Bone metastasis (BM) has become an important health problem. In recent years, studies on BM are growing rapidly, but there were no bibliometric studies regarding BM. This study aimed to illustrate the overall knowledge structure and development trends of BM.Research datasets were acquired from the Web of Science database. The time span was defined as “1980–2020”. VOS viewer and Citespace software was provided to analyze the data and generate visualization knowledge maps. Annual trends of publications, distribution, H-index status, co-authorship status, and research hotspots were analyzed.Amgen Inc. (43). Supportive Care in Cancer (24) published the most papers on BM. “Safety”, “skeletal related event”, “open label”, “management”, “health”, and “prognosis” are the research hotspots in the recent years.Six hundred eighty-two publications met the requirement. USA published most papers , and both total citations  and H-index (57) of USA ranked first. The most productive institution on BM is Amgen Inc. published the largest number of articles, Supportive Care in Cancer was the most productive journal related to BM. “Safety”, “skeletal related event”, “open label”, “management”, “health”, and “prognosis” are the research hotspots in recent years. We believe this study can not only show the global research overview in past 40 years but also point the research trend of BM in the future.In this study, we conduct a systematic and comprehensive analysis on the research in BM field. The publication number was rising in recent years stably. USA contributed mostly not only in quality, but also in quantity.  Therefore, malignant tumor BM has become one of the hot issues in clinical orthopedics research.The bone is the third most common site of metastasis for a wide range of solid tumors including lung, breast, prostate, colorectal, thyroid, gynecologic, and melanoma, with 70% of metastatic prostate and breast cancer patients harboring bone metastasis (BM). It has been applied to evaluate citation counts and collaboration in countries, institutions, journals, and authors, and to predict key word trends in the research field. So it plays a great role in evaluating scientific fields.Bibliometrics is the cross-disciplinary science of quantitative analysis of all knowledge carried by mathematical and statistical methods.However, to our knowledge, bibliometric studies concerning the trend of the published literature of articles published in the field of BM has not yet been reported. This study aimed to intuitively show the research framework, overall knowledge structure, and development trends of the field of BM. We hope this study will help scientific scholars better understand the research status and development trends.22.1The data for this study were collected from the Web of Science (WOS) and its Core Collection. WOS is a most widely accepted and suitable database for the subsequent bibliometric analysis of scientific publications due to its strict evaluation process and the most influential and credible information it could provide.The literature search was also limited to articles that were published from January 1, 1980 until August 1, 2020 (a span of 40 years). The search terms were integrated as “bone metastasis” OR “bone metastases” AND “solid tumor”. Original articles were included in this study, while letters, editorials, basic research articles, duplicate articles, non-English literatures, and corrections were excluded in our finalize data set. To perfect the research, 2 independent researchers reviewed and evaluated the cited articles, respectively. Any different opinions were discussed until consensus was reached.2.2P < .05. VOS viewer  and Citespace (Chaomei Chen) are used to quantify information, visualize co-occurrence networks utilizing various layouts, and create timeline view of the keywords.,7All data were extracted and imported into Microsoft Excel 2017. Annual trends of publications, distribution, citation and H-index status, co-authorship status, research hotspots, and co-citation status were analyzed. Chi-square analysis was performed using SPSS version 20.0 (SPSS Inc.). Statistical significance was considered at 33.1A total of 746 articles on BM were identified in the WOS database as a result of the search. With an additional manual screening according to the inclusion criteria, a total of 682 articles were analyzed finally. Due to the absence of relevant information such as the author, the journal, or years, 64 study with limited information were removed. One hundred eighty-one papers are reviews and 501 papers are articles. The selection flow chart is shown in Figure Only 1 article was published in 1981, and the growth was found in the following year. There was a peak in the number of studies from 2009 to 2014. A total of 59 articles (8.65%) were published in 2011, the highest number in all years, followed by the year 2013  and the year 2012 . The results showed that the most efforts and exploration have been made on BM from 2011 to 2013. However, 52 articles were published in 2019, which indicated that research trends on BM are gradually picking up in recent years. Figure 3.2A total of 51 countries contributed to the field of bone metastases research. But the majority of the papers were published in only a few countries. There were 549 papers (80.49%) published in the top 5 countries, and most of the studies were from North America and Europe. The United States published the largest number of articles , followed by Italy , Canada , China , and UK . H-index is a reliable and authentic parameter for academic evaluation. The United States had the highest H-index (57), followed by Canada (32), UK (28), Italy (26), and China  papers. At the second position was Cancer Journal with 14 (2.05%) papers, followed by Journal of Oncologist and Journal of Bone Oncology with 13 (1.9%), and Cancer Treatment Reviews with 11 (1.6%). The 5 journals account for 10.99% of all the papers. The cited time of Journal of Clinical Oncology ranked first (2925), followed by Cancer (1638) and Cancer Research (1016). The H-index of Cancer ranked first (12), followed by Oncologist (11) and Supportive Care in Cancer (11)  journals published more than 10 papers. The journal with the greatest number of publications was 3.4Amgen Inc. published the largest number of articles (44), followed by Massachusetts Gen Hospital (20), University Sheffield (19), University Texas MD Anderson Cancer Center (19), and University Washington (18). The H-index of cited time of Amgen Inc. and University Sheffield ranked first (17), followed by University Washington (13), Massachusetts Gen Hospital (13), and University Texas MD Anderson Cancer Center (13). The cited time of Mem Sloan Kettering Cancer Center ranked first of all the institutions (2078), follow by Amgen Inc. (1906) and Massachusetts Gen Hospital (1752). Only institutes with a minimum of 5 articles were included in co-authorship analysis. It shows that Amgen Inc., Massachusetts Gen Hospital, and Washington University were at the center of researches. In general, cooperation between the institutions were relatively strong , follow by Saad F (24), Body JJ (23), Smith MR (14), and von Moos R (14). The cited time of Lipton A ranked first (2429), followed by Saad F (2116) and Hirsh V (1995). The H-index of Lipton A (21) ranked first of all the authors, followed by Saad F (15) and Body JJ (13). Only authors published a minimum of 5 articles were included. It shows that authors in the same country have relatively close collaboration. Nevertheless, cooperation between authors from different country is weak  made the majority of publications (80.49%), while the top productive institutions were all from these countries. This result showed that the global research on BM concentrated in North America, West Europe, and East Asia.Bibliometric analysis has been applied vastly to assess the merits of a specific field as a mature tool. USA and Canada contributed most in this field with the highest total publications and H-index. It indicates that USA and Canada were the leader in the quantity and the quality. The most important reasons for USA and Canada's achievement may be the rapid development in medical technology, economy, and academy. In addition, adequate research funds are invested in medical research to increase the quality of researches in USA and Canada. While in the top 10 most productive countries, China had the lowest H-index and cited number, which means China's qualities of publications concerning BM were relatively low. China has an advantage in recruitment of participants with the large population and high prevalence of tumor diseases, however China's research ability was relatively weak comparing with West Europe and North America. On the other hand, the amount of invested government funds was much lower than USA and Canada. Only account for 2% to 3% of the total government funds were invested to the medical research in China. But China still has the significant influence and development potential in the field of BM, with the huge population and rapid development of the country.The number of citations can reflect the quality of a paper. The H-index is a widely used parameter to quantify and standardize researchers’ scientific impact.Amgen Inc. ranked first, as well as the H-index, while Mem Sloan Kettering Cancer Center was the most cited institution. It indicated that these organizations dominated studies in the field of BM both in terms of quantity and quality. The journal with the greatest number of publications was Supportive Care in Cancer, the H-index of Cancer ranked first and Journal of Clinical Oncology ranked first in cited time, this reflected that these journals were in the leading position and have the great influence in this field. They were the most attractive choice for authors to submit for publication undoubtedly.In publications number of BM field, Co-authorship research is a meaningful focal point of bibliometrics. The level of research collaboration reflected the current development status of this field. The network map showed that the centrality and density values of the study are not high and relatively weak interaction between countries, institutions, or authors. Considering this result, it is necessary to develop the global collaboration between countries/regions and institutions and build an international academic net of the BM research.4.2 While the patients’ survival benefited, SRE risks also increased.–15We can find that the research focus on BM in early years was related to pathogenesis and diagnosis, but skeletal related events (SRE), safety and prognosis are the hotspots in recent years. With the advancement of treatment methods and techniques, the survival time of advanced cancer patient was gradually extended. For instance, advanced lung cancer patients’ median survival time was extended to 1 year. The risk of SRE in patients with bone metastases dominated by osteolytic lesions was high. The pain caused by SRE  seriously affect the patients’ life quality. While controlling the primary disease, actively preventing and treating BM SRE are particularly important.BM of malignant tumor can be divided into the following 3 types according to the characteristics of the lesion, osteolytic, osteogenic, and mixed. Psychotherapy for BM patients is indispensable while antidepressants and anti-anxiety drugs can be used for cancer patients’ anxiety and depression symptoms.–20On the basis of the systemic treatment of the primary disease, multiple department treatment should be taken to BM patients. Formulating individualized comprehensive treatment plans in a planned and reasonable manner can reduce or delay the occurrence of BM complications and SRE, which will improve patient's life quality. On the other hand, studies have suggested that among cancer patients, the total prevalence of psychological distress is 35.1%.4.3,22 Second, the main evaluation index in this study is citation number and H-index, but there are many factors that affect citation rates.As far as we know, the current study is the first to analyze the quality and quantity of researches using bibliometric analysis and visualization tool in the field of BM. The systematic literature analysis conducted by us consists of comprehensive statistic from various aspects in BM field. As a result, we can get an objective and exhaustive cognition of the global research in BM. Except these obvious strengths, we still found some weaknesses about this study. First some public and commercially available bibliometric databases were not contained in current study such as Medline, Google Scholar, and Scopus. No bibliometric database is considered superior, and there are wide variations in citations data in each database.,25 As for H-index, many scholars think that there is an obvious positive correlation between the H-index and journal or region's total publish amount. According to the definition of H-index, it cannot exceed the limit of publication. As a result, it is not conducive to the regions, journals, or authors with small publications and large citation number.For example, this strategy may favor older articles. Journal and author self-citations, incomplete citing, and omission bias also significantly contribute to citation rates.5Amgen Inc. published the largest number of articles, Supportive Care in Cancer was the most productive journal related to BM. Safety, skeletal related event, open label, management, health, and prognosis are the research hotspots in recent years. We believe this study can not only show the global research overview in past 40 years but also point the research trend of BM in the future.In this study, we conduct a systematic and comprehensive analysis on the research in BM field. The publication number was rising in recent years stably. USA contributed mostly not only in quality, but also in quantity. Conceptualization: Kai Huang.Data curation: Kai Huang.Methodology: Kai Huang.Project administration: Kai Huang.


Background: Uric acid (UA) is proposed as a potential risk factor for stroke in adult, yet the results from published studies are not generally accordant.Method: We included prospective studies that explored the relationship between serum UA (SUA) and strokes. In this study, strokes include ischemic stroke and hemorrhagic stroke, which consists of intracerebral hemorrhage and subarachnoid hemorrhage. The effect-size estimates were expressed as hazard ratio (HR) and 95% confidence interval (CI). Sensitivity and subgroup analyses were performed to assess the robustness of the pooled estimation and potential sources of heterogeneity between studies.Results: We meta-analyzed 19 prospective cohort articles, which involve 37,386 males and 31,163 females. Overall analyses results showed a significant association between a 1 mg/dl increase in high levels of SUA and the risk of total stroke , ischemic stroke , and hemorrhagic stroke . No significant difference was found between ischemic stroke and hemorrhagic stroke. In the subgroup analyses, the association of high SUA levels and the risk of total stroke was statistically significant in females  and males . Coincidentally, the association was also statistically significant for ischemic stroke, both in females  and in males . However, for hemorrhagic stroke, it was only statistically significant in females . Our dose–response research indicated the J-shaped trend between the ascending SUA levels and the higher risk of suffering from a stroke.Conclusions: Our findings indicate that elevated SUA is a significant risk factor for adult stroke, both for ischemic stroke and hemorrhagic stroke, and especially in females. Stroke is believed to be the second leading cause of death and a major contributor to disability-adjusted life-years (DALYs) lost worldwide . AccordiUric acid (UA), one metabolic end product of purine, exists in the form of UA salt with high solubility in organisms. Regularly, serum UA (SUA) levels range from 1.5 to 6.0 mg/dl for women and 2.5 to 7.0 mg/dl for men under a healthy status, which is hard upon the upper limit of UA dissolution in serum . Up to dThis meta-analysis was carried out in line with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement , which iWe finished literature search by looking through PubMed, EMBASE, and Web of Science databases as of December 26, 2020. The following medical nomenclature are considered: (uric acid OR ua OR urate OR hyperuricemia OR hyperuric OR ammonium acid urate [Title/Abstract]) AND . In order to avoid underlying missing points, reference lists of retrieved articles and systematic reviews were scanned.Two researchers (Tianci Qiao and Hongyun Wu) examined all retrieved articles independently, and they seriously assessed preliminary qualification based on the titles, abstracts, and full texts when necessary.We included the articles when they met the following criteria: (1) the study has a prospective design (prospective cohort or prospective nested case-control study); (2) the study outcomes were stroke, including ischemic stroke and any kinds of hemorrhagic stroke ; (3) enrolled participants were free of stroke at baseline; (4) studies that reported the definition of outcomes in participants with stroke; and (5) hazard ratio (HR) and corresponding 95% confidence interval (CI) of the association between UA and stroke were reported. Articles were excluded if they were reviews, proceedings, letters, case reports, or meta-analyses, or they were not reported in English languages, or the subjects of the studies were not stroke patients, or they were of duplicated publications or studies using overlapping data.Two investigators (Tianci Qiao and Hongyun Wu) excerpted data from each qualified article and imported them into a standardized Excel spreadsheet independently, including name of the first author, year of publication, location where study was conducted, sample size, sex, baseline age, follow-up period, ascertainment of UA and stroke, type of stroke, levels of UA, effect estimation, adjusted confounders, and other traditional risk factors, if available. The disagreements were resolved by reevaluating original articles jointly and, if necessary, by a third author (Wei Peng).Z-test as reported by Altman and Bland  was used to regulate and analyze the data. The random-effects model was employed without considering the magnitude of between-study heterogeneity. Effect size estimates were indicated by HR and its 95% CI. The difference between the two estimates was tested by using nd Bland . Generalnd Bland  was usedI2), which represents the percentage of multiplicity observed between studies whose result is from chance rather than a casual result. A higher I2 value indicates a higher degree of heterogeneity. If the I2 value is higher than 50%, significant heterogeneity would be recorded. As for multiple sources of heterogeneity possibly from clinical and methodological fields, plenty of prespecified subgroups were analyzed according to the baseline age, gender, region, follow-up, factor correction, including whether body mass index (BMI) was adjusted, smoking status, hypertension or blood pressure, diabetes mellitus or blood glucose, hyperlipidemia or lipid, or renal factors.Heterogeneity between studies was assessed by inconsistency index  tool was used to assess the quality of the cohort studies, shown in P < 0.001), ischemic stroke , and hemorrhagic stroke  .After pooling the results of all eligible prospective cohorts together , there w= 0.046) . This asP = 0.00), ischemic stroke (P = 0.00), and hemorrhagic stroke (P = 0.05). Further filled funnel plots showed that there was one potentially missing study in total stroke, 28 missing studies in ischemic stroke, and 13 missing studies in hemorrhagic stroke due to the publication bias to have a symmetrical plot.Begg's funnel plot was used to assess publication bias for the association between SUA levels and risk of stroke, and all of them seemed symmetrical, shown in P < 0.001) and men  (two-sample Z-test P = 0.088). It was also statistically significant for ischemic stroke in women  and men  (two-sample Z-test P = 0.015). The association of SUA levels and risk of hemorrhagic stroke was statistically significant in women , but not in men  (two-sample Z-test P = 0.025).A sequence of subgroup analyses was conducted to investigate the possible causes of between-study heterogeneity for SUA levels and risk of stroke . By gendP = 0.03), as well as ischemic stroke  and hemorrhagic stroke . In Europe, however, there was only statistically significant association for SUA levels and risk of total stroke  and ischemic stroke .By geographic locations, in Asia, there was a statistically significant in association between SUA levels and risk of total stroke  and ischemic stroke . For  years, total stroke  and ischemic stroke  were observed to be statistically related to a high level of SUA. While for  years as well, the association of the SUA levels and risk of total stroke  and ischemic stroke  was statistically significant.By follow-up years, in sector of  years, significance was observed for association of the SUA levels and risk of total stroke  years: HR = 1.08; 95% CI: 1.02–1.14; P = 0.01, and  years: HR = 1.28; 95% CI: 1.17–1.40; P < 0.001]. Similarly, for ischemic stroke, statistically significance was observed . While for hemorrhagic stroke, only marginal significance was observed among age group of 50–90 years .By age, total stroke was significantly associated with SUA levels in all subgroups [ years: HR = 1.12; 95% CI: 1.04–1.21; P < 0.001, non-fatal stroke: HR = 1.16; 95% CI: 1.16–1.23; P < 0.001). The same trend was absorbed in ischemic stroke  and hemorrhagic stroke .By the stratification for stroke severity, we classified the severity of a stroke as fatal and non-fatal, and we found high SUA levels were significantly associated with both fatal and non-fatal stroke  (p for non-linear trend = 0.32) for females   and a li females .J-shaped trend between the ascending SUA levels and the higher risk of stroke. However, no obvious distinction was found between ischemic stroke and hemorrhagic stroke. More importantly, we found high SUA levels were significantly associated with an increased risk of fatal stroke. Our findings highlight the prominence and the necessity of closely regulating SUA, especially for elderly females, who have a high risk of suffering from cerebrovascular disease.To the best of our knowledge, this is to date the most panoptic meta-analysis that has investigated the association between SUA levels and risk for stroke. The key findings of this study are that elevated SUA is a significant risk factor for adult stroke, both for ischemic stroke and hemorrhagic stroke, and the risk is more evident in females than that in males. Our sensitivity analyses and subgroup analyses also revealed that the relationship between SUA and stroke was robust and not affected by multifactor correction. Moreover, dose–response analysis presented the Several systematic reviews and meta-analyses have evaluated the impact of high SUA on the onset of stroke. Pooling the results of 13 prospective studies by Zhong et al.  showed tThe concentration of UA is the key point of the mechanisms underlying the association of UA with development of stroke. As one of the most abundant antioxidant molecules in humans, UA has the valid ability to clear out peroxynitrite, nitric oxide, and hydroxyl radicals; hence, it can prevent protein nitration and lipid peroxidation , 39. StuIn our study, we took ischemic stroke and hemorrhagic stroke as the main subtypes, and we found elevated SUA levels have similar adverse effects on the development of stroke in these two subtypes. Evidence showed that ischemic stroke and hemorrhagic stroke both cause local hypoxia that damage brain tissue, and they could be converted to each other. There was a high risk of hemorrhagic transformation during the treatment of ischemic stroke . HoweverSex differences in the association of elevated SUA with stroke-related risk factors were found in our study. Statistically, females have a higher risk of experiencing a stroke-related fatality than males. Meanwhile, a J-shaped trend between the ascending SUA levels and higher risk of stroke for men and a liner trend for women had been explored. It is universally acknowledged that stroke is a sexually dimorphic disease. For one reason, females have a longer average lifespan, which increases the odds that they will have a stroke. Besides, females suffer greater susceptibility to depression and anxiety and often report higher levels of stress than males do –56. OtheJ-shaped trend is worthy of our attention in the relationship of SUA and risk of stroke in this meta-analysis. Thirdly, although a large panel of subgroup analyses were undertaken to account for possible sources of heterogeneity, significance still persisted in some subgroups, limiting the interpretation of pooled effect-size estimates. Finally, similar to any observational studies, a causal relationship could not be fully established.Some limitations for the present meta-analysis should be acknowledged. Firstly, we were unable to carry out further subgroup comparison of hemorrhagic stroke because the corresponding data were not available in the original articles. The mechanisms and risk factors for subarachnoid hemorrhage and intracerebral hemorrhage are different in important ways, as are treatment and outcomes . More clJ-shaped trend between the ascending SUA levels and the higher risk of suffering from stroke. Moreover, high SUA levels are associated with an increased risk of fatal stroke. Further investigations on the molecular mechanisms linking SUA to adult stroke are also warranted.Our study found that elevated SUA is a significant risk factor for adult stroke, both for ischemic stroke and hemorrhagic stroke, especially in females. Our dose–response research revealed a The original contributions presented in the study are included in the article/TQ reviewed the articles and wrote the manuscript. HW helped with the article review. WP was the editor of the manuscript and helped with the preliminary qualification. 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.


Background and Objectives: The standard diagnostic procedure for a patient with a suspected polytrauma injury is computed tomography (CT). In individual cases, however, extended acute imaging using magnetic resonance imaging (MRI) can provide valuable and therapy-relevant information. The aim of our cohort study was to find such cases and to describe their characteristics in order to be able to give possible recommendations for MRI application in acute trauma situations. Materials and Methods: In the study period from 2015–2019, an evaluation of the imaging performed on polytrauma patients was carried out. The specific diagnostic and therapeutic criteria of the MRI group were further defined. Results: In total, 580 patients with an ISS ≥16 (injury severity score) were included in the study. Of these 580 patients, 568 patients received a CT scan and 12 patients an MRI scan as part of the initial diagnostic. Altogether, 66.67% of the MRIs took place outside of regular service hours. The main findings for MRI indications were neurological abnormalities with a focus on myelon injuries. Further MRI examinations were performed to rule out vascular injuries. All in all, 58.3% of the MRIs performed resulted in modified therapeutic strategies afterward. Conclusions: MRI in the context of acute diagnostic of a severely injured patient will likely remain reserved for special indications in the future. However, maximum care hospitals with a high flow of severely injured patients should provide 24/7 MR imaging to ensure the best possible care, especially in neurological and blunt vascular injuries. Acute care of polytraumatized patients and especially the scope of initial diagnosis continues to challenge clinicians around the world. In routine clinical practice, when a potentially life-threatening injury is suspected, a full-body computed tomography (CT) is recommended and performed as a standard of care ,2,3,4. TIn certain cases, however, an additional MRI is required to provide further information to rule out or confirm the critical diagnosis. For example, MR imaging is used more frequently for expected isolated spinal injuries, also in emergency situations ,6.The knowledge gained from this imaging can be crucial for the decision of surgical or conservative treatment. MRI is helpful for patients with post-traumatic spinal cord dysfunction or in case a patient’s symptoms cannot be explained by findings on radiographs or CT or when a reliable neurologic exam cannot be obtained ,8.However, MR imaging has several limitations due to its longer scan times, higher expenses, and the need for highly trained staff . EspeciaThis retrospective cohort study was designed to evaluate the utility of immediate MR imaging in the setting of polytrauma injury care and to define further potential indications and limitations.In this retrospective cohort study, all patients with multiple injuries, who were admitted between 2015 and 2019 to a level one trauma center via shock room of the emergency department, were included. The data were collected by a study assistant on call 24 h/365 d, who was not included in the treatment and diagnostic workup. The study was approved by the institutional ethical review board (14-101-0004).Inclusion criteria for our evaluation was an ISS ≥16 (injury severity score), graded after complete diagnostics, including computed tomography (CT) and/or MRI.In order to be able to compare the findings of the MRI group in the context of routine care with an isolated CT, we carried out the evaluations for both CT and MRI.Patients were divided into 2 groups. Patients who received CT diagnostics exclusively as part of acute diagnostics were assigned to the CT group. Patients who received MRI diagnostics exclusively or additionally were assigned to the MRI group.Age, gender, ISS, intubation rate, Glasgow Coma Scale (GCS), and the time from admission to the shock room until the end of acute radiologic diagnostic (CT or MRI) were recorded. The demographic data are shown in All patients receiving a CT were examined using a 2 × 128 detector row dual-energy scanner , fulfilling the requirements stated in the national S3—Guideline “Polytrauma/Schwerverletzten—Behandlung”. In our university hospital, this scan is set up as a split-scan, including a dedicated head-and-neck CT-angiogram (10).A. ascendens. It reached from the aortic arch covering the outlets of supraaortic branches up to the vertex. Volume and concentration of the contrast agent used  were standardized to a total of 120 mL, with 120 mL injected for the head-and-neck CT-A. The contrast agent injection was followed by a flush with 20 mL of saline. Both contrast agent and saline flush were injected with rates of 3.5 mL/s. ECG-gating is not routinely used in our protocol. The third scan was a venous phase delayed scan, covering the thorax, abdomen, pelvis, and upper half of the thigh; in select cases, the scan length was modified to cover the knees. The scan was performed with a fixed delay of 30 s after the CT-A. The standard field of view was 500 mm; the slice thickness was 5.0 mm; the increment was 5.0 mm; the pitch was 0.60; kV and mAs were calculated and set automatically  based on the scan topogram. A soft-tissue kernel with medium edge attenuation (B26f medium) was used for the calculation of axial, coronal, and sagittal views of the head and neck. Additional thick-slab axial maximal intensity projection (MIP) was rendered (10 mm) axial, sagittal, and coronal. Reconstructions were rendered using a B60f kernel for lung tissue , a B60f sharp kernel for bones , and a B30f kernel for soft tissue . Further reconstructions were calculated at the radiologists’ discretion depending on the findings or suspicions drawn from the standard datasets.First, a non-contrast-enhanced scan of the neurocranium was acquired in 0.75 mm slices . The second scan was the contrast-enhanced head-and-neck CT-A, triggered in the MRI scans were performed either on a 1.5 T Symphony or 1.5 T Avanto  depending on availability when needed. In accordance with the posed questions, sequences for suspected spinal trauma included at least T1 TSE sagittal, T2 TSE sagittal and axial, T2 STIR sagittal and for suspected cervical artery injury, PD fat-sat axial (neck), DWI/ADC (head) axial, T2 FLAIR (neck and head) axial, contrast-enhanced MR-angiography or time-of-flight (TOF) MR-angiography (neck). Additional sequences were acquired at the discretion of the board-certified radiologist in charge.Image interpretation (CT and MRI) was performed using a standard three-monitor workstation using the Syngo and Syngo.via picture archiving and communication system . All imaging studies were read and validated by a board-certified radiologist.A descriptive statistical analysis was performed. Due to the small cohort size of the MRI group, we were unable to perform meaningful statistical analyses.In total, 580 patients met the inclusion criteria . In the CT group, the majority of patients were male (72.2%). The MRI group showed an equal gender distribution . Ten patMRI imaging as part of the acute diagnosis of a polytrauma patient is rarely indicated in routine clinical practice. In this study, we were able to evaluate special indications for this imaging.Overall, it should be noted that there is currently very little meaningful literature on MRI diagnosis in polytrauma patients. Thus, our study can provide a valuable contribution to the development of guidelines in acute diagnostics.By far, the leading indication for MRI in our patients in the acute diagnosis of polytrauma was spinal injury with concomitant neurologic symptoms 66.67%). This is consistent with the recommendations of Sarani et al., O’Connor et al., and Chandra et al., who recommended adding further MR imaging in patients with unremarkable CT of the spine but abnormal neurology ,7,9. How%. This iIn our study, it is noticeable that the patients in the MRI group showed a lower prehospital intubation rate. In our view, one possible explanation is that, especially in the case of unclear neurological abnormalities, which turned out to be one of the main indications for MRI in our study, the patient was transported awake for better clinical assessment. Another explanation might be due to the somewhat more difficult handling of patients requiring ventilation in MRI. A lower ISS was, therefore, not a reason to perform an additional MRI.Though, to date, studies on MRI examinations of the spine in the setting of polytrauma do not exist. With our results, we can provide initial insights into this. The second most common indication was advanced diagnostic of cervical vascular injuries (25%). An important point in the context of polytrauma diagnostics is the time factor. Here, there was a clear difference between the CT and MRI group. The door-to-image time of the CT group was 27.48 ± 8.03 min compared to 111.45 ± 45.9 min in the MRI group. This is due to the fact that ten patients first underwent a CT and only then an MRI. Patients who are in a cardio-pulmonary unstable state due to the injury can, therefore, not receive MRI diagnostics as part of acute diagnostics. Depending on the CT findings, these patients must be transferred quickly to the operating theater for initial treatment or into the hands of the intensive care specialists. After stabilization, MRI imaging can then be performed for diagnostic expansion if required.In our opinion, the main arguments against the use of MRI, including whole-body MRI, in the shock room phase are availability and the possibly considerable delay in therapy due to excessively long examination times. MRI has a high value after the secondary survey or in the follow-up because of the comparable or higher sensitivity in intracranial or spinal injuries . An emerFor regional and local trauma centers, 24/7 MRI availability presents a difficult problem to solve. Due to the infrequent indication from the shock room, even with high polytrauma numbers, 24/7 availability should initially be sufficient at level one trauma centers. Fixed and routine implementation of MRI imaging in the polytrauma algorithm is necessary due to the heterogeneous volume of injuries and the often associated acute need for surgery. As for the trauma-CT-scans, different imaging protocols can be established. For MRI, the variety of options presents a significant challenge. We, for now, recommend sagittal T1, T2, and T2 STIR plus axial T2 in suspected spine trauma. For cervical artery dissections, axial PD and T1 fat-sat plus contrast-enhanced MR-angiography and/or time-of-flight MR-angiography, especially for dissections near or within the skull base, revealed a lot of dissections in a step-up approach . Fast whTwo further indications for MRI diagnostics, which were not observed in our study, is the implementation in pediatric diagnostic. Hauwe et al. highlighted the relevance of MRI imaging and equivalent radiation reduction in pediatric diagnosis . The DGUThe main limitation of our study is the large difference in group size, which means that limitations in statistical significance must be taken into account.Another limitation of our study is that no compelling indications for extended acute MRI imaging can be given in the context of polytrauma care. In our view, this is explained by the great heterogeneity of the injury patterns of these patients. For example, a patient may show symptoms of an incomplete transverse section, which cannot be assigned to an exact level and thus require further imaging, but a simultaneously existing splenic rupture with cardio/pulmonary instability requires immediate surgical treatment. However, we were able to show typical red flag injuries , which should be diagnosed by MRI in cardio/pulmonary stable patients.Already in 2009, Provenzale et al. concluded in their review that sensitivity and specificity of MR-angiography and CT angiography are similar for the detection of cerebrovascular injuries in blunt trauma . With reMRI in the context of the acute diagnostic of a severely injured patient will likely remain reserved for special indications in the future. In this special patient clientele, the clinical condition of the patient is the decisive limiting factor for time-consuming MRI diagnostics. However, maximum care hospitals with a high flow of severely injured patients should provide 24/7 MR imaging to ensure the best possible care, especially in neurological and blunt vascular injuries.


Oculocerebrocutaneous syndrome (OCCS), also known as Delleman syndrome (DS), is a rare congenital anomaly featuring focal skin defects, orbital anomalies, and central nervous system malformations. Diagnosis of Delleman syndrome is based on the triad of eye, central nervous system (CNS), and cutaneous defects and confirmed by magnetic resonance imaging. A 23-day-old girl was referred to our department for brain imaging. The infant had multiple cutaneous appendages on the right side of her face. There also was a fleshy mass measuring about 12 mm over her right eye. Brain MRI demonstrated the evidence of colpocephaly, agenesis of the corpus callosum, nodular subependymal heterotopias adjacent to the right lateral ventricle, aplasia of the cerebellar vermis, hypoplasia of the right cerebellar hemisphere, and widening of CSF space in the posterior fossa. There was also an exophytic skin lesion on her right cheek, measuring about 13 × 12 mm in size. In the orbital MRI, there was a mixed cystic solid mass measuring about 25 × 20 mm in her right orbital cavity. The orbital content was abnormal and suggestive of rudimentary orbit. Considering the findings, diagnosis of oculocerebrocutaneous syndrome (Delleman syndrome) was established for the patient. Because of the variations in orbital and CNS manifestations, all patients with clinical suspicion of DS should be assessed by brain and orbital MRI and managed by a pediatric neurologist and ophthalmologist. Oculocerebrocutaneous syndrome (OCCS), also known as Delleman syndrome (DS), is a rare congenital anomaly featuring focal skin defects, some form of orbital anomaly  and central nervous system malformation . This syndrome was described first in two Dutch children by Delleman and his colleagues in 1981, and since then, about 45 cases have been reported. Some of the newly reported cases are associated with vertebral abnormalities, hydrocephalus, cleft lip, cleft palate, and facial cleft [Diagnosis of Delleman syndrome is based on the triad of eye, central nervous system (CNS), and cutaneous defects and confirmed by magnetic resonance imaging (MRI) which usually demonstrates multiple ocular, cerebral, and cerebellar cysts and malformations .We recently studied a patient with all the clinical and radiological features of DS.A 23-day-old girl was referred to our department for brain imaging. She was the second child of a nonconsanguineous couple and born at full term by caesarian section. Birth weight was 2400 g (<3rd percentile), length was 47 cm (15th percentile), head circumference was 32 cm (3rd percentile), and her Apgar score was 8/10 at one minute and 10/10 at 5 minutes. The infant had multiple cutaneous finger-like appendages on the right side of her face. There also was a fleshy mobile, skin-colored mass measuring about 12 mm over her right cheek .Her sister was about 5 years old without any anomalies or developmental delay. The parents had no medical problems, including no history of abortion or miscarriage. During the pregnancy, the mother was properly under midwifery-led care and there were no antenatal or maternal problems. Also, the mother denied any teratogenic exposure during pregnancy. Physical examination revealed three finger-like, firmed, and skin-colored cutaneous appendages on her right cheek and the right periauricular and mandibular area. Ophthalmologic examination showed a fleshy mass in the place of the right orbit. The right eye was completely blind, and the left eye seemed to have a normal vision. Her echocardiogram showed no structural abnormalities. Her abdominopelvic ultrasound study was unremarkable. The extremities and genitalia were normal. Also, no report of seizure had been documented since birth.The patient was referred to the department of radiology for imaging work-up. Brain and orbit MRI was performed which showed colpocephaly and agenesis of the corpus callosum. Also, there were nodular subependymal heterotopias, adjacent to the right lateral ventricle. Aplasia of the vermis, hypoplasia of the right cerebellar hemisphere, and widening of the CSF space in the posterior fossa were some other findings in her brain MRI. There were also some skin lesions with exophytic appearance in the face up to 13 × 12 mm in the infraorbital area. In the orbital MRI, there was a mixed cystic solid mass measuring about 25 × 20 mm in her right orbital cavity. The orbital content was abnormal and suggestive of rudimentary orbit. The left orbit was completely normal .Finally, based on the findings, diagnosis of oculocerebrocutaneous syndrome (Delleman syndrome) was established for the patient.As described before, oculocerebrocutaneous (Delleman) syndrome (OCCS or DS) is a sporadic genetic abnormality characterized by eye, CNS, and cutaneous anomalies .The exact etiological mechanism of DS is still unknown, but one strong hypothesis suggests a sporadic mutation in the fifth or sixth week of development as the underlying cause in DS. This mutation may be associated with a somatic mosaicism that plays a pivotal role in ectodermal development. Another hypothesis has suggested the possibility of an association between the X chromosome and DS, resulting in the higher prevalence of this syndrome in the male population .All previously reported cases seem to be sporadic, and there have been no cases of familial DS. Also, there have been no reports of its recurrence in siblings or children of affected adults in previous cases. In our case, similarly, no evidence of genetic relation and consanguinity was found .To date, there are few reported cases of this syndrome. Eye anomalies in such cases have included orbital cysts, microphthalmia, anophthalmia, and palpebral colobomas , 2. The A recent case of DS by De Cock and Merizian presented with eye coloboma and a large translucent cyst protruded from the left orbit. In contrast to our case, the parents of the aforementioned case were first cousins .Common cutaneous malformations in this syndrome are focal hypoplasia and aplasia. Skin tags and unusual skin appendage in the periorbital area is the characteristic of this syndrome . The preCNS involvement usually includes malformations of the cortical, subcortical, and brainstem-cerebellar complex that are easily recognized in modern imagings . MalformSimilarly, a DS case reported by Ortiz-Basso et al. had bilateral aplasia cutis and slight hypoplasia of the central vermis. However, he also had a small lesion of aplasia cutis in the lumbar area surrounded by hair. That case had several pits on the cheek . Our casIn some previous cases, palatine fissure, lip cleft, and facial cleft were seen too .The other less-frequent anomalies in previously reported cases with DS are urogenital anomalies, rib defects, and ear and nose malformations . But, ouIn conclusion, because of the variations in orbital and CNS manifestations, all patients with clinical suspicion of DS should be assessed by brain and orbital MRI and managed by a pediatric neurologist and ophthalmologist.


We evaluated a large-scale pilot program in Shaanxi Province, western rural China, which integrated prenatal screening interventions for congenital abnormalities into routine antenatal programs.We surveyed 1,597 mothers who gave birth between 2009 and 2016. Adopting the interrupted time-series design, we evaluated the program's impact on awareness, coverage, and cost, by comparing two counties with only supply-side policies, and two counties from the neighbouring province with no policies; and among the two counties with both supply- and demand-side policies and the two counties with only supply-side policies. We adjusted the sampling procedure and women's background characteristics. We conducted subgroup analyses by women's education.After one year of implementation, the coverage of prenatal foetal aneuploidies and B-ultrasound screening rose by 25.0% and 23.5%. The program's supply-side policies attributed to 17.2 percentage points (90%CI 7.8–26.6%) and 27.3 percentage points (90%CI 16.2–38.5%) in coverage, and contributed to a higher median cost of 796.5RMB (90%CI 595.5–997.5). These significantly affected women with secondary education and above. However, the program's demand-side measures, that is, vouchers, seemed to be effective only in the mountainous regions, which raised awareness, and increased coverage of prenatal foetal aneuploidies screening by 28.6 percentage points (90%CI 13.4–43.8%), while not increasing costs. These significantly affected women with primary education and below. Education-related inequalities widened post-program in counties with only supply-side policies, but no inequalities existed in counties with demand-side policies.Shaanxi's program made a pilot study to other provinces of China to integrate antenatal services. Government subsidies might be more effective in targeting specific geographic locations and people with primary education and lower. Evidence before this studyThe global health community is calling for integrated maternal, new-born, and child health care. However, two latest systematic reviews from low- and middle-income countries (LMICs) concluded that there was still a striking lack of evidence on integration and delivery strategies. Prenatal screening of congenital abnormalities, that is, serum screening for foetal aneuploidies and B-ultrasound screening for structural malformation, is an important prophylaxis intervention. Our systematic search of the literature showed that no study has investigated the coverage and inequality of prenatal screening in rural China, particularly for the western part that encountered great challenges in promoting maternal, neonatal, and child health. Vouchers have been widely considered by policymakers and program managers in many LMICs to promote equity for antenatal care. However, systematic reviews revealed important literature gaps for implementation. First, no study has explored whether and how vouchers can help to facilitate the integration of other interventions into routine care. Second, no study has explored the mechanisms of how vouchers work, considering contextual factors.Added value of this studyThis study examined the first pilot program from rural China that attempted to integrate congenital abnormalities’ screening interventions into routine antenatal care. We found that after one year of implementation of this program, the coverage of the extended interventions increased substantially, which was independent of women's geographic access to health care, demographic factors, and socioeconomic status. On the one hand, the program's supply-side efforts increased the coverage of the extended interventions and contributed to a rising median cost. These significantly affected women with secondary education and above. On the other hand, the program's demand-side measures, that is, vouchers, seemed to be effective only in the mountainous regions and increased coverage of the extended interventions, while not increasing costs. These significantly affected women with primary education and below. In addition, education-related inequalities widened after one year's implementation in counties with only supply-side policies. However, in counties with demand-side policies, no inequalities existed.Implications of all the available evidenceOther regions in China and Western Pacific may learn from this case to promote integrated antenatal care that built constructive accountabilities that link families, communities, and health providers. The Chinese government should also pay careful attention to the varied contexts while designing and tailoring voucher-based programs. It might be more effective to target specific geographic locations and people with primary education and lower.Alt-text: Unlabelled box1There has been a strong global commitment to universal health coverage, and the extension of essential preventive services is one of its central features Demand-side financing consists of a group of innovative tools to promote equity in essential health services st, 2015, aimed at integrating the two types of interventions that screen congenital abnormalities into routine antenatal care: prenatal foetal aneuploidies screening and prenatal B-ultrasound screening.China has been scaling up its National Essential Public Health Program, which has been providing five free routine antenatal visits since 2009 Specifically, Shaanxi Province implemented two types of managerial measures. Appendix Table 1 describes the policies in detail. Briefly, on the supply side, the government advocated universal uptake of prenatal screening services and established mechanisms to coordinate health providers and guide service procedures. Whereas on the demand side, the government directly subsidized families who used the extended interventions through the existing vouchers-based system within the National Essential Public Health Program. Notably, supply-side measures were universally introduced in Shaanxi, while demand-side measures  for the new integrated services were piloted in only about one quarter of the counties predetermined by the provincial government, prioritizing poor counties and those having maternal mortality above the provincial average.In this study, we evaluated the impact of the Program on coverage and equity. Comparing between counties, we tried to differentiate the impacts of the Program's supply- and demand-side managerial measures. By considering the contextual factors, we draw lessons for the Chinese government on how to proceed with integration and promote equity in similar settings.22.1According to data from China's national surveillance Using survey data, we conducted an observational study that compared between counties that had policies and similar counties that did not. First, to evaluate the impact of the Program's supply-side integration measures, we compared between two counties in Shaanxi Province where only supply-side measures were conducted, and two counties in Ningxia Province where integration had not yet commenced. We chose Ningxia because it is a neighbouring province of Shaanxi, and vouchers were used in both of the two provinces to deliver routine antenatal care. Second, to evaluate the impact of the Program's demand-side measures, we compared four counties within Shaanxi Province, where supply-side measures were universally carried out, but demand-side measures were only conducted in two of them, as a means to promote integration. In addition, the four counties within Shaanxi came out from two different contexts, where two neighbouring counties were from the mountainous regions and the other two neighbours were from the plain regions. For each pair, one had demand-side policies for integration and the other did not. .2.2We surveyed mothers who gave birth during the 2009–2016 period in the six counties from July to August 2016 using a stratified, clustered sampling procedure. First, to define the stratum, we ranked all the townships in each county based on their travel time (distance) to the county hospital using Baidu Maps. We then classified the townships into three groups based on this travel time, where each group was a sampling stratum. Second, we sampled 3–4 townships within each stratum. The number of townships that were selected ranged from 10 to 12 for each county. For each township that was selected, we considered the distance of each village from the township maternal and child health doctor who was in charge of the National Essential Public Health Program. We then sampled at least two villages - one far from, and one near the township hospital. Third, we obtained lists of names of all the mothers living in the sampled villages from the local maternal and child health doctor. The lists of names contained the basic information - including name, address, date of birth, and telephone number - of all the mothers and children that were recorded in the annual report system. We investigated all the families on this list that were at home during the survey. Fourth, we defined seven age groups according to the mothers’ date of delivery before the survey: 0–6 months, 6 months to 1 year, 1 to 2 years, 2 to 3 years, 3 to 4 years, 4 to 5 years, and 6 to 7 years. The sample size was determined by the time window of the study. For each age group, we selected a minimum number of mothers for the study. For the 0–6 months’ age group, we surveyed at least 100 women, while for the other age groups, we surveyed at least 20 women in each group. We recruited and trained students from the author's institute, to interview the mothers using a structured questionnaire. Verbal informed consent was obtained from the participants of the study. The study was approved by Peking University (IRB00001052–14070).In total, we approached 1615 mothers of which 16 (1.0%) refused to participate in the study, and the other 170 (10.5%) participants had important missing values. For the 170 participants, our student interviewers contacted them at least three times through phone calls to complement the missing questions, of which we excluded 18 questionnaires. We finally had 1597 (98.9%) valid questionnaires for this analysis. We input the data using the EpiData software version 3.0. Each questionnaire was double-entry and checked for inconsistencies. Data were then exported to Stata 13.1 for further recoding and analysis.The first author designed the survey and developed the questionnaire with consultations to statisticians and epidemiologists in the author's institution. One section of the questionnaire requested the mothers to recollect the frequency, contents, and total costs of the antenatal care received. We built the following coverage indicators, defined as the proportions of women who declared having used such services: prenatal foetal aneuploidies screening, prenatal B-ultrasound screening, and at least five routine antenatal visits. We ascertained 2 cost-related indicators, i.e. the total medical and non-medical costs associated with antenatal care. Medical costs referred to the out-of-pocket payments to health providers to receive antenatal care, while non-medical costs referred to the costs of travel and accommodation that were directly related to the activities in seeking antenatal care.In addition, the questionnaire investigated the respondents’ awareness of the government program and their benefit from it. These data comprised four indicators in this analysis: 1) knowing about the five free routine antenatal care visits; 2) having used antenatal care vouchers; 3) knowing about the Extended Antenatal Care Program; 4) having used the extended interventions free of charge. We also collected information on the following covariates: mothers’ education, households’ income per capita, mothers' health insurance, distance, parity, and age.2.3We described women's characteristics by types of interventions and regions. We analysed trends in awareness and coverage, adjusting confounding factors using Poisson regression with sandwich robust standard errors. We reported 90% confidence intervals (CIs) that accommodate higher type I errors because this is a pilot study with relatively small sample sizes. We adopted the interrupted time series approach to model the Program's impact 2.4The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and all authors shared the responsibility for the decision to submit for publication.3st, 2015. Correspondingly, the coverage of prenatal foetal aneuploidies and B-ultrasound screening rose from 44.5% and 52.1% to 69.5% and 75.6%, respectively. In Ningxia, however, there were no obvious trends in coverage of these two types of interventions , coverage of five routine antenatal visits , prenatal foetal aneuploidies screening , and prenatal B-ultrasound screening  rose faster in the control group rather than in the intervention group. P = 0.3106 and 0.7857 testing differences). In terms of coverage as well, there were no education-related inequities before the Program (P = 0.5638 and 0.4277 respectively). However, after the Program, women with secondary education and above had 45.2 (P<0.0001) and 26.5 (P = 0.0002) percentage points higher coverage of prenatal foetal aneuploidies screening and B-ultrasound screening, respectively, compared to those with primary education and below. In addition, persistent education-related inequalities were observed for at least five routine antenatal visits during the study period .P = 0.0030, 2.3 percentage points, P = 0.7049 before and after the program, respectively). Similar patterns were observed in the coverage of routine antenatal care and the two types of extended interventions.4The Sustainable Development Goals (SDGs) and the Global Strategy for Women's, Children's, and Adolescents’ Health are calling for countries to deliver integrated care for maternal, neonatal, and child health Prenatal screening of congenital abnormalities, including serum screening for foetal aneuploidies and B-ultrasound screening for structural malformation, are important secondary prophylaxis interventions. To date, we identified only two studies in urban China that analysed women's uptake of services Our survey shows that the coverage of both types of prenatal screening interventions had already been rising with a faster speed in the counties that were to receive demand-side interventions (vouchers) in plain regions of Shaanxi, which explains why we found an “inverse” impact of vouchers in this setting. Coverage of B-ultrasound screening rose fast in the mountainous regions of Shaanxi before the Program as well. Foetal aneuploidies screening services were newly introduced technologies in rural China, whilst the B-ultrasound scanning service  was already available before the program. This helps to explain the differences across interventions. Hospitals may have incentives to import new technologies to attract more patients. However, whether the government chose counties with higher coverage to put forward subsidies is unknown. Further research is warranted to understand how technology infusion per se may affect coverage in rural settings.,While integration did play a role in improving coverage, our data showed that supply-side integration efforts alone might come at costs that undermine equity, consistent with experiences from other settings [3]Importantly, we found that women with higher educational achievement, that is, more knowledgeable women, were more likely to uptake the new interventions. The effects of vouchers varied across contexts and women's education as well, which were independent of women's wealth level, location, and other socio-demographic characteristics. These findings question the mechanism of how the voucher works in this specific context. In fact, in the plain regions, we found that vouchers had no effect on women's knowledge, that is, women from the county that had only supply-side policies had similar level and trends in awareness of the government program; whilst in the mountainous settings, where one-third of women had to travel more than an hour and a half to reach the county hospital, vouchers took a substantial effect in promoting knowledge of the government program. In the Program, the county maternal and child hospital took the responsibility to advertise the new interventions. Information was released in public media, such as TV, newspapers, and radios, or in the form of posters and booklets that were distributed in the location of county maternal and child hospital. Women living far might have found it harder to access these channels but the process of distributing vouchers make a chance for them to receive such information directly. This might explain why the impact of vouchers in the mountainous areas was greater among women with primary education and below, compared to those with secondary education and above, because the latter might be more likely informed by the public media. Taken together, vouchers’ effectiveness may stem from targeted acknowledging the recipients of the services rather than removing financial barriers. Global debates continue on whether and how to target while implementing demand-side measures, where means-test for the poor are costly and often ineffective in LMICs This study has several important limitations. First, this was an observational study that was based on a natural experiment from a government pilot program, we are not able to draw causal conclusions. We intentionally chose counties for the investigation. Although geographic factors were considered in the design and the comparisons were made between neighbours, these counties may still vary in background and baseline characteristics. To tease out the policies’ impact, we used an interrupted time-series approach that further adjusted demographic and socioeconomic factors, which might help to reduce biases The other provinces in China could learn from Shaanxi's pilot program that intended to deliver integrated antenatal care to women living in rural settings. This program has made good progresses to build constructive accountabilities Xing Lin Feng designed the research, organised the survey, analysed the data and wrote the paper. Other authors participated in the critical interpretation of the findings.Newton Advanced Fellowship jointly supported by the 10.13039/501100000691Academy of Medical Sciences and 10.13039/501100001809China National Natural Science Foundation (71761130083), and China National Natural Science Foundation Excellent Young Scientist Program (71422009). Both are fellowship projects that support the PI to do basic research in China. The funders played no role in this study.The evaluation study is funded by Individual participant data that underlie the results reported in this article will be available, with researchers who provide a methodologically sound proposal, beginning 9 months and ending 36 months following article publication. Please contact the corresponding author at fxl@bjmu.edu.cn.Xing Lin Feng declared no conflicts of interests.Chunmei Wen works in the Health Commission of the Shaanxi Province. She is the department head in charge of maternal and child health of Shaanxi Province. She led her team in designing and implementing the Extended Antenatal Care Program in Shaanxi.


Postural instability marks a prevalent symptom of Parkinson’s disease (PD). It often manifests in increased body sway, which is commonly assessed by tracking the Center of Pressure (CoP). Yet, in terms of postural control, the body’s Center of Mass (CoM), and not CoP is what is regulated in a gravitational field. The aim of this study was to explore the effect of early- to mid-stage PD on these measures of postural control in response to unpredictable visual perturbations. We investigated three cohorts: (i) 18 patients with early to mid-stage PD ; (ii) a group of 15 age-matched controls (ECT); and (iii) a group of 12 young healthy adults (YCT). Participants stood on a force plate to track their CoP, while the movement of their entire body was recorded with a video-based motion tracking system to monitor their CoM. A moving room paradigm was applied through a head-mounted virtual reality headset. The stimulus consisted of a virtual tunnel that stretched in the anterior-posterior direction which either remained static or moved back and forth in an unpredictable fashion.We found differences in mean sway amplitude (MSA) and mean velocities of CoP and CoM between the groups under both conditions, with higher MSA of CoP and CoM for PD and higher mean velocities of both variables for PD and ECT when compared with YCT. Visual perturbation increased mean CoP velocity in all groups but did not have effects on mean CoM velocity or MSA. While being significantly lower for the young adults, the net effect of visual perturbation on mean CoP velocity was similar between patients with PD and age-matched controls. There was no effect of the visual perturbation on mean CoM velocity for any of the groups.Our simultaneous assessment of CoP and CoM revealed that postural control is reflected differently in CoM and CoP. As the motion of CoM remained mostly unaffected, all groups successfully counteracted the perturbation and maintained their balance. Higher CoP velocity for PD and ECT revealed increased corrective motion needed to achieve this, which however was similar in both groups. Thus, our results suggest increased effort, expressed in CoP velocity, to be an effect of age rather than disease in earlier stages of PD. Due to the ongoing demographic transition and subsequent over-aging of modern societies in many industrialized countries, neurodegenerative diseases are gaining in prevalence, with Parkinson’s disease (PD) being the second most common after Alzheimer’s disease , which allows for video-based full-body motion tracking, as well as the Nintendo Wii Balance Board  to replace a research-grade force platform  and mean velocity of both parameters between patients with early-to-mid stage PD (PD), a control group (ECT) of age-matched healthy adults and a third group of young (YCT) healthy adults. To assess potential differences which occur before the onset of recurrent falls due to postural instability, we purposely recruited patients in early to mid-stages of the disease. This study may hence provide a proof-of-concept to demonstrate the feasibility of postural assessment using a low-cost set-up in patients with PD. By this means, we aim to lay a foundation for the long-term goal of our research which is to establish nuanced and sensitive measures to detect PD patients at risk of falls before the onset of clinically apparent postural instability.Postural behavior was evaluated under two conditions: (i) during quiet standing, while participants’ visual field remained stable; and (ii) while they underwent unpredictable perturbations of their visual surroundings in the anterior-posterior (AP) direction. By testing three different groups, our goal was to differentiate between potential disease-specific and age-related alterations in body sway during quiet stance as well as under visual perturbation, which might be expressed differently in CoP and CoM. We hypothesized: (1) that patients with PD show the largest MSA and highest velocity of both parameters under both conditions, followed by the elderly healthy adults, while both parameters will be smallest for the young group. Moreover, we expected to find (2) that MSA and mean velocity of both parameters increase under visual perturbation in all groups. Lastly, we hypothesized (3) that these increases will again be strongest for the group of patients and weakest for the group of young healthy adults.Freezing of Gait before or during the experiment. All of the patients were assessed “on” their regular dose of dopaminergic medication . The two control groups consisted of 15 age-matched healthy individuals  as well as 12 young healthy participants .Eighteen patients with PD  diagnosed based on the Movement Disorder Society diagnostic criteria  or orthopedic  disorders which could affect their balance and upright stance as well as cognitive impairment based on the Montreal Cognitive Assessment as a screening tool for general cognitive abilities with a cut-off score of 24 points . All research was conducted in accordance with the Declaration of Helsinki.Participants stood on a Wii Balance board  to track their CoP . WearingIn the virtual world, participants stood inside a tunnel that was world-fixed and stretched in the AP direction. The visual stimulus was custom made, based on the open-source Python pyopenvr frameworkTo prevent participants from falling, they were secured by a harness which was attached to the ceiling. We ensured that the harness guaranteed subjects’ safety but was not providing lift during trials. The setup has successfully been established and described in more detail in previous work  where the tunnel remained motionless and 20 trials of the unpredictable condition (UC), during which the tunnel was moving back and forth in an unpredictable fashion. In this way, every subject performed a total of 30 trials. The order of trials was pseudorandomly shuffled. The unpredictable motion of the tunnel was made up of a series of random tunnel displacements along the AP axis which were based on a flattened random frequency spectrum (random white noise). This was to ensure that all frequencies were equally present in the sequence, which improved comparability between trials and avoided biases towards specific frequencies that might have interfered with the body sway of individual subjects. The maximum step size was set to 80 cm. At the beginning of each trial, the tunnel remained motionless and—in the UC—started moving after a randomized onset time between 5 and 8 s. The motion lasted for 30 s, after which the tunnel remained static for another 5 s to provide the subjects with relaxation time. In this way, the duration of each trial was 40–43 s.As soon as the subjects indicated by a verbal command that they were ready, the experimenter started the next trial. To signal its beginning, the fixation dot changed its color from red to white. During the 30 s motion phase (or static phase), the fixation dot occasionally shifted its color to black in a transient fashion. This event occurred randomly between zero and 10 times over the course of each trial. Participants’ task was to pay attention to these shifts and keep track of their numbers to ensure that they kept fixating. After the end of each trial, subjects had to report the number of changes they noticed. If the reported number was off by more than two, the respective trial was discarded. After each trial, subjects had time to relax and adjust their posture as long as they needed. Across all trials, every subject had a minimum of two larger breaks to prevent fatigue. During these breaks, participants were able to leave the setup and sit down or walk around. The entire experiment took about 2 h to complete.A custom-made Python script was used for recording and storing raw data. Further analyses were conducted in MATLAB . For all following analyses, we extracted the time-courses of CoP and the 3-D body segments which corresponded to the AP-directions. Time courses of the CoP, which more precisely reflect the displacement, and the 3-D body segments from individual trials were aligned to the respective stimulus onset.To determine the position of CoM, we calculated the 3-D center positions of 16 body segments and summed them with individual weighting factors taken from Winter , p. 86. Lastly, to gain insight into the net effect of the unpredictable condition on the motion of CoP and CoM we subtracted MSA values obtained during the static condition from the MSA values obtained during visual perturbation for each parameter, respectively. In the same way, we calculated the net effect of the visual perturbation on the mean velocities of both parameters.post hoc pairwise comparisons are reported as effect sizes based on correlation coefficients (r) using z-standardized test statistics. To test the influence of the unpredictable movement of the tunnel on MSA and the mean velocities of CoP and CoM within each group, we performed a Wilcoxon signed-rank test. We considered 95% confidence intervals (p < 0.05) to reject the null hypothesis. Statistical analyses were performed in SPSS .We used non-parametric testing on ranked data due to our unequal group size, the relatively small number of participants, and subsequent non-comparable variance. Kruskal-Wallis tests with follow-up pairwise comparisons using Dunn’s test with Bonferroni correction were used to evaluate group differences . Differences between groups according to H(2) = 20.21, p < 0.001) and on mean CoP velocity (H(2) = 14.91, p = 0.001). As displayed in post hoc pairwise comparisons, there were significant differences between PD and ECT  and between PD and YCT . However, there was no difference between ECT and YCT . A similar trend became apparent in mean CoP velocities, displayed in p = 0.255, r = 0.35) nor between ECT and YCT . Only the higher mean CoP velocity of PD deviated significantly from the mean CoP velocity of the YCT group .In a first step, we analyzed baseline data, i.e., MSA and velocity of CoP and CoM while the tunnel remained static (SC). There was a significant effect of group on the mean CoP sway amplitude (H(2) = 17.157 p < 0.001). Here, a similar trend emerged as in the CoP data. Post hoc comparisons revealed significant differences between PD and ECT (p = 0.013 r = 0.50) and between PD and YCT (p < 0.001 r = 0.72). There was no statistically significant difference between the YCT and ECT (p = 0.68 r = 0.23). Further, the effect of group was also significant for mean CoM velocities (H(2) = 14.288, p = 0.001), accompanied by a similar trend as for CoP , while CoM of YCT moved significantly slower in comparison to PD . It also moved considerably slower than CoM of the elderly healthy adults, albeit not reaching statistical significance (p = 0.079 r = 0.43).Regarding mean CoM sway amplitude , there w for CoP . Here, tH(2) = 14.42, p = 0.001; CoM: H(2) = 13.63, p = 0.001) and mean velocities (CoP: H(2) = 14.76, p = 0.001; CoM: H(2) = 13.25, p = 0.001). The results are displayed in panels C and D of p < 0.001, r = 0.69), but neither between PD and ECT  nor between ECT and YCT . Furthermore, like in the SC, we did not observe statistical difference in mean CoP velocity between PD and ECT . However, there were significant differences between a higher mean CoP velocity of PD as compared to YCT  as well as between higher values of ECT as compared to YCT . Investigation of mean CoM sway amplitudes during the unpredictable condition showed the same trend. There was a significant difference between PD and YCT . However, neither PD and ECT  nor ECT and YCT  exhibited significant differences in their CoM MSA. The same applied to the mean CoM velocities. Here, there was also only a significant difference between the PD and YCT groups .In a second step, we compared responses to the unpredictable visual movement of the tunnel between the groups in terms of MSA  and the YCT  groups when compared with the SC. On the other hand, we could not find any difference between the different conditions within the PD group . Mean CoM sway amplitudes were not influenced by the visual perturbation.In addition to the differences between groups in both the SC and the UC, we also investigated the effect that the visual influence had on each group. For the mean CoP sway amplitude under visual perturbation, we were able to find an increase for both the ECT . This was also observed in the mean velocity of CoM, albeit to a much smaller extent. Here, statistical tests only yielded significant effects for ECT  and YCT .Unpredictable motion of the tunnel significantly increased mean CoP velocity in all groups when compared with the static condition (PD: H(2) = 5.41, p = 0.067 and CoM: H(2) = 6.06, p = 0.048). Even when Kruskal-Wallis testing of CoM data yielded p < 0.05, this could not be confirmed in the subsequent pairwise comparisons with corrected p-values.As the motion of the tunnel led to an increase in mean velocity in each respective group and of MSA of CoP in ECT and YCT, we also investigated the net effect of visual perturbation (UC) on MSA and mean velocity of both parameters. To this end, for each group, we subtracted the average MSA during the static condition from the average MSA during perturbation. The same was done for the mean velocities. Even though in the case of CoM the increase in both parameters was rather small, for comparison, we also calculated the net effect of visual perturbation on CoM MSA and velocity. The results for the MSA data are displayed in panel A of p = 0.013, r = 0.52) as well as between ECT and YCT . There was no significant difference between PD and ECT . To gain additional insight into the temporal dynamics of this effect, we sorted the mean CoP and CoM velocities of each group in temporal bins, as described in our methods. The resulting binned time series for mean CoP velocity can be seen in Nevertheless, the net difference revealed that visual perturbation led to a strong increase of mean CoP velocity in both PD and ECT, while it had only a slight effect on YCT. This was backed by statistical testing, which yielded unpredictable visual perturbation to have a significantly different net effect on mean CoP velocity between PD and YCT  as well as in response to random visual perturbations  by simultaneously assessing mean sway amplitude and mean velocity of CoP and CoM. For this purpose, we recruited three different cohorts: a group of patients with PD (PD), a group of age-matched healthy adults (ECT), and a group of young healthy adults (YCT).Considering mean sway amplitude and mean velocity of both CoP and CoM, we hypothesized the highest amount of body sway for the group of patients with PD in both visual conditions, SC and UC, respectively. This was confirmed for MSA in both parameters which corroborates previous research  and velocities between groups under both conditions separately, we also investigated the net effect of the visual perturbation on both parameters inside each group –7. ThereWith regard to mean velocity, temporal dynamics did not only confirm the difference in behavior between both elderly groups and the young adults, but now also revealed that CoP velocity increased at a very short latency with respect to stimulus onset for all groups . MoreoveTo our surprise, there was barely a noticeable net effect on CoM mean velocity, also considering temporal dynamics . None ofpost hoc sample size calculation, the strong effect size regarding the influence of the mean CoP velocity by the stimulus compared to static condition translated into the minimum required sample sizes  that were satisfied by the number of participants in each group. Still, there is a risk that the study may have been underpowered for detecting meaningful differences in other measures between older healthy controls and participants with PD considering the trends in the data that did not reach statistical significance . Furthermore, there was a rather large variety of disease duration, motor disease severity, and dosage of dopaminergic medication in the PD group. On the other hand, considering the large variability within PD itself regarding disease progression, this sample represents a typical cohort of PD patients in the early and mid-disease stages. Only three patients were diagnosed with postural instability, while the majority were in the early stages of the disease. However, despite postural impairment being claimed to only become present in advanced stages of the disease . The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.JS: conceptualization, formal analysis, investigation, data curation, writing—original draft, and visualization. DE: conceptualization, methodology, software, validation, formal analysis, writing—review and editing, visualization. LT: validation, writing—review and editing. FB: conceptualization, validation, resources, writing—review and editing, supervision, project administration, and funding acquisition. JW: conceptualization, validation, resources, writing—review and editing, supervision, and project administration. 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. 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Multiple sclerosis (MS), as the most common neurologic disorder of the central nervous system, with growing incidence and prevalence worldwide and in the Middle East. This article aimed to find out the potential relationship between MS and air pollution in Iran.By assessing the published articles on MS and air pollution in Iran, the situation of MS as well as air/soil pollution in Iran was clarified. Then, studies on air pollution and its potential effect on Iranian MS patients were checked until 2020.The MS prevalence is distributed across Iran Provinces with highest rates in Isfahan, located in the center of Iran. The higher rates of MS in Isfahan and Tehran (the Metropolitan) might be due to industrial pollution of these cities, but this hypothesis is not true for non-industrial provinces. Based on the published atlas of MS in Iran, it seems that there is a high-risk “belt” from northwest to southeast.There are many risk factors of MS in Iran including age, gender, Vitamin D deficiency, smoking, and air pollution. The potential main risk factor of MS might be air pollution considering Isfahan and Tehran provinces. However, Chahar Mahal and Bakhtiary Province, with non-industrial nature, has the second highest MS rates which does not follow this hypothesis.By finding the air pollution as the main potential risk factor of MS in big provinces including Isfahan and Tehran, its effect of this factor can also be considered during diagnosis and treatment. Multiple sclerosis (MS) can be considered as the most common neurologic disorder of the central nervous system (CNS) which is diagnosed by inflammation, demyelination of neurons, and damages to the CNS . MS is tMS has even some effects on the personality of individuals: while MS patients with disease duration less than or equal 1 year have more likely type A personality, MS patients with more disease duration may have more likely type B personality . In geneThere are potential limitations regarding interoperation of the researches; for example, it is not longitudinal in nature, so one cannot assess patient exposure throughout their lifetime and influence on MS risk . MoreoveIn 1980, Kurtzke hypothesized north-south latitude hypothesis, that in higher latitude, the prevalence of MS is larger; he classified world geographical areas into three regions based on MS prevalence: (1) High with more than 30/100,000, (2) intermediate between 5 and 25/100,000), and (3) low risk with less than 5/100,000. He mentioned that Middle-Eastern countries can be generally classified as low-risk areas . HoweverAnalyses of studies on MS epidemiology have found an almost universal increase in prevalence and incidence of MS over time . The preGlobal burden of disease (GBD) 2010 study report has suggested that disability-adjusted life years (DALYs) lost due to MS has increased from 1990 to 2010 for both genders and all age groups in Iran . In addiIran has traditionally been thought to be a low-risk area for MS; however, epidemiologic publications on MS either from the Isfahan MS center or other parts of Iran consistently have revealed that Iran now is intermediate to high-risk region . Based oDifferent factors such as the increased rate of smoking, lifestyle changes, modernization, and contact with toxic solvents might be considered as reasons for this sudden rise in the prevalence of MS in Iran; however, they are not definite causes . The risDue to improving general health in Iran, which is consistent with “hygiene hypothesis”, it may be suggested the potential increase of the chance of autoimmune disorders like MS with lower exposure to external antigens . In addiThe declining pattern of MS incidence, especially after 2004, might be because of the time lag between disease onset and diagnosis as well as registering to national MS registry and less likely caused by real decline . MoreoveBased on the data of Iranian Ministry of Health, while the crude MS prevalence rate increased from 24.26/100,000 in 2006 to 54.51/100,000 in 2013, and the crude MS incidence increased from 3.77/100,000 in 2007 to 5.87/100,000 in 2013 . The numWithin Iran in 2014, the highest and lowest prevalence was reported in Isfahan  and Golestan , respectively ,33. ConcPrevious publications reported that Isfahan, a central province of Iran, could be considered as an area with a medium to high-risk of MS, especially in the young female population . HoweverIn a study to compare Armenian MS patients, the only Christian minority of Isfahan province, resided in Isfahan city from 2003 to 2014, with Persian MS patients, there was a significant difference between MS prevalence rates of two groups: 559.04 and 99.2/100,000 in Armenian and Persian patients, respectively . HoweverDifferent causes can be considered for MS consist of infectious, social, and environmental. Most important infectious disease could be Epstein-Barr virus (EBV) infection . MoreoveIn addition to environmental factors, effects of genetic factors as well as mutuality of gene-environment interaction should also be considered . MoreoveMS is an autoimmune disease of the CNS that affecting women more than men . In 2020Majority of patients (about 90%) are diagnosed between the ages of 20 and 50 years, although MS can also occur in young children and older adults . MS is iCognitive deficits in early life might be associated with prenatal and postnatal air pollutant exposures, which can affect on brain structural, volumetric, and metabolic changes in adolescence and even early adulthood with remarkable cognitive deficits which may impact negatively on the education, work, and social performance of the exposed individuals .In a population-based study from 1999 to 2015 in Tehran, the most part of relatives with MS were first-degree relatives, especially siblings and familial recurrence were correlated with relative type . The MS The relationship of HLA-DRB1 polymorphism and MS susceptibility or resistance has been investigated through a systematic review and meta-analysis until June 2017 . While HThe substantial role of Vitamin D deficiency in MS, especially among youngers and high school students, has been reported in Isfahan and Tehran ,67. It iThe most substantial environmental factors include:There is evidence about a higher risk of developing MS among populations with higher living standards; the potential explanation would be the potential weaker adaptation of the immune system to foreign agents in better economic status communities during childhood . Urban lThere is an association between smoking and the increased risk of MS  ; but, itAlthough there is no reliable evidence for the association between MS development and occupational or non-occupational exposures to chemicals ; there aIran has been considered as a low-risk area for MS due to the inverse correlation between UV radiation and MS prevalence . TherefoRadon can also be considered as a potential risk factor for developing MS . There aThe effects of redox-active metals (iron and copper) and redox-inactive metals (cadmium) on MS have been studied in recent decades . While, A significant etiologic role has been suggested for exposure to toxic elements on MS risk . As a reThere are few studies assessing the incidence of MS with soil heavy metal concentrations . In addiIn a Taiwan study conducted on new MS patients in 1997-2008, soil heavy metal factors records were consist of lead, cadmium, chromium, copper, arsenic, mercury, nickel, and zinc from 1986 to 2002 [To better understanding of high MS rates in Iran, a study assessed the association of soil heavy metals with MS distribution in Isfahan . AbsorbaTo measure blood lead and cadmium concentration and potential association with smoking habit, a case–control study was conducted in Tehran using patients registered from 2013 to 2014 . While t2, CO, and lead) were statistically associated with higher pediatric MS [10, SO2, NO2, and NOx in MS cases compared with controls; which confirm that the long-term exposure to air pollutants can be act as an environmental risk factor in MS [10 on the risk of relapse in MS patients, might be through oxidative stress mechanisms [Although in a study in USA, the exposure to PM air pollution was not related to MS risk , recent atric MS . Howeveratric MS . The othatric MS . In a stor in MS . There ichanisms . The expchanisms .2, from 1995 to 2002 [2 concentration was seen during 6-12 h and during the winter season especially in January [2 concentration [2 concentration [The knowledge of air pollution and its quality over periods and the process of air pollutants’ changes in various locations, and detection of high risk places can play a substantial and efficient role in managing of the urban health management and land use policymaking . In fact to 2002 . Measure to 2002 . Annual, January . This st January . In addi January . The stuntration . Surfacentration . Findingntration . This trntration . The mosntration .2 was also found in a study [10 reported the possibility of occurring a pollutant in different locations, based on location information [2), nitrogen oxides (NOx), particulate matter (PM10), and sulfur dioxide (SO2) were estimated using the previously developed land use regression (LUR) models [2, NO2, PM10, and NOx was observed in MS cases compared with controls [2, NO2, PM10, and NOx [A significant seasonal difference in the spatial variation of nitrogen oxides in Tehran, especially NO a study . Moreoveormation . In anotormation . The locormation . Moreove) models . The stucontrols . The stucontrols . The fin and NOx .10, SO2, and NO2, on some health consequences such as cardiovascular and respiratory diseases ), one study in Shiraz, south of Iran, has been conducted [2 and NO2 was categorized into three age-groups including<15, 15-65, and≥65 years old [Similarly, to quantify effects of health impacts of short-term exposure to specific air pollutants including PMonducted . This stonducted . The estears old . The stuears old .There is a close association between MS prevalence and modernization, lifestyle changes, industrial growth, and urbanization in Iran . MS prevMS is a complex disease, with several potential environmental factors which are thought to act together in genetically susceptible individuals to trigger the pathophysiologic process . Environ2.5) that does not meet the guideline values set by the World Health Organization [The estimates from the GBD study indicated that approximately 87% of the global population is exposed to ambient concentrations of fine particulate matter  in Tehran using 2010 data from 23 fixed monitoring stations through developing a systematic algorithm for spatial modeling [2, 0.64 for NO, and 0.58 for NOX. In addition, seasonal differences in spatial patterns of pollution were likely driven by differences in source contributions and meteorology [Urban air pollution modeling is a complex forecasting problem and one or two assumptions are not sufficient to cope with it . It is nthe city . By consmodeling . The mosmodeling . The anneorology . The modeorology .The related issues to trade liberalization and its impact on the environmental quality have become important since late 1996 . There aMS prevalence across Iran is geographically different, from 5.3 to 74.3/100,000 . This diThe future of Iran starts today; tomorrow will be too late, then some suggestions such as increasing public transfer facility, extending network of the metro in the big cities, banning of old technology of vehicles and industries, encouraging the industries to obey the standards of air quality, controlling traffic, controlling automobile factory for upgrading technology and using up-to-date standards to design engine and protecting the environment against air pollution can be adopted by the local government for enforcing the existing laws for environmental conservations .