Earlier research has determined that amblyopia or strabismus may cause remarkable brain anatomical and functional variations. Nonetheless, thus far, the spontaneous changes in brain activity in children with strabismus amblyopia (SA) remain unclear. The purpose of this study was to determine the association between abnormal brain activity in children with SA and its behavioral manifestations.?A total of 24 children with SA  as well as 24 healthy controls (HCs), including 10 male and 14 female children were closely matched in sex and age, and examined using resting-state functional magnetic resonance imaging (fMRI). The regional homogeneity (ReHo) technique was applied to evaluate spontaneous cerebral activity variations in children with SA and HCs. Moreover, associations between altered ReHo values in distinct cerebral areas and the degree of strabismus were assessed using Pearson correlation analysis.Remarkably increased ReHo values were observed in the right lingual, right superior frontal medial, bilateral superior parietal, and right inferior parietal gyri of children with SA compared with HCs. In contrast, mean ReHo values in children with SA were lower in the right cerebellum, left superior frontal gyrus, and left putamen nucleus. Furthermore, esotropia showed a positive correlation with ReHo values of the left putamen.The anomalous spontaneous activity changes in several brain areas that are caused by SA may indicate neuropathologic mechanisms of visual deficits and oculomotor disorders in children with SA. Strabismus and amblyopia are two common ocular diseases. Strabismus is an ophthalmic disease owing to the disorder of extraocular muscles, which is considered relevant to the dysplasia of cerebral visual pathways that regulate eye movements. Both the eyes of the strabismus patients cannot focus on the target at the same time, and the optical axes of both eyes are separated. In addition, amblyopia is a visual disorder caused by ocular maldevelopment, which can be detected by decreased visual acuity and sensitivity. Still, there were no organic lesions in the eye examination. Strabismus amblyopia (SA) is one form of amblyopia caused by strabismus. During the early phase of visual development, strabismus can cause the production of two separate images by the eyes that do not coincide, leading to abnormal vision, including double vision or visual confusion . In suchIn pediatric populations, strabismus reportedly has a marked influence on the development of amblyopia. The combined condition, SA, leads to functional deficiency, including defective motor, visual, and sensory cognition as well as impaired stereoscopic depth perception . These iFunctional magnetic resonance imaging (fMRI) is a common method that can precisely detect brain function. Its main advantage compared with traditional MRI is its ability to display subtle microscopic structural differences and satisfactory spatial resolution. When a person looks at an object, light passes through the retina, and nerve impulses are relayed along the visual pathway to the cerebral cortex, which produces the corresponding cortical activity to generate vision. This cortical activity can be observed and recorded by fMRI. Patients with SA differ from persons with normal vision in terms of the location, range, and degree of activation in cortical areas, which can also be detected by fMRI technology. Previously, fMRI techniques have been applied to detect cerebral activity alternations in either amblyopia or strabismus patients, separately .The regional homogeneity (ReHo) is an extensively applied method that belongs to the resting-state fMRI (rs-fMRI), which is deemed dependable and accurate. Previous studies have shown that it has a high neurobiological relevance and test-retest reliability. A decline in ReHo values represents reduced synchrony and disordered activity. However, an increased ReHo value suggests increased synchrony of spontaneous neuronal activity. The ReHo technique has been successfully used in many researches on eye disorders ; Table 1Here, the ReHo technique was applied to analyze the alternations of spontaneous cerebral activity between children with SA and healthy controls (HCs) and to determine the relevance between the altered ReHo values and abnormal vision.Twenty-four children with SA, including 10 male patients and 14 female patients, from the Ophthalmology Department of the First Affiliated Hospital of Nanchang University, were recruited to participate in this study. The following are the inclusion criteria: (i) children under 12 years old; (ii) diagnosed with SA; (iii) with a best-corrected visual acuity (VA) ≥0.20 logMAR units, and central fixation of both eyes with greater than one line difference; and (iv) no other eye diseases . Patients meeting the following criteria were excluded: (i) had eye operation record (intraocular and extraocular were both included); (ii) had other disorders besides eye disease ; (iii) had a mental disease or cerebral infarction; (iv) was either addicted to illicit drugs or was an alcoholic.Twenty-four HCs matched to those basic clinical characteristics of the SA group, like sex and age were also incorporated in this research, including 10 boys as well as 14 girls. All HCs conformed to the following standards: (i) an absence of abnormal MRI in the brain; (ii) no ophthalmic surgery history and best-corrected VA not greater than 0 logMAR units; (iii) a state of sanity; (iv) no MRI examination contraindications . Our study has gained the approval of the Medical Ethics Committee of the First Affiliated Hospital of Nanchang University, and the protocol adhered to the principles of the Declaration of Helsinki. All participants (including the child and their parents) gave informed consent and details of the objectives of the research, and the latent danger to patients were explained in detail.We used a 3-T magnetic resonance scanner  to undergo the MRI scanning. During the entire scanning process, we asked all participants to breathe smoothly and remain their eyes closed, but keep awake. A three-dimensional spoiled gradient recalled echo sequence was applied to collect the data. Relevant details about the apparatus are as follows: 176 structural images : 1,900 ms; echo time (TE): 2.26 ms; thickness: 1.0 mm; field of view: 250 × 250 mm; flip angle: 9°; acquisition matrix: 256 × 256). In addition, 240 functional images  were likewise acquired. The duration time of the whole scanning process is 15 min.1 was applied to analyze the collected data. Then, we used the Data Processing Assistant for rs-fMRI software (DPARSF)2 and the Statistical Parametric Mapping 8 (SPM8) to preprocess the received information. We removed the data of the first 10 time points to eliminate interference which may be caused by an unsteady magnetic field. Furthermore, slice timing was carried out to correct time differences.Firstly, the MRIcro softwareOwing to the differences in brain volume and structure between subjects, spatial standardization was used to process the available images. During this process, we unified the images according to the Montreal Neuroscience Institute standard (MNI152_T1_3mm. nii), and the voxels were immediately re-sampled with a resolution of 3 mm × 3 mm × 3 mm. To dislodge the linear chemotactic effect produced while the subject adapts to the scanning environment, the linear drift was eliminated. Eventually, to reduce high-frequency physiological noise, such as the heartbeat or respiration, only data between 0.01 and 0.08 Hz were collected.t-test and the Representational state transfer (REST) software to analyze distinctions between this two groups. When the p-value < 0.05, it was deemed as statistically significant. The collected data were compared and analyzed by AlphaSim. Corrected thresholds were set at P < 0.01, and the cluster size at > 40 voxels. Then, the REST software is used to identify brain regions with significantly changed ReHo values as regions of interest (ROI). The mean ReHo of all voxels in each brain area was taken as the ReHo value of this ROI. In addition, the Pearson correlation analysis was applied to distinguish between the ReHo value and the degree of strabismus in SA individuals.We used the SPSS 20.0 software  to compare the ReHo values of certain brain areas in the SA and HC groups, and used the two-sample p > 0.999) and age (p = 0.902) between the two groups. However, significant differences appeared in the best-corrected VA of both eyes  (There are no significant differences were observed in gender (ctively) .r = 0.8975, p < 0.0001) , right superior frontal medial (RSFM), bilateral superior parietal (SP), and right inferior parietal (RIP) . However 0.0001) .Children with SA showed increased ReHo values in the RL, RSFM, RIP, and SP areas compared with the HCs, while the mean ReHo values for the RC, LSF, and LP regions were significantly lower .The lingual gyrus is located in the occipital lobe and has connections with the parahippocampal and the fusiform gyrus. It is a crucial part of the ventral visual stream, which processes visual details, like color, form, and size, processes complex visual stimuli by identifying essential characteristics. Therefore, this area is vital for visual attention and judgment. Earlier research reported an increased ReHo value of the lingual gyrus in patients with concomitant strabismus (CS) . In our The frontal lobes are the largest cortical region in the human brain. It is also regarded as a very vital and the most complex area because it has extraordinary rich connections (including afferent and efferent connections) with almost all other parts of the central nervous system . EspeciaParietal lobules are somatosensory areas, which integrate information about feeling, touch, and vision, and facilitate the recognition and recall of size, shape, texture, and the weight of objects. A previous study has confirmed that the parietal lobe has a strong relationship with the visual cortex . Ouyang The cerebellum is involved in motor and balance control, including precise eye movements . The V1 The putamen plays an integral role in the learning and memory system, as well as in the processing of visual information . Lee et In addition, we also found some statistically significant voxels in MRI images in white matter. In previous MRI studies, activated signals are often found in the white matter of the brain. However, whether this signal has the significance for some potential neural activities has been controversial. White matter contains connecting fibers specialized in processing signals between different brain regions, accounting for about half of the brain . Most ofIn this study, we speculate that the activated white matter signal may be a compensatory development of the brain of children with SA to compensate for the abnormal visual experience. In addition, it has been reported that in childhood and early adolescence, the development of the whole brain’s white matter tract will increase, which contributed to improving cognitive ability . TherefoIn summary, the abnormal spontaneous brain activity in children with SA demonstrated in the present study could be attributed to both the development of SA and resultant visual compensation.From the second trimester of pregnancy, the volume of gray matter brain cells increased rapidly and peaked before the age of six. Similarly, the volume of subcortical gray matter peaked at 14.5 years old. From the second trimester of pregnancy to early childhood, the volume of white matter also increased rapidly . TherefoThe 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 Medical Ethics of The First Affiliated Hospital of Nanchang University (No: 2020038). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Written informed consent was obtained from the minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.S-WT, G-QC, and Q-YL: conceptualization. S-WT, YG, and Y-CP: methodology. S-WT, L-JZ, and Q-MG: formal analysis and investigation. S-WT, H-YS, X-JZ, and YS: writing—original draft preparation. S-WT, G-QC, and YS: writing—review and editing. YG and YS: funding acquisition. S-WT, H-YS, and YS: resources. S-WT and Y-CP: supervision. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Evidence from observational studies suggests that Sjögren’s syndrome (SS) may contribute to an elevated risk of Parkinson’s disease (PD) and dementia. However, few studies have been undertaken to summarize and assess the consistency of the data quantitatively. Therefore, we evaluated the risk of dementia and PD in SS patients through a systematic review and meta-analysis approach.Two reviewers independently conducted a systematic search of PubMed, Embase, and Web of Science databases  to identify published literature on the association between SS and dementia or PD. The risk estimates of dementia or PD in patients with SS were pooled using fixed or random-effects models.P < 0.001), and such risk in females with SS was similar to that in males. The risk of PD was 1.36 times higher in SS . The association between SS and PD risk appeared to occur primarily in female patients . No significant effect of age was observed on the risk of developing PD and dementia in SS patients.Of the 631 studies initially searched, 10 were eventually included. Pooled results suggested that the risk of developing dementia significantly increased in patients with SS (HR = 1.24, 95% CI: 1.15–1.33, Our study supports that people with SS are at higher risk of PD and dementia than the general population. Further studies are needed to elucidate the underlying mechanisms and to assess whether interventions for SS have the potential to affect dementia and PD development. Sjögren’s syndrome (SS) is an autoimmune disorder that plagues 35 million people worldwide. Its main clinical manifestations include dry eyes and dry mouth as well as lymphocytic infiltration of glandular tissues . SS is cSince the beginning of the twenty first century, population aging has become a prominent issue, challenging all countries in the world . China nAn association between neuropsychiatric symptoms and autoimmune diseases has been increasingly noted. Several observational studies have explored the association between SS and dementia/PD. Therefore, the present study aimed to quantify the association between SS and dementia/PD. To achieve this end, data were collected to (1) investigate the comprehensive results of the association between SS and dementia, and that between SS and PD; (2) validate the main results by analyzing the results in different subgroups and determining the sources of heterogeneity; (3) test the robustness of the results through sensitivity analysis and assess the potential for publication bias.The study was reported according to the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-p) statement . We systStudies were eligible for inclusion if they were longitudinal case-control studies or cohort studies, entailed a clear definition of SS, dementia, and PD, or applied standard clinical diagnostic criteria to identify relevant cases. Included studies also should meet the following criteria: assessing the association between SS and dementia as well as SS and PD, or reporting effect estimates and corresponding 95% confidence intervals (CIs). The studies should also include relevant data to calculate hazard ratios (HRs) for the associations between SS and dementia/PD. We excluded reviews, conference abstracts, commentaries, reprinted literature, and studies with duplicated or incomplete data. To avoid omitting any studies, we manually searched the literature cited in the reference lists of included studies.The final screening results were compared by two authors (WZZ and SZ) based on the same inclusion and exclusion criteria, and any disagreements were resolved by third-party authors. An MS Excel form was created to record essential data from the included studies, including first author, year of publication, study type, country, sample size, the mean age of samples, exposure definition, factors adjusted for the outcome, eligible subgroups, and follow-up periods. All authors approved the final version of the template. Two independent reviewers (WZZ and SZ) extracted data using the pre-determined form, and any discrepancies were addressed through discussion. The corresponding authors of the included literature were also contacted for further information when necessary.Two independent reviewers (WZZ and SZ) scored the quality of the included case-control and cohort studies, following the Newcastle-Ottawa Quality Assessment Scale. Studies were rated as high-quality if scored between 7 and 9, medium-quality (5∼6), and low-quality (≤4) .I2 < 50% and p > 0.05, and a fixed-effects model was used for analysis. A random-effects model was applied when I2 ≥ 50% or p ≤ 0.05. HR, an effective indicator for meta-analysis, was used to calculate pooled effect values, and forest plots were drawn. Further subgroup analyses were conducted based on the available data from the included studies. Sensitivity analysis was performed to evaluate the stability of the results. Publication bias was assessed using Begg’s and Egger’s tests and graphing funnel plots. All statistical analyses were done using Stata 16.0 software.The HRs were pooled to examine the relationship between SS and PD/dementia risk . HeterogThe screening process is summarized in the flow chart . We idenAll included studies were published between 2017 and 2021. Of the 10 included studies, three were case-control studies  and seveThe Newcastle-Ottawa Quality Assessment Scale scores for the included studies are shown in I2 = 2.0%, p (heterogeneity) = 0.395]. Therefore, a fixed-effects model was used to pool the effect size of each study to determine the association between SS and the risk of dementia (p < 0.001).We performed meta-analyses and calculated pooled effect estimates for five studies that included 190 704 subjects . Heterogdementia . The oveOur subgroup analyses were conducted by age (<65 and >65) and sex . Corresponding subgroup analyses of follow-up time and comorbidities on risk were not performed due to the lack of data on the effect .p = 0.004), and this risk was similar in patients with SS under 65 years of age . Two studies were included in the subgroup analysis by sex .In terms of stratified analysis for age, people with SS had a 26% higher relative risk of dementia than those without SS among those over 65  . FurtherI2 = 74.5%, p (heterogeneity) = 0.003), so a random-effects model was adopted. Pooled results showed that SS was significantly associated with a subsequent increased risk of PD   .We conducted a meta-analysis of subgroups according to age, sex, and duration of follow-up . In the p = 0.000) in female SS patients and 1.00  in male SS patients. These results revealed that the correlation between SS and PD risk seemed to be applicable primarily to female patients.In the subgroup analysis by sex, two cohort studies  examinedOnly Begg’s and Egger’s tests as well as funnel plots were used to assess potential publication bias. No potential publication bias was present (Begg = 0.806 and Egger = 0.242) . The robTo our knowledge, this meta-analysis is the first to comprehensively investigate and quantify the association between SS and the risk of dementia/PD. We found a 1.24-fold greater risk of dementia in people with SS compared to the general population; age and gender appear to have no significant effect on this risk. The risk of PD in SS patients was 1.36 times higher in SS individuals. This elevated risk, interestingly, appeared to be prevalent solely in female individuals. Age had no significant effect on the risk of developing PD in SS patients. Based on the fact that over 10,000 patients with both SS and dementia or both SS and PD were involved, the study provided convincing information for the association between SS and PD.In recent years, the prevalence of dementia has been rising at an alarming rate in our aging population . DementiThe influence of neuroinflammation on dementia remains a controversial topic. The interaction between SS and dementia is becoming more obvious, yet the factors that contribute to progression are unclear. Vasculitis, autoantibodies, immune complex deposition, and cellular inflammation are potential pathways through which SS may elevate the risk of dementia, resulting in nerve damage, cognitive impairment, and initial dementia . PreviouNoteworthily, PD is the second most common neurodegenerative disease after Alzheimer’s disease, and it is expected to place an increasing medical and economic burden on society as the population ages . TypicalIt is crucial to determine the causal relationship between SS and PD. In several of the included studies, all patients with PD were diagnosed after an episode of SS . In the SS is known to be mediated by the interaction of genetic, epigenetic, and environmental factors causing immune dysregulation, which leads to an aggressive autoimmune disease affecting the central nervous system (CNS) and peripheral nervous system , often eThere are still some limitations to our meta-analysis. First, we could not distinguish whether SS was primary or secondary to another autoimmune disease in our meta-analysis. Failure to fully elucidate the clinical severity of SS and the subtypes of dementia and PD may lead to inaccurate estimates of their genuine association. Secondly, most of the eligible studies were conducted in Taiwan region (China), which may lead to geographical bias and relatively high overlap of included samples. Therefore, it is unclear whether this association holds for other races and regions in the world. In addition, none of the 10 included studies assessed the effect of monitoring bias on outcomes. Since subjects with SS typically experienced more medical visits than those without SS, they were more likely to be diagnosed with dementia or PD. In this way, the risk of dementia or PD for subjects with SS may be skewed higher in the overall analysis results. Finally, all original studies were designed retrospectively and their data collection did not consider the need for specific scientific research, thus limiting the completeness and homogeneity of the data.The results of this study reveal that patients with SS are at significantly elevated risk of developing PD and dementia and that regular neurological screening of SS patients may be warranted. More prospective studies from different regions are necessary to elucidate the underlying mechanisms and to further characterize the impact of SS on development of PD and dementia.The original contributions presented in this study are included in the article/Z-ZW, M-SL, and ZS developed the protocol, participated in the literature search, extracted data, and drafted the manuscript. X-LZ and M-LZ was responsible for the analysis and interpretation of the data. KX contributed to statistical expertise. FZ supervised the study. All authors contributed to the article and approved the submitted version.


Langerhans cell histiocytosis (LCH) is the most frequent type of histiocytosis and is characterized by both “inflammation/immune dysregulation” and “neoplastic disorder.” Although overall survival has remarkably improved through consecutive previous studies, the relapse-free survival rate is still only 60% to 70%, even in the latest clinical trials. Relapse of LCH is the most significant risk factor for permanent consequences in the central nervous system, such as diabetes insipidus, anterior pituitary hormone deficiency, and neurodegenerative diseases. In this trial, we evaluated the safety and effectiveness of hydroxyurea and methotrexate in recurrent LCH. Treatments in this study consisted of only orally administered drugs and not intravascularly administered drugs. Hydroxyurea therapy for patients with LCH is expected to be safer, less painful, and more cost-effective than other treatments for LCH. The results of this study could provide new therapeutic alternatives for recurrent LCH.This study was a non-blinded, multicenter, single-arm study. Recurrent (relapsed) LCH is defined as the appearance of new lesions or the enlargement of preexisting lesions due to LCH. In this study, all patients received hydroxyurea, and if the treatment response was unsatisfactory, methotrexate was added. The duration of treatment was 48 weeks. The primary endpoint was the rate of non-active disease achievement, which was 24 weeks after initiating hydroxyurea administration. No active disease is defined as the resolution of all the signs and symptoms related to LCH. LCH-II, LCH-III) using “vincristine/vinblastine based chemotherapy” and the Japan LCH Study Group  using “cytarabine based chemotherapy.” Although the overall survival of LCH patients has improved to over 90%, the relapse-free survival rate remains at 60% to 70%, even in the latest clinical trials.,8,9 The major relapse organs of LCH are the bone and skin, and relapse involving high-risk organs of LCH  is rare. In recurrent LCH, the treatment response is high and does not cause active disease in 85% of the cases. The most significant risk factor for permanent central nervous system consequences, such as central diabetes insipidus, anterior pituitary hormone deficiency, and neurodegenerative disease is a relapse of LCH.,12The prognosis for LCH has remarkably improved through consecutive clinical trials conducted by the Histiocyte Society  involving the skin and bone with or without lymph node involvement were treated with hydroxyurea. After worsening signs and symptoms were observed due to LCH, 10 patients were treated only with hydroxyurea, and 5 patients were treated with combination therapy of hydroxyurea and methotrexate. The average duration of therapy was 10 months (range: 1–24 months). Twelve of the 15 (80%) patients achieved either complete or partial responses. After treatment with hydroxyurea, 6 (40%) patients showed progression or relapse after the initial response to hydroxyurea. This report demonstrates that treatment with hydroxyurea may be an effective therapeutic option for some LCH patients with relapse.Zinn et al recently reported that hydroxyurea, which has previously been shown to be effective in the treatment of myeloid neoplasms  and sickle cell disease (SCD), is also effective in the treatment of LCHTherefore, we conducted a pilot study to evaluate the safety and effectiveness of hydroxyurea and methotrexate for recurrent LCH.In this study, we evaluated the safety and effectiveness of hydroxyurea and methotrexate in recurrent LCH. Recurrent (relapsed) LCH is defined as the appearance of new lesions or the enlargement of preexisting lesions due to LCH.This was a non-blinded, multicenter, single-arm study. In this study, all patients received hydroxyurea, and if the treatment response was poor, methotrexate was added. We estimated the rate of non-active disease (NAD) at 24 weeks. NAD is defined as the resolution of all signs and symptoms related to LCH .The rate of NAD achievement at 24 weeks after initiating hydroxyurea administration.Treatment response rate after 6 weeks of hydroxyurea treatment. The evaluation criteria of treatment response rate after 6 weeks are divided into good response (GR), partial response (PR), stable disease (SD), and progressing disease (PD), as detailed in “Evaluation criteria.”Treatment response rates after 12, 24, 32, 40, and 48 weeks of hydroxyurea treatment. The evaluation criteria of treatment response rates at these time points are divided into NAD, active disease regression (AD-r), Active disease stability (AD-s), and active disease progression (AD-p), as detailed in “Evaluation criteria.”The number of patients treated with methotrexate.Frequency of adverse events associated with hydroxyurea administration.The frequency of adverse events associated with the combination of hydroxyurea and methotrexate.The number of hospital days and outpatient days during the study period.Swimmer plot of all enrolled patients.Relationship between hydroxyurea blood concentration and NAD, AD-r, AD-s, and AD-p achievement rates at 12, 24, and 48 weeks of treatment.We registered patients who satisfied all inclusion criteria and did not meet any of the exclusion criteria, as described below.The patient can take the capsule formulation.Histopathologically diagnosed LCH at the time of initial or recurrent disease.Recurrence of LCH (regardless of the number of recurrences).Treatment for the recurrence of LCH has not been started, excluding local therapy.Without the high-risk organ involvement of LCH, including the liver, spleen, and hematopoietic system.Without the complication of hemophagocytic lymphohistiocytosis.Fully maintained organ functions, including liver, kidney, cardiac, and respiratory functions.Eastern Cooperative Oncology Group performance status (PS) score of 0 to 2.Written informed consent to participate in this study is provided by the patient and/or legal representatives.Central diabetic insipidus recurrence on its own.With active infectious disease.With signs/symptoms of active bleeding.With active signs/symptoms of the central nervous system.®).With a history of hydroxyurea  Good response (GR)GR was defined as the disappearance of the signs or symptoms of LCH. Bone lesions on radiology were not clear at the 6-weeks evaluation after hydroxyurea administration. Therefore, the disappearance of bone lesions in radiology is not required.ii) Partial response (PR)PR was defined as patients meeting all the following criteria: ≥30% decrease in the sum of the longest diameter of the LCH lesions, regression (>50%) of skin or mucosa LCH lesions, and no new lesion of LCH compared with baseline. Bone lesions on radiology were not reduced at the 6-weeks evaluation after hydroxyurea administration. Therefore, reduction of bone lesions in radiology is not required at this point as well.iii) No response (NR)Patients with NR satisfy the following criteria: ≤30% decrease in the sum of the longest diameter of the LCH lesions or regression (<50%) of skin or mucosa LCH lesions with or without the appearance of any new LCH lesion compared to baseline.iv) Progressing disease (PD)PD is defined as the worsening of signs or symptoms due to LCH and/or the appearance of new LCH lesions.Treatment response at these time points after hydroxyurea administration is evaluated as follows.i) No active disease (NAD)NAD is defined as the complete resolution of signs and symptoms due to LCH.ii) Active disease regression (AD-r)AD-r is defined as a continuous regression of signs and symptoms due to LCH, except for permanent consequences.iii) Active disease stable (AD-s)AD-s is defined as LCH-related signs and symptoms that remain stable in the absence of new LCH lesions.iv) Active disease progression (AD-p)AD-p is defined as the worsening of signs or symptoms caused by LCH or the development of any new LCH lesion.In addition, relapse is characterized as the appearance of new LCH lesions  or enlargement of baseline LCH lesions after the achievement of GR/PR or NAD.The investigators collected all adverse events that had occurred in the patients during the study period. Adverse event severity was determined using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.We analyzed the rate of NAD achievement 24 weeks after initiating hydroxyurea administration, which is the primary endpoint when the data of all registered patients up to 48 weeks after starting hydroxyurea administration are fixed. Analysis of secondary endpoints was performed after the final follow-up data for all patients was fixed.Data collected and stored via REDcap software during this study. REDCap has been privacy and security protected. The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.This study monitored on a regular basis. Monitoring ensured that the study was conducted safely and in accordance with the protocol. It also determined whether the data are accurately recorded and properly stored. Any changes to the protocol would be reapproved through the Central Institutional Review Board of the National Center for Child Health and Development.The patients were not involved in the design, conduct, reporting, or dissemination plans of our research.This trial was performed in accordance with the ethical principles of the Declaration of Helsinki and the Clinical Trial Act. This trial was approved by the Central Institutional Review Board of the National Center for Child Health and Development. Informed consent was obtained from the patients and/or their parents before registration. All data was collected confidentially from the investigators using an electronic data capture system. We will present the results of this trial at national and international conferences and publish them in an international, peer-reviewed journal. bisphosphonate, indomethacin, 2-chlorodeoxyadenosine, and clofarabine. However, there has been no clear standard therapy until now. Hydroxyurea, a myelotoxic ribonucleotide reductase inhibitor, was first approved in 1966. Daily oral hydroxyurea treatment has a low toxicity profile. Similar to adults, treatment with hydroxyurea is safe and tolerable in children. The Hydroxyurea Safety and Organ Toxicity (HUSOFT) trial revealed that the toxicity profile of long-term hydroxyurea therapy (mean duration of hydroxyurea was 4.9 ± 1.3 years) for infants with SCD was limited, and that long-term hydroxyurea usage did not affect their growth rate. Additionally, other reports showed that pubertal development in patients with SCD was also maintained after long-term use of hydroxyurea.,20We conducted a pilot study to evaluate the safety and efficacy of hydroxyurea and methotrexate in recurrent LCH. Various treatments for LCH patients with relapse have been reported, such as using the same agents from the first-line therapy ,Moreover, the treatments in this study consisted of only orally administered drugs and not intravascularly administered drugs. Some patients with LCH have multiple relapses and require frequent hospital visits and hospitalization to receive intravenous drugs. From this perspective, the burden on patients is quite significant, and less burdensome treatment is desired. In this study, the burden on patients was considerably minimized by using an oral formulation of the drug. Regarding cost, one capsule of hydroxyurea (500 mg per capsule) costs 241 Japanese yen, making the treatment highly cost-effective.Based on these findings, hydroxyurea therapy for LCH patients is expected to be safer, less painful, and more cost-effective than other treatments, including intravenous administration of drugs for LCH. The results of this study could provide new therapeutic alternatives for recurrent LCH.K.S., Y.S., K.K., and M.S. conducted the pilot study. K. S. and Y. S. managed the study. T.T. and M.K. developed an electronic data-capture system for this study.Conceptualization: Kenichi Sakamoto, Yoko Shioda.Data curation: Miho Kato, Tetsuya Takimoto.Funding acquisition: Yoko Shioda.Project administration: Kenichi Sakamoto, Kayoko Kikuchi, Mayumi Sako, Yoko Shioda.Writing – original draft: Kenichi Sakamoto.Writing – review & editing: Kayoko Kikuchi, Mayumi Sako, Miho Kato, Tetsuya Takimoto, Yoko Shioda.


Given the role of insulin resistance in several cancers, we hypothesized that consumption of a diet that reduces insulin resistance might lower the risk of breast cancer.The present study was designed to assess the association between consumption of “diabetes risk reduction diet” (DRRD) and odds of breast cancer among a large group of women in a Middle Eastern country.via a validated 106-item Willett-format semi-quantitative dish-based food frequency questionnaire. A DRRD score was included based on 9 dietary factors . For food and nutrient items with a protective association with diabetes in earlier studies, participants were given the score as the quintile of that food item, but for food groups with unfavorable association with diabetes, we did vice versa. Total DRRD score ranged from 5 to 45.This population-based case-control study enrolled 350 newly diagnosed cases of stage I-IV breast cancer and 700 age-matched apparently healthy individuals as controls. We collected dietary data P-trend = 0.002). Stratified analysis by menopausal status indicated a significant inverse relationship in postmenopausal women , but not in premenopausal women . Moreover, by BMI status, we found statistically significant inverse association between adherence to the DRRD and odds of breast cancer among normal-weight women  but not in overweight women . Conclusions: Significant inverse associations were found between adherence to DRRD and breast cancer, especially among postmenopausal and normal-weight women.Mean age of cases and controls was 65.28 and 61.04 years. Mean BMI of patients with breast cancer and controls was 25.5 and 21.0. We found that individuals with the greatest adherence to the DRRD were 0.41 times less likely to have breast cancer than those with the lowest adherence (OR: 0.59; 95% CI: 0.38, 0.90, and  The prevalence of breast cancer and mortality due to cancer is higher in patients with diabetes than in healthy individuals , 2. A meIn terms of dietary factors, construction of a dietary pattern including high glycemic index –14, refiTo date, no study has examined DRRD score with risk of breast cancer in the Middle Eastern population, where the risk of diabetes and breast cancer is increasing and the traditional dietary pattern is different from current typical diets in Western countries . ConsumpThis case-control study was performed on women over 30 years of age between 2013 and 2015 in Isfahan, Iran. We recruited cases from patients who were referred to private hospitals or clinics or were being treated for breast cancer, including tumor resection, chemotherapy, or radiotherapy, or all of them. Breast cancer was pathologically confirmed in cases who had been diagnosed with this condition in the past 6 months through physical examination and mammographic findings. Given that patients were only asked to answer some of the questionnaires, more than 90% of them accepted to take part in the study. The sample size was calculated considering the type I error as 5% and the study power as 80%. In addition, we hypothesized that unhealthy dietary pattern might increase the odds of breast cancer by 1.5 times. Considering the common ratio of 0.25 and the ratio of controls to cases as 2, we needed ~350 patients with breast cancer and 700 apparently healthy controls. In this study, we did not include people with a history of any neoplastic lesions or cysts (except breast cancer) and those who had previously been treated with any hormone replacement therapy. In addition, we did not include people on a special diet in the project. The control group was consisted of Iranian women who had no history of malignancy, cysts, or pathological disease and had no specific diet or hormone replacement therapy. Healthy women in the control group were matched with cases in terms of age and socioeconomic status. Individuals in the control group were chosen from healthy women with no family history of breast cancer by multi-stage cluster random sampling. Finally, a total of 1,050 eligible women, including 350 cases and 700 controls, were recruited to participate in our study. All participants provided informed written consent. The study was ethically approved by the Bioethics Committee of Tehran University of Medical Sciences, Tehran, Iran.We collected usual dietary intakes of subjects using a 106-item Willett-format semiquantitative dish-based food frequency questionnaire (FFQ), which was designed specifically for Iranian adults. Details of developing this questionnaire as well as further information about its validity and reliability were reported elsewhere . All theBased on earlier knowledge about the association between various food items and diabetes, DRRDS was constructed using previously published reports. Nine food items including cereal fiber, nuts, caffeine, whole fruits, ratio of polyunsaturated fat to saturated fat, GI, trans fats, SSBs/fruit juices, and red and processed meats were considered in this scoring method. First, we classified participants in terms of quintiles of these components. For food and nutrient items with a protective association with diabetes in earlier studies , participants were given the score as the quintile of that food item; that is individuals in the highest quintile of these foods and nutrients were given the score of 5 and those in quintiles 1, 2, 3, and 4 were given the scores of 1, 2, 3, and 4, respectively. For nutrients and food groups  with unfavorable association with diabetes, we did vice versa; such that individuals in the highest quintile were given the score of 1 and those in the lowest quintile received the score of 5. Similarly, individuals in quintiles 2, 3, and 4 were given the scores of 4, 3, and 2, respectively. Total DRRDS was computed by summing up the scores of participants received for all nine components. This score ranged from 5 to 45 .The diagnosis of breast cancer was done using physical examination and mammography. Pathological evaluation was also performed to confirm the diagnosis. We included women of Iranian nationality who had been diagnosed with breast cancer for the maximum of previous 6 months and also had stage I–IV breast cancer.via pretested questionnaires. In order to assess the level of physical activity, the short form of the International Physical Activity Questionnaire (IPAQ) was used, in which the metabolic equivalents-hour per week (MET-h/week) was computed to state the activity level for each study participant , past medical history, family history of breast cancer, history of breastfeeding and dietary supplement use dietary supplements  were collected ticipant . Weight post-hoc comparison for pairwise differences. To examine the relationship between DRRD adherence and breast cancer, multivariate logistic regression was used in several models for all participants. The obtained findings were modified for confounding factors including age, residence, marital, menopausal and socioeconomic status, education, family history of Breast cancer, breast feeding, history of disease, and dietary supplement use. Further adjustment for BMI was applied in the last model. Stratified analyses by menopausal status as well as BMI were also conducted. We used quartile categories as an ordinal variable, in order to assess the trend of odds ratios across increasing quartiles of DRRD score. All analyses were done via Statistical Package for Social Sciences . P < 0.05 were identified as statistically significant.We categorized participants into quartiles according to DRRD adherence. In order to compare general characteristics of study population across quartiles DRRD adherence, one-way ANOVA for continuous variables and Chi-square test for categorical variables were applied. Dietary intakes of study participants across categories DRRD adherence were evaluate by ANOVA, with Tukey's 2 was 271 (77.4%) among cases and 352 (50.2%) among controls. Also, the participants with BMI ≥ 25 kg /m2 were 79 (22.5%) in the cases and 348 (49.7%) in the control group. General characteristics of the study population across quartiles of DRRDS are presented in P < 0.01 for all). Moreover, a lower percentage of them were residing in urban areas. No other significant differences were found across categories of DRRDS in terms of other general characteristics.A total of 1,050 female participants with a mean age of 62.5 years were included in the study. Number (percentage) of individuals with BMI < 25 kg/mP < 0.001). The Tukey's post-hoc analysis was performed to compare pairwise differences between dietary intakes of study participants across quartile categories of DRRDS in P < 0.001 for all). In contrast, the consumption of fat (P: 0.012), trans fatty acids (P < 0.001), and red and processed meats (P < 0.049) of participants in the third category was lower than that of the first category. Also, individuals in the top quartile of DRRD had higher energy (P: 0.001), carbohydrate (P < 0.001), protein (P < 0.001), fiber (P < 0.001), cereal fiber (P < 0.001), nuts (P: 0.003), caffeine (P < 0.001), whole fruits (P: 0.012), higher PUFA to SFA ratios (P: 0.010), and GI (P: 0.006), than participants in the lowest quartile. In addition, those with the highest quartile had lower intakes of fat (P < 0.001), trans fatty acids (P < 0.001), SSBs / fruit juices (P: 0.002), and red and processed meats (P < 0.001), vs. those with the lowest quartile.Dietary intakes of the study population across quartiles of DRRDS are displayed in P-trend < 0.001). Further adjustment for BMI did not change the mentioned association . When we did the analysis stratified by menopausal status, we found that postmenopausal women with the highest DRRDS score had 37% lower odds for having breast cancer compared with those with the lowest score . This inverse association remained significant after adjustment for several potential confounding variables , even BMI . However, no significant association was seen between DRRDS and odds of breast cancer in premenopausal women, either before  or after adjusting for potential covariates .Crude and multivariable-adjusted ORs and 95% confidence intervals (CIs) for breast cancer across categories of DRRDS score are outlined in P-trend = 0.006) or after controlling for potential confounders . No significant associations were seen between DRRDS and odds of breast cancer in obese women, comparing top vs. bottom quartiles . Adjustment for potential confounders did not affect the findings .We repeated the regression analysis according to BMI status , in whicTo the best of our knowledge, the current study is the first in the Middle East to investigate the association between DRRDS and odds of breast cancer. In this case-control study among 1,050 Iranian women, we found a significant inverse association between DRRDS and odds of breast cancer. This inverse association was also observed in postmenopausal women, either before or after controlling for confounders. Separately by BMI status, this inverse relationship was seen among normal weight women, but not in overweight or obese people.Breast cancer is a growing public health concern worldwide . Along wn = 199) may explain lack of a significant relationship between DRRDS and the odds of breast cancer, but it must be kept in mind that such an association was not also seen in a previous cohort study with a large sample size of premenopausal women  are the most important negative regulators of the sex hormone-binding globulin (SHBG) synthesis pathway  of ways , 68. In  of ways , 69. The of ways , 69. DRR of ways –73. ThusThe present study contains several strengths. This is the first study in the Middle East to examine the association between DRRDS and breast cancer. Adequate number of studied people, accurate assessment of potential confounders and controlling for them in the analysis are also among the strengths of the present study. Another strength of this study was that the food questionnaires were completed in a face-to-face interview by a trained nutritionist. The use of the USDA food composition table, which was modified for Iranian local foods using the nutrient composition of Iranian food items, was another strength of this study. The limitations of the study include the following points: (1) the study type is case-control which would prevent the inference of causation and (2) this study is subject to selection and recall bias. However, applying the population-based study, we tried to reduce the possibility of selection bias, (3) measurement errors are unavoidable and would lead to misclassification of participants, (4) proportion of postmenopausal women was higher than premenopausal, which might explain finding the expected association in this group only, (5) failure to assess insulin resistance, and (6) lack of data on the hormonal status of breast cancer and medication use in this people are another limitation.Overall, we found that consumption of “diabetes risk reduction” diet was associated with a reduced odds of breast cancer, in particular among normal-weight women and postmenopausal women. Additional studies in other countries of the Middle East are needed to further examine this hypothesis in the region.The raw data supporting the conclusions of this article will be made available by the authors, on reasonable request to the corresponding author.The studies involving human participants were reviewed and approved by Ethical Committee of Tehran University of Medical Sciences approved the study protocol. The patients/participants provided their written informed consent to participate in this study.LA and SB-K contributed to data collection, assisted in designing the study, conceptualized, and oversaw this study. AB and AE provided substantial contributions to the editing of the paper. SE took primary responsibility for drafting this manuscript. AB and SE provided guidance on the analysis. AE conducted the analysis. All authors contributed to the article and approved the submitted version.The financial support for this study comes from Tehran University of Medical Sciences, Tehran, Iran.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.


This study assesses the experiences of parents/caregivers regarding the refusal to childhood immunization. A cross-sectional study was conducted among the parents/caregivers of children under two years old from January 2019 to June 2019 who were residents of either Pathan Colony or Orangi Town, Karachi. In this study, the data collectors targeted parents/caregivers of 440 households who showed a refusal mark “R” in the Expanded Program of Immunization (EPI) H-chalking system. These households were approached using a 30 × 7 multistage-stratified-cluster random sampling technique and were interviewed using a structured questionnaire. The study sample produced two different types of refusals: true refusal (absence) and potential refusal (presence), based on the absence and presence of a vaccination card at the time of the survey. Multivariate logistic regression was used to analyze the data using Jamovi (V-1.6.13). A total of 230 households consented to participate in this study, of which 141 (61.3%) represented true refusals, while 89 (38.7%) represented potential refusals. More than half of the participants from both groups complained about fever and pain at the injection site following immunization. The use of alternative medicines and a history of adverse events following immunization (AEFI) were associated with increasing the odds of immunization refusals by four-to-five fold. However, advanced paternal age, a long distance to the clinic, a lack of trust in government, and the influence of community/religious leaders were associated with lower immunization refusal odds. Thus, an unawareness about self-limiting vaccine-related adverse events, the use of alternative medicines, and an increased concern about the safety and efficacy of vaccines were found to be barriers to immunization, which can be improved by increasing public awareness through media campaigns and policy reform. Immunization is an effective tool for preventing and controlling morbidity and mortality associated with vaccine-preventable diseases (VPDs) . GloballImmunization refusal is a global threat, defined as a deliberate delay or refusal of vaccination by parents and/or caregivers and/or the community without any vaccine logistics or supply issues ,8. FactoIn 1988, the World Health Organization (WHO), in consultation with the United States Centre for Disease Control and Prevention (US-CDC), United Nations Children Funds (UNICEF), Rotary International, and various other national and local bodies, introduced the concept of supplemental immunization activities (SIAs) to improve the immunization coverage at a regional, national, and global level . SIA impA community-based door-to-door household survey was performed among parents and caregivers of children under two years of age who were residents of either Pathan Colony or Orangi Town, Karachi, from January 2019 to June 2019 to investigate the reasons behind the vaccine refusals for their children. In this study, the research team captured houses marked with an “R” on the H-household chalking used by the Expanded Program of Immunization (EPI) teams. The EPI team of Pakistan designed an H-household chalking system, which helps to identify vaccination activities performed by each vaccination team in the designated household. Thus, H-chalking can identify the EPI team, the number of children, and the refusals (defaulters) from each household. The H-household chalking has six different sections, and the description of H-household chalking is presented in True refusal: The research team classified all the households who did not show vaccination cards at the time of visit as true refusals, which means they were not given a vaccination card because they did not bring their children for routine immunization. Potential refusal: The refusals who refused child vaccination from the mobile vaccination team during the SIAs instead provided vaccination to their children from vaccination centers. Moreover, the potential refusers showed vaccination cards to the research team. Households with a language barrier to Urdu were excluded from this study’s survey.The “R” sign in the H-household chalking system indicates “Refusals”. The study team identified two different types of refusals, based on the presence or absence of a vaccination card. The availability of vaccination was considered to be indicator in the classification of true refusals and potential refusals, because all the public and private hospitals, clinics, and community centers of Pakistan issued a vaccination card to the parents/caregivers of all vaccinated children for their immunization record and follow-up visits. Thus, based on the presence or absence of a vaccination card, the research team identified two different types of refusals: true refusal and potential refusal. Since no official report exists regarding the immunization refusal rate, the national immunization coverage was considered for calculating the sample size of this study. Considering the national immunization coverage of 84% , confideA 30X7 multistage-stratified-cluster random sampling technique was used to assess the precision of an immunization program. The research team initially created two strata to represent each study area, i.e., Orangi Town and Pathan Colony. However, to select the target population of this study, the data collector with the aid of different community stakeholders, such as union council members and the mobile vaccination team, received a list of households. Based on the list of households, the research team then created 30 clusters from each area, and these clusters were composed of around 150–250 households. From each cluster, the data collector selected the targeted household of this study by reading the H-chalking identified by the EPI team of Orangi Town and Pathan Colony. For systematic selection, every seventh household with a refusal mark “R” in the H-chalking system were selected for the data collector. The H-chalking was placed either outside the entrance door or on the wall of each household. After identifying targeted households with a refusal mark “R”, the data collector presented verbal consent to determine the households’ eligibility, and to each eligible household, the data collector issued a written consent form for study participation.An objective-driven self-made questionnaire was designed after an extensive literature review to assess the vaccination refusals among the parents or caregivers of children in selected areas of Karachi. The questionnaire had different sections, of which the first three sections described the participant screening, eligibility assessment, and enrolment. A four-digit enrolment number was assigned to each parent/caregiver who consented to participate in the study.From each participant enrolled, information collected was related to the socio-demographic profile, parents’ experiences, and behaviors associated with the immunization refusals. Content related to the parents’ behavior regarding immunization was adapted from the study by Khaliq et al. in 2016 . In addiThe questionnaire was then translated Into Urdu—the local language. A pediatric public health specialist checked the content validity of the questionnaire, and further validation was conducted by the Management Review Committee (MRC) of the Institute of Business Management (IoBM), Pakistan. The face validity and reliability of the questionnaire were tested on 10% of the sample . The Cronbach alpha value after pilot testing for 20 items was 0.714 by the test-re-test method, indicating good reliability .p-value over 0.05 were removed sequentially from the model using the backward elimination method. In the final model, only significant predictor variables were considered. The data were analyzed using Jamovi software version 1.6.13 (www.jamovi.org) [The data were first analyzed descriptively. The outcome variable of this study was vaccine refusal: true refusal and potential refusal. Unadjusted and adjusted odds ratios (oRs) were calculated using binomial logistic regression, and all the statistically insignificant variables with a ovi.org) .Ethical clearance was sought from the MRC of the MBA Health and Hospital Management (MHM) program at IoBM, Karachi, Pakistan (21905-2019-MBA-MHM).A total of 440 households with a refusal mark “R” were identified; 67.2% (n = 296) were eligible. Of the eligible households, 230 consented to participate (53%) .Of the 230 parents/caregivers interviewed, there were 141 (61.3%) true refusals and 89 (38.7%) potential refusals. The mean number of children who refused vaccination was 2.77 + 1.89 years, and the majority (64.8%) belonged to low socioeconomic backgrounds. The mean age of their mother and father was 30.4 ± 6.26 years and 37.9 ± 7.47 years, respectively. Most mothers were not working (97.8%) and were not educated (81.3%). Meanwhile, 97.4% of the fathers were working and 63% of them had received some education.Around 60% of both true and potential refusals reported having a fever and pain at the injection site as common AEFI, while inflammation, allergic reactions, hospitalization, disability, and death were reported mainly by true refusals .The reasons for not vaccinating among true refusals were the cost, side effects and contraindications of vaccines, rumors, and alternative medicines. However, the distance to clinics, reduced clinic timing, community/religious leader influence, and a lack of trust in the government were mainly reported by potential refusals. Both true and potential refusals reported that new vaccines are not safe for the health of their children .p < 0.05). In contrast, the use of alternative medicines and a history of vaccine-related side effects, allergic reactions, and disability were significantly associated with increased odds of immunization refusals (p < 0.005)  .This study has identified the reasons for immunization refusal among the parents/caregivers of children under two years of age. The findings reveal that parents/caregivers refused to vaccinate their children because of a history of AEFI, vaccine-related side effects (VREs), and complementary and alternative medicine (CAM) adoption to prevent VPDs. Earlier studies also support the notion ed that a lack of confidence in vaccine preventive efficacy and a fear of VREs majorly contribute to immunization refusal ,28,29.Earlier studies have reported a significant association between maternal education, empowerment, and wealth status with immunization practices ,31,32. SThis study identified young paternal age as an important predictor of immunization refusal. A systematic review conducted by Sadaf et al. (2013) reflected that immunization refusal is continuously emerging worldwide among parents . It is eThe distance to vaccination centers is an important determinant for immunization practices. This study identified that an increase in the distance to the vaccination center significantly decreased the odds of immunization refusal, which signifies that parents appreciate the door-to-door vaccination service. Earlier studies from Pakistan have also reported that a long distance to the vaccination center is a barrier to immunization ,29.An insignificant relationship between immunization refusal with commonly reported AEFI, such as fever, swelling, pain at the injection site, diarrhea, and cold/cough, was reported. This reflects the fact that commonly reported AEFI are not associated with immunization refusals. However, a significant relationship was reported between immunization refusal with hospitalization and paralysis (disabilities). Although, no association between death following immunization has been reported in a systematic review . SimilarImmunization refusal has received global attention as vaccines help prevent disease and save millions of people worldwide. The risks and benefits are the most cited reasons behind hesitancy internationally . AlthougMoreover, parents’ education was assessed subjectively and due to this, no significant turn points for future studies can be made from the study’s maternal and paternal education findings. This study has represented the views of parents living in Pathan Colony and Orangi Town, Karachi, Pakistan, and conclusions from two localities of Karachi cannot be generalized to the whole population of the city. Additionally, opinions from key stakeholders, such as community workers, community physicians, union council members, and religious leaders, were not considered. Therefore, there is a need for more studies that assess immunization refusal during the routine and the SIAs, and this will help the exploration of the ground realities of immunization refusal from a specific campaign.Immunization refusal is a basic reason for low immunization coverage and the emergence of diseases that can be prevented through immunization. Poverty and illiteracy act as major barriers to vaccination. Unawareness about self-limiting vaccine-related adverse events, i.e., fever, pain and swelling at the injection site, a lack of trust in the government, and an increased concern about the safety and efficacy of vaccines were found to be barriers to routine immunization. Thus, parents refuse to vaccinate their children due to many factors.


Distinguishing Crohn's disease (CD) and intestinal Behçet's disease (BD) is difficult in clinical practice.To evaluate the ability of CT enterography (CTE) to enhance the diagnostic value of endoscopy in differentiating CD from intestinal BD and to establish differential diagnosis models.A total of 113 patients with CD and 70 patients with intestinal BD from seven tertiary inflammatory bowel disease centers were enrolled. The univariate and multivariate analyses were used by SAS software version 9.2. Three differential scoring models based on the multivariate analysis of endoscopic features alone (model 1), endoscopic features combined with clinical symptoms (model 2), and endoscopic features combined with clinical symptoms and CTE (model 3) were established.The results showed that model 2 increased the efficacy of model 1 in differential diagnosis and model 3 had the highest accuracy of 84.15% at a cutoff value of two points. The scoring of model 3 was as follows: genital ulcer (−3 points), skin lesions (−3 points), oval ulcer (-2 points), longitudinal ulcer (1 point), number of ulcers > 5 (3 points), inflammatory polyps (2 points), mucosal severe enhancement (2 points), and fibrofatty proliferation (1 point).Clinical symptoms and CTE increased the ability of endoscopy to differentiate CD from intestinal BD. What is known:- Crohn's disease (CD) and intestinal Behçet's disease (BD) have many similarities and differential diagnosis is difficult.- Crohn's disease and intestinal BD have different prognoses.What is new here:- Endoscopic and imaging indicators significantly improved the ability to differentiate between CD and intestinal BD.This model in our study is useful to differentiate CD from intestinal BD.Crohn's disease (CD) is a chronic and recurrent inflammatory disorder with the appearance of intestinal and colon ulcerations, which is difficult to distinguish from intestinal Behçet's disease (BD). BD is a chronic recurrent systemic inflammatory disease, typically presenting as oral and genital ulcerations and ocular lesions. Intestinal BD, the incidence of which accounts for 5–25% of BD, is diagnosed when typical intestinal ulcerations exist , 2. CD aTo date, there are few studies on the differential diagnosis of CD and intestinal BD. Lee et al. compared and analyzed the endoscopic characteristics of the two diseases and established a differential diagnosis model, including ulcer shape and distribution with an accuracy of 92% . HoweverComputed tomography enterography (CTE) is a newly developed technique that can disclose the extent of the lesion involved, visualize the thickening of the intestinal wall, and reveal the characteristics of the mucosal and serous surfaces and mesentery around the lesion. CTE can also detect small intestinal lesions that cannot be observed by colonoscopy. There are few studies on the value of CTE to differentiate CD from intestinal BD. This study aimed to compare and evaluate the accuracy of endoscopic features alone and the enhanced effect of combining clinical symptoms, and endoscopic and CTE features in differentiating the two diseases. Furthermore, this study was also designed to establish the differential scoring models with the expectation that the models can be applied to clinical practice for precise diagnosis and treatment.A total of 70 patients with intestinal BD and 113 patients with CD with clinical, endoscopic, and CTE data who were diagnosed and treated in the Peking Union Medical College Hospital, the First Affiliated Hospital of Sun Yat-Sen University, the Sixth Affiliated Hospital of Sun Yat-Sen University, Renji Hospital Affiliated to Shanghai Jiaotong University, Shanghai Tenth People's Hospital, Xijing Hospital, and the Sir Run Run Shaw Hospital from 1 January 2004 to 30 June 2018 were enrolled in the study. This study was approved by the Institutional Review Board of Peking Union Medical College Hospital (No. S-K1101).The inclusion criteria were as follows: (1) patients with clinically or pathologically confirmed CD or intestinal BD and (2) patients with complete clinical, endoscopic, and CTE data. Endoscopic and CTE data included the original images and reports.The exclusion criteria included the following: (1) postsurgery or posttreatment patients and (2) patients with an uncertain diagnosis.The diagnosis of CD was reviewed and confirmed according to the European Crohn's and Colitis Organization (ECCO) and Chinese consensus based on clinical manifestations, endoscopic and CTE features, or pathological features , 8.The diagnosis of intestinal BD was based on the pathological diagnosis or the diagnostic criteria developed by Cheon et al. . ConfirmAmong the 70 patients with intestinal BD, three intestinal BD cases were pathologically confirmed, nine intestinal BD cases were clinically confirmed, 36 intestinal BD cases were clinically diagnosed as probable, and 22 intestinal BD cases were clinically suspected. There were no statistical significances in the CTE features among the confirmed, probable, and suspected groups , furtherDemographic and clinical data included patient sex, age at the onset of gastrointestinal symptoms, clinical presentations, personal and past history, extraintestinal manifestations, and complications shown in , 3.Endoscopic features included the lesion site, segmental lesions, ulceration morphology , the number of ulcerations , ulceration diameter , ileocecal valve involvement, inflammatory polyps, mucosal bridge, and cobblestone appearance .Segmental lesions meant more than two areas with discontinuous ulcerative lesions. Longitudinal ulceration was one with a length longer than 4 cm. If the ulcer occupied more than half of intestinal circumference, we called it an annular ulcer. Aphtha was defined as a tiny, punched out, raised, or flat red lesion with a white center. Cobblestone appearance was defined as a mucosal pattern with raised nodules, resembling the paving of the “Roman” road .All the endoscopic data were read independently by two experienced endoscopists blinded to the patients clinical data, and the final diagnosis was made after discussion if they disagreed with each other.Imaging items of CTE included the length of the longest lesion segment, the thickness of the intestinal wall at the site of the lesion, enhancement degree, stratified mural hyperenhancement, asymmetric mural hyperenhancement, polypoid lesion of the mucosal surface, fibrofatty proliferation, and engorged vasa recta .The degree of lesion enhancement was defined according to CT value, with mild enhancement defined as lower than 20 Hounsfield units (HU), moderate enhancement defined at 20–40 HU, and severe enhancement defined as above 40 HU. Stratified mural hyperenhancement was defined as hyperenhancement of the inner (bilaminar) or both the inner and outer (trilaminar) aspects of the bowel wall. Polypoid lesions of the mucosal surface meant protruding and polypoid lesions in the intraluminal surface of the bowel wall. Fibrofatty proliferation, which is also called creeping fat, referred to hypertrophy of the mesenteric fat adjacent to diseased bowel segments with an influx of inflammatory cells and fluid. Engorged vasa recta, which are also known as comb sign, were defined as enlarged blood vessels that supply and drain an inflamed bowel loop –14.All the CTE data were reviewed independently by two experienced radiologists blinded to the patient's clinical data, and the final diagnosis was made after discussion if they disagreed with each other.t-test or the Wilcoxon rank sum test was used for univariate analysis. Variables with a p-value<0.05 in the univariate analysis were included in a logistic regression model. The receiver operating characteristic (ROC) curve analysis was used to determine the threshold value for continuous variables presenting a linear assumption; otherwise, Locally Weighted Scatterplot Smoothing (LOWESS) function was used. A 10-fold cross-validation method was used to verify the model.Categorical variables were described as ratios; the chi-squared test or Fisher's exact test was used for univariate analysis. Continuous variables having a standard normal distribution were presented as mean ± SD; otherwise, they were described as median and interquartile ranges. The At last, the regression coefficients were divided by the smallest coefficient, and each predictor can get an integer score by rounding. Each patient can have a total risk score by adding the scores of all the predictors. All the data were analyzed by SAS version 9.2 .The flow diagram of this study is shown in p < 0.0001). The age of onset of gastrointestinal symptoms for patients with intestinal BD was significantly more than that for patients with CD (p = 0.001). However, there were no statistical significance in the history of appendectomy, smoking, or drinking alcohol (p> 0.05).As seen in p = 0.0343). The incidence rates of diarrhea and perianal lesions in CD were higher than those in intestinal BD (p < 0.0001). There is a slight difference in onset symptoms between the two groups.p< 0.05), while patients with intestinal BD were more prone to intestinal perforations (p = 0.0123).In respect of complications, patients with CD were more prone to intestinal stenosis and intestinal obstructions than patients with intestinal BD (p < 0.0001). In addition, skin lesions, thromboembolic diseases, and myelodysplastic syndrome were more common in intestinal BD (p < 0.05).In terms of extraintestinal manifestations, patients with intestinal BD had a significantly higher proportion of oral and genital ulcerations than patients with CD (p < 0.0001). The incidence rates of segmental lesions, longitudinal ulcers, irregular ulcers, and aphtha were higher in patients with CD, while deep ulcers, annular ulcers, and oval ulcers were more common in patients with intestinal BD (p < 0.0001). In terms of the number of ulcers, 52.86% of patients with intestinal BD had a single ulcer, and 49.56% of patients with CD had more than five ulcers, showing a significant difference between intestinal BD and CD (p < 0.0001). In addition, the incidence rates of inflammatory polyps, mucosal bridge, and cobblestone appearance in patients with CD were higher than those in patients with intestinal BD (p < 0.05).Based on colonoscopy, there were statistical significances in the ulceration distribution, type, number, and diameter between the two groups . The ilep < 0.0001). In addition, patients with CD were more likely to have polypoid lesions of the mucosal surface (p = 0.0001). Fibrofatty proliferation and engorged vasa recta were also more common in patients with CD .The results showed  that theIn order to compare the abilities of different markers to differentiate CD from intestinal BD, we established three score models based on the multivariate analysis of endoscopic features alone (model 1), combining endoscopic features with clinical manifestations (model 2), and combining CTE and endoscopic features with clinical manifestations (model 3).p = 0.0027), whereas longitudinal ulcer, number of ulcers >5, and inflammatory polyps were independent predictors for CD (p < 0.05). Scores of model 1 are shown in Model 1  showed tModel 2 Model 3  showed tp< 0.05)  . The goo< 0.05) .The scoring model was verified by 10-fold cross-validation. For these three models, the areas under the ROC curves verified by a 10-fold cross-validation were 0.8072 in model 1, 0.8912 in model 2, and 0.9148 in model 3, as shown in The results indicated that the model based on the clinical, endoscopic, and CTE features had a better ability to distinguish CD from intestinal BD compared to the model based on endoscopic features and clinical symptoms, followed by the model based on endoscopic features alone.Crohn's disease and intestinal BD have many similarities in clinical characteristics and endoscopic features, but the prognosis of intestinal BD was worse than that of CD; therefore, the differential diagnosis is very important. There are only a few comparative studies about differential diagnosis. In 2009, Lee et al. compared the colonoscopic findings between 115 patients with intestinal BD and 135 patients with CD and developed a simple decision tree differential model based on endoscopic features with a specificity of only 60.3% when applied to Chinese patients, which had limited discriminating value. Compared with previous studies , 6, our In our study, we reassessed the value of the endoscopic model to differentiate CD from intestinal BD. We found that features, such as oval ulceration, longitudinal ulceration, and the number of ulcerations > 5, were still important for differential indices consistent with other studies , 6. BesiModel 2 was improved by adding clinical symptoms into model 1. We found that clinical symptoms significantly increase the ROC area of model 1 from 0.8469 to 0.9372. Genital ulceration and skin lesions were the two differential symptoms included in model 2. We all know that skin and mucosal lesions were the most characteristic presentations of BD. More than 75% of patients with intestinal BD had genital ulcers, which often occur in the scrotum , 16.In order to enhance the efficacy of the scoring model further, we incorporated imaging features with endoscopic features and clinical symptoms. Compared with model 1 and model 2, model 3 was the best model with an accuracy of 84.15%. Moreover, model 3 in our study was superior to the Korean differential model, including endoscopic features and clinical manifestations, with an accuracy of 78.2%, indicating that CTE features played an important role in the diagnosis of CD and intestinal BD and should be considered in clinical practice. Previous studies showed that mucosal surface severe enhancement is highly correlated with histological activity in patients with CD . HoweverThe strengths of this study are as follows. First, the scoring methods adopted in this study are based on the regression coefficients of multivariate models. The scoring based on weighing different factors is relatively reasonable and reliable. In addition, this method is simple, convenient, and easy for clinical application. Second, 10-fold cross-validation helps to reduce the overfitting phenomenon. Third, this was a multicenter study, which reduced the selection bias. However, our study also has some limitations. First of all, a prospective study with more patients should be performed to validate these scoring models in the future; second, some laboratory tests, which have the potential differentiating ability such as antiendothelial cell antibodies (AECAs), were not included in this study –23.In conclusion, our results suggest that endoscopic indices combined with CTE examinations and clinical symptoms are of great value in the differentiation of CD and intestinal BD. For hospitals without the ability to perform CTE, clinical symptoms can also increase the differential ability of endoscopic features. It is expected that prospective studies will further validate the models and can be applied in clinical practice.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.HY and JQ: study design, data collection, analysis support, and critical revision of the manuscript. HZ: data collection, analysis, and drafting of the manuscript. WL, WH, TG, YL, BT, CW, MC, XG, ZR, ZL, KW, and QC: data collection. WH: data analysis. All authors contributed to the article and approved the submitted version.This study was supported by the National Nature Science Foundation of China (81570505 and 81970495), the Beijing Municipal Natural Science Foundation (7202161), the Health Research and Special Projects Grant of China (201502005), and the CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-3-001 and 2019-I2M-2-007).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.