of different treatment strategies must be weighed separately. Multicenter prospective validation with long-term follow-up using these scoring scales comprehensively is also required to better guide clinical practice.Results from the Randomized Trial of Unruptured Brain Arteriovenous Malformations42 This restriction to 4 risk factors may, to some extent, reduce the accuracy of the score while increasing its convenience. With deeper investigation of genetic information and radiomic data, a larger number of variables associated with AVM rupture could be uncovered, at which point artificial intelligence could be used to develop a more comprehensive and precise model. Second, the relatively low number of hemorrhagic events in the conservative treatment validation cohort produced a lower annual rupture rate than that of other studies.29 This difference can partly be ascribed to the exclusion of patients with ruptured AVMs but without prerupture imaging data in the retrospective group within the conservative treatment validation cohort. Selection bias can result in variations in incidence rates but does not change the association between these factors and rupture risk. That said, the hemorrhage-free survival probability derived from this cohort should be interpreted with caution because it might be overestimated. Third, development and validation of the VALE scoring system were performed in a predominantly Chinese population, so its generalizability to other populations remains to be assessed by other international collaborations, such as the Multicenter AVM Research Study.29This study has several limitations. First, to serve as an applicable tool in clinical practice, our model only included 4 variables derived from imaging data despite the identification of other significant factors in the selection process and literature review.In this prognostic study, the VALE scoring system, consisting of 4 central imaging features, was developed to stratify the risk of rupture among patients with AVM and provide estimated hemorrhage-free probability for future years. The stratification of unruptured AVMs may enable patients with low risk of rupture to avoid unnecessary interventions. These findings suggest the VALE scoring system is a reliable and applicable tool that may be used to help identify those who can benefit from early intervention, reduce unnecessary interventions or unexpected AVM ruptures, facilitate decision-making for both clinicians and patients, and guide future clinical research toward more personalized design.


However, after adjustments for these covariates, the hazard ratios for CERT2 remained statistically significant for predicting atherosclerotic events such as myocardial infarction and stroke, major adverse cardiovascular events and heart failure over a follow-up period of 10 years. It also predicted cardiovascular death. The CERT2 score augmented the use of measures of the ceramides species alone (CERT1), which was refined in part and implemented into clinical practice at the Mayo Clinic a few years ago.c-statistic superior to the ASCVD risk calculator in discriminating outcomes. It appears that this performance may be augmented further by CERT2. In the present study, Hilvo et al. found that although the c-statistics for CERT1 and CERT2 were similar, CERT2 led to better reclassification indices, highlighting the added value of the additional phospholipids. The study also provided new insights into patients with type 2 diabetes. In this group, the CERT2 score identified patients at higher risk compared to the established SCORE system. This led the authors to propose a modified SCORE risk assessment system incorporating CERT2 to enhance risk stratification in the general population, which may be helpful to clinicians.Interestingly, in the current study, the CERT2 score was also associated not just with cardiovascular events but also with non-cardiovascular death for reasons that are presently unclear. The stratum of patients deemed at the highest cardiovascular atherosclerotic risk by the CERT2 score seemed to be more robustly identified. In this category, atherosclerotic events and MACE were 10-fold more frequent. In a recent study from the Mayo Clinic, CERT1 was found to be superior to the guideline-endorsed score tool, the ASCVD (Atherosclerotic CardioVascular Disease) risk calculatorc-statistics for CERT1 and CERT2 were similar, suggesting similar test performance. The CERT2 score was only superior using reclassification indices, which are less robust than c-statistics.The current investigation has some limitations that should be appreciated. The FINRISK population is a Northern European population and therefore the generalizability of these results should be considered with caution. The original FINRISK study also was criticized as having less than ideal outcome validation. Finally, as acknowledged by the authors, it is unclear why CERT2 prediction of non-cardiovascular death was so robust, i.e. there is no clear explanation for this finding. Finally, the Taken together, these data should draw the attention of the preventive cardiologist. CERT2 appears to be at least comparable to SCORE and may well have additive value. It is clearly superior to traditional risk factors for atherosclerotic events especially in identifying high-risk patients in the general Northern European population, which otherwise could potentially be missed in clinical practice. Finally, the test appears to be particularly robust in the risk stratification of patients with type 2 diabetes. It would be interesting to probe CERT2 in other community populations and compare the test with other established risk calculators used in clinical practice to stratify atherosclerotic risk. Thus, more validation studies are warranted before considering implementing CERT2 into routine clinical practice for primary prevention.Conflict of interest: A.S.J. presently or in the past has consulted for most of the major diagnostic companies.