Characterization of the postoperative structural integrity of cortex in adults who have undergone cortical resection surgery for the management of epilepsy has yielded mixed findings. In some cases, patients show persistent or accelerated cortical atrophy, while in others, atrophy decelerates or even reverses. Whether this variability applies as well to a paediatric population, for whom postoperative plasticity may be greater, remains to be determined.In this case-control study, high resolution structural T1 MRI data were acquired from 32 patients with childhood epilepsy surgery and 51 non-neurological matched controls. Using enhanced automated segmentation capabilities of FreeSurfer Software Suite, we quantified morphometrics of the preserved hemisphere at the level of gross anatomy . Additionally, cortical thickness, volume, and surface area were measured for 34 cortical regions segmented based on the Desikan-Killiany atlas, and, last, volumes of nine subcortical regions were also measured. Morphometry comparisons were made between patients’ preserved hemisphere be it left (LH) or right (RH) against the corresponding hemisphere of age-matched, typically developing controls; and then the two patients groups (LH versus RH) were compared.Patient groups had larger ventricles and reduced total white matter volume relative to controls, and only patients with a preserved RH, but not patients with a preserved LH, had reduced total grey matter volume relative to controls. Furthermore, patients with a preserved RH had lower cortical thickness and cortical volume and significantly greater cortical surface area of several cortical regions, relative to controls. Patients with a preserved LH had largely no differences in thickness, volume, or area, of any of the 34 cortical regions, relative to controls. Moreover, both LH and RH patients showed reduced volumes in select subcortical structures, relative to controls.That left-sided, but not right-sided, resection is associated with more pronounced reduction in cortical thickness and volume and increased cortical surface area relative to typically developing, age-matched controls suggests that the preserved RH undergoes plastic processes to an extent not observed in cases of right-sided paediatric resection. Given the importance of understanding outcomes following surgery to the LH versus RH, the post-operative characterisation of morphometrics noted here provides a foundation for future work to understand differences in plasticity as a function of the side preserved post-resection. Future work probing the association of the current findings with neuropsychological outcomes will be necessary to understand the implications of these structural findings for clinical practice. Importantly, the extent of reversal is correlated with better seizure control,10 as well as positive cognitive outcomes.14 Furthermore, reversed cortical volume (CV) loss has also been observed at younger ages, albeit in a small sample size limited to patients with anterior temporal lobectomy.15 An explanation of the discrepant atrophy versus recovery in the postoperative period is elusive, and further studies are warranted. Such studies are particularly important given the growing consensus that surgery is underutilised and should be considered a first-line intervention for DRE.18 If the surgical outcome is of progressive, rather than reduced atrophy, alternative, disease-modifying treatments might be needed to halt further progression.Reports on the postoperative structural integrity of non-resected cortex have yielded mixed findings. Post-surgically, persistent and possibly accelerated reduction in cortical thickness (CxT), a proxy for structural integrity of the brain,19 have distinct genetic profiles, life span trajectories, and associations with disease;22 and are differentially associated with cognitive development and neurodevelopmental disorders.25 Whereas CxT development follows a linear decrease with age,26 CSA and CV follow a curvilinear trajectory with CV peaking earlier than CSA.21 The complementary information gleaned from these measures offers unique insights to any structural perturbations. Lastly, although postsurgical reduction in cortical thinning affects both hemispheres equally in adults,10 here we determined for this paediatric sample, whether any postsurgical structural differences depended on the preserved hemisphere’s being left or right. We focus our analyses here on the preserved hemisphere, as the hemisphere ipsilesional to surgery may have structural abnormalities directly related to the surgery itself, which confounds any postoperative plasticity that we hypothesise occurs post-paediatric resection.Here, we compared the postsurgical morphometry of the preserved hemisphere of 32 children with DRE and 51 age-matched typically developing controls on (i) gross anatomical measures of the lateral ventricles (LV), grey matter (GM), and white matter (WM); (ii) CxT , CV, and cortical surface area (CSA) separately for 34 cortical parcels; and (iii) volume of nine subcortical structures. CxT, CV, and CSA in particular are commonly utilised in studying DRE;27We employed general linear modeling (GLM) to compare patients vs. controls and patients’ preserved LH vs. patients’ preserved RH. We also adopted multivariate regression to reveal a model that uses structural parameters to predict group assignment and, in the patients, seizure burden using the International League Against Epilepsy (ILAE) outcome classification schema.Thirty-two paediatric patients with DRE and subsequent cortical resection or ablation were recruited for this study. There were 13 patients with LH surgery and a preserved RH  and 19 patients with RH surgery and a preserved LH . The patients’ demographic information and medical history are detailed in F=1.12; p=.30), gender (z(30)=0.65; p=.51), age at first surgery =0.03; p=.87), seizure-onset age =0.01; p=0.93), and binned ILAE outcome scales28 (z(30)=1.29; p=.20). Most patients underwent surgery at University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, and additional patients were recruited with the assistance of the Pediatric Epilepsy Surgery Alliance. Given the rarity of this patient population, data were not collected prospectively; retrospective analyses were conducted on available control and patient scans from 2013 to 2022.The two patient groups were matched on age =1.18; p=.28) or by hemisphere =0.17; p=.69 | RH: F=1.88; p=.18) and were matched to the patients on gender (aggregate: z(81)=0.54; p=.59 | LH: z(68)=0.80; p=.42 | RH: z(62)=0.06; p=.95). All participants received $75 per hour for their participation. Where possible, participants signed assent or consent, if appropriate, and guardians consented to a protocol approved by the Institutional Review Boards of Carnegie Mellon University (CMU) and the University of Pittsburgh.The 51 control participants  did not differ from the patients in age, either in aggregate, . The images were obtained from either a Siemens Verio 3T scanner with a 32-channel head coil at CMU  or a Siemens Prisma 3T scanner with a 64-channel head coil at the CMU-Pitt BRIDGE Center .31 and, finally, the output was manually inspected. As the recon-all pipeline does not generally result in accurate segmentation of hemispherectomy/hemispherotomy/hemidecortication patients, in these patients, the intact hemisphere was mirrored using affine and non-linear transformations  previously shown robust to anatomical aberrations.33 Only the data from the actual non-resected hemisphere were analyzed.The anatomical images were preprocessed , then segmented with the recon-all pipeline of FreeSurfer (v7.1.0),gross measures of volume of GM, WM, and LV; (ii) cortical morphometry for 34 regions of interest, parcellated according to the Desikan-Killiany cortical atlas;37; and (iii) subcortical structures35 with the volume of nine regions, each normalized to total hemisphere volume . For the cortical morphometry, for each participant, we calculate CxT in mm, which we did not normalize ; CSA in mm2 by taking the area of each region and dividing it by the mean of all of the regions in that hemisphere only; and CV in mm3 normalized by total hemisphere volume.41Morphometric measures were derived from the preserved hemisphere of the patients and, separately, from each hemisphere of the controls, as follows: (i) 42 .Data were analyzed in Rp-values.For each dependent measure, using GLM, the intact LH or RH of the patients was compared to the controls’ corresponding LH or RH, and then the two patient groups were compared against each other with hemisphere as a between-subjects factor. To avoid concern for committing Type 1 errors with multiple comparisons, we applied specified methods for multiplicity of testing with family-wise correction on all the p-value was then calculated as the percentage of occurrences in which the absolute value of the β-coefficient from the simulated distribution exceeded the absolute value of the true β-coefficient. Significance was ascertained at an α-criterion of .05, and, per measure, the Benjamini-Hochberg correction45 was applied to p-values across the total number of ROIs. In addition, for further adjudication of the findings, Bayes factor (BF) was computed by comparing the model with the group term to a null model without the group term.47 This was especially important to examine null results and to obtain further evidence to inform the absence of significant effects. BFs below 0.33 and above 3 were interpreted as evidence for the alternative hypothesis and for the null hypothesis, respectively.Given the relatively small sample sizes in all analyses, for each dependent measure, permutation testing was implemented by randomly shuffling the group label, and a GLM was then fit with group as the primary predictor of interest and age and gender as covariates. This was repeated 1,000 times to create a distribution of the β-coefficients for the effect of group. A r2 of the regression models are provided using the well-established Nagelkerke measure , and the factors entered are terminated when the model change is less than .001. The Nagelkerke values indicate that a value of 0.2 or less indicates a weak relationship between the predictors and the outcome, a value of 0.2 to 0.4 indicates a moderate relationship, and a value of 0.4 or higher indicates a strong relationship. Because we are only interested in values indicating at least a moderate or a strong relationship, we only report those computed r2 values that are greater than 0.25 and, for those below 0.25, we simply report the presence of a weak relationship between the predictors and outcome and do not interpret further.The above analyses examined each dependent measure separately between patients and controls and between the two patient subgroups. To elucidate which measures, alone or in combination, predicted group membership for each patient group and the matched hemisphere of the controls and between patient groups, we conducted forward binary logistic regression analyses. Such a procedure yields the variables that account for significant variance, over and above other significant variables already entered into the model. Last, we predicted ILAE outcome (high versus low) for the patients using a multivariate approach. The For all analyses, the statistical comparisons are reported in the following sequence. First, we report the findings of each GLM, separately, relative to their corresponding matched controls. We then describe the findings from comparisons of the two patient groups against each other. Note that age and gender are included as covariates in every analysis. Thereafter, we report the results of a forward binary logistic regression analysis identifying the factors that best predict group assignment.p=.02, BF=0.57) and significantly smaller WM volume , and no difference on GM volume . Relative to the RH of the controls, the RH patient group had significantly larger LV volume , significantly smaller WM volume  but also significantly smaller GM volume . The volume of the LV did not differ across the two patient groups , nor did the volume of the WM differ . However, the LH patient group had significantly greater GM volume than the RH patient group . The data and results of these analyses are shown in GLM revealed that relative to the LH of the controls, LH patients had significantly larger LV volume (p < .05 for entry criterion: LH patients and LH controls could not be reliably discriminated (model with low r2 indicating a weak relationship between the predictors and outcome). Restricting this same analysis to RH patients and RH controls yielded a model of GM and LV, in that order, but not WM, with an r2 of 0.5. GM alone was the best predictor of which hemisphere is preserved in direct comparison of the patient subgroups with a r2 = 0.28. Last, we examined whether these gross anatomical measures might predict seizure burden post-surgery using ILAE scores: no predictor/s were able to differentiate the ILAE binned scores of the patients.To evaluate which of these three dependent measures, LV, GM, and WM, singly or in combination predicted group membership, we used forward binary logistic regression with Together, the results of the GLM analyses were well supported by the logistic regression models. Patients with a preserved LH differed from their matched controls on LV and WM, but not GM, but the group differences were not reliable on binary regression analysis. The patients with a preserved RH differed significantly from controls on all three measures of gross anatomy; however, just GM and LV, and not WM, combined into a moderately predictive regression model. GM alone predicted patient group membership across the two patient groups, and ILAE outcome could not be predicted by any dependent measure/s.2, and CV in mm3. We then report forward binary regression analyses, as above, separately for the three dependent measures, to determine the model/s that best predict group membership and ILAE binned scale. Last, we conduct a full multivariate regression including all three dependent variables for each of the 34 regions for predicting LH and RH patients against their respective controls and then against each other to determine side of non-resected hemisphere.This section presents the GLM analyses separately for three dependent measures, CxT in mm, SA in mmp and BF values.)As shown in r2=0.8, included the CxT of the caudal middle frontal, frontal pole, lateral occipital, lingual, pars orbitalis, and transverse temporal regions. A model with r2=0.89 which included CxT of entorhinal, rostral middle frontal, and superior temporal regions differentiated LH from RH patients. No viable model was able to separate the patients into ILAE high vs. low binned scores.A forward regression analysis with CxT indices of all 34 regions of LH patients vs. LH controls resulted in no predictors passing initial criterion for inclusion, indicating that patients and controls cannot be differentiated on LH CxT. A model with a strong association between the predictors and RH patient vs. RH control groups, p and BF values.)As depicted in r2=0.83 and included the CSA of the entorhinal, lateral orbitofrontal, paracentral, rostral middle frontal, and superior temporal regions. The two patient groups were differentiable by a model containing just the CSA of the pars orbitalis area, with r2=0.95, and a model with r2=0.33 including just the paracentral area predicted ILAE outcome score.In a forward logistic regression analysis with CSA of all 34 areas entered as independent measures for the LH patients and matched controls, no model could be derived that associated predictor (region) with outcome (group membership). For the RH patients and controls, the most predictive model contained a high p and BF values.)On the final dependent measure, CV, as shown in r2=0.57, which included the rostral middle frontal and pars orbitalis volume predicted group membership for the RH patients vs. RH controls. The RH and LH patients were well differentiated by a model containing pars opercularis and pars orbitalis with r2=0.9. ILAE score was also highly predicted by a model containing CV of paracentral, pars triangularis, and superior parietal volume, with r2=0.71.A forward logistic regression analysis with the measures of CV for each of the 34 regions entered predicting the differences between LH patients and controls had no significant predictors. A model with For a summary of all logistic regression analyses, see We used the FreeSurfer atlas to segment the preserved hemisphere in patients and both hemispheres in controls, into nine subcortical regions, namely, the nucleus accumbens (here referred to as accumbens), amygdala, caudate, cerebellum, hippocampus, pallidum, putamen, thalamus, and ventral diencephalon; and extracted the volume of these regions.p and BF values.)Compared with the LH of controls, patients with a preserved LH showed a significant volume reduction of the accumbens, caudate, pallidum, and putamen. Patients with a preserved RH had significantly reduced volume in the accumbens and hippocampus compared to controls. The LH patient group had significantly lower volume in the caudate and putamen relative to the RH patient group .  bins.To evaluate which of these nine subcortical measures, singly or in combination, best predicted group membership, we used the same forward binary logistic regression procedure as above. The model differentiating LH patients and LH controls yielded a model which included putamen and accumbens, with In sum, the GLM results clearly differentiated the LH and RH patients from their matched controls on four and two of the nine subcortical regions, respectively, with the accumbens having lower volume for both patient groups vs. controls. The preserved LH patients had smaller volume than the RH patients in the putamen and caudate. The regression model identified the accumbens and the putamen as predicting LH patients from controls, and the accumbens alone as predictive of group membership in RH patients vs. controls. The putamen alone separated the two patient groups, which is unsurprising given the two direct patient-controls comparisons, and the ILAE outcome could not be predicted by any variable/s. These findings indicate that the accumbens and/or putamen are the key subcortical structures  that differentiate patients from controls, and the putamen is key for differentiating side of preserved hemisphere in the patients.r2 = 0.48 discriminated between the RH patients and RH controls.One possible explanation for the differences between the findings for the LH and RH patients is that the number of cases of resection and ablation vary for the two groups, with a larger proportion of the LH than RH patients having an ablation rather than a resection: LH – 7 ablation, 12 resection; RH – 2 ablation, 11 resection. Considering this, we recomputed all the binary logistic regression analyses with just the resection cases . Notwithstanding the loss of statistical power with this data reduction, the findings using the three gross measures  largely mirrored that of the analysis including all patients: whereas no model could predict group membership between LH patients and controls or between LH patients and RH patients, a model with LV and GM with r2=0.27–which included the fusiform and the inferior parietal regions–predicted group membership for LH patients vs. LH controls. A stronger association between group membership (patient vs. control) for the RH was observed with the CxT of just two areas, the frontal pole and posterior cingulate playing a predictive role, and a strong prediction of side of preserved hemisphere (LH vs. RH) was obtained for separating the two patient groups. For CSA, no model predicted patients vs. controls for the LH comparisons. However, a model with r2=0.76  separated patients and controls in the RH comparisons, and a very strong model of r2=0.9 just with the pars orbitalis separated the two patients groups. Last, the findings of differences in CV were well substantiated in the no-ablation analysis.Additionally, the analysis of the cortical regions with just the resection patients revealed largely similar results to that conducted with all the patients. With respect to CxT, a relatively weak model of r2=0.56 including the accumbens and putamen separated the LH patients from their controls; a model with r2=0.33 and including the accumbens separated the RH patients from their controls, while a model with r2=0.66 and including only the putamen separated the two patient groups.Last, the regression analysis using the subcortical regions essentially replicated the analysis with all the patients and perhaps yielded results that were even statistically stronger. A model with p<.0002) between the gross measures, the volumes of subcortical regions, and the three dependent measures for each of the 34 cortical parcels, and we did this separately for all patients (N=32), and then only LH patients and only RH patients. In no analysis did any correlation survive the most stringent multiple comparison.In this final analysis, we examine whether changes in gross measures, for example, the size of the LVs are statistically associated with subcortical or cortical measures. Because the cranium is a fixed size cavity, a large increase in one major feature/tissue like CSF and LV volume will necessarily induce a large decrease in the rest, such neighbouring white matter. To examine this, we performed bivariate correlations .7 Almost all such studies have been carried out in adults with temporal lobe epilepsy or anterior temporal lobectomy, and have largely focused on just one variable, such as CxT or CV .We undertook a comprehensive characterisation of the structural integrity of the post-surgical preserved hemisphere in a sample of DRE paediatric patients. Studies of postsurgical brain anatomy in DRE adults have yielded conflicting findings: whereas some have reported reduction, and even reversal, of progressive cortical thinning (i.e. an increase in CxT)18Here, we elucidated the morphometry of the preserved hemisphere in individuals following surgery for the management of epileptic seizures in childhood, an age of greater opportunity for plasticity than in adulthood. A clear depiction of the non-resected hemisphere is increasingly pressing as surgery for those with DRE, especially during childhood, is becoming a first-line form of intervention.We recruited 32 post-surgical patients, with different forms of intervention ranging from large resections such as hemispherectomy to more focal alterations such as after robot-assisted laser ablation and compared their preserved hemisphere to that of matched controls. We then compared the morphometry of the patients with preserved LH with that of patients with preserved RH. We derived a host of morphometric measures from gross indices of LV, GM, and WM volumes, multiple indices of 34 cortical parcels, and volumes of nine subcortical regions. We also examined differences as a function of which hemisphere was preserved, redid the analysis to exclude laser ablation , and examined correlations across the various metrics. Statistical analyses were conducted using both GLM and binary logistic regression analyses to provide different vantage points on the data, and the results were largely, although not always perfectly, converging.Several key findings emerged from the data . The volume of GM alone successfully predicted whether the LH vs. RH was preserved with less atrophy in the LH than RH.2 and CV in mm3).For the analysis of the 34 cortical regions, we adopted multiple measures for quantification  was the CSA of the superior temporal region. The cortex of patients with a preserved RH differed from their controls on all three dependent measures in both binary logistic and GLM analyses. For example, measures of cortical thickness revealed reductions in a host of frontal, temporal, and occipital areas and in the isthmus, insula, and precuneus. Counterintuitively, the patients had larger CSA than controls in lateral orbitofrontal, parahippocampal, and paracentral areas, and a subset of these areas predicted the group membership (patient vs. control) in the best fit regression model. Lastly, the RH patients evinced reductions in the CV of the rostral middle frontal area , which, together with the pars orbitalis gave rise to good assignment of membership into patients vs. controls.A direct comparison between the two patient groups revealed a host of differences with greater reduction in CxT in frontal, entorhinal, and superior temporal regions, along with, for preserved RH vs .LH, reduced CSA in frontal cingulate and transverse temporal regions, but also greater CSA in, for example, frontal pole, parahippocampal and pars orbitalis. Last, those with a preserved RH had smaller CV (more atrophy) in a set of frontal and temporal regions, and, consistent with the CSA measurements, larger volume in the inferior parietal and pars orbitalis regions. It is particularly noteworthy that between patient groups, differences in the pars orbitalis and the pars opercularis manifested as key sites in the CSA and CV GLM and regressions analyses.With respect to the nine subcortical regions, the volume of the putamen and accumbens  was reduced in both patient groups vs. controls, and the volume of the putamen alone (less volume in LH than RH) was able to differentiate the two patient groups from each other.Last, there were no correlations between gross measures and any other subcortical or cortical metrics that survived stringent familywise correction indicating independence between the morphometric changes of LV, WM and GM volume, and other measurements.The key findings include the presence of numerous differences in all three dependent measures between those with a preserved RH and their matched controls or between them and those with a preserved LH. In almost all instances, the preserved RH has reductions in CxT and CV but, surprisingly, has larger CSA in a few regions including orbitofrontal and parahippocampal regions. This relative decrement in the preserved RH is accompanied by some alterations in subcortical regions, namely in the accumbens, caudate, and putamen.Because the two groups were matched on age, gender, age at first surgery, age of seizure-onset age, and ILAE scores, and age and gender were included as covariates in all GLM analyses, none of these factors obviously account for the hemispheric differences. One potential difference is that the data were acquired on two different scanners, with arguably different resolution, but this, too, does not obviously explain the asymmetry as both patient groups were roughly equally represented on each scanner  and, moreover, the data were harmonised across magnets.N=7 and N=2 in the LH and RH patient groups, respectively. The re-analysis of the data  data see , with on49Scrutiny of the specific regional differences between those with preserved LH vs. RH may offer a possible explanation of the hemispheric asymmetry. The primary regional differences arise in the pars orbitalis and pars triangularis, but also in the caudal middle and superior frontal, middle and superior temporal, and transverse temporal regions. These findings, derived from an unbiased and whole brain data-driven analysis appear to converge largely on regions that are implicated in language function. Resecting some, most, or all of the LH (preserved RH group), and, likely, the native dominant language areas in childhood, is likely the source of alterations of LH homologues of language areas in the preserved RH. In contrast, a resection of some, most, or all of the RH (preserved LH group) results in remarkably few structural or anatomical differences relative to the matched controls’ LH and, indeed, such children with a preserved LH have been shown to have better cognitive and language outcomes.51) potentially trigger the morphometric changes in the RH. Much evidence attests to the fact that, in early childhood, both hemispheres are predisposed to language function. For example, in significant contrast to the marked aphasias evident in adults with brain injury, children with unilateral brain injury performed within the normal range of language function, and this was true independent of hemisphere of injury.52 Likewise, adolescents and young adults who suffered a perinatal ischemic stroke to the LH nevertheless displayed sentence processing abilities equal to that of non-neurological controls, presumably a result of RH language engagement.53 The idea of RH plasticity for language has also been confirmed in neuroimaging studies: individuals with peri- or prenatal periventricular damage to the LH evinced RH blood-oxygen-level-dependent activation during a silent word generation task, and the extent of the activation equaled that of the LH in right-handed controls.54 Findings such as these attest to the remarkable plasticity and potential for functional reorganisation of language to the RH homotopic frontotemporal regions.The hypothetical account, then, is that after LH cortical resection, regions of the preserved RH that are homotopic with LH language regions come to assume language functions. The process of accommodating language function in the RH .What remains to be explained is why we see reduction in these RH homotopic language regions rather than maintenance or even expansion, which is often associated with the assumption of a new function. Also, the changes in the RH are widespread: almost 50% of RH cortical regions show significant reduction in CxT. Of note, almost all of these areas in the RH are homotopic with or proximal to standard LH language areas . Presumably, as is also true over the course of normal development, cortical regions are pruned as functions are acquired through the removal of inefficient synapses, dendrites, and neurons. Many have suggested that the cortical tissue loss reflects improved neural processing by optimising brain circuits for particular operations.15 and specifically, in post-surgical vs. presurgical cortical regions, could not be assessed. Because of our one-time snapshot, whether the profiles of the childhood DRE brains improved specifically over presurgical profiles or not and the relationship between these changes over time, hemisphere of resection, and cognitive  outcome remain unaddressed and serve as rich fodder for future studies.Given the cross-sectional, rather than longitudinal design, of the current study, we are unable to evaluate changes over time and their relationship to behaviour. Reversal of progressive thinning and recovery from atrophy and thinningSupplement 1


Currently, there is a growing concern about the disease burden of child asthma particularly due to high body mass index (BMI). The prevalence and disease burden of asthma differ between developing and developed countries, with implications on disease intervention. Therefore, we provide a comparative analysis of childhood asthma between China and the United States of America (USA).Using the Global Burden of Disease (GBD) 2019 data, we estimated and compared the age-standardized prevalence, disability-adjusted life years (DALYs), years of life lost (YLLs), years of lost due to disability (YLDs), DALYs due to high BMI of asthma in children aged 1–14 years in China and the USA. Joinpoint regression analysis was applied to assess changes in temporal trends.DALYs due to high BMI and the ratio of DALYs to DALYs due to high BMI in children with asthma showed a significant upward trend in both countries and were higher in males than in females. Almost all epidemiological indicators of asthma showed a hump of curve from 2014 to 2019, and peaked in 2017. There was a decreasing trend of YLLs for asthma in children both countries, while China has a saliently greater decreasing trend.The disease burden caused by high BMI of childhood asthma was on the rise in children with asthma in both China and the USA. High BMI needs to be taken more into account in the development of future policies for the prevention, control, and treatment of childhood asthma. However, the increasing trend of this disease burden in American children was significantly lower than that in Chinese children. We recommend learning from the American government to impose a high-calorie tax, increase physical exercise facilities, and provide better health care policies. Asthma is one of the most common chronic diseases in children, with wheezing, coughing, and airflow restriction as clinical manifestations, affecting children’s daily life . The incHowever, the etiology of childhood asthma is yet to be elucidated. Therefore, identifying its risk factors and exploring possible mechanisms is necessary for early detection and intervention to prevent further adverse outcomes . CurrentThere are differences in the prevalence and disease burden of asthma between developing and developed countries . The dirhttp://ghdx.healthdata.org/gbd-results-tool).The Global Burden of Disease (GBD) 2019 is a cross-border collaborative project covering 204 countries and regions. It collected data from disease surveillance sites, surveys of the National Health Service, and published literature data to estimate descriptive epidemiological information on the incidence, prevalence, disability-adjusted life years (DALYs), years of lost due to disability (YLDs), and years of life lost (YLLs) for 369 stratified diseases and injuries using the DisMod-MR 2.1 as a Bayesian meta-regression model ,15. The DALYs are a summary metric of YLDs calculated by multiplying the prevalence of individual sequelae by the disability weights, and YLLs that are the actual loss of life that occurs from death at each age modified by parameters such as the standard life expectancy at the corresponding age . As a noJoinpoint Regression Program version 4.9.0.0  was used to analyze the changes in trends in specific disease burden indicators from 1990 to 2019. The ordinary least squares method was used to fit the regression model under the assumption that the error random variables were homoskedastic. To increase the credibility of the results, we set the maximum number of joinpoints to 3 and determined the locations of the joinpoints and the corresponding p-values by Monte Carlo permutation test. Log-linear regression was used to calculate their annual percentage change (APC) and average annual percentage change (AAPC) . T-distrThe temporal trends in the age-standardized prevalence of childhood asthma by sex and age strata in China and the USA are presented in The temporal trends in the age-standardized DALYs and DALYs due to high BMI of childhood asthma by sex and age strata in China and the USA are shown in The temporal trends in the age-standardized YLDs and YLLs of childhood asthma by sex and age strata in China and the USA are shown in The ratio of DALYs to DALYs due to high BMI in children with asthma showed a consistent upward trend in both China and the USA . The ratOur findings revealed that the prevalence of asthma among children of all ages in China showed a slow increase from around 2006 to 2014, which can be attributed with the environmental pollution due to industrialization and urbanization in China, as well as the increase in children with high BMI ,20. The Overall, the prevalence and DALYs of childhood asthma in the USA showed an increasing trend from 1990 to 2019. Part of the reason for this is related to the significant increase in the consumption of sugary drinks such as nutritional/energy drinks, juice drinks, and sweet tea among American children, and sugary drinks are thought to be associated with childhood asthma . HoweverHigh BMI is a risk factor of great concern for childhood asthma . Our stuThe prevalence, DALYs and DALYs due to high BMI were higher in boys than in girls across all age groups in both countries. Boys also have a relatively narrow airway, and are more inclined to vigorous exercise with their greater range of motion, and thus, are more likely to get exposed to allergens. This corroborates the findings of Ellie et al. that boys are more likely to develop allergic diseases than girls based on blood-specific IgE assays and skin prick tests for common allergens . In bothOur study has some limitations. The GBD 2019 lacks data on other risk factors such as high-fat diet and tobacco exposure for asthma in children aged 1–14 years, as well as interactions between risk factors in the estimates, these factors may have introduced bias in the study. In addition, the diagnosis of asthma in children aged 1–4 years is based primarily on clinical judgment and assessment of symptoms and physical findings, which may lead to a failure to reliably diagnose asthma in this age group .DALYs rates due to high BMI and ratio of DALYs rates to DALYs rates due to high BMI were on the rise in children with asthma in both China and USA. High BMI needs to be taken more into account in the development of future policies for the prevention, control, and treatment of childhood asthma. Although both indicators of asthma in children in the USA are higher than in those China, the increasing trend is significantly lower than that in Chinese children of almost all ages. Therefore, it is recommended to learn from the American government to impose a high-calorie tax, increase physical exercise facilities, and provide better health care policies. Besides, we appeal that children increase their physical activity and maintain a healthy diet and that parents encourage and safeguard it. Children aged 5–9 years had the highest prevalence and DALYs in both countries. Careful attention and targeted intervention should be considered in this population, who are particularly at high risk for asthma. 4 Jan 2023
 PONE-D-22-30916

 Analysis of disease burden due to high body mass index in childhood asthma in China and the USA based on the Global Burden of Disease Study 2019

 PLOS ONEDear Dr. Pan,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.==============================ACADEMIC EDITOR: Dear authors, please revise your manuscript according to the referees’ and editor's comments and upload the revised file. First thing is that you need to revise rationale for a comparison of China and USA. You just mentioned that there is no such a study and that you decided to do it, however, you have to state precisely why is it so important, to make a comparison exactly between these two countries. Furthermore, the aims in your Introduction section are mentioned twice and are not completely clear. Be sure to define them accurately. Both reviewers indicated that the manuscript lacks in more details on situation in USA. Further, try to provide more in-depth analysis throughout the whole manuscript. Finally, please, double-check the reference number 22.==============================plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.Please submit your revised manuscript by Feb 18 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at
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Please do not edit.]Reviewers' comments:Reviewer's Responses to Questions  Comments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?  The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: PartlyReviewer #2: Partly**********  2. Has the statistical analysis been performed appropriately and rigorously?   Reviewer #1: YesReviewer #2: Yes**********  3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: Dear authors:We are very grateful for your submission of the manuscript to Plos One. The research topic is considered to be very interesting but the article requires an in-depth review of the results and, in particular, a further discussion of childhood asthma in the USA. Also, the introduction, materials and methods are not detailed enough.Sincerely.Reviewer #2: The authors have chosen an interesting study topic to quantify the disease burden due to high body mass index in childhood asthma. The GDB methodology is currently a very important approach to global descriptive epidemiology with the intention of knowledge translation. Hence, the results of the GBD studies should be understandable not only to the academic audience but also to the stakeholders and decision-makers in the health policy domain. In this sense, all improvements to the text should enable the achievement of these goals. There are no ethical issues concerning this paper.The text in the Introduction (lines 57-59) needs a reference. Consider excluding Ref 8 and deleting the sentence from P 4, line 60. Also, the authors should include an additional reference which is recently published on this topic The Protocol for the global burden of diseases, injuries, and risk factors study  should be the reference added (and used) to the Method section.The results are extensive. However, it seems difficult for authors to extract a meaningful message from the results section to emphasize the rationale for comparing the findings from China and USA. They haven’t concluded anything about disease burden due to the high body mass index in childhood asthma in the USA . Thus, I suggest rewriting of the conclusion section.In the Discussion section, I suggest that authors delete the sentence ; it is irrelevant to this paper.I am confused with the text in the Reference section (lines 360-457). Please, check if it is an addition of ref. 22, and, is it necessary.**********  6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.If you choose “no”, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.  Yes: Enrique Gea-IzquierdoReviewer #1: Reviewer #2: No**********https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool,  2 Feb 2023February 2, 2023Dear Editor,Thank you very much for giving us the opportunity to revise our manuscript entitled “Analysis of disease burden due to high body mass index in childhood asthma in China and the USA based on the Global Burden of Disease Study 2019”. The manuscript ID is PONE-D-22-30916. We would also like to thank the editorial board and all the reviewers for their constructive and insightful comments, which helped us improve our manuscript.We have ensured that all reviewer comments were adequately answered. For example, in accordance with the suggestions given by Reviewer 1, we have enriched the content of the “Introduction” and “Materials and methods” sections. As for the concerns raised by the two reviewers and the editor, we have added a more in-depth discussion of the prevalence, DALYs, and effect of the risk factor high BMI on disease burden of childhood asthma in children in the USA. Responses to the reviewers’ comments are provided below in a point-by-point manner. All the changes made are marked in red in the revised manuscript. We hope that our revisions satisfactorily address all concerns raised by the reviewers.https://doi.org/10.17026/dans-zvj-qgp4. In addition, we reworked the files to confirm compliance with journal style requirements. For example, our figure files have been corrected by the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool. Besides, we have uploaded the data from this study to a stable public repository. The data links are as follows: Zhang, C.Y.  (2022): Epidemiological data on childhood asthma in China and the United States. DANS. We wish to thank you again for carefully reviewing and considering our manuscript. Sincerely yours,Chengyue ZhangResponse to CommentsAcademic EditorDear authors, please revise your manuscript according to the referees’ and editor's comments and upload the revised file. First thing is that you need to revise rationale for a comparison of China and USA. You just mentioned that there is no such a study and that you decided to do it, however, you have to state precisely why is it so important, to make a comparison exactly between these two countries. Furthermore, the aims in your Introduction section are mentioned twice and are not completely clear. Be sure to define them accurately. Both reviewers indicated that the manuscript lacks in more details on situation in USA. Further, try to provide more in-depth analysis throughout the whole manuscript. Finally, please, double-check the reference number 22.Response: Thank you for this comment. We have added a rationale for choosing China and the USA for comparison, as well as a more in-depth discussion of the prevalence, DALYs, and effect of the risk factor high BMI on disease burden of childhood asthma in children in the USA. In addition, we apologize for not clearly expressing the objectives in the “Introduction” section; thus, we have reordered the statements, expanded the content, and optimized the “Introduction” section. For reference number 22, we apologize for this error. We have checked the style of the cited reference and have made corrections.Reviewer 1Dear authors:We are very grateful for your submission of the manuscript to Plos One. The research topic is considered to be very interesting but the article requires an in-depth review of the results and, in particular, a further discussion of childhood asthma in the USA. Also, the introduction, materials and methods are not detailed enough.Response: Thank you for your constructive comment. We have deepened the analysis of the study results in the “Discussion” section, particularly by adding a discussion of the disease burden of childhood asthma in American children. Our manuscript has been revised as follows: “Overall, the prevalence and DALYs of childhood asthma in the USA showed an increasing trend from 1990 to 2019. Part of the reason for this is related to the significant increase in the consumption of sugary drinks such as nutritional/energy drinks, juice drinks, and sweet tea among American children, and sugary drinks are thought to be associated with childhood asthma [1]. However, the upward trend of both indicators from around 2010 to 2019 was significantly reduced compared to that in the period from 2005 to 2009. The prevalence and DALYs of childhood asthma decreased in children aged 1-4 years between 2010 and 2019. This may be related to the enactment of the Clean Air Act amendments in 2011 and the Clean Power Plan in 2015 in the USA. In particular, the Regional Greenhouse Gas Initiative (RGGI) has contributed significantly to the reduction of greenhouse gases in the power sector and toxic air pollutants associated with the onset of asthma, such as PM2.5, over the past decade [2]. Another possible reason is that most US states enacted a tax on sugar-sweetened beverages (SSB) by 2010, which plays a role in reducing SSB-induced high BMI [3]. The prevalence and DALYs of asthma were higher in children in the USA than in those in China. The main reason may be related to the health hypothesis, indicating that less exposure to infection during childhood may result in a greater chance of developing asthma later in life [4]. YLLs in children in both countries account for a minimal proportion of DALYs, and are associated with a very low mortality rate in children with asthma [5]. High BMI is a risk factor of great concern for childhood asthma [6]. Our study found an increasing trend in DALYs due to high BMI and the ratio of DALYs rates to DALYs rates due to high BMI in Chinese and American children with asthma. One reason for this is that certain parents of children with asthma are concerned about exercise-induced bronchoconstriction (EIB), and thus impose restrictions on the physical activities of their children, consequently affecting weight management [7]. However, in reality, exercise can increase lung function, promote cardiopulmonary fitness, and control asthma [8]. Adequate warm-up before exercise is also recommended [9]. Another reason is that children with high BMI are more inclined to consume a high-fat diet, which can increase bronchial hyperresponsiveness and exacerbate the symptoms of asthma [10]. Positive effects of weight loss on asthma-related outcomes have been demonstrated [11]. The latest Global Initiative for Asthma (GINA 2021) lists obesity as a modifiable risk factor [6]. Since the global prevalence of high BMI is constantly rising, increasing exercise and reducing high-fat food intake to control high BMI are necessary to reduce the risk of asthma [12]. Although the DALYs rates due to high BMI and the ratio of DALYs rates to DALYs rates due to high BMI were both higher in American children than in Chinese children, the increasing trend of both indicators was significantly higher in Chinese children of almost all ages than in American children. Chinese boys of all ages had a higher percentage of high BMI than girls, which is consistent with the findings of Guo et al. [13]. A study of disease burden, injury, and risk factors by state in the USA from 1990 to 2016 found that high BMI was the most important risk factor in the USA, and that exposure was steadily increasing [14]. They believe that renewed efforts to control weight at the community level are important, and that controlling high BMI needs to be a priority for all stakeholders such as physicians, nurses, policy makers, patients, and families. Liu et al. found that the American government partially eliminated the adverse effects of obesity on asthma by imposing a high-calorie tax, increasing the proportion of nutritious food advertisements, banning the sale of soft drinks, increasing opportunities and venues for physical activity, and implementing better health care policies [15]. Therefore, it is recommended that high BMI be taken more into account in the future development of policies for the prevention, control, and treatment of childhood asthma. Moreover, we recommend that children reduce their BMI by increasing physical activity and eating a healthy diet, which parents should encourage and safeguard [16]. The prevalence, DALYs and DALYs due to high BMI were higher in boys than in girls across all age groups in both countries. Boys also have a relatively narrow airway, and are more inclined to vigorous exercise with their greater range of motion, and thus, are more likely to get exposed to allergens. This corroborates the findings of Ellie et al. that boys are more likely to develop allergic diseases than girls based on blood-specific IgE assays and skin prick tests for common allergens [17]. In both China and the USA, the prevalence and DALYs were highest in the 5-9 years age group. This could be due to the fact that children in this age group are at high risk of upper respiratory tract infections because of their low self-management skills and immune levels [13]. In addition, upper respiratory tract infections are important triggers for asthma in children. Moreover, the YLLs for girls aged 10-14 years in the USA have the highest levels than that for girls in the other groups, which is considered to be associated with the increased levels of estrogen and progesterone during the luteal phase in girls of this age group, resulting in increased inflammation of the airway wall [18].” In addition, we have expanded the “Introduction” and the “Materials and methods” sections. Modifications in the “Introduction” section:“Asthma is one of the most common chronic diseases in children, with wheezing, coughing, and airflow restriction as clinical manifestations, affecting children's daily life [19]. The incidence, prevalence, and medical costs of this disease have been increasing in recent years . A survey revealed that the prevalence of asthma in Chinese children increased from 0.91% to 2.12% between 1990 and 2010 [21]. Respiratory health during early life may have a lifelong impact on lung health and life expectancy; thus, prevention and control of childhood asthma is particularly crucial to promote individual health and reduce the societal burden of the disease [22]. However, the etiology of childhood asthma is yet to be elucidated. Therefore, identifying its risk factors and exploring possible mechanisms is necessary for early detection and intervention to prevent further adverse outcomes [23]. Currently, reported risk factors for asthma include genetic factors, tobacco exposure, dampness/humidity, animal contact, climate, and inhalation of small particles . High body mass index (BMI), which is considered as the seventh-leading level 2 risk factor for attributable disability-adjusted life years (DALYs) of diseases in 2019, is also a risk factor for asthma [25]. It is thought to be associated with dietary habits, lifestyle, and food intake [26].There are differences in the prevalence and disease burden of asthma between developing and developed countries [4]. The direct and indirect economic costs of childhood asthma are high, and there is a link between the disease burden of asthma and the economic level of the country [27]. It is well known that China is the largest developing country in the world and that the United States of America (USA) is the major developed country . However, to the best of our knowledge, there has been no comparative analysis between China and the USA in these areas. Thus, this study aimed to investigate the prevalence of asthma, DALYs, and the effect of the risk factor high BMI on disease burden in children aged 1-14 years in China and the USA, to compare and analyze the differences between them, to provide information for resource allocation, and to learn from the prevention and control strategies of developed countries such as the USA, which can provide some prevention and control strategies to reduce the disease burden of childhood asthma in developing countries such as China.” Modifications in the “Materials and methods” section:“The GBD estimation process uses 86,249 sources that are broad and representative, including censuses, household surveys, health service use, civil registration and vital statistics, air pollution testing, etc.” “In this study, we obtained data on the prevalence, DALYs, YLDs, YLLs, and DALYs due to high BMI of childhood asthma in children aged 1-14 years in China and the USA from GBD 2019.” “All epidemiological data obtained were age-standardized to match the characteristics of the different national reference populations and finally expressed in terms of 100,000 population [30].” “Comparing AAPC with 0, the curve shows an increasing or decreasing trend with 95% CI not including 0 when the AAPC value is positive or negative. When the 95% CI of AAPC includes 0, the value is stable.” Reviewer 2General CommentThe authors have chosen an interesting study topic to quantify the disease burden due to high body mass index in childhood asthma. The GDB methodology is currently a very important approach to global descriptive epidemiology with the intention of knowledge translation. Hence, the results of the GBD studies should be understandable not only to the academic audience but also to the stakeholders and decision-makers in the health policy domain. In this sense, all improvements to the text should enable the achievement of these goals. There are no ethical issues concerning this paper.Response: Thank you for this comment. We have added a more in-depth analysis of the discussion, particularly on the disease burden of asthma in children in the USA. In addition, we have added a description of American policies to prevent and control childhood asthma and provided relevant recommendations for policy development in the field of public health and for children's own measures to prevent the disease. Our manuscript has been revised as follows: “Overall, the prevalence and DALYs of childhood asthma in the USA showed an increasing trend from 1990 to 2019. Part of the reason for this is related to the significant increase in the consumption of sugary drinks such as nutritional/energy drinks, juice drinks, and sweet tea among American children, and sugary drinks are thought to be associated with childhood asthma [1]. However, the upward trend of both indicators from around 2010 to 2019 was significantly reduced compared to that in the period from 2005 to 2009. The prevalence and DALYs of childhood asthma decreased in children aged 1-4 years between 2010 and 2019. This may be related to the enactment of the Clean Air Act amendments in 2011 and the Clean Power Plan in 2015 in the USA. In particular, the Regional Greenhouse Gas Initiative (RGGI) has contributed significantly to the reduction of greenhouse gases in the power sector and toxic air pollutants associated with the onset of asthma, such as PM2.5, over the past decade [2]. Another possible reason is that most US states enacted a tax on sugar-sweetened beverages (SSB) by 2010, which plays a role in reducing SSB-induced high BMI [3]. The prevalence and DALYs of asthma were higher in children in the USA than in those in China. The main reason may be related to the health hypothesis, indicating that less exposure to infection during childhood may result in a greater chance of developing asthma later in life [4]. YLLs in children in both countries account for a minimal proportion of DALYs, and are associated with a very low mortality rate in children with asthma [5]. High BMI is a risk factor of great concern for childhood asthma [6]. Our study found an increasing trend in DALYs due to high BMI and the ratio of DALYs rates to DALYs rates due to high BMI in Chinese and American children with asthma. One reason for this is that certain parents of children with asthma are concerned about exercise-induced bronchoconstriction (EIB), and thus impose restrictions on the physical activities of their children, consequently affecting weight management [7]. However, in reality, exercise can increase lung function, promote cardiopulmonary fitness, and control asthma [8]. Adequate warm-up before exercise is also recommended [9]. Another reason is that children with high BMI are more inclined to consume a high-fat diet, which can increase bronchial hyperresponsiveness and exacerbate the symptoms of asthma [10]. Positive effects of weight loss on asthma-related outcomes have been demonstrated [11]. The latest Global Initiative for Asthma (GINA 2021) lists obesity as a modifiable risk factor [6]. Since the global prevalence of high BMI is constantly rising, increasing exercise and reducing high-fat food intake to control high BMI are necessary to reduce the risk of asthma [12]. Although the DALYs rates due to high BMI and the ratio of DALYs rates to DALYs rates due to high BMI were both higher in American children than in Chinese children, the increasing trend of both indicators was significantly higher in Chinese children of almost all ages than in American children. Chinese boys of all ages had a higher percentage of high BMI than girls, which is consistent with the findings of Guo et al. [13]. A study of disease burden, injury, and risk factors by state in the USA from 1990 to 2016 found that high BMI was the most important risk factor in the USA, and that exposure was steadily increasing [14]. They believe that renewed efforts to control weight at the community level are important, and that controlling high BMI needs to be a priority for all stakeholders such as physicians, nurses, policy makers, patients, and families. Liu et al. found that the American government partially eliminated the adverse effects of obesity on asthma by imposing a high-calorie tax, increasing the proportion of nutritious food advertisements, banning the sale of soft drinks, increasing opportunities and venues for physical activity, and implementing better health care policies [15]. Therefore, it is recommended that high BMI be taken more into account in the future development of policies for the prevention, control, and treatment of childhood asthma. Moreover, we recommend that children reduce their BMI by increasing physical activity and eating a healthy diet, which parents should encourage and safeguard [16]. The prevalence, DALYs and DALYs due to high BMI were higher in boys than in girls across all age groups in both countries. Boys also have a relatively narrow airway, and are more inclined to vigorous exercise with their greater range of motion, and thus, are more likely to get exposed to allergens. This corroborates the findings of Ellie et al. that boys are more likely to develop allergic diseases than girls based on blood-specific IgE assays and skin prick tests for common allergens [17]. In both China and the USA, the prevalence and DALYs were highest in the 5-9 years age group. This could be due to the fact that children in this age group are at high risk of upper respiratory tract infections because of their low self-management skills and immune levels [13]. In addition, upper respiratory tract infections are important triggers for asthma in children. Moreover, the YLLs for girls aged 10-14 years in the USA have the highest levels than that for girls in the other groups, which is considered to be associated with the increased levels of estrogen and progesterone during the luteal phase in girls of this age group, resulting in increased inflammation of the airway wall [18].” Meanwhile, we have rewritten the conclusions as follows:“DALYs rates due to high BMI and ratio of DALYs rates to DALYs rates due to high BMI were on the rise in children with asthma in both China and USA. High BMI needs to be taken more into account in the development of future policies for the prevention, control, and treatment of childhood asthma. Although both indicators of asthma in children in the USA are higher than those in China, the increasing trend is significantly lower than that in Chinese children of almost all ages. Therefore, it is recommended to learn from the American government to impose a high-calorie tax, increase physical exercise facilities, and provide better health care policies. Besides, we appeal that children increase their physical activity and maintain a healthy diet and that parents encourage and safeguard it. Children aged 5-9 years had the highest prevalence and DALYs in both countries. Careful attention and targeted intervention should be considered in this population, who are particularly at high risk for asthma.” Specific Comment1. The text in the Introduction (lines 57-59) needs a reference. Consider excluding Ref 8 and deleting the sentence from P 4, line 60. Response: Thank you for this comment. We apologize for the error. We have cited Ref 8 in the original lines 57-59 and deleted the sentence in the original line 60:“High body mass index (BMI), which is considered as the seventh-leading level 2 risk factor for attributable disability-adjusted life years (DALYs) of diseases in 2019, is also a risk factor for asthma [25].” 2. Also, the authors should include an additional reference which is recently published on this topic Response: Thank you for this comment. We have studied this in depth and cited this reference in our discussion. The revisions are as follows:“Liu et al. found that the American government partially eliminated the adverse effects of obesity on asthma by imposing a high-calorie tax, increasing the proportion of nutritious food advertisements, banning the sale of soft drinks, increasing opportunities and venues for physical activity, and implementing better health care policies [15].” 3. The Protocol for the global burden of diseases, injuries, and risk factors study  should be the reference added (and used) to the Method section.Response: Thank you for this comment. We have added a relevant reference for the GBD protocol to increase the introduction to the GBD database: “The Global Burden of Disease (GBD) 2019 is a cross-border collaborative project covering 204 countries and regions. It collected data from disease surveillance sites, surveys of the National Health Service, and published literature data to estimate descriptive epidemiological information on the incidence, prevalence, disability-adjusted life years (DALYs), years of lost due to disability (YLDs), and years of life lost (YLLs) for 369 stratified diseases and injuries using the DisMod-MR 2.1 as a Bayesian meta-regression model .” 4. The results are extensive. However, it seems difficult for authors to extract a meaningful message from the results section to emphasize the rationale for comparing the findings from China and USA. They haven’t concluded anything about disease burden due to the high body mass index in childhood asthma in the USA . Thus, I suggest rewriting of the conclusion section.Response: Thank you for this comment. In the “Discussion” section, we have further analyzed meaningful results and added a discussion of the disease burden of childhood asthma in American children, particularly that resulting from high BMI. Our manuscript has been revised as follows: “Overall, the prevalence and DALYs of childhood asthma in the USA showed an increasing trend from 1990 to 2019. Part of the reason for this is related to the significant increase in the consumption of sugary drinks such as nutritional/energy drinks, juice drinks, and sweet tea among American children, and sugary drinks are thought to be associated with childhood asthma [1]. However, the upward trend of both indicators from around 2010 to 2019 was significantly reduced compared to that in the period from 2005 to 2009. The prevalence and DALYs of childhood asthma decreased in children aged 1-4 years between 2010 and 2019. This may be related to the enactment of the Clean Air Act amendments in 2011 and the Clean Power Plan in 2015 in the USA. In particular, the Regional Greenhouse Gas Initiative (RGGI) has contributed significantly to the reduction of greenhouse gases in the power sector and toxic air pollutants associated with the onset of asthma, such as PM2.5, over the past decade [2]. Another possible reason is that most US states enacted a tax on sugar-sweetened beverages (SSB) by 2010, which plays a role in reducing SSB-induced high BMI [3]. The prevalence and DALYs of asthma were higher in children in the USA than in those in China. The main reason may be related to the health hypothesis, indicating that less exposure to infection during childhood may result in a greater chance of developing asthma later in life [4]. YLLs in children in both countries account for a minimal proportion of DALYs, and are associated with a very low mortality rate in children with asthma [5]. High BMI is a risk factor of great concern for childhood asthma [6]. Our study found an increasing trend in DALYs due to high BMI and the ratio of DALYs rates to DALYs rates due to high BMI in Chinese and American children with asthma. One reason for this is that certain parents of children with asthma are concerned about exercise-induced bronchoconstriction (EIB), and thus impose restrictions on the physical activities of their children, consequently affecting weight management [7]. However, in reality, exercise can increase lung function, promote cardiopulmonary fitness, and control asthma [8]. Adequate warm-up before exercise is also recommended [9]. Another reason is that children with high BMI are more inclined to consume a high-fat diet, which can increase bronchial hyperresponsiveness and exacerbate the symptoms of asthma [10]. Positive effects of weight loss on asthma-related outcomes have been demonstrated [11]. The latest Global Initiative for Asthma (GINA 2021) lists obesity as a modifiable risk factor [6]. Since the global prevalence of high BMI is constantly rising, increasing exercise and reducing high-fat food intake to control high BMI are necessary to reduce the risk of asthma [12]. Although the DALYs rates due to high BMI and the ratio of DALYs rates to DALYs rates due to high BMI were both higher in American children than in Chinese children, the increasing trend of both indicators was significantly higher in Chinese children of almost all ages than in American children. Chinese boys of all ages had a higher percentage of high BMI than girls, which is consistent with the findings of Guo et al. [13]. A study of disease burden, injury, and risk factors by state in the USA from 1990 to 2016 found that high BMI was the most important risk factor in the USA, and that exposure was steadily increasing [14]. They believe that renewed efforts to control weight at the community level are important, and that controlling high BMI needs to be a priority for all stakeholders such as physicians, nurses, policy makers, patients, and families. Liu et al. found that the American government partially eliminated the adverse effects of obesity on asthma by imposing a high-calorie tax, increasing the proportion of nutritious food advertisements, banning the sale of soft drinks, increasing opportunities and venues for physical activity, and implementing better health care policies [15]. Therefore, it is recommended that high BMI be taken more into account in the future development of policies for the prevention, control, and treatment of childhood asthma. Moreover, we recommend that children reduce their BMI by increasing physical activity and eating a healthy diet, which parents should encourage and safeguard [16]. The prevalence, DALYs and DALYs due to high BMI were higher in boys than in girls across all age groups in both countries. Boys also have a relatively narrow airway, and are more inclined to vigorous exercise with their greater range of motion, and thus, are more likely to get exposed to allergens. This corroborates the findings of Ellie et al. that boys are more likely to develop allergic diseases than girls based on blood-specific IgE assays and skin prick tests for common allergens [17]. In both China and the USA, the prevalence and DALYs were highest in the 5-9 years age group. This could be due to the fact that children in this age group are at high risk of upper respiratory tract infections because of their low self-management skills and immune levels [13]. In addition, upper respiratory tract infections are important triggers for asthma in children. Moreover, the YLLs for girls aged 10-14 years in the USA have the highest levels than that for girls in the other groups, which is considered to be associated with the increased levels of estrogen and progesterone during the luteal phase in girls of this age group, resulting in increased inflammation of the airway wall [18].” Meanwhile, we have rewritten the conclusions as follows:“DALYs rates due to high BMI and ratio of DALYs rates to DALYs rates due to high BMI were on the rise in children with asthma in both China and USA. High BMI needs to be taken more into account in the development of future policies for the prevention, control, and treatment of childhood asthma. Although both indicators of asthma in children in the USA are higher than those in China, the increasing trend is significantly lower than that in Chinese children of almost all ages. Therefore, it is recommended to learn from the American government to impose a high-calorie tax, increase physical exercise facilities, and provide better health care policies. Besides, we appeal that children increase their physical activity and maintain a healthy diet and that parents encourage and safeguard it. Children aged 5-9 years had the highest prevalence and DALYs in both countries. Careful attention and targeted intervention should be considered in this population, who are particularly at high risk for asthma.” 5. In the Discussion section, I suggest that authors delete the sentence ; it is irrelevant to this paper.Response: Thank you for your comment. We have deleted the relevant sentence. 6. I am confused with the text in the Reference section (lines 360-457). Please, check if it is an addition of ref. 22, and, is it necessary.Response: Thank you for your comment. We apologize for the mistake of Ref. 22. 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