The coronavirus disease 2019 (COVID-19) pandemic is having a dramatic impact on acute stroke care. Its effects may accompany stroke care for a long time. We compared the treatment, short-term and long-term functional outcomes of patients with AIS from 2019 to 2020. Our objective was to evaluate the effect of COVID-19 epidemic on mechanical thrombectomy (MT) in patients in our hospital.We collected information on subjects treated with MT in 2019–2020, including age, sex, time from the onset to arterial sheath insertion, time from the onset to recanalization, the rate of lung infection and hemorrhagic transformation, modified Rankin scale (mRS), NHISS, and ASPECTS.p = 0.025). The pretreatment ASPECTS score for 2020 was significantly higher than 2019 (p = 0.004). Besides, the patients were more likely to develop lung infection  and had a higher risk of hemorrhagic transformation  in 2019. The discharged mRS reflected the worse short-term functional prognosis of patients with MT in 2019 . In the subgroup analysis of bridging thrombolysis (BT), more patients with BT are expected to have a poor short-term functional prognosis in 2020, according to the discharged mRS . However, there was no difference in mRS at 180 days between the two groups (p = 0.094).The number of patients with MT decreased significantly by 26.6% in 2020 (For patients with MT, both short- and long-term functional outcomes were not significantly affected due to the mild condition of patients admitted to hospital in 2020. For patients with BT, the COVID-19 pandemic has prolonged the green channel time of stroke, leading to a poor short-term functional prognosis of patients with stroke in the pandemic period. There was no difference in the effectiveness of direct MT and BT during the COVID-19 pandemic. Stroke, a cerebrovascular accident, prevails in all patient populations and can be a significant cause of morbidity and mortality. Every year, an estimated two million people suffer from a stroke . NumerouWe have watched the treatment and prognosis of patients with MT treatment during the outbreak. The situation of the patients treated with MT between 2019 and 2020 was compared. In addition, we sought to investigate and compare the number and treatment rates of hospitalized patients treated with direct MT and bridging thrombolysis (BT), including short- and long-term outcomes during the COVID-19 pandemic in 2020. We hope this will contribute to neurologists choosing the best treatment to help patients during the outbreak of COVID-19 in the future.This was a single-center, observational, retrospective study conducted at the largest cerebrovascular disease medical center in the Wenzhou region . Data from January 2019 to December 2020 were examined, covering patients admitted to the hospital 24 h after the symptom onset and treated with reperfusion. The patients included in the data analysis met the following criteria: (1) the patients above the age of 18; (2) clinical diagnosis of AIS confirmed by CTA, MRA, or DSA, with symptoms lasting more than 30 min and no improvement before treatment; (3) all the patients were treated with MT. We excluded all the patients due to the following exclusion criteria: 388 patients were treated with IVT alone or pharmacological endovascular treatment (EVT), 80 patients were not followed up, or lacked critical outcome data at 180 days. Finally, 326 people were enrolled in the main analysis. The study was approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University (YS2018002) and conducted in accordance with the ethical guidelines of the declaration of Helsinki in 1975. All the participants or their guardians were well aware of our study and signed written informed consent.We collected information on subjects treated with MT in 2019–2020. The steps of information collection were as follows: First, we obtained data from the green channel of stroke, including age, sex, time from the onset to arterial sheath insertion, time from the onset to recanalization, the rate of lung infection and hemorrhagic transformation, etc. The data of modified Rankin scale (mRS), pretreatment NHISS, and discharged NHISS were collected from inpatient medical records of the neurology department. Short-term prognosis-dependent mRS assessment at discharge was divided into two components, 3–6 scores for functional dependence or death at discharge and 0–2 scores for suggesting a better prognosis. Long-term follow-up depends on mRS assessment at 180 days.During the Spring Festival, more than 90,000 people from Wuhan returned to Wenzhou, making the city hard hit by the coronavirus . Wenzhoup < 0.05 was considered statistically significant and was calculated using IBM SPSS statistical software Version 26 for Windows.Categorical variables were expressed in proportion, and the chi-square test was used for differences between groups. According to the distribution of continuous data, mean ± SD was used to describe the normal distribution, and Student's T-test was used to evaluate the difference between groups. Median  and Mann–Whitney U tests were used for skewness distribution. We created an Excel line chart to highlight the difference in time from the onset to arterial sheath insertion between 2019 and 2020. The correlation analysis graph in Graphpad was used to compare the correlation of short- and long-term functional outcomes with the time from the onset to arterial sheath insertion in the pandemic. A two-tailed p = 0.025). Age (p = 0.276), gender (p = 0.516), pretreatment NHISS (p = 0.494), the number of patients receiving BT treatment (p = 0.185), the time from the onset to arterial sheath insertion (p = 0.091), and the time from the onset to recanalization (p = 0.082) did not show any significant differences. When we compared the ASPECTS scores of the anterior circulation between the years 2019 and 2020, we found a significant difference . In 2020, there were substantially more patients with MT with ASPECTS 8-10 scores than in 2019 (68.8 vs. 46.8%) (As shown in . 46.8%) .p = 0.042) and had a higher risk of hemorrhagic transformation . The rate of successful reperfusion (mTICI 2b/3) in 2019 was substantially lower than that in 2020 . We examined the discharged mRS evaluation and followed mRS assessment for 180 days to determine the short- and long-term outcomes of patients with MT. We found the discharged mRS reflected the patients with MT in 2019 had a worse short-term functional prognosis . But no significant difference exists in long-term functional outcomes between 2019 and 2020 (p = 0.464)  within 2 years. According to the findings, the patients with MT in 2019 were more likely to develop lung infection  .p = 0.016). In terms of time, from the onset to arterial sheath insertion between 2019 and 2020, we observed an increase from a median (IQR) of 4.9 (4.0–5.9) h to 5.8 (4.9–6.2) h (p = 0.012). The time from the onset to arterial sheath insertion in each month showed that February, March, April, June, July 2020 were significantly higher than 2019 , discharged NHISS (p = 0.823), postoperative lung infection (p = 0.06), hemorrhage transformation (p = 0.444), and successful reperfusion rate (mTICI 2b/3) (p = 0.605) of patients with BT in 2019 and 2020. However, more patients with BT are expected to have a poor short-term functional prognosis in 2020, according to the discharged mRS . Through follow-up surveys, we found mRS at 180 days also showed a trend toward poorer long-term functional outcomes in more patients with BT in 2020, although there was no statistical difference . In addition, an interesting finding was that the longer the time from the onset to arterial sheath insertion, the worse the short-term functional prognosis of patients with BT, showing a positive correlation  showed some significant differences between direct MT and BT. Lung infection, hemorrhagic transformation, successful reperfussion (mTICI 2b/3) rates after treatment, and the discharged NHISS did not differ between both groups, neither a good clinical outcome at discharge  and 180 days , nor for mortality .In Acute stroke treatment requires effectiveness, as early as possible to dredge blood vessels, can save more brain tissue and brain cells, and achieve a better prognosis, so time is the brain. At present, the main treatment methods are intravenous thrombolysis (IVT), direct mechanical thrombectomy (MT), and bridging thrombolysis (BT). This article provides accurate data on patients treated with MT throughout the year during the COVID-19 pandemic in 2020, compared to the same data in 2019.Firstly, we found that the number of patients with acute stroke treated with MT decreased significantly in 2020, consistent with the decline in the number of patients seen in medical systems worldwide during the COVID-19 pandemic. A similar research in the UK showed the number of patients admitted to hospital for stroke fell by 27.7% in MT cases in the COVID-19 pandemic . AnotherSecondly, in our study, the patients admitted in 2019 had a worse ASPECTS score of anterior circulation, more postoperative lung infections, higher hemorrhagic transformation, and a lower successful regenerative rate than the patients admitted in 2020. Following this, the short-term functional outcomes were worse in 2019, but there was no difference in long-term functional outcomes at 180 days between the 2 years. The main reason is that the patients accepted in 2019 had a relatively large infarct area, severe condition, and more postoperative complications, so the short-term functional prognosis was poor. Some studies have proved that core volume, infection, hemorrhagic transformation, and reperfusion rate were significant predictors of good outcomes . PatientThirdly, the subgroup analyses for patients with BT treatment showed different results. We found that the time from the onset to arterial sheath insertion increased in 2020, meaning that patients had a longer time from the onset to arrive at hospital or a longer hospital stay before endovascular treatment. More importantly, the time from the onset to arterial sheath insertion was observed to increase in February, March, April, June, and July 2020. This trend is consistent with our previous study on IVT during epidemics . The maiIn addition, data showed that the short-term functional prognosis of patients with BT during the pandemic was worse than in 2019, and there was no difference in a long-term functional prognosis. Considering that there was no difference in the preoperative infarct core area and postoperative complications between the 2 years, this may have amplified the effect of the time from the onset to arterial sheath insertion on short-term functional outcomes, resulting in worse treatment outcomes in 2020. An interesting finding was that the longer the time from the onset to arterial sheath insertion, the worse the functional outcome of discharge. However, it was not associated with long-term functional outcomes. The possible reason is that “time is brain” is reflected in the process of BT treatment. The most famous New England Journal published the results of MR CLEAN's study in 2015, and the analysis showed that the time when patients started endovascular therapy was highly correlated with the prognosis . With thFinally, in the context of the COVID-19 pandemic in 2020, this study concluded with a comparison of direct patients with MT and patients with BT. There was no difference in lung infection, recanalization rates, bleeding complications, functional recovery, and mortality. This is consistent with the research of Sebastian Bellwald, MD* et al. . A pre-pIn summary, our study supported the number of patients with AIS treated with MT decreased significantly in 2020. The COVID-19 pandemic especially prolonged the time of green channel for stroke, which led to the worse short-term prognosis of patients with BT. In addition, there was no difference between direct MT and BT in a clinical prognosis during the pandemic. Therefore, building rapid green channels, ensuring adequate medical resources, improving care systems, and choosing the most appropriate treatment strategy will effectively improve patient outcomes during the pandemic.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This study was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University (YS2018002). Written informed consent was obtained from all participants, or the participants' legal guardian/next of kin, for participation 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.JL and WT designed the study and wrote the protocol. DG, XX, XL, LQ, LC, JC, BW, MX, and AE conducted literature searches and provided summaries of previous research studies. XL conducted the statistical analysis. DG wrote the first draft of the manuscript and all the authors contributed to and have approved the final manuscript.This research was supported by a Grant from Wenzhou Municipal Sci-Tech Bureau Program (Y2020421).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.


Objectives: To explore the influencing factors of residents' psychological status during standardized training in COVID-19 for finding ways to promote their mental health.Methods: A total of 760 residents were surveyed with a structured questionnaire. Correlation analysis was used to analyze the influencing factors of psychological status of the residents, and a mediation model was constructed to verify the mediating role of satisfaction.Results: Age, willingness to study medicine, and satisfaction were positively correlated with negative psychological status (P < 0.05). And gender, only child or not, and annual household income (RMB) were negatively correlated with negative psychological status (P < 0.01). Residents' satisfaction with standardized training mode plays a complete mediating role between annual household income and negative psychological status.Conclusions: Our findings emphasize the importance of concentrating on resident's psychological status and family economic situation. And relative departments should take action to optimize the standardized training mode to improve the satisfaction. The world has been facing a pandemic of Corona Virus Disease 2019 (COVID-19), and this public health emergency was first reported in Wuhan, China, at the end of 2019 . Some scStandardized training in China started late and the system is not yet comprehensive, causing many residents to be dissatisfied with the training model, then lead to psychological pressure. According to a survey in 2015, only 33% of trainees were satisfied with the standardized training mode in Shenzhen, China . SimilarFamily factors are also often reported to be associated with negative attitudes, with family economic situation being most often concerned. Family income instability was shown to worsen depression among college students during COVID-19 epidemic , which iStandardized training is an important part of post-graduation education for medical students and is extremely important for training high-level clinical physicians and improving the quality of medical care. Residents can experience the whole standardized training process most directly, and their satisfaction with the training model and mental health are very worth exploring and improving, but there are few researches on the mechanism. This study focuses on the psychological status of residents during standardized training in the public health emergency, and aims to analyze the impact of residents' family economic situation and their satisfaction with the training model on their psychological status, for providing the guidance for promoting mental health.2, α = 0.05, Z1−α/2 = 1.96, p = 35% [according to a research in 2021 from January 2021 to April 2021. The sample size was estimated using the calculation formula of cross-sectional survey: N ≥ h in 2021], δ = 0.Annual family income, psychological status, and satisfaction of standardized training mode (henceforth referred to as satisfaction) were assessed by different items.Annual family income (RMB) 1 ≤ 50,000, 2 = 50,000–100,000 , 3 = 100,000–150,000 , 4 ≥ 150,000.Psychological status was measured using the DASS-42  . DASS-42Satisfaction Respondents were asked about their satisfaction with standardized training mode (1 = very satisfied and 5 = very dissatisfied).Other variables Family factors include only child , marriage , willingness to study medicine , family members with a medical background .Statistical analysis was conducted using the SPSS 24 version program. The descriptive analysis was used to determine the demographic characteristics of the participants. Pearson correlation analyses of the study variables were conducted. The SPSS Process was used to test the effects of family income on psychological status through satisfaction. The bootstrapping method was used to verify mediation effects. In this study, we bootstrapped 5,000 samples from the data, and 95% bootstrap confidence intervals (CI) were calculated. The conceptualized model was shown in n = 373) were male. A total of 508 (66.8%) participants were only child. Majority of respondents followed their own wishes when choosing a medical specialty. Over 80% participants were not satisfied or very dissatisfied with the standardized training mode. The mean age of the participants was 26.60 years (SD = 1.92). The sample consisted of 760 residents. 49.1% . Age was positively correlated with negative psychological status (P < 0.05). And annual household income (RMB) was negatively correlated with negative psychological status (P < 0.01). More details were presented in In our study, gender, only child or not, willingness to study medicine and satisfaction with standardized training mode were most significant influencing factors  have higher levels of postpartum depression symptoms . CollegeThe mediation result of the study showed that satisfaction was a very important mediator between annual household income and negative psychological status. Actually, economic situation is the basis of a family, and different economic conditions may lead to different family structures and family atmosphere. Moreover, a wide variety of family factors can affect a person's personality characteristics and then probably influence a people's thoughts and behaviors . For exaThere were several limitations in our study. First, our study used convenience sampling, and a more precise sampling method may need to be used in future studies. Second, given the study's cross-sectional design, it is difficult to draw definitive causal conclusions regarding the long-term effect of the current pandemic. Third, selection bias cannot be excluded, and the results may not be applicable to all countries. However, the results are in line with those reported by previous similar cross-sectional study on psychological state of residents. Indeed, the study that examined the psychological impact of COVID-19 on Italian orthopedic residents found that the pandemic had an important social impact on residents' perceptions and emotional well-being , manifesThe present study verified the fully mediating effect of satisfaction. Relevant departments also need to improve the training model for improving the satisfaction of residents. And Hospitals need to care about the family economic situation of residents and pay targeted attention to their psychological status.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of Wuhan Mental Health Center, Huazhong University of Science and Technology. The patients/participants provided their written informed consent to participate in this study.DX and BLia: writing-original draft, writing-review and editing, and analyses. YW and BC: methodology. CX and SZ: conceptualization, writing-review and editing, and supervision. BLi, JP, and CY: conceptualization and analyses. All authors contributed to the article and approved the submitted version.This work was supported by the Wuhan Municipal Health Commission (WX18Q35).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.


Crohn’s disease (CD) is a condition that can occur in any part of the gastrointestinal tract, although usually forms in the colon and terminal ileum. Magnetic resonance imaging (MRI) has become a beneficial modality in the evaluation of small bowel activity. This study reports on a systematic review and meta-analysis of magnetic resonance enterography for the prediction of CD activity and evaluation of outcomes and possible complications.Following the PRISMA guidelines, a total of 25 low-risk studies on established CD were selected, based on a QUADAS-II score of ≥ 9.χ2 = 81.83 and I2 of 80.3%. Also, a specificity of 89% was calculated, with heterogeneity of χ2 = 65.12 and I2 of 70.0%.A sensitivity of 90% was revealed in a pooled analysis of the 19 studies, with heterogeneity of It was concluded that MRI provides an effective alternative to CT enterography in the detection of small bowel activity in CD patients under supervision of radiologist for assessment of disease activity and its complications. Its advantages include the avoidance of radiation exposure and good diagnostic accuracy. MRI may be considered as an effective diagnostic technique in moderate to severe CD patients.It plays an increasingly important role as non-invasive and effective method to evaluate the small-bowel involvement and the possible intestinal and extra-intestinal complications, in patients affected by CD.MARIA score found it to be the most sensitive and specific tool.Crohn’s disease (CD) is a form of inflammatory bowel disease (IBD), with an approximate frequency of 20.2 per 100,000 person-years in North America, 12.7 per 100,000 person-years in Europe, and 5 person-years in Asia . While tAn analysis of the medical history and a physical examination of the patient is the first step towards the diagnosis of CD, supported by pathologic, endoscopic, and laboratory data, using a variety of clinical severity indices, such as the Crohn's Disease Activity Index (CDAI), Harvey and Bradshaw Index, Simple Index, Oxford Index, van Hees Index, and Cape Town Index. Clinical disease activity is categorized by the European Crohn’s and Colitis Organization (ECCO) into severe, moderate, and mild . While dThe Montreal and Paris classifications of CD group patients based on localization, behavior, growth, and onset; the behavior is subdivided into penetrating, non-stricturing/non-penetrating, and stricturing . The mosThere is no consensus about the preferred MRE score and they are not routinely utilized. Several MRE-based indices are common for analysis, including the Clermont score, the magnetic resonance index of activity (MaRIA), the Crohn’s disease magnetic resonance imaging index (CDMI), the Lemann index, and the magnetic resonance enterography global score (MEGS) –13. ThisThis mixed-studies review incorporates a systematic search strategy and quality appraisal method, and is based on the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines for researchers. A comprehensive search strategy was carried out using electronic databases, such as EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, and MEDLINE. All forms of study designs were included with the exception of qualitative studies and management reviews, since the main focus of the review was the quantitative assessment of MRI. Also, all relevant studies were included that examine disease type and activity in patients with CD where MRI was involved as a diagnostic tool. Patients with an established diagnosis of CD were the target population.Prospective and retrospective studies that were given focus examined subtypes of CD, detection and characterization of the disease using MRE, diagnostic modality , and patient population . No restrictions were made regarding country, patient’s age, or gender. The review is restricted in terms of the written language of articles, only including those in English. The search was limited to articles published from 1 January 2000 to 1 October 2019.Two independent reviewers reviewed the retrieved studies. Any disagreements were resolved either by a third reviewer or through a consensus approach. The two reviewers extracted the data independently from the selected studies. The data extraction method was established prior to the study commencement and included information on imaging characteristics, such as bowel preparation, radiologist experience, oral and intravenous contrast, MRI strength, and time interval. Also, information on study characteristics were included, comprising age, gender, number of patients, type of study, reference standard, patient population, location studied, year, and country. Particular values were calculated or extracted for the selected studies which provided data regarding individual patients, such as false positive, false negative, true positive and true negative. All outcomes used in the selected articles regarding MRI, CD, clinical examinations, and imaging characteristics were considered as primary for this review. The following keywords were used: (disease type OR behavior type) AND  AND  OR (MARIA OR MRI activity index) AND Crohn’s disease.The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-II) tool developed for diagnostic studies was used to assess the risk of bias, applicability, and quality. Studies with scores greater than 9 were classified as low risk.I2 test was used to assess the heterogeneity.A summary of the results exhibits the effectiveness of MRE in detecting activity, including MARIA, using sensitivity and specificity values for studies that did not provide raw data. For studies that provided raw data, contingency tables were constructed using true positive, true negative, false positive, and false negative information. Likelihood ratios, sensitivity, specificity, and 95% confidence intervals were calculated for each study. Summary receiver-operating characteristic (ROC) curves and forest plots were presented through graphical representation, which were made using the Comprehensive Meta-Analysis software (CMA), version 3 by Biostat, Inc. For a pooled analysis, 0.5 was added to all cells that comprised a value of 0 to include all studies in the analysis. The The preliminary database search yielded 2567 articles. These were reduced further by sorting according to title, resulting in a yield of 252 articles; these were then further reduced to 35 articles based on an appraisal of abstracts. A total of 25 articles fulfilled the inclusion criteria after consideration of the full articles and following contact with authors for missing information , 14–30. In the 25 articles that met the inclusion criteria, a total of 2120 patients took part, out of which, 1470 patients were incorporated into a meta-analysis. The largest sample size among those patients included in the pooled analysis was 305. In an examination of the data of these 1470 patients, 150 underwent endoscopy and MR within 30 days to evaluate the distal ileum condition, which resulted in an MRI pooled specificity of 80% and a sensitivity of 88% in predicting CD activity.χ2 = 61.38 and I2 of 60.7%. A specificity of 59% was reported for the pooled analysis with a heterogeneity of χ2 = 65.12 and I2 of 70.0%. The negative predictive ratio was 0.21 and the positive predictive ratio was 6.1 using a random effects model.A sensitivity of 61% for predicting disease type or subtype was revealed in a pooled analysis of 19 studies , 31–33 wAphthous ulcers in the penetrating type of CD is demonstrated in MRE studies as a high signal intensity nidus, covered by moderate signal intensity area best seen on high-resolution SSFP images with fat suppression . Oral coMagnetic resonance enterography (MRE) can detect fibrostenotic disease of stricturing type, observed as a fixed narrowing of the affected segment , 37. BotThe diagnostic power of the markers was determined through a logistic regression analysis when differentiating between the Montreal behavioral classes Table . Small bThe studies presented in Table Small bowel CD activity determined through the use of MRE was presented through forest plots based on sensitivity, specificity, and ROC curves. The aggregate sensitivity and specificity of MRE in assessing CD activity was 79.25% and 74.25%, respectively.Thia et al. based study on the evolution of Crohn's disease reported 19% of patients with known penetrating or stricturing complications within the first 90 days of diagnosis based on Montreal classification, while patients diagnosed with non-stricturing and non-penetrating disease at baseline had intestinal complication on progression, 76.7% of these patients required bowel resection surgery .Penetrating disease, hospitalization for flares or consequences of the illness, surgery, extra-intestinal manifestations (EIMs) affecting two systems, or poor response to presently available medications are all signs of aggressive CD .The current systematic study is the largest systematic study of MRI for small bowel identification in CD. Previous research and reviews looked at the sensitivity and specificity of MR imaging in detecting small bowel movement , 43. We The gold standard diagnostic approach for assessing intra- and extra-luminal CD complications is MR imaging . For the identification of stenosis, we discovered a high specificity with a moderate sensitivity. Previously, studies found a high detection rate for stenosis in both small and large bowel illness , 44 CT iThe lack of uniformity of imaging indications suggestive of ongoing illness, especially with the expanding number of sequences available, is one of the challenges in replacing the gold standard with MR imaging. Previous research has shown that wall enhancement, mucosal lesions, and wall T2 hyperintensity are the most reliable indications of inflammation for MR , 44. AddIf the results of MR imaging influence physician management, this is a significant factor. Mendoza et al. found that MR aided decision-making in more than half of patients, particularly when biological treatments and surgery were involved . MessariMany researches looked at the use of ultrasound and computed tomography as alternate imaging modalities. Ultrasound has the advantage of avoiding ionising radiation and being very affordable . PreviouThis review may be limited in terms of the varied lengths of time between MRI and the reference standard. Thus, some of the findings might be nominally inaccurate in determining disease activity because clinical activity can change relatively quickly, particularly with the use of medication. This article could not differentiate between severity of small bowel activity and other clinical features, owing to a lack of data. A number of other studies have recommended that MRI has better association with CD severity indices , 40. AlsThis review has shown the effectiveness of MRE in detecting CD, and illustrated its considerable accuracy in detecting disease activity: a MARIA score found it to be the most sensitive and specific tool. MRE was able to predict disease types and subtypes to a high degree of accuracy, permitting radiologists to initiate a selection of the disease type or subtype from MRI features. However, radiologists may need to provide the essential characteristics of the disease in arriving at a final diagnosis of disease types and subtypes, because the sensitivity and specificity of MRE are not high enough to determine these accurately, specifically in comparison with endoscopic techniques.


Protein–protein interactions govern cellular processes via complex regulatory networks, which are still far from being understood. Thus, identifying and understanding connections between proteins can significantly facilitate our comprehension of the mechanistic principles of protein functions. Coevolution between proteins is a sign of functional communication and, as such, provides a powerful approach to search for novel direct or indirect molecular partners. However, an evolutionary analysis of large arrays of proteins in silico is a highly time-consuming effort that has limited the usage of this method for protein pairs or small protein groups. Here, we developed AutoCoEv, a user-friendly, open source, computational pipeline for the search of coevolution between a large number of proteins. By driving 15 individual programs, culminating in CAPS2 as the software for detecting coevolution, AutoCoEv achieves a seamless automation and parallelization of the workflow. Importantly, we provide a patch to the CAPS2 source code to strengthen its statistical output, allowing for multiple comparison corrections and an enhanced analysis of the results. We apply the pipeline to inspect coevolution among 324 proteins identified to be located at the vicinity of the lipid rafts of B lymphocytes. We successfully detected multiple coevolutionary relations between the proteins, predicting many novel partners and previously unidentified clusters of functionally related molecules. We conclude that AutoCoEv, can be used to predict functional interactions from large datasets in a time- and cost-efficient manner. The biological function of proteins is carried out through an association and communication with various molecules, the majority of which are other proteins. Thus, screening for novel interactions, either direct or indirect, is of high importance for deciphering the complexity of protein networks. It has been shown that relations between proteins can be extrapolated from the evolutionary history of their genes via in silico analysis of coevolution ,2.The evolution of proteins is influenced by structural and functional constraints between amino acids, enforcing their adaptation in a concerted manner. Detecting intra- or inter-molecular coevolution is regarded as a sign of functional co-dependence between residues within the same protein or between sites belonging to different partners, respectively . VariousHere, we developed an automated computational pipeline called AutoCoEv for the large-scale screening of protein interactions, which is user-friendly and ready to use by the broader public. In the centre of the workflow is CAPS2  software, which compares the evolutionary rates between sites in the form of their correlated variance .a and b, belonging respectively to proteins A and B, by extrapolating correlation from their evolutionary variation. The evolutionary variation for site a is derived from the transitions between the amino acids within its column in the multiple sequence alignment (MSA) of the orthologous sequences, corrected for the divergence time of the sequences by the BLOSUM matrix. For this, CAPS2 first estimates the phylogenetic relations between the sequences within the alignment of protein A by calculating/parsing a phylogenetic tree and performing an ancestral reconstruction at all inner nodes. The transition parameter at site a is calculated from the pairwise amino acid substitutions within the MSA columns and the total numbers of transitions across the phylogenetic tree. The same is done analogously for site b from protein B, and the evolutionary variation scores of a and b are compared. Correlation is estimated using Pearson’s coefficient and, similarly, each column for protein A is compared against each column from protein B. As a result, the coevolving amino acids between the two proteins, A and B, are reported.As described in Fares and Travers (2006) , and theBy driving 15 programs, AutoCoEv achieves a high level of automation and flexibility, as well as processing parallelization, enabling the analysis of hundreds of proteins on a regular computer. We demonstrate the performance of the pipeline by analysing 324 lymphocyte lipid raft-resident proteins , identifThe preparation pipeline for most coevolutionary analyses has a relatively simple concept. Typically, for each protein of interest, a multiple sequence alignment (MSA) is produced from its orthologues in different species, optionally combined with a phylogenetic tree. However, this process requires the correct identification of orthologues, their sequences retrieval, and high-quality alignment, all tied together by various filtrations and file format conversions. Automating these steps also necessitates a robust quality check during and after the process, all of which can present significant challenges if done manually. While developing AutoCoEv, we paid significant attention to incorporating ways to evaluate the quality of the key preparatory steps and, finally, to evaluate the results for their robustness.AutoCoEv is written in BASH and offers a simple menu-driven command-line interface (CLI), in which the individual steps are enumerated A. OptionAs an input, AutoCoEv requires a list of proteins with their UniProt identifiers , and a lEukaryota, Metazoa, Vertebrata, Tetrapoda, or Mammalia). This level, or node, is specified by the user and depends on the species group, from which orthologues are to be searched. The script will report proteins with missing OG IDs at OrthoDB, as well as species for which no orthologue was found.For each protein in the user-provided list, AutoCoEv consults with OrthoDB, searching for homologues from the species of interest  distance-based phylogenetic trees from the protein MSAs at runtime. The trees are not made available to the user; therefore, we patched the program to print the tree to the output, allowing for an inspection. Alternatively, trees calculated by another program can be used, which may improve the sensitivity of CAPS2. If this is preferred, AutoCoEv calls PhyML (Phylogenetic estimation using Maximum Likelihood)   where coevolution was detected in the first run are subjected to a second run, this time reversing the order , by slightly renaming the files  for the probability of error in rejecting the null hypothesis (type I error) when significant coevolving sites are detected. Amino acid pairs that pass the threshold are reported in the results of CAPS2, however, the actual p-values of their correlations are not. This poses limitations to statistical analyses, such as the control of the false discovery rate (FDR), critical for large datasets. Therefore, we patched CAPS2 to calculate and output p-values when inter-protein coevolution is searched (see 2) test when more than two proteins are analysed, based on the number of detected coevolving amino acids between them. In our pipeline, CAPS2 always runs for just two proteins at a time, therefore AutoCoEv replicates the χ2-test, when the analyses of all protein pairs are completed , quality of the alignment regions (determined by Gblocks), and MSA column gaps (less than 20%), obtaining a smaller network, with an overall organization very similar to the parent  protein with multi-catalytic activity, involved in de novo synthesis of pyrimidine . Cad wasBy GO analysis, Cad and its 10 coevolving proteins were suggested to play roles in angiogenesis, ER, endothelium, membrane transport, and translation . The prohttp://caps.tcd.ie/caps/). However, the availability of CAPS2 for offline use grants a great deal of flexibility achievable via scripting. Requiring only a list of proteins and a list of species, AutoCoEv automatically performs database searching and the identification of orthologous sequences with a best hit. The pipeline offers further automation, parallelization, and quality assessment on the subsequent steps and seamlessly achieves the batch processing of hundreds of input proteins. AutoCoEv also incorporates post-analysis tools, enabling the efficient analysis and ranking of the results. We propose that the automated prediction of coevolution provides a potent and affordable tool to facilitate the selection of candidates from large protein datasets for further analysis. In this work, we present the AutoCoEv pipeline: an interactive script for the large-scale prediction of inter-protein coevolution by CAPS2. Searching for signs of coevolution in silico is a powerful means to predict novel functional interactions between proteins. By default, inter-molecular analysis in CAPS2 was designed for a handful of proteins, or a single pair, as illustrated by its web interface . The queue/runtime was ~22 h for MISTIC, while MISTIC2, DCA, and BIS2 crashed. GREMLIN and ContactMap did not accept the MSA over 1000 and 1100 amino acids, while GREMLIN had the additional warning that 85 jobs were currently running and that our submission “may take forever to complete”. Thus, it is clear that large-scale analyses cannot be practically performed using the server-based tools accessible online, though they are powerful and user-friendly. On the contrary, AutoCoEv runs locally on Linux, thus avoiding queue waiting times and other limitations that arise when using a public server. The only results we obtained from MISTIC were very challenging to interpret, since the program detected numerous intra-molecular coevolving sites, making it virtually impossible to distinguish the inter-molecular coevolution. For comparison, running the CAPS2 bidirectional step via AutoCoEv took ~48 h on an i7-9700KF CPU (8 cores @3.6 GHz) with 64GB RAM for 46,775 protein pairs. In addition, CAPS2 does not have limitations to the MSA-length limitation , allowing also the processing of large proteins, such as Cad. The post-run processing by AutoCoEv provides users with a comprehensive table that can also be directly imported in Cytoscape for further network analysis.At the moment, we have not tested the script with a larger dataset, but the pipeline was designed to process input protein numbers in the thousands. Provided that enough computing resources, disk space, and time are available, the number of proteins that AutoCoEv can process has virtually no limit. The CAPS2-run . Development was done on Slackware (http://www.slackware.com/) and CRUX (https://crux.nu/) distributions of GNU/Linux.AutoCoEv is written in BASH and is under MIT license, freely available from the GitHub repository of our group  or Debian (https://www.debian.org/). We provide a pre-compiled, static binary of CAPS2 with our patches applied, and a virtual machine image with all requirements pre-installed. See AutoCoEv on GitHub for details, manual, as well as for instructions for setting up the pipeline on Ubuntu (https://www.orthodb.org/): odb10v1_all_fasta, odb10v1_gene_xrefs, and odb10v1_OG2genes. The script also communicates with UniProt (https://www.uniprot.org/), accessed on 18 October 2021 (324 raft proteins dataset), 3 February 2022 (Negatome database proteins) and 12 February 2022 . Conversely, protein complexes were obtained from CORUM  and sorted by size. The first 10 largest complexes (subunits > 10) from a mouse were retrieved , whereas coevolution was found within 5 complexes .Protein networks were compared against STRING  and Mammalia as OrthoDB node level (taxid: 40674) in settings.conf. For the reciprocal BLAST, we set the minimum allowed alignment identity to 35% and the maximum allowed gaps to 25%. Guidance was used with MUSCLE and had a cut-off of 0.95. Three MSA methods were used in independent runs: MUSCLE, MAFFT alias L-INS-I, and PRANK, while Gblocks allowed gaps were set to half (-b5=h). When PhyML trees were used, PhyML was run with default settings and the produced trees were rooted by TreeBeST. At the protein pairing step, the minimum required common species between every two proteins was set to 20. CAPS2 was run with bootstrap threshold 0.6 and convergence option (-c).In our analyses, we used 50 mammalian species  and confhttp://smart.embl-heidelberg.de/) and Pfam [http://pfam.xfam.org/), both accessed on 17 February 2022. Disordered region binding sites were predicted by Anchor2/IUPred3 [https://iupred3.elte.hu/). Graphical representation of proteins was rendered using Pfam custom domain generator (http://pfam.xfam.org/generate_graphic/).Protein sequence functional information was retrieved using UniProt. Domain organizations was searched at SMART  (Simple and Pfam  (http:///IUPred3  (https:/https://www.r-project.org/) and Gnumeric spreadsheet (http://www.gnumeric.org/). Gene Ontology was done by clusterProfiler (4.2.2) package for R [https://inkscape.org/), while icons artwork in http://tango.freedesktop.org/).Post-run analyses were done by R (ge for R . Venn dige for R . Networkge for R . All figHere, we present AutoCoEv—an automated computational pipeline for the prediction of protein–protein coevolution. The pipeline can be used offline and it introduces the parallelization of key processes, tremendously speeding up the analysis time. The automation of the workflow makes it easy to use and ensures the seamless processing of large datasets. We demonstrate the power and efficacy of AutoCoEv by analysing an input of >300 proteins. We detected intriguing novel protein partners and possible protein complexes that can provide an important first step towards the selection of proteins for future studies.


There was a strong positive correlation (r = 0.961) between initial weight and weight at the last visit (p < 0.001). Ready-to-use therapeutic food is effective in improving development potential as well as promoting weight gain in children aged under five with uncomplicated SAM if provided according to WHO guidelines.The objective of this study was to assess whether the standard therapy of ready-to-use therapeutic food in the treatment of uncomplicated severe acute malnutrition (SAM) is effective in improving developmental potential and weight gain in children aged under five years. A multicenter pretest-posttest study was conducted among 91 children aged under five with uncomplicated SAM in Pakistan. Study participants completed their eight weeks’ therapy of ready-to-use therapeutic food according to the World Health Organization’s (WHO) standard guidelines. The study outcome was the proportion of children with improved developmental potential in all domains in comparison with the pretreatment status and children gaining >15% of their baseline weight; mean weight-for-height/length z-score after completing eight weeks’ therapy of ready-to-use therapeutic food. The Denver Development Screening Tool II was used for developmental screening. Significant changes ( Severe acute malnutrition (SAM), also known as severe wasting, is a highly prevalent and critical form of under-nutrition. Approximately 16.4 million children suffer from this condition globally . The disAccording to the standards of the World Health Organization (WHO), anthropometric criteria for the diagnosis of SAM are weight-for-height < −3 standard deviations (SD) or mid-upper arm circumference (MUAC) < 11.5 cm . FurtherChild development designates the progression of the child in all domains of human functioning, i.e., social, cognitive, motor, hearing, and speech . ChildreReady-to-use therapeutic food (RUTF) and basic medical care are the mainstays of treatment in a community setting for the management of uncomplicated SAM. RUTF is a high-calorie, energy-dense, micronutrient-enriched food ,12,15. IThe paradigm of the hospital-based approach to home treatment has merged with the effectiveness of RUTF to increase the acceptability of CMAM programs in the treatment of children with SAM in a cost-effective manner . The PakTo our knowledge, all of these studies or retrospective study designs only look for children’s weight gain. No study has been conducted with a prospective design to demonstrate that this micronutrient-enriched paste is also effective in improving the development quotient of children along with their weight. For that reason, we hypothesized that ready-to-use therapeutic food would be equally effective in improving developmental potential along with weight gain in the management of children with SAM. We tested this hypothesis by conducting a pretest-posttest study in rural areas of Pakistan to check the efficacy of RUTF for child development along with growth.A multicenter pretest-posttest study was conducted at three basic health units and one rural health center in Dera Ghazi Khan, a district of Southern Punjab, Pakistan. This district has a high illiteracy rate and the majority of the population consists of individuals with low socio-economic status. It is also an underprivileged district that has a high prevalence of malnutrition and poverty . ChildreOverall, 91 children, both girls and boys, were enrolled after their parents gave permission. The inclusion criterion was severe wasting accessed by the WHO protocols (weight for height < −3 SD and MUAC < 11.5 cm), which was not accompanied by any complications of malnutrition . ChildreThe sample size was calculated by the following formula, keeping the power of the study equal to 90% and the level of significance equal to 5%:Desired power = 90%Desired level of significance = 5%Population standard variance = 12.8881 Population mean weight before = 5.08 kgPopulation mean weight gain = 3.3 kgAccording to this formula, a sample size of 86 participants was required for the analyses. We decided to recruit 100 children to allow for non-responses in the posttest.A pretested sociodemographic and nutritional questionnaire was utilized to obtain information about the child’s age, gender, household income, household size, immunization status, parents’ education, parents’ professions, history of infections, complimentary feeding practices, breastfeeding, and access to medical assistance. Family monthly income from all sources was asked for in Pakistani rupees, and children’s current immunization status was checked from their immunization card according to the Pakistan Expanded Program on Immunization . In thisA child appetite test was performed by offering a small sample of RUTF and watching how much the child consumed of the offered amount. After three feeding attempts, a child was labelled as having poor appetite if they failed to eat a minimum of one third of a pack of RUTF. As per the protocol, these children were also not included in this study and were transferred to hospital.A physical examination according to WHO and national guidelines was then carried out to assess the children’s alertness, hydration status, severe palmar paleness, severe edema, lower respiratory tract infections, hyperpyrexia, and hypoglycemia before enrolment and start of treatment ,19. WherIn cases of facility-based delivery, the children’s gestational age was obtained by consulting the antenatal record; for home delivery, information was supported by maternal report. For children who were ≤ 24 months of age and born prematurely, before 37 weeks of gestation, their age was adjusted by deducting the total weeks of missed gestation from the present age. This information was acquired from mothers and caregivers at health units.The anthropometric evaluations were carried out by qualified nutrition supervisors who were specially trained for these evaluations. Weight was measured using the UNISCALE to the nearest 10 g by weighing children in very light clothing or, if required, without clothing. When a child was unable to stand, their mother was weighed while holding the child and afterwards the mother’s weight was subtracted. The child’s length was estimated using a length measuring board  to around 0.1 cm accuracy. The height of children who were able to stand, and who were more than 87 cm tall, was measured in the standing position without shoes ,4. WeighOnce the eligibility criteria were met, children undertook a developmental assessment with the support of a pediatrician by following the Denver II Developmental Screening Tool (DDST II) . This deThe study outcome was the proportion of children with improved developmental potential in all domains in comparison with the pre-treatment developmental potential, and children gaining > 15% of their baseline weight, mean weight-for-height/length z-score, after completing a standard eight weeks’ therapy of ready-to-use therapeutic food.All of the children were enrolled for eight weeks’ therapy of RUTF provided by the Department of Health of the Government of Punjab, sponsored by UNICEF, at CMAM centers. By following national and WHO guidelines, RUTF was provided to families weekly according to the weight of the children, which equates to approximately 1.5–5.0 sachets/day ,19. RUTFParents were provided with a CMAM registration card and were assisted to attend outpatient centers with their children. During the study’s duration, and in line with standard practice, children were examined on a weekly basis at CMAM centers. The reason for this was to acquire their RUTF and be assessed for any medical or nutritional complication. In cases where complications were reported, children were referred to hospital for further evaluation and treatment. Post-treatment anthropometry and developmental assessment of the children were conducted by CMAM staff and a study pediatrician after they had completed their eight-week course of RUTF.t-test was used to compare paired observations for z-scores and weight gain. A p-value of <0.05 was taken as statistically significant.Data was entered and cleaned using SPSS version 25.0. Frequencies and percentages of categorical variables like age, gender, monthly income, and educational status were calculated. Mean (SD) was calculated for the pre- and post-intervention quantitative variables, such as weight and weight for length/height z scores. The Chi-Square test was used to assess the association between pre- and post-intervention developmental status. A paired Written informed consent was received from caregivers or parents after the study had been explained to them. Ethical approval for the current study was obtained from the District Health Office of Dera Ghazi Khan (Ref.: 838/ADGHS/IRMNCH) and the Ethical Review Board of the University of the Punjab.Overall, 100 children with uncomplicated SAM were enrolled in the study; 91 of them completed the study in line with the study protocol and were included in the analysis. The mean age was 15.2 ± 9.69 months, and most children were aged < 12 months (60.4%). More than half of study participants were females (58.2%) and the majority had a low household income. The mean height was 66.68 ± 8.97 cm, mid-upper arm circumference was 9.89 ± 0.99 cm. Immunization was mostly completed (79.1%), and most (81.3%) were not exclusively breastfed. Poor hygiene practices were witnessed among most participants (93.4%). A weight gain of >15% in the eight weeks of eating RUTF was observed in most cases (86.8%) . This study indicates that RUTF is not only effective in encouraging weight gain, but also in improving developmental potential among children aged under five. Many studies have already been conducted on the effectiveness of the CMAM program in the community setting. However, until now only limited evidence has been available on the effectiveness of RUTF in improving the development quotient of children along with weight gain.Previous research has concluded that there is an inverse relationship between child development and nutritional status, because children with low nutritional status are unable to attain their full developmental potential in order to lead a productive life ,8,26. OuInadequate nutrient supply may cause abnormalities such as reduced brain size, adverse impacts on cell maturation resulting in behavioral abnormalities, and delay in personal social development ,27. In mFor treating children with uncomplicated SAM, effective community-based care for acute malnutrition, including RUTF, has established a solid reputation. The developmental delay was significantly reduced with the treatment of uncomplicated SAM using RUTF in terms of the gross motor, personal/social, fine motor, language and global development assessed through Denver II. The study results were consistent with a study from Pakistan and Ethiopia qualitatively assessing the barriers to SAM treatment .After an eight-week follow up with RUTF management, we found that children with uncomplicated SAM showed profound improvement in all developmental domains in comparison with their pretreatment developmental potential. RUTF contains therapeutic doses of all the micronutrients and macronutrients required for the catch-up growth and brain development of children ,12. ThusAccording to WHO guidelines, the proper utilization of recommended RUTF is key for attaining the required weight gain and complete recovery . We haveThe strength of our research is that developmental screening was conducted (1) by pediatricians who were experts in the developmental testing of children and (2) by using validated and reliable development screening scales . The ratThe limitations of our study relate to the comparatively short duration of the study period. Because of this short duration, we could not determine whether children were able to maintain this recovery of weight and development in order to gain the maximum advantage in the long term. Another limitation was that, due to financial constraints, we could not conduct any lab tests to assess the deficiency and recovery of micronutrient status in the pre- and post-examination phases. The lack of a control group was also a limitation, meaning that true differences could not be attributed as similar findings might have been noted in the control group. Further studies with an increased sample size, duration, and effect of therapies other than RUTF, along with biochemical testing in diverse locations, are required in order to advance and replicate these promising results. Furthermore, a randomized controlled study design with a control group is needed.The study concluded that RUTF is beneficial for improving the developmental potential and weight gain of children with SAM aged under five if it is given in a timely manner and in line with the WHO recommended amounts. Community-based programs should be implemented and supported in order to gain improvements at the population level, particularly for vulnerable subgroups.


A significant interaction between SES and group allocation was observed to change in fruit intake (p = 0.01). Among children from low SES families, only those from the comparison group decreased their fruit intake (group means: −40.0 g/d (95% CI: −56.0 to −23.9) vs. 9.3 g/d (95% CI: −16.1 to 94) in the intervention group, p = 0.006). The present study found no convincing effect of introducing a multi-component intervention on dietary intake except a small beneficial effect on whole-grain bread consumption. However, beneficial intervention effects in fruit intake were found particularly among children from low SES families.The diet of Danish children is often not in accordance with dietary guidelines. We aimed to evaluate changes in the intake of selected foods and beverages during a multi-component school-based physical activity intervention, and to investigate if changes were modified by socioeconomic status (SES). The study included 307 children  with information on dietary intake pre- and post-intervention as well as on SES. Linear regression models were conducted to assess the effect of the intervention on changes in dietary factors. Children from the intervention group increased their intake of whole-grain bread during the intervention (group means: 6.1 g/d (95% CI: 2.2 to 10.0) vs. 0.3 g/d (95% CI: −3.1 to 3.7) in the comparison group,  There is a high prevalence of childhood overweightness and obesity in many countries, including Denmark ,2. ChildA healthy diet, with regular physical activity, is considered important for the prevention of overweightness and obesity , as wellThe World Health Organization (WHO) and the Danish health authorities recommend increasing the intake of fruit, vegetable, legumes, fish, whole grains and nuts; to limit the consumption of red meat, sugars, salty and total fats; to replace saturated fat with unsaturated fats; and to drink more water ,20. HoweOne arena that is considered ideal for introducing health-promoting initiatives to children is within public schools , and thuWe hypothesized that: (1) the intervention would result in children from the intervention schools having a higher intake of fruit and vegetables and a lower intake of sweets and SSBs than the children from the comparison schools, and (2) that maternal education level would modify the potential effects of the intervention.The intervention introduced in the local schools in the municipality of Ballerup was multi-component and has been reported in detail elsewhere . BrieflyThe intervention was initiated and implemented by the municipality of Ballerup, while the research team performed pre- and post-evaluations of dietary intake, physical activity level and anthropometrics. The municipality of Tårnby was chosen as a comparison municipality since the sociodemographic characteristics resembled those of Ballerup .Participants, teachers, school leaders and researchers were blinded to the study condition assignment. Prior to the intervention (the children were 6 years old), information on dietary intake and socioeconomic status was obtained from the children and their parents. Weight and height were measured at enrollment by trained researchers. Height was measured to the nearest 1 mm by a Harpenden stadiometer. Weight was measured to the nearest 0.1 kg by an electronic scale . Habitual physical activity was measured on 4 consecutive days (2 weekend days + 2 weekdays) by the MTI 7164 activity monitor . Children were required to wear accelerometers at all times, except when sleeping and/or engaged in water activities. Only children with a cumulative activity time of more than 8 hours per day for at least 3 days were included in the analysis. Similarly, this information was collected after the three-year intervention (when the children were 9 years old).n = 1024 children). The pre-intervention characteristics of all the participants have been reported elsewhere . . n = 292The study was approved by the Ethical Committee of Copenhagen County (case no. KA00011gm) and all procedures were in accordance with the Helsinki Declaration of 1975, as revised in 1983. Written information about the study was given to all school leaders, teachers and parents prior to the study. Informed consent was obtained from the parents/caregivers of the participants. Parents or caregivers recorded the dietary intake of the children through 7-day food records  both pre- (spring 2002) and post-intervention (spring 2005). The food records were divided into 4 parts: breakfast, lunch, dinner and snacks. Each meal was further divided into beverages, bread, cereals, vegetables, etc. Household measurements and photo series illustrating the serving sizes and 4 or 6 different quantities of common foods were used to assess the amount of food consumed ,36,37. After completion the food records were scanned using Eyes & Hands version 5.2 and the dietary intake of each child was calculated using the General Intake Estimation System  and the Danish Food Consumption Databank (version 6) .In the present study, we focused on the intake of fruits , vegetables ), fruit juice (100% apple juice and 100% orange juice), SSBs (soft drinks (carbonated sugar-sweetened soft drinks) and squash), sweets , white bread (bread reported as white bread in the food records), whole-grain bread , dark rye bread  and fish  . The fooPrior to the intervention, the mothers provided information on their education level in a questionnaire using two questions . The firPre-intervention characteristics of the children participating in the study were assessed according to the intervention status or SES, and differences between the two groups were tested using a Wilcoxon rank-sum test for continuous variables and Chi-squared test for categorical variables.Linear regression models were conducted to assess the effect of the intervention on changes in dietary factors. First, crude models were conducted with information on outcome, intervention status and baseline/pre-intervention measure of outcome, only. Secondly, adjusted analyses with added information on sex, age and maternal education were carried out. Potential effect modification by maternal education status was explored by adding product terms to the models, and subgroup analyses were performed when significant interactions were observed.Normality of continuous variables and model assumptions  were assessed through visual inspection of histograms and residual plots. As some discrepancies from the model assumptions were observed, all results were presented with 95% bootstrap confidence intervals (CIs).All statistical tests were two-tailed, with a significance level at 0.05. Analyses were performed using Stata SE 14 .n = 184; comparison group: n = 123) with complete information on dietary intake and maternal education level. The intervention and comparison groups differed slightly pre-intervention with respect to age and maternal education level (p = 0.01 for both)  . An oldep = 0.004). Pre-intervention the intakes of the selected foods and beverages were comparable between the intervention and comparison groups , however2 (IQR: 15.0 to 16.7), 15.7 kg/m2 (IQR: 14.9 to 16.6) and 15.5 kg/m2 (IQR: 14.7 to 16.4) (p = 0.19)); and the incidence of overweightness or obesity was 15.8%, 15.8% and 12.5% (p = 0.52) in the children from the low, middle and high SES groups, respectively . The further analyses stratified by maternal education level revealed a significant difference in changes in fruit intake between the intervention  and the comparison groups  for those children whose mothers had short education, while no group differences were observed for those children with mothers with medium or long educations (A significant interaction was seen between maternal education level and intervention status in relation to changes in fruit intake (ucations . No inteThis study evaluated the effect of a three-year multi-component school-based intervention on food and beverage intake and found only little indication that the overall food intake changed as a consequence of the intervention. Compared to children in the comparison group, the intake of whole-grain bread increased slightly among the children from the intervention group; no other overall differences were observed. However, the analyses also revealed that the biggest difference in fruit intake during the three-year intervention period was seen among children from low SES families, which is encouraging since children from low SES families often have a diet that is less in accordance with dietary guidelines than children from high SES families . Indeed,Insufficient fruit and vegetable consumption has been found among children with low academic achievement and at a higher risk of obesity as well as other obesity-related illnesses ,49. TherIn the present study, we did not find significant differences in changes in the intake of SSBs, fruit juice and sweets between the intervention and the comparison group, but SSB intake decreased in both the intervention and comparison groups over the three-year intervention period. These results are in agreement with results from another study, which showed that the intake of SSBs among adolescents decreased from 2002 to 2018 . In our The present study showed a slightly higher increase in intake of whole-grain bread in the intervention group compared to the comparison group. Whole-grain bread is rich in healthy nutrients that may contribute to the prevention of several diseases, including cardiovascular disease, cancers, diabetes and gastrointestinal problems . Among cIt was not possible to determine which intervention initiatives were useful since the intervention was multi-component. In addition, not all initiatives were introduced on the first day of the intervention, for example, school canteens. It was assumed that school canteens and the information provided to parents about preparation of healthy food through the newsletter were the main interventions that influenced children’s dietary intake. We did not have information on the number of children using the school canteen, the number of parents receiving the newsletter or whether the canteen staff followed the recipes provided. Thus, we were unable to evaluate the effectiveness of these initiatives further. Finally, it cannot be excluded that the significant findings related to intake of whole-grain bread may be a chance finding. In any case, an increase in the intake of whole-grain bread of 6 g/day has little nutritional implication.The strengths of the present study included that the dietary information was obtained using a 7-day food record which enabled analyses at the individual level. Moreover, we had information on maternal educational levels that allowed for stratified analyses by socioeconomic status. Additionally, since this study was initiated and handled by the municipality, our results may be applicable if a similar initiative is implemented in other schools. Furthermore, the results were adjusted for some relevant potential confounders. However, some limitations should also be noted: The dietary assessment used in the present study may lead to misreporting ,62 and rSelection bias may have affected the results due to a high dropout rate between the baseline and thethree-year follow-up. There were only a few differences in characteristics and diet intake between included and not included children. In this study, the included children consumed more vegetables and whole-grain bread, and their mothers’ BMI was lower than that of the non-included children . AssuminOverall, the present study found no convincing general effect on dietary intake of introducing a multi-component school-based intervention except for a slightly increased intake of whole-grain bread in the intervention group. However, children from low SES families seemed more likely to increase their intake of fruit after the three-year multi-component school-based intervention, which seem encouraging, as children from low SES families are generally considered to be harder to reach with interventions. Future studies should aim at developing more effective ways to improve dietary intake among young school-aged children.


Purpose: This retrospective cohort study was conducted to determine the glaucoma risk associated with metabolic disease (MetD) using insurance claims data of Taiwan. Methods: From the database, we identified patients with newly diagnosed hypertension, diabetes and/or hyperlipidemia from the years 2000 to 2002 as the MetD cohort  and an age-gender-diagnosis-date matched control cohort without MetD with a two-fold sample size than that of the MetD cohort. Both cohorts were followed until the development of glaucoma, death, or withdrawal, until 31 December 2013. The incidence of glaucoma, and the Cox method estimated hazard ratio (HR) of glaucoma were calculated. Results showed that the incidence of glaucoma was two-fold higher in the MetD cohort than in the controls (1.99 versus 0.99 per 1000 person-years), with an adjusted HR of 1.66 (95% CI: 1.50–1.85). The glaucoma incidence was higher in patients with diabetes than those with hypertension and hyperlipidemia . The incidence increased to 5.67 per 1000 person-years in patients with all three comorbidities, with an aHR of 4.95 (95% CI: 2.35–10.40). We also found higher incidence rates of primary open-angle glaucoma and primary angle-closure glaucoma with aHRs of 2.03 and 1.44, respectively. It was concluded that glaucoma risk increased with the number of MetD. Health providers need to monitor patients with MetD to prevent glaucoma. Glaucoma is the second leading cause of irreversible blindness worldwide . Vision Metabolic diseases (MetD) have become a worldwide public health concern because a cluster of conditions may occur together, including key components of hypertension, hyperglycaemia, and dyslipidaemia with low serum high-density lipoprotein and visceral obesity ,11. A reStudies have indicated that hypertension ,19 and dStudies have shown components of MetD are associated with POAG ,22 or PAThe present population-based retrospective cohort study retrieved data from the Longitudinal Health Insurance Database (LHID) 2000, which is one of the databases of Taiwan’s NHI Research Database (NHIRD) of all NHI beneficiaries, covering over 99% of Taiwan’s population. LHID 2000 was created for research purposes by systematically and randomly selecting one million individuals from all populations registered in 2000 to represent the entire population. This database included information on demographic status of the beneficiaries and claims data for medical services provided to them from 1996 to 2013. The disease diagnoses were encoded in accordance with the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). To protect personal privacy, the patients’ personal identifications were encrypted from data released from National Health Research Institutes. Therefore, patient consent is not required to access the NHIRD. A large volume of research has been published based on the NHIRD in peer-reviewed international journals. This study was approved by the Ethical Research Committee at China Medical University and Hospital (CMUH104-REC2-115[CR-2]).N = 42,036) were included as the study cohort of MetD. The first date of diagnosis of MetD was defined as the index date. For each patient with any MetD, two controls free of any MetD were randomly selected from the LHID2000, frequency-matched by sex, age (in 5-year age bands) and index year as controls of the non-MetD cohort . Both cohorts were tracked from baseline until the development of glaucoma, loss to follow-up, withdrawal from NHI, or December 31, 2013 to examine the risk of glaucoma.Comorbidities that were considered as potential covariates in the inference of the association between MetD and glaucoma included hypothyroidism, OSA, depression, anxiety, headaches, liver diseases, peptic ulcers, cataract, central retinal vein occlusion (CRVO), and age-related macular degeneration (AMD).Studies have indicated that some medications commonly used in patients may affect both PACG and POAG, including adrenergic drugs, anticholinergics, cholinergics, and sulfa-based medications ,25. We at test were used to examine the categorical and continuous data, respectively.SAS software version 9.1  was used for the data analyses. We compared the distributions of sociodemographic characteristics and baseline comorbidities between cohorts with and without MetD. Medications that might associate with the development of glaucoma were also compared between the two groups. The Chi-square test and Student’s The Kaplan–Meier method was used to calculate and plot the cumulative incidences of glaucoma for both cohorts and the log-rank test was used for comparison. We pooled data of both cohorts to calculate incidence rates of glaucoma (per 1000 person-years) for both cohorts and by sociodemographic status, comorbidity and the use of medication. The hazard ratio (HR) of glaucoma with a 95% confidence interval (CI) was calculated using the Cox proportional hazards regression analysis. The adjusted hazard ratio (aHR) was estimated using the multivariable regression analysis, after controlling for variables significant in measuring the crude HR. We also assessed the incidence rate and HRs of glaucoma associated with individual component and multi-components of MetD. Data analysis further estimated the incidence rate and HRs of PACG and POAG. All analyses were performed with a significance level using α = 0.05.p < 0.05) . The MetD cohort had significantly higher comorbidities of obesity, hypothyroidism, OSA, depression, headaches, liver diseases, peptic ulcers, cataracts, AMD, and more users of glaucoma associated drug than the controls did ( < 0.05) . Howeverp < 0.001).With minimum and maximum follow-up times of 0.003 and near 14.0 years, respectively, the mean follow-up was longer in the MetD cohort than in the control cohort (11.4 (SD 2.97) versus 7.88 (SD 4.62) years). The numbers of study population at risk reduced to 23752 persons and in the MetD cohort and 21,885 persons in the control cohort. p < 0.0001). The incidence of glaucoma was higher in women than in men with an aHR of 1.13 (95% CI = 1.03–1.25). Glaucoma incidence increased with age. Compared with the incidence of patients less than 40 years old, the incidence in those aged 40–64 years was near three-fold higher and that in the older patients was six-fold higher . Among comorbidities, AMD had the strongest association with the risk of glaucoma , followed by cataract  and peptic ulcer . Moreover, the study results indicated that some drugs might have an association with developing glaucoma, but not significantly so .p < 0.001). Among patients having two diseases, the glaucoma incidence was greater in those with diabetes mellitus and hypertension than in those with diabetes mellitus and hyperlipidemia, and those with hypertension and hyperlipidemia (3.77 versus 2.70 and 1.48 per 1000 person-years).Among the three types of MetD, individuals with diabetes mellitus had a stronger association with glaucoma than those with other two diseases, with an aHR of 2.14 (95% CI = 1.80–2.55) compared to controls . The glaThrough this retrospective cohort study, we found that the incidence of glaucoma (both PACG and POAG) was higher in patients with MetD, which confirms a significant association between MetD and glaucoma. This finding is consistent with findings in previous studies and supports the hypothesis that patients with MetD are at a higher risk of glaucoma than those without MetD are . The gloIn our study, we observed that women were more likely than men to develop glaucoma. According to Healthy Vision 2010, women have a higher risk of visual impairment from glaucoma, particularly from PACG ,27. The This study shows that the incidence of glaucoma among the age groups seems to be linear, and is the highest in older patients. Studies have concluded that age is a crucial factor related to the development of glaucoma and that the risk of developing glaucoma increases exponentially with age ,29. In aStudies have reported that some drugs might be associated with the development of glaucoma ,25,32. FThrough this study, we demonstrated the association between MetD and glaucoma. The findings revealed that patients with three types of MetD concurrently, namely diabetes mellitus, hypertension, and hyperlipidaemia are at the highest risk (aHR = 4.95) of developing glaucoma. Individuals with both diabetes mellitus and hypertension also had a higher risk aHR = 2.87) of developing glaucoma than those with a single MetD did. In addition, we analyzed the relationship between a single MetD and glaucoma. The results indicated that diabetes mellitus was independently associated with a higher risk of the development of glaucoma (HR: 2.14). A longitudinal study demonstrated that diabetes mellitus and hypertension, independently or in combination, were associated with an increased risk of developing POAG . The res.87 of deEvidence revealed that hyperlipidaemia is significantly associated with an increased risk of glaucoma. In our study, hyperlipidaemia was an independent risk factor (HR: 1.79) for glaucoma, which was similar to the findings of another meta-analysis study . HoweverThe findings of the present study showed that MetD had a significant association with hypothyroidism, OSA, depression, headaches, liver diseases, peptic ulcers, cataract, CRVO, and AMD, consistent with the results of another study in Taiwan . HoweverMetD has long been considered a risk factor for glaucoma ,21,41. HThe major strengths of this research are as follows. First, we analyzed the relationship between MetD and the risk of developing glaucoma of two subtypes (POAG and PACG) and found the risk was greater for the subtype of POAG than that of PACG. Second, the study cohorts were matched by age, gender, and index year to exclude potential confounding effects of these variables. Third, the large sample size and long follow-up period increased the validity of the study. Fourth, patients were diagnosed as having MetD and glaucoma by physicians rather than based on patient self-reports. The accuracy of diagnosis is increased.However, the study also has some limitations. First, information on laboratory and anthropometric measurements is not available in the claims data. We were unable to use measurements of body mass index, waist circumference, blood pressure, blood sugar, triglycerides, and high-density lipoprotein (HDL) to define the MetD cohort for this study. We therefore used the healthcare providers’ diagnoses of hypertension, hyperglycaemia and dyslipidaemia available in the claims data to select the study cohorts. Secondly, information regarding the potential confounding effects of family history and personal lifestyle  could not be obtained owing to database limitations. Third, patients with MetD and glaucoma were identified based on the physician’s diagnosis rather than through the research assignment.Further research is underway to validate the role of glaucoma-related obesity among patients with MetD in the development of glaucoma. Additionally, control of other characteristics related to the development of glaucoma, such as alcohol consumption, smoking, waist circumference, body mass index, and physical activity, must be considered.The results of our study showed that the risk of developing glaucoma increased with MetD components. Patients with MetD were at a higher risk for POAG than for PACG compared with patients without MetD. As glaucoma is usually relatively asymptomatic, we recommend that primary care physicians provide appropriate screening for the risk of glaucoma and counsel patients with MetD. It is particularly important to detect glaucoma at an early stage in older patients with diabetes and provide treatment for blindness prevention.