Younger age and faster walking pace had a strong association with PA in all the four types of cancer (p < 0.01). Smoking status had a strong association with PA in the lung cancer group, while obesity had a strong association with PA in female breast, colorectal, and prostate cancer (p < 0.01). Higher levels of pre-diagnosis MVPA (≥1.5 h/day) were associated with a significantly lower all-cause mortality risk. Conclusions: The present study suggests that lung cancer patients are the most inactive population before diagnosis. The identified difference in correlates of PA suggest that cancer-specific approaches are needed in PA research and practices. This study also highlights the importance of high PA for individuals with high cancer risk.Purpose: Physical activity (PA) plays an important role in health outcomes for people with cancer, and pre-diagnosis PA influences PA behaviors after cancer treatment. Less is known about the PA of lung cancer patients, and the strong history of smoking could influence pre-diagnosis levels of PA and place them at risk for health problems. This study aimed to compare pre-diagnosis PA and its correlates in patients with lung cancer and other types of cancer  and examine the relationship between pre-diagnosis PA and all-cause mortality. Methods: This study used data from the UK Biobank, which is a national cohort study with accelerometry data. We included 2662 participants and used adjusted linear regressions and survival analyses. Results: Male and female lung cancer groups spent a mean of 78 and 91 min/day in pre-diagnosis moderate to vigorous PA (MVPA), respectively; this is lower than the 3 other types of cancer ( Physical activity (PA) provides numerous health benefits for cancer patients. Physical activity improves health outcomes including cardiovascular fitness, muscle strength, cancer-related fatigue, health-related quality of life, and depression ,2,3. PhyMuch of the prior research focuses on PA after cancer diagnosis, but it is important to examine the entire continuum. The PA and Cancer Control (PACC) framework proposes six cancer-related time periods: two pre-diagnosis (pre-screening and screening) and four post-diagnosis  . Most exLung cancer is the second most common cancer and the leading cause of cancer-related death worldwide . HoweverSeveral socio-demographic and health-related characteristics have been identified as correlates of PA in cancer survivors  ,25,26,27This study used data collected from the UK Biobank, which is a national cohort study in the UK. Demographic and health-related data were collected from 500,000 participants (aged 40–69 years) between 2006 and 2010, with a reassessment of 20,000 participants between 2012 and 2013 (the most recent data were used—this is referred to as baseline data for the purpose of this current study). Between 2013 and 2015, participants were re-contacted and invited to wear an accelerometer  if they provided a valid email address at the baseline assessment. Of the total recruited 500,000 UK Biobank sample, 236,519 participants were asked to join the accelerometer study to obtain objectively measured PA data under free-living conditions. A total of 106,053 agreed to wear a PA monitor (response rate to invitations = 44.8%), and 103,720 participants returned data between 2013 and 2015 . Data frWe included participants if they: (1) were diagnosed with primary lung cancer, female breast cancer, colorectal cancer, or prostate cancer after completing accelerometer data collection  start wearing the accelerometer device immediately after receiving it, (2) wear it for seven continuous days on their dominant wrist, (3) carry on with their normal activities, and (4) mail the device back to the research center, in a pre-paid envelope, after the seven-day monitoring period . The rawHealth-related factors were collected at baseline (2006–2010 and 2012–2013). (1) Self-reported overall health was rated as excellent, good, fair, or poor. (2) Self-reported comorbidities were measured using a 13-item comorbidity check list. For the purposes of this research, we analyzed data from patients with the most common cardiovascular and pulmonary comorbidities  and diabetes. The number of comorbidities ranged from 0 to 7. (3) Self-reported walking pace was measured using an item “How would you describe your usual walking pace?” with response options of slow, steady/average, or brisk. Participants could access further information which defined a slow pace as less than three miles per hour, a steady/average pace as between three and four miles per hour, and a brisk pace as more than four miles per hour. (4) Grip strength was assessed in each hand using a hydraulic hand dynamometer , which can measure isometric grip force up to 90 kg . Grip stSocio-demographic characteristics were collected at baseline (2006–2010 and 2012–2013), including age, sex, ethnicity (white/non-white), Townsend Index of deprivation (high scores indicated higher levels of socioeconomic deprivation) , body maDate of cancer diagnosis and death were linked to the UK Biobank dataset. The included participants were diagnosed with lung/female breast/colorectal/prostate cancer between 2013 and 2020 (at 4 days–6.5 years after accelerometer data collection). We followed participants from their date of cancer diagnosis to their date of death as provided by UK Biobank’s linkage to death registration data or to the latest follow-up date for mortality data (21 March 2021) if they did not have a death record.p-value of less than 0.01 was considered statistically significant for all analyses.Stata SE 17.0 software  was used for data analysis. Descriptive statistics  were calculated for socio-demographic, health-related characteristics, and accelerometer-measured PA in each type of cancer, stratified by sex. We compared the socio-demographic, health-related characteristics, and accelerometer-measured PA among different cancer groups stratified by sex. Chi-square tests of independence were used for categorical variables, and ANOVA tests were used for continuous variables. A To address the three study aims (see Introduction Section), we used linear regressions and survival analyses. Aim 1: Linear regression was used to compare time spent in MVPA between patients with lung cancer and other types of cancer, stratified by sex . The linear regression models included both unadjusted and adjusted estimates that control for socio-demographic characteristics. The unadjusted and adjusted coefficients and 95% confidence intervals (95% CI) were reported.Aim 2: Linear regressions were used to examine the correlates of PA for each type of cancer . The linear regression models included both unadjusted and adjusted estimates that control for other socio-demographic and health-related characteristics. The unadjusted coefficients, adjusted coefficients, 95% CI, and adjusted standardized coefficients were reported.Aim 3: Survival analyses (Cox regressions) were used to assess the potential impact of time spent in MVPA on all-cause mortality. We used Cox regressions to model time-to-death as a function of time spent in MVPA per day and controlled for socio-demographics, cancer types, and comorbidities. The unadjusted and adjusted Hazard Ratio (HR) and 95% CI for all-cause mortality were reported. Interaction analysis was performed to explore whether cancer types modified the association between MPVA and all-cause mortality.p < 0.01). In addition, participants in the female lung cancer group were older than the female breast cancer and female colorectal cancer groups (p < 0.001). Participants in the male lung cancer group reported less frequent alcohol consumption, worse overall health, and more comorbidities and had lower grip strength compared to the prostate cancer and male colorectal cancer groups (p < 0.01) . The time spent in MVPA per day was 91 and 78 min/day in female and male lung cancer groups, respectively; this was lower than other types of cancer (p < 0.001)  see .p < 0.001) and 10.93  more minutes in MVPA, respectively, compared with participants in the lung cancer group. The difference disappeared with adjustment for socio-demographic characteristics  and 23.54  more minutes in MVPA, respectively, compared with participants in the lung cancer group. With adjustment for socio-demographic characteristics, the difference between colorectal and lung cancer was not statistically significant, but participants in the prostate cancer group still showed 15.32 more minutes in MVPA per day compared with lung cancer  . In the lung cancer group, higher pre-diagnosis PA was also associated with never smoking, more frequent alcohol consumption, and lower anxiety and depression (p < 0.01)  see .p < 0.01). In addition, smoking status had a strong negative association with PA in the lung cancer group, while obesity had a strong negative association with PA in female breast, colorectal, and prostate cancer (p < 0.01)  see .p < 0.01) (see p > 0.05). Compared to lung cancer, patients with other types of cancer had a significantly lower all-cause mortality risk  . There were 426 deaths among 2661 participants during the follow-up period (1 participant died on the same day of cancer diagnosis). Cox regression analyses showed that higher levels of pre-diagnosis MVPA (≥1.5 h/day) were associated with a significantly lower all-cause mortality risk after cancer diagnosis  see . However001) see . There w001) see . The assTo our knowledge, this study is the first to compare pre-diagnosis PA and its correlates between patients with lung cancer and other types of cancer  using a national cohort dataset with objective measures. The present study found that lung cancer patients were the most physically inactive population before diagnosis compared to female breast and colorectal cancer, but this difference could be explained by socio-demographic characteristics. This study identified correlates of pre-diagnosis PA among patients with each type of cancer and detected differences between lung cancer and other types of cancer . Specifically, smoking status was negatively associated with pre-diagnosis PA in lung cancer only, while obesity was negatively associated with pre-diagnosis PA in the female breast, colorectal, and prostate cancer groups. Furthermore, the present study found that higher MVPA before diagnosis (≥1.5 h/day) was associated with a lower all-cause mortality risk after lung, female breast, colorectal, and prostate cancer diagnosis.The present study found that lung cancer patients had lower pre-diagnosis MVPA, and their lower pre-diagnosis MVPA could be explained by socio-demographics. This was also observed by Sweegers et al. (2019) for post-diagnosis MVPA . SweegerThe pre-diagnosis MVPA in the present study appears high in comparison to previous estimates ,38 and tThe present study found two strong correlates of pre-diagnosis MVPA in all four types of cancer: age and walking speed. Age is a well-established predictor of PA. Prior studies with accelerometers reported a negative association between age and PA in general cancer survivors ,38 and pThe differences in PA correlates between cancer types were observed by prior studies with self-reported PA measures ,15. The The present study supports the finding of prior studies that focused on only one of these cancer types, and it also helps to explain the inconsistent findings of prior studies with mixed cancer populations. Future studies may consider the similarity within and differences between cancer types when merging a mixed cancer population. The identified differences in PA and its correlates between cancer types suggest that cancer-specific approaches are needed to identify patients at high risk of physical inactivity. For example, PA interventions in lung cancer could target smokers, who are at higher risk for low PA than non-smokers. Given the correlation between smoking and PA, behavioral change interventions might be more effective if smoking cessation and PA promotion strategies were combined for smokers.The present study, with a national cohort and accelerometer data, confirms the findings from previous studies of self-reported PA measures  and suppThis study has major strengths that include a large sample from a national cohort and objective measures of PA, but it also has several limitations. First, the accelerometer data were not collected immediately prior to the cancer diagnosis: there is a time interval (4 days–6.5 years) between PA assessment and cancer diagnosis. Thus, this may not be representative of participants’ overall pre-diagnosis PA levels. We assumed that PA remained roughly the same before cancer diagnosis while controlling for age. Second, we did not have information on cancer stage and cancer treatments, which are confounding variables in PA and survival. Third, accelerometer study participants represent a subset of the UK Biobank participants who were willing and able to join a study on the objective measurement of PA but may not be representative of the broader UK population . Fourth,Understanding pre-diagnosis PA and its correlates is helpful in promoting PA and ultimately improving health outcomes in cancer patients. This study is the first to compare objectively measured pre-diagnosis MVPA and its correlates between patients with lung cancer and other common cancers, and the first to examine the dose–response relationship between MVPA and all-cause mortality, using a national cohort. Lung cancer patients are the most physically inactive population before diagnosis compared to female breast and colorectal cancer, but this difference could be explained by socio-demographic characteristics. Age and walking speed were strong PA correlates in all four types of cancer, while smoking status was a unique correlate in lung cancer. This study confirms the finding of prior studies that focused on only one of these cancer types and suggests cancer-specific approaches in PA research and practice, especially for lung cancer. Higher pre-diagnosis MVPA (>1.5 h) is associated with a lower all-cause mortality risk, which highlights the importance of high PA for individuals with high cancer risk.


SDHx mutations. In children however, very little data is available. In this report, we present the case of a 12-year-old female with a SDHB-related metastatic paraganglioma treated with surgery followed by temozolomide therapy. The patient presented with symptoms of palpitations, sweating, flushing and hypertension and was diagnosed with a paraganglioma. The primary mass was surgically resected six weeks later after appropriate alpha- and beta-blockade. During the surgery extensive nodal disease was identified that had been masked by the larger paraganglioma. Histological review confirmed a diagnosis of a metastatic SDHB-deficient paraganglioma with nodal involvement. Post-operatively, these nodal lesions demonstrated tracer uptake on 18F-FDG PET-CT. Due to poor tumour tracer uptake on 68Ga-DOTATATE and 123I-MIBG functional imaging studies radionuclide therapy was not undertaken as a potential therapeutic option for this patient. Due to the low tumour burden and lack of clinical symptoms, the multi-disciplinary team opted for close surveillance for the first year, during which time the patient continued to thrive and progress through puberty. 13 months after surgery, evidence of radiological and biochemical progression prompted the decision to start systemic monotherapy using temozolomide. The patient has now completed ten cycles of therapy with limited adverse effects and has benefited from a partial radiological and biochemical response.There is increasing evidence to support the use of temozolomide therapy for the treatment of metastatic phaeochromocytoma/paraganglioma (PPGL) in adults, particularly in patients with  A 12-year-old girl presented to a clinic appointment with a two-year history of sweating, intermittent flushing and occasional headaches. After monitoring her heart rate using a wearable device, she and her parents noted tachycardia even at rest, with a heart rate ranging from 120 to 145 beats per minute.th centile) while her target height was near the 70th centile. In the absence of any pubertal development, she was also diagnosed with delayed puberty.Upon presentation, she was tachycardic, hypertensive (207/184 mmHg) and a left parasternal heave was palpable. She was noted by the assessing clinician to be of short stature, with a current height of 136.4 cm (0.4A magnetic resonance imaging (MRI) scan of the abdomen was performed, which showed a 6 cm x 3 cm right-sided suprarenal mass abutting the liver, inferior vena cava and hilum, but without features of direct invasion on imaging (68Ga-DOTATATE positron emission tomography (PET-CT) was performed. The mass demonstrated heterogenous 68Ga-DOTATATE uptake  spectroscopy was performed . Due to Six weeks after the patient’s presentation, an open resection of the mass was performed. As the mass was adherent to the gallbladder and liver, a cholecystectomy and partial caudate lobe resection were necessary. Additionally, the mass was found to be invading the inferior vena cava, requiring resection and reconstruction of the retro-hepatic vena cava with a deceased donor aortic graft. Intra-operatively, extensive nodal disease (not identified on pre-operative imaging) was noted including para-aortic and hilar nodes; some of the latter involved the first order bile ducts at the hilar plate which were not amenable to resection.SDHB-deficient paraganglioma. Extensive lymph node involvement was also shown, confirming the diagnosis of a malignant SDH-deficient paraganglioma. Post-operatively a restaging 18F-fluorodeoxyglucose (FDG) PET-CT was performed  and predictive testing has identified several SDHB carriers on the maternal side of the family  single positron emission computerised tomography (SPECT-CT) scan was carried out  are neuroendocrine tumours arising from neural crest cells. These can be functional (catecholamine-secreting) or non-functional. The term phaeochromocytoma refers exclusively to tumours arising within the adrenal medulla, whilst tumours arising in sympathetic and parasympathetic paraganglia elsewhere in the body are referred to as paragangliomas. PPGL are rare tumours in children, with an estimated overall incidence of 0.6 per 100,000 person-years . Of thesSDHx) also predispose to the development of PPGL. Such pathogenic variants are autosomal dominant, and require biallelic inactivation for tumorigenesis to occur (SDHx-deficient cells lead to increased stabilisation of hypoxia-inducible factor 1α (HIF-1α), as well as DNA hypermethylation. This can lead to neoplasia by driving angiogenesis, anaerobic metabolism and promoting hypermethylation (Up to 80% of paediatric PPGL cases are thought to have a hereditary basis . These ito occur . Higher hylation .SDHA/B/C/D). Of these, pathogenic variants in the SDHB gene confer the highest malignant potential, such that the majority (80%) of metastatic PPGL in children occur in patients with SDHB variants , gastrointestinal stromal tumours (GISTs) and pituitary adenomas  . Of thesSDHB mutation . 131I-MIBG is an effective palliative treatment for PPGL , but this is associated with significant side effects such as myelosuppression, peripheral neuropathy and gastrointestinal toxicity . Systemifor PPGL , but canfor PPGL . If the nt stays . In SSTRnt stays .SDHx-deficient PPGL includes a child aged 13 within its cohort ’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.CU drafted and revised the initial manuscript, Ruth Casey obtained funding from GIST Support UK.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.


Current diagnostic markers for hepatocellular carcinoma are compromised and limited by their low sensitivity and specificity. In this study, circulating microRNAs were utilized as a diagnostic tool to segregate hepatocellular carcinoma patients from healthy subjects.We analyzed 2 public datasets for differences in plasma microRNA expression profiles of hepatocellular carcinoma patients and healthy controls to identify biomarkers related to hepatocellular carcinoma. Plasma samples from hepatocellular carcinoma patients and control subjects were then collected for next-generation microRNA sequencing analysis. The differential microRNAs obtained from the above 3 parts were intersected to obtain microRNAs that were significantly different between the 2 groups. We then analyzed 58 specimens, which come from hepatocellular carcinoma and the control group, for validation through a quantitative polymerase chain reaction. The diagnostic value of these differentially expressed miRNAs was assessed by receiver operating characteristic curve analysis.P < .05) and the level of miR-126 was lower (P < .05) in patients with hepatocellular carcinoma than in healthy subjects. Receiver operating characteristic analysis established a powerful diagnostic accuracy when miR-206, miR-222, and miR-126 were combined (area under curve = 0.887), which was similar to that of the marker α-fetoprotein (area under curve = 0.889). When the microRNAs were combined with α-fetoprotein, the accuracy of hepatocellular carcinoma diagnostic potential was further improved (area under curve = 0.989).The levels of miR-206 and miR-222 were significantly higher (We identified 3 microRNAs significantly altered in the plasma of hepatocellular carcinoma patients and they can screen patients at risk of hepatocellular carcinoma. We identified 3 microRNAs (miRNAs)  that could be used to screen patients at risk of hepatocellular carcinoma (HCC).The 3 miRNAs have a powerful diagnostic accuracy when they were combined.By combining the panel of 3 miRNAs and α-fetoprotein, the specificity and sensitivity of HCC detection will be further improved.1 A total of 905 677 new cases of liver cancer and 830 180 deaths were reported globally in 2020, of which more than half of the deaths came from China.2 Since patients with early HCC have no obvious clinical symptoms, early diagnosis of liver cancer is very difficult and insufficient. At present, screening for liver cancer mainly relies on imaging, such as computed tomography, magnetic resonance imaging, and tumor markers, especially α-fetoprotein (AFP). However, these screening methods still have major shortcomings, such as a low AFP-positive rate for early liver cancer. For the early stage of HCC, approximately 40% of AFP was negative. For advanced HCC, the rate was 25%.3 The practice guidelines of the American Association for the Study of Liver Diseases have excluded AFP as a diagnostic marker for HCC, and support for this change has been confirmed in other related studies.5 In addition, pathological tests are invasive and can lead to complications such as bile leaks, bleeding, and infection. These shortcomings suggest that if we want to improve the early diagnostic rate of HCC patients, we must find new and more reliable diagnostic markers.The rate of hepatocellular carcinoma (HCC) incidence ranks fourth among all tumors and its mortality rate ranks third.8 by regulating the expression of target genes.10 Increasingly, miRNA profile analysis has shown significantly dysregulated miRNAs in human malignant tumors. Many miRNAs are related to tumor occurrence, progression, and even tumor response to treatment. Even under unfavorable conditions, such as low temperature or low pH, the physical properties and expression of miRNAs are very stable in various body fluids, including plasma, serum, and urine.11 Moreover, miRNA expression levels are easy to estimate and some even demonstrate tissue specificity.12 These characteristics of miRNAs make them prime candidates for early cancer diagnosis and treatment monitoring.MicroRNAs (miRNAs) play an important role in the development and progression of HCCBased on the above characteristics of miRNAs, we hypothesized that developing a diagnostic platform based on the combination of multiple miRNAs would improve the sensitivity and specificity of HCC detection. Herein, we carried out a systematic and comprehensive miRNA biomarker detection process to establish a new HCC-specific miRNA expression profile for the early detection of HCC. Our findings were initially confirmed in an analysis of multiple large public data sets and then rigorously validated and evaluated in an independent clinical cohort.Plasma samples were collected from 38 newly diagnosed primary HCC patients, from March 2019 to April 2020. At the same time, plasma from 20 healthy subjects, who were confirmed to have no HCC, was collected. All HCC patients were initially diagnosed with HCC and did not receive surgery or other treatment. Do not combine with the other tumor. In addition to chronic hepatitis B, the HCC patients do not contain other chronic diseases, such as chronic hepatitis C, autoimmune hepatitis, and so on. All the volunteers may have had chronic hepatitis infection, but no other diagnosed diseases were found. All participants signed a written consent form approved by the Ethics Committee (Approved 20200804) prior to participation. Clinical examinations were conducted, including the determination of AFP levels using the Diagnostic Kit for Alpha-fetoprotein (ELISA) according to the manufacturer’s instructions .https://portal.gdc.cancer.gov, accessed on April 23, 2020), (Supplementary Table 1). Likewise, GSE50013-processed miRNA expression profiling data  were downloaded from the Gene Expression Omnibus (GEO) database  (Supplementary Table 2).Two large public datasets (The Cancer Genome Atlas (TCGA) and GSE50013) were used to search for differential plasma miRNA expression profiles in HCC patients and healthy controls to avoid the potential bias of single-center data. The Cancer Genome Atlas miRNA expression profiling data were downloaded from the Genomic Data Commons (GDC) . Qualified libraries were used for next-generation high-throughput sequencing and quantitative polymerase chain reaction (qPCR). P < .05 as the screening criteria (Supplementary Table 3).Total RNA extracted from plasma and passing quality control checks was used for high-throughput small RNA sequence analysis using an Illumina HiSeq2500 . For miRNA identification, we compared the read sequence of the reference genome with the mature miRNA sequence in the known miRNA database miRBase (v21). Reads with the same sequence as the known miRNA were considered to be known miRNAs identified in this project. When detecting differentially expressed miRNAs, we used edgeR software for differential screening using fold change > 1.5 and8 copies of Caenorhabditis elegans mir-39 spike-in control RNA  were added to each plasma sample. RNA quality was analyzed spectrophotometrically and electrophoretically. Total RNA concentration was estimated using a Nanodrop spectrophotometer (ThermoFisher Scientific) and 500 ng/2.5 μg total RNA was used for cDNA synthesis for miRNA from plasma using miScript PCR Starter Kit (Qiagen) and Revertaid reverse transcriptase (ThermoFisher Scientific), respectively.Total RNA was extracted from plasma using TRIzol according to the manufacturer’s instructions . Before isolation, approximately 5.6 × 10C. elegans mir-39, respectively. Expression analysis was quantified using the 2−ΔΔCt method.Complementary DNA was quantified using the SYBR GREEN PCR Master Mix (ThermoFisher Scientific) and the QuantStudio 6 Flex RealTime PCR system (ThermoFisher Scientific) with gene-specific primers (Supplementary Table 4). Internal and external miRNA controls included hsa-miR-16-5p and P < .05 was considered statistically significant.For the clinical samples, receiver operating characteristic (ROC) curves and area under curve (AUC) values were determined using MedCalc  and GraphPad Prism . Statistical Package for the Social Sciences 23.0  was used to analyze differences in various indicators between the 2 groups; The detailed study protocol is presented in To confirm the correlation between the 3 miRNAs and HCC, we conducted a qPCR validation analysis in 58 verified patient samples . The results were consistent with the difference analysis results -c.We used ROC curves and AUC values to evaluate the possibility of each of the 3 miRNAs serving as potential non-invasive diagnostic markers for HCC by discriminating between the experimental group and the control group -c. FurthIn an attempt to improve diagnostic accuracy, ROC curves were plotted for the combined miRNAs in HCC compared with healthy control subjects. The combination of the 3 miRNAs improved the accuracy of the miRNAs as a diagnostic marker . CombiniP = .024), high levels of miR-222 , and low levels of miR-126  were independent risk factors for HCC (P < .05). The risk score model was as follows: −0.064 + (−1.534 × miR-126) + (2.357 × miR-206) + (0.60 × miR-222).Multivariate analysis showed that high levels of miR-206 (odds ratio (OR) = 2.953, 95% CI 1.156-7.542,  for HCC . CombinaThe liver cancer diagnostic accuracy of miR-206 and miR-126 combined was similar to that of AFP based on comparative ROC curve analysis . This su13 miR-221,14 and miR-125b,15 have a biomarker effect on the early diagnosis and prognostic detection of different cancers.12 The miRNAs miR-433 and miR-191 can be used as circulating biomarkers for prostate cancer and breast cancer, respectively.17 Nishiwada et al18 found that joint application of miRNAs improved the diagnosis of pancreatic ductal adenocarcinoma patients at risk for lymph node metastases.A number of studies have shown that circulating miRNAs, such as miR-21,P value of miR-222 > .05 and no change in AUC value before and after the inclusion of miR-222 in the equation. This may be caused by multicollinearity.In the current study, 3 HCC-related miRNAs  were assessed in the plasma of HCC patients. The median plasma levels of miR-206 and miR-222 were significantly upregulated in HCC patients, whereas miR-126 was markedly reduced. We used ROC analysis to determine the HCC diagnostic capabilities of these 3 miRNAs and observed that none of them on their own performed better than AFP in distinguishing HCC. As we all know, the use of a combination of 2 or more biomarkers overcomes the limitations of the sensitivity and specificity of a single marker to detect HCC. Therefore, we tested different combinations of miR-126, miR-222, miR-206 in the HCC diagnostic test and achieved a maximum diagnostic efficiency , which is similar to that of AFP (AUC = 0.889). When the miRNAs were combined with AFP, the accuracy of the HCC diagnostic potential was further improved (AUC = 0.989). Interestingly, during the logistic regression analysis, we found that the 19 previously reported that miR-126 was downregulated in the blood of HCC patients, which confirms our findings. The Zhao et al19 study also showed that miR-126 induced apoptosis by targeting the Sox2 gene, exerting its anti-tumor activity. However, Faranda et al20 reported increased expression of miR-126 in HCC patients. The conflicting findings suggest that further studies are needed. Unlike miR-126, our results and those of a similar study21 showed that the plasma level of miR-222 was significantly upregulated in HCC patients. Upregulation of miR-222 has been found to induce hepatocyte proliferation by inhibiting cell cycle participant P27.22 However, Wang et al23 reported a significant reduction in miR-222 levels in patients with HCC, which is contrary to previous experimental results and this study. Our study found that the third miRNA, miR-206, was weakly expressed in the plasma of HCC patients, findings consistent with those of Mirzaei.24Our study showed that compared with the control group, the level of miR-126 in the plasma of HCC patients was significantly downregulated. Zhao et al25 and poorly employed methods.26 For example, in the process of miRNA quantification, insignificant hybridization during reverse transcription-PCR may be a source of variation.27 In addition, improper selection of reference genes and different experiment guidance may lead to inconsistent quantification of circulating miRNA levels in different tissues.28 For example, one study found that the level of miR-122 in HCC tissues and cell lines decreased, whereas, in serum, the level increased.29 Other studies have shown that miRNAs can be released in the form of free molecules or microvesicles, which can be detected in most biological fluids.30 Different disease states may have specific miRNA states; thus, miRNAs in these specific states have the potential to be exploited as markers for disease diagnosis.As is evident from these various reports, the experimental results are not always consistent across studies. These inconsistencies require further refinement of the study design to produce more consistent and reliable results. Among the possible reasons for these inconsistencies are flaws in sample preparationAlthough the study was successful, there are still some shortcomings, such as a small amount of sequencing samples and insufficient qPCR sample size. We hope that related studies with a larger sample size can corroborate our experimental results.miR-206, mi-R-126, and miR-222 significantly altered in the plasma of HCC patients, and they can screen patients at risk of HCC.


Children with intellectual disability (ID) are more vulnerable to health conditions than their typically developing peers. Evidence of effective interventions is scarce. A randomized controlled trial was conducted in 30 overweight and obese children with intellectual disability (ID) in China to evaluate a 12-week school-based physical activity intervention for obesity, health-related physical fitness (HRPF), and blood pressure. The intervention consisted of 24 physical activity (PA) sessions , with exercise intensity progressively increasing from a moderate level to a vigorous level. All participants were followed up for 12 weeks after the intervention period to evaluate sustained effects. Outcomes were repeatedly measured at baseline, after the intervention, and after follow-up. The intervention was effective in reducing some obesity-related outcomes (including weight and body mass index) and improving some HRPF-related outcomes , with the significant effects being sustained after the 12-week follow-up. No effect was observed on blood pressure. The findings of this study contribute to the development and implementation of PA interventions to reduce obesity and improve HRPF in children with ID. Childhood obesity accompanied with poor health-related physical fitness (HRPF) is an alarming public health issue and has attracted much attention in recent years . It has Children with intellectual disabilities (ID), characterized by significant limitations in intellectual and adaptive functioning and accounting for 1.83% of the entire global pediatric population, are more vulnerable to obesity and lower levels of HRPF than their counterparts without ID ,8. PreviThere are numerous factors associated with these conditions in general pediatric populations, including genetics, metabolic factors, medications, physical activity (PA), diet, etc. . Except Though children with ID have higher risks for obesity, lower levels of HRPF, and hypertension, intervention studies for this special population are scarce . EvidencClinicalTrials.gov (Ref. No.: NCT04554355) and the research protocol was published elsewhere [This study was a randomized controlled trial (RCT) with two groups, including an intervention group (IG) and a wait-list control group (CG), which was developed based on the findings of our systematic review and meta-analysis aiming to identify effective lifestyle interventions in children with ID , along wlsewhere . The Conlsewhere  and the The study was implemented in four special schools in China between June 2020 and April 2021. A sample size of 30 participants (15 in each group) was estimated using the G*Power , with an alpha of 0.05, a power of 80%, an effect size (Cohen’s f) of 0.27 for body mass index  , and a dThere was a total of 24 sessions in the PA intervention, delivered at a frequency of twice a week with each session of 60 min. All sessions were divided into three levels and each level lasted for four weeks. Exercise intensity increased progressively from 40% heart rate reserve  at Level 1 to 70% HRR (vigorous intensity) at Level 3 .Target exercise heart rates (target HRs) of the participants were estimated before each training level using the equations listed in The PA programmes were conducted in the participants’ schools. A fixed sports area in each participating school was provided. The training session was arranged in fixed non-class timeslots during the school activity and implemented by well-trained tutors who were educated in sports sciences and had experience in teaching students with special needs. A tutor-to-participant ratio of 1:3 was applied to ensure that each participant received sufficient supervision. In addition, the PE teacher from each participating school was on site to assist with the delivery of the intervention. All participants (in both groups) were not permitted to join other PA or obesity-related programmes.The participants in the wait-list control group received no intervention. They were asked to remain their PA and eating habits and not to join any other programs aiming to reduce obesity and/or improve HRPF. After the completion of the study , all participants in the control group received the same intervention. In addition, the programme manual and other materials were shared with the four participating special schools.Obesity-related and HRPF-related outcomes were measured as primary outcomes, whilst systolic blood pressure and diastolic blood pressure were involved as secondary outcomes. Children’s background information, health-related behaviors  and pubertal stage were collected via questionnaire and used as control variables. All measurements were repeated three times at pre-intervention (T1), post-intervention (T2), and after the follow-up (T3). A detailed description was reported elsewhere .2), and body fat percentage (%), measured using a TANITA digital scale (TBF-410) and a height gauge (SECA 0123); (2) waist circumference (cm) and waist-to-height ratio (%), measured using a flexible metre ribbon. HRPF-related outcomes were assessed with the 6 min walk test , 30 s sit-to-stand test , 1 min sit-up test , handgrip strength test , and sit-and-reach test . Systolic blood pressure and diastolic blood pressure (mmHg) were measured using an Omron blood pressure monitor (HBP-9020) following a standard protocol. In terms of the control variables, PA (daily minutes) and sedentary behavior (daily hours) were measured using a modified Chinese version of the Global Physical Activity Questionnaire (GPAQ), sleep duration (daily hours) was asked in a typical week, eating habits were assessed with a dietary questionnaire developed by the Central Health Education Unit of Hong Kong for school-aged children, and the pubertal stage was estimated with an illustrated Tanner pubertal questionnaires [In brief, obesity-related outcomes consisted of: (1) weight (kg), BMI  was used for data analysis. Independent variables consisted of group (the between-subjects: IG and CG) and time . Dependent variables included primary outcomes (obesity-related outcomes and fitness-related outcomes) and secondary outcomes (blood pressure). Control variables consisted of baseline outcomes and lifestyle confounders. Mean with standard deviation and number with percentage were used to describe the distribution of continuous and categorical variables respectively. Independent t-test and Fisher’s exact test were applied to test between-group differences in dependent variables and control variables at baseline respectively.Cohen (1988), partial η2 = 0.01, 0.06, and 0.14 represent small, medium, and large effects respectively [Within-group differences for each group across the three time-points  were examined respectively using one-way analysis of variance (ANOVA) for repeated measures. Whenever there was a violation in the sphericity assumption, the Greenhouse–Geisser correction was used. Post-hoc analysis using Bonferroni correction was carried out to explore the differences between T1 vs. T2, T1 vs. T3, and T2 vs. T3. Between-group differences in changes from T1 to T2 and T3 were examined separately using analysis of covariance (ANCOVA) . Covariaectively .A total of 42 children were assessed for eligibility and 12 of them were excluded. The remaining 30 participants were equally and randomly assigned to two groups and all of them completed the study .2 . Few participants were living with autism  and Down syndrome . No other comorbidities existed among the participants. No significant difference between the two groups was observed at baseline.p = 0.034, Fisher’s exact test). Thus, puberty was used as a covariate in the ANCOVA to examine between-group differences in the outcome variables.The distribution of the lifestyle confounders at baseline, post-intervention, and post follow-up are listed in 2), while their changes in the CG was insignificant (nificant . In addi2 and −0.47 kg/m2) were found from T1 to T2 and T3 respectively. The between-group differences in other obesity-related changes were insignificant. No participants reported adverse effects of the intervention during the entire study period.The study had a retention rate of 100.00% and an overall attendance rate of 96.94%. This study developed and evaluated a school-based PA intervention for reducing obesity-related indicators, improving HRPF levels, and reducing blood pressure in 30 overweight and obese children with ID. The intervention consisted of 24 60-min sessions delivered twice per week for 12 weeks. Both aerobic games and resistance training were offered in each session, with exercise intensity progressively increasing from moderate (40%HRR) to vigorous (70%HRR). The intervention was effective in reducing some obesity-related outcomes (including weight and BMI) and improving some HRPF-related outcomes (including the 6MWT and the 30 s sit-to-stand test), with the significant effects being sustained for 12 weeks after completion of the intervention, as shown in the ANCOVA results. Handgrip strength was significantly improved right after the intervention. However, the effect reduced and became insignificant after the follow-up. The intervention was ineffective in changing blood pressure. During the study period, no participant reported any adverse effects. In addition, the retention and attendance rates were high. Feedback regarding effectiveness and arrangement from parents and teachers was positive.The participants in the IG reported a significant reduction in weight and BMI at T2 compared with the participants in the CG. This finding is consistent with previous research, specifically with three studies evaluating the effects of similar short-term PA programmes on reducing weight and BMI in children with ID ,28,29. HApart from weight and BMI (the most widely used measures for obesity), other obesity-related outcomes  were also included in this study to estimate the study effects on body fat distribution . Althoug2 = 0.149), which is consistent with our previous findings from a systematic review and meta-analysis for children with ID [2 = 0.010–0.600). Among those reporting effective (including this study), the interventions with vigorous intensity (compared with moderate intensity), those following the progression principle (compared with constant intensity), and those combined aerobic and resistance training (compared with aerobic training only) tended to generate larger effect sizes  [In this study, cardiopulmonary fitness was examined by the 6MWT. Our findings suggest that the 12-week PA intervention can improve the 6MWT distance  ,29,33,352 ranging from 0.010 to 0.170 across the individual studies. Compared with those studies, we observed a larger effect . The superior treatment effects in our study might be due to the progressive increments in the exercise intensity, which was not the case in those studies. Four interventions measured handgrip strength [2 = 0.0002) [2 = 0.276). Considering the specificity principle of training, the significant improvement in handgrip strength in our study may be attributable to the involvement of exercises for the upper limbs . We failed to observe a significant effect on abdominal muscular strength and endurance in the 1 min sit-up test, though significance was reached in changes in the IG without considering the control. The relatively small number of participants may play a role in the insignificant outcome. In addition, similar to this finding, three previous studies with the same 12-week intervention period as ours also reported it as ineffective [Several tests were employed in this study to examine the intervention effects on muscular strength and endurance, of which significant improvements were achieved in the 30 s sit-to-stand test for lower limb strength and endurance and the handgrip strength test for upper limb strength and endurance, but not in the 1 min sit-ups test for abdominal muscular strength and endurance. To our best knowledge, there were three previous interventions for children with ID that employed the 30 s sit-to-stand test ,29,38. Astrength ,29,35,37 0.0002) . Our stuffective ,37,39. Fffective .Flexibility, measured by the sit-and-reach test, was not significantly improved in this study. Findings from previous studies on this were mixed. In our previous systematic review and meta-analysis, only two out of six studies involving this test observed significant improvements . The twoAgainst our hypothesis, we did not observe any significant improvement in blood pressure. The effects of exercise on treating and preventing hypertension in populations without ID have been well established, with the recommended routine being moderately intense aerobic exercise for 30 min on most days supplemented by resistance training two to three days per week . HoweverIn this study, the participants were followed up for 12 weeks to examine the sustained effects of the intervention. First, significant body weight and BMI reductions were maintained at the follow-up examination. These findings provide new insight into the sustained effects of PA intervention on obesity-related outcomes, as no previous research has examined this aspect. Such sustainability strengthens the intervention effects on reducing obesity in children with ID. Future studies are suggested to examine the sustained effects over a longer follow-up period. Secondly, the significantly improved cardiopulmonary fitness (indicated by distance covered in the 6MWT) and muscular strength and endurance of the lower limbs (indicated by complete repetitions in the 30 s sit-to-stand test) right after the intervention were also maintained after the follow-up. To date, two studies evaluated the sustained effects of PA interventions on cardiopulmonary fitness, one reporting positive results after a 24-week follow-up  and the The strengths of the study include (1) the intervention was developed based on findings from our systematic review and meta-analysis, aiming at identifying effective interventions for reducing obesity and improving HRPF in children with ID ; (2) theHowever, the study has the following limitations: (1) the sample size, estimated using BMI, was small. Thus, it may not be sufficient for other outcomes, and therefore limited the power to identify significant differences in changes in those outcomes; (2) the confounding variables  were collected via a questionnaire, which may have resulted in report bias and recall bias; (3) some medication may act as a risk factor of weight gain . HoweverThe 12-week PA intervention was found effective in reducing the degree of obesity in children with ID, as weight and BMI in the IG decreased significantly compared with the CG. These effects were sustained 12 weeks after the intervention. In addition, the intervention effectively improved cardiopulmonary fitness, lower limb muscular strength and endurance, and hand and forearm strength, while only the effect on hand and forearm strength did not sustain at the follow-up evaluation. Moreover, the intervention was ineffective on blood pressure. Overall, this study provides practicable evidence for reducing obesity and improving HRPF in children with ID. Future PA interventions with large sample sizes, specifically designed for study objectives, and supported by school policy changes are suggested to elucidate for this special population.


A magnetic resonance linear accelerator (MR-Linac) provides superior soft tissue contrast to evaluate inter- and intra-fraction motion and facilitate online adaptive radiation therapy (ART). We present here an unusual case of locally advanced castrate-resistant prostate cancer treated with high-dose palliative ultra-hypofractionated radiation therapy on the MR-Linac with significant inter-fraction tumor regression.The patient was a 65-year-old man diagnosed with metastatic prostate cancer to bone and pelvic lymph nodes 7 years prior. At diagnosis, he presented with a PSA of 23 ng/ml and was commenced on a luteinizing hormone-releasing hormone agonist, achieving a PSA nadir of 4.68 ng/ml at 12 months. The patient subsequently had progressive lower urinary tract symptoms, his PSA increased to 47 ng/ml, and there was a markedly enlarged pelvic mass involving the prostate with gross extra-capsular disease and invasion into the posterior bladder wall. The patient was referred for palliative radiation to the pelvic mass due to urinary symptoms, pain, and lower limb paraesthesia. Treatment was planned to be delivered on the MR-Linac with a schedule of 36 Gy over 6 weekly factions allowing for maximal target dose delivery while minimizing surrounding organs at risk (OARs) radiation exposure. Unexpectedly, the target volume had a marked 49% (453 cc to 233 cc) reduction that was accounted for in the online adaptive process. A new reference plan was generated after 3 fractions to add sacral plexus as an OAR, previously not visible due to mass encroachment. The patient reported ongoing reduction in urinary symptoms, pelvic pain, and lower limb paresthesia by the end of treatment.Using daily MR-guided ART, improved visualization of the changing target and OARs ensured safe dose escalation. The unexpected positive response of the target and improved patient outcomes demonstrated the added value of the MR-Linac for online adaptive radiotherapy in this setting. Image-guided radiation therapy (IGRT) enables the visualization, quantification, and correction of patient setup errors, monitoring changes to ensure high-quality dose delivery , 2. ReceAs prostate cancer is characterized by a low α/β ratio, hypofractionation or stereotactic body radiation therapy is increasingly prevalent to improve radiation efficacy while minimizing toxicity –10. The We present here an unusual case of a patient with metastatic castrate-resistant prostate cancer requiring palliative pelvic radiotherapy that resulted in large volume inter-fraction tumor regression that demonstrated a role of the MR-Linac in online adaptation.The patient was a 65-year-old man diagnosed with metastatic prostate cancer to bone and pelvic lymph nodes 7 years prior. At the time of diagnosis, he presented with a prostate-specific antigen (PSA) of 23 ng/ml, and prostate biopsies confirming Gleason grade 4 + 5 = 9 disease with 12/12 cores involved and 80% overall involvement. Staging bone scan and CT thorax, abdomen and pelvis demonstrated multiple bone metastases and pelvic lymphadenopathy. The prostate was described as enlarged and heterogeneous with irregular margins. He commenced on a luteinizing hormone-releasing hormone (LHRH) agonist and achieved a PSA nadir of 4.68 ng/ml 1 year following androgen deprivation therapy (ADT) institution.The patient subsequently had progressive lower urinary tract symptoms with nocturia x 5 and weak stream. His PSA had risen to 47 ng/ml and re-staging CT showed progressive bone metastases together with soft tissue disease and a 5.5-cm left adrenal metastasis. Additionally, there was a markedly enlarged pelvic mass centered on the prostate with gross extra-capsular extension and invasion into the posterior bladder wall  was used for reference planning, and the CT image was used to provide electron density information. The target , bladder, rectum, and large bowel were contoured by the radiation oncologist (RO), and a planning target volume (PTV) was created using a 5-mm uniform expansion around the CTV. A reference plan of 36 Gy over 6 weekly factions was generated in the MR-Linac treatment planning system  using a 9-field IMRT technique. The plan derived was purposefully heterogeneous allowing central tumor region dose escalation to 48 Gy. The OARs assessed included rectum, large bowel, and small bowel where dose constraints were strictly observed. The majority of the dose-escalated tumor mass was posterior–superior and no attempt was made to include the urethra in the dose-escalated volume. It was observed at fraction 2 that there had been substantial target volume reduction (17%) mostly in the superior and posterior directions. A new reference plan was generated after 3 fractions to add the sacral plexus contours and constraints (previously not visible due to mass encroachment) and also accounted for the changing tumor mass.Loc) was acquired. The reference plan was used as a starting point to generate an adapted plan based on the contours redefined in-session on the MRLoc by the RO. While quality control checks, including secondary monitor unit verification and multi-disciplinary plan quality review on the adapted plan were performed, a verification MR (MRVer) was acquired to ensure the target was encompassed within the PTV. A third beam on MR (MRBO) was acquired during radiotherapy beam on, which allowed assessment of the internal anatomy during treatment delivery. The patient completed the patient-reported outcome tool, Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP), prior to each treatment.For each MR-Linac treatment session, a localization T2-weighted MR image  using deformable image registration (DIR). To generate a high-quality DIR, manual contours were generated on the MRBO images and these contours were used as controlling regions of interest (ROIs) for the hybrid intensity and structure-based DIR between the reference MR and each MRBO. Following manual review of the DIR quality, dose for each adapted fraction as well as the simulated no-adaptation dose was deformed to the reference MR using the deformed vector field for evaluation on the reference MR.To determine the delivered dose for each treated fraction, the clinically treated daily adapted beams were computed on the MRThe average MR-Linac treatment time was 64 min (range 59–77 min). Over the course of 6 fractions, the CTV decreased in volume from 453 to 233 cc (49%) Figure 2Treatment was well tolerated with no patient-reported acute toxicities. Patient-reported outcomes collected through EPIC-CP indicated no worsening urinary and bowel symptoms throughout treatment. More so, urinary symptoms improved during treatment, corresponding with treatment response. The score for need to urinate frequently became a small problem by fraction 2, reduced to a very small problem by fraction 4, and resolved to no problems for fractions 5 and 6. The patient experienced very small problems with hot flashes and feeling depressed for the first 3 fractions, resolved to no problems for either factor over the last 3 fractions. Finally, the patient experienced a very small problem with a lack of energy for the first 4 fractions, increasing to a small problem on fraction 5, and moderate problem on fraction 6.One month following radiation treatment, the patient’s PSA reduced to 21 and there was evidence of partial radiological response within the prostate  for the publication of any potentially identifiable images or data included in this article.WL wrote the first draft of the manuscript. JW, JP, and PC wrote sections of the manuscript. WL, JD, and VK contributed to image review and contouring. JW performed dose accumulation and generated figures. All authors contributed to manuscript revision, read, 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.


The most significant adverse events following SARS-CoV-2 vaccination are myocarditis and pericarditis. Myositis and dermatomyositis have been reported following SARS-CoV-2 infection, but vaccine-induced dermatomyositis (DM) has not been reported. Our case series aimed to characterize new onset dermatomyositis or disease-related flares following SARS-CoV-2 vaccination.A total of 53 patients from our institution with a new or pre-existing diagnosis of DM were recruited and consented. Phone interviews were conducted to obtain vaccination status and symptoms following vaccination. Electronic medical records were reviewed to extract age, sex, autoantibody profiles, comorbidities, immunomodulatory therapies, creatine kinase (CK) values, and SARS-CoV-2 vaccination dates from the provincial vaccination registry. For patients who reported disease flares, records were reviewed for the onset and nature of symptoms, extent of organ involvement and changes in immunomodulation.On average, patients received 2.62 vaccine doses (range 1–3 doses). A total of 3 of 51 patients (5.88%) experienced dermatomyositis symptoms following vaccination. Two patients were newly diagnosed with dermatomyositis, one requiring hospitalization. Reported symptom onset following vaccination ranged from 1 to 30 days. Of note, all of these patients had normal CK values, even though there was muscle biopsy-confirmed myositis in one patient. Eight patients in the cohort (15.1%) had asymptomatic CK elevation (<1.5 X ULN).New onset dermatomyositis or flare up of pre-existing dermatomyositis may be a rare complication in SARS-CoV-2 vaccination although no studies can support a true correlation. Several pathophysiologic mechanisms are proposed. As of May 2022, 84.9% of the population of Canada (32.4 million) received at least one dose of the vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . Of the Dermatomyositis (DM) is associated with systemic inflammation of the skin and muscles. Cases of DM in the context of COVID-19 infection have been previously reported in the literature –13 and DTo determine the risk of DM flare after SARS-CoV-2 vaccines, we performed a single-institution retrospective case series compromising all patients with the diagnosis of DM. We report two cases of new-onset DM and three cases of exacerbations of DM following SARS-CoV-2 vaccination among a series of 53 DM patients. We discuss the potential causal relationship between vaccination and DM.All patients recruited in our study had a diagnosis of DM, and met the 2017 ACR/EULAR classification criteria for DM . All patDisease exacerbation or “flare” was defined as at least two or more of the following: increased fatigue, increased muscle soreness and/or weakness, and development or worsening of cutaneous findings in dermatomyositis such as heliotrope rash or Gottron’s papules. Although the predetermined questionnaire inquired about onset of subjective symptoms within 1 week of vaccination, the accepted time period for vaccine-associated DM exacerbation was 0–30 days. Any patients who subjectively reported disease exacerbation received a follow-up unscripted phone interview from MO or AC to further clarify their symptoms. These patients and their laboratory investigations were subsequently adjudicated by three members of the study team . Consensus was reached by discussion.via phone interviews, then confirmed using EMR for all patients. For patients with a notable vaccine-associated DM flare, symptoms and extent of organ involvement as per Myositis Intention to Treat Activity Index (MITAX) , immunomodulatory therapies prior to vaccination and in response to increased disease activity, and creatine kinase (CK) levels up to 1 year following the first dose of vaccination were collected from the electronic medical record (EMR) for all patients. Vaccination status and dates were obtained from patients directly  (MITAX)  were extThe demographics of our cohort are summarized in Of 51 patients with existing diagnoses of DM, three patients (5.88%) experienced DM symptom flares following vaccination  with a mOn average, participants received 2.62 vaccinations against SARS-CoV-2, with a range of one to three doses at the end of the study period. A total of 84.9% of patients had no dose mixing. A total of 9.43% of patients had mixed doses. Three patients (5.66%) self-reported having received at least one vaccination dose of Pfizer-BioNTech; however, the records could not be confirmed with the provincial vaccine registry due to limitations in the EMR for these particular patients.For patients with historical DM, a majority of them were on combination immunomodulatory therapies with the most common therapies including hydroxychloroquine (37.7%), methotrexate (37.7%), and intravenous immunoglobulins (37.7%).We have summarized the specific case summaries for the patients with a new diagnosis of DM (cases 1 and 2), and those with a disease-associated flare .Patient 1 presented with internal iliac vein thrombosis and bilateral basilar pulmonary emboli, accompanied by wedge shaped consolidative opacity at the right base, approximately 4 weeks after receiving COVAUVec vaccine. This was treated with rivaroxaban. Approximately 5 weeks after anticoagulation, the patient presented with fever, joint pain , and worsening shortness of breath. Troponin and C-reactive protein (CRP) were elevated, and the patient was positive for SSA antibodies (MITAX score 26). Positron emission tomography (PET) scan showed bilateral scattered consolidative opacities more prominent at the lung bases, along with borderline enhanced mediastinal, hilar, and axillary lymphadenopathy. The patient was started on prednisone 40 mg daily, methotrexate, and hydroxychloroquine for presumed Sjogren’s disease. However, as prednisone was tapered, she developed a skin rash, fever, severe dyspnea and chest pain, and was rehospitalized 6 months later. CT scan showed evolution of the previous lung lesions to basal-predominant subpleural reticulation with associated bronchiectasis/bronchiolectasis, showing the pattern of usual interstitial pneumonia (UIP) or non-specific interstitial pneumonia (NSIP). Hospital stay was complicated by atrioventricular nodal reentry tachycardia requiring rate control with amiodarone and diltiazem, and cardiac MRI showed pericarditis. Diagnosis of dermatomyositis  was made based on skin findings, PL-12 autoantibodies, and a positive muscle biopsy . Treatment with prednisone and mycophenolate mofetil (MMF) led to an improvement of her symptoms. This was followed by a course of intravenous immunoglobulins (IVIG).Patient 2, a previously healthy female, developed fatigue, voice hoarseness and skin lesions on the arms, trunk, and face, 3 weeks after her second dose of the Pfizer-BioNTech vaccine. On examination, she presented with proximal muscle weakness and skin signs of dermatomyositis (MITAX 11). Serology for anti-SAE-1 was positive. Nailfold video capillaroscopy revealed severe capillary disorganization with capillary enlargement and microhemorrhages. She initially did not respond to prednisone monotherapy, but disease improvement was achieved with the use of MMF and IVIG.Patient 3 had a previous history of TIF-1γ positive DM and was in complete remission for a period of 2 years on hydroxychloroquine. After receiving the second dose of the Pfizer-BioNTech vaccine, she developed a heliotrope rash and prominent muscle weakness which spontaneously improved within 2 weeks (MITAX 5). We maintained watchful observation, but during the following month the cutaneous lesions flared, and she developed proximal muscle weakness. The patient declined systemic steroids, and IVIG was initiated.Patient 4 had a previous history of anti-Mi-2 DM that was in full remission for the last 18 months, maintained on azathioprine, hydroxychloroquine, and monthly infusions of methylprednisolone. One day following her second dose of the Moderna vaccine, she developed ill-defined erythema on her cheeks, V-neck sign, and mild myalgia which spontaneously improved over 2 days (MITAX 3). She did not require any change in medications and had not developed symptoms with her first dose of Moderna, or her third dose of Pfizer-BioNTech.Patient 5 had a previous history of inclusion body myositis which was relatively quiescent, diagnosed by muscle biopsy in August 2019. Within 1 week of her first dose of the Pfizer-BioNTech vaccine, she developed shawl sign and Gottron’s papules, with no myalgia. She received her second dose of Pfizer-BioNTech 4 weeks after the first dose, and noted mild myalgia, and worsening of the shawl sign and Gottron’s papules. Her skin findings continued to progress to include her scalp and legs, until she was diagnosed with dermatomyositis/inclusion body myositis overlap syndrome based on complement staining on skin biopsy in August 2021, and subtle perimysial pathology on repeat muscle biopsy. After her third dose of Pfizer-BioNTech in November 2021, she noted significant worsening of fatigue, myalgia, and her skin rashes (MITAX 5). She did not have CK elevation despite her myalgias. Throughout these reactions, she remained on IVIG during all three doses; she had been unable to tolerate prednisone, methotrexate, and mycophenolate mofetil in the past.We have observed two patients who have new presentations and three patients with exacerbations of existing DM following receiving a vaccine for SARS-CoV-2. This represents a small but significant proportion of patient series (9.8%) compared to the general population which has been reported to have 0.6% prevalence of adverse events overall in Canada . There wThe incidence of DM exacerbation before and after the onset of COVID-19 is difficult to compare as the literature is limited and definitions for disease exacerbations are not standardized. However, the incidence of disease exacerbation in our case series is low in comparison to one survey of 524 patients from 2018 to 2019 on patient-reported exacerbation in dermatomyositis and polymyositis, where 378 patients (72.1%) reported at least one flare in the past 12 months . One thon = 5) at the time of the questionnaires; the cause of death for patients was unknown, and a relationship to vaccination cannot be excluded as their records were not reviewed. Recall bias is another limitation as patients may not have remembered their symptoms, and symptoms of exacerbation are subjective. Our questionnaire was conducted from November to December of 2021. First dose vaccination was available to the general public in Canada around April 2021, however, each individual patients’ first doses varied between January 2021 to December 2021. For this reason, the CK values up to 1 year post-vaccination were reviewed during data extraction in January 2022 to evaluate for possible trends or asymptomatic elevation. We also acknowledge the limitations of asking patients about symptoms of exacerbations in a closed-ended format and within a restricted short time period of 1 week, as this may also have led to under-reporting, although the patients that experienced vaccine-associated flares were closely followed by MO and RG, and frequently interacted with them.We acknowledge certain limitations in our methodology as well. Approximately 50% of patients were unable to be reached by telephone, which introduces the possibility of selection bias. There was also a small number of patients who were deceased  and DM develop elevated type I interferon responses in the prodromal phases anteceding clinical manifestations of their disease , 28. TheWe speculate that one potentially protective mechanism for patients with DM and/or SLE is the use of TLR7 inhibitory anti-rheumatic therapies such as antimalarial therapies . These agents are known to attenuate TLR7 signals through a variety of mechanisms . This obFinally, an intriguing theory may suggest a role for molecular mimicry as a potential cause for vaccine-associated flares in DM patients. Megremis et al.  reportedOur observations suggest a possible correlation between SARS-CoV-2 vaccination and exacerbation of dermatomyositis. There are no current studies with appropriate design to establish a relationship between vaccination and disease exacerbation. However, there are several emerging pathophysiological arguments that support this hypothesis including that spike (S) protein-coding SARS-CoV-2 vaccines may induce or exacerbate dermatomyositis, analogously to what was shown in patients with COVID-19 disease. Most of the patients with disease-associated flares experienced proximal muscle weakness  and typical cutaneous findings and nailfold capillary changes described in DM. DM-related flares can result in cardiac and/or pulmonary involvement which is important to distinguish from COVID-19 vaccine-induced myocarditis, pericarditis and interstitial lung disease. The mechanism of vaccine-induced dermatomyositis remains unknown although we speculate that it may be promoted by aberrant TLR7 signaling, and possible molecular mimicry between viral spike glycoproteins, anti-idiotype antibodies, and dermatomyositis autoantigens.The original contributions presented in this study are included in the article/The studies involving human participants were reviewed and approved by Research and Ethics Board at the University of Alberta (Pro00116853). 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.AC: literature search, study design, data collection, data analysis, and writing. JC, EY, GF, and PH: review and editing. DR: data collection. MO and RG: study design and writing. All authors contributed to the article and approved the submitted version.


It is still not well known whether a 3rd booster-vaccination is also associated with functional and/or structural changes regarding cardiac status. The aim of this study was to assess the possible occurrence of peri-/myocarditis in healthy volunteers and to analyze subclinical changes in functional and/or structural cardiac parameters following a mRNA-based booster-vaccination.n = 41; m = 23, f = 18) were enrolled for a CMR-based serial screening before and after 3rd booster-vaccination at a single center in Germany. Each study visit comprised a multi-parametric CMR scan, blood analyses with cardiac markers, markers of inflammation and SARS-CoV-2-IgG antibody titers, resting ECGs and a questionnaire regarding clinical symptoms. CMR examinations were performed before (median 3 days) and after (median 6 days) 3rd booster-vaccination. There was no significant change in cardiac parameters, CRP or D-dimer after vaccination, but a significant rise in the SARS-CoV-2-IgG titer (p < 0.001), with a significantly higher increase in females compared to males (p = 0.044). No changes regarding CMR parameters including global native T1- and T2-mapping values of the myocardium were observed. A single case of a vaccination-associated mild pericardial inflammation was detected by T2-weighted CMR images.Healthy volunteers aged 18–50 years (There were no functional or structural changes in the myocardium after booster-vaccination in our cohort of 41 healthy subjects. However, subclinical pericarditis was observed in one case and could only be depicted by multiparametric CMR. Without any doubt, COVID-19 vaccines are a blessing and prevented many millions of people world-wide from becoming either very ill or even dying due to a COVID-19 infection. Nevertheless, various reports showed that particularly mRNA-based COVID-19 vaccines are associated with rare but sometimes serious cases of acute peri-/myocarditis . We stilMagnetic resonance imaging (MRI) is the non-invasive gold standard in the diagnosis of myocardial inflammation . In thisSo far, there are only limited data available regarding the frequency of vaccine-associated peri-/myocarditis following a 3rd booster vaccination for COVID-19 and regarding the value of CMR , 7. HencHealthy volunteers aged 18–50 years were enrolled for a CMR-based serial screening before and after 3rd booster vaccination in the CMR-Center of University Hospital Muenster, Germany. Each study visit comprised a CMR scan, blood analyses with cardiac markers, markers of inflammation and SARS-CoV-2-IgG antibody titers, resting ECGs and a questionnaire regarding clinical symptoms. After their baseline examination, the study subjects received their 3rd booster dose of a mRNA-based COVID-19 vaccine with either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) within 1–10 days. The follow-up examination was performed 4–10 days after booster vaccination.Cardiovascular magnetic resonance imaging was performed on a 1.5 T-scanner  with a modified standard protocol used in clinical practice for suspected myocarditis . The prop-value ≤ 0.05 was considered statistically significant.Skewed variables are expressed as median and interquartile range (IQR). Categorical variables are expressed as frequency with percentage. A Between November 2021 and January 2022, we prospectively examined 41 healthy, individuals with a median age of 35 years before (median 3 days) and after (median 6 days) their 3rd booster vaccination. The subjects  had no history of any cardiac disease or prior COVID-19 infection. There was one loss of follow up, because one participant experienced a COVID-19 infection in the interval between the third vaccination and the follow-up appointment. 30% of the subjects received mRNA-1273 (Moderna) and 70% received BNT162b2 (BioNTech) for booster . No assop < 0.001) in our study population. In addition, females showed a significantly higher increase in SARS-CoV-2-IgG titer (p = 0.044) compared to males.There was no pathological elevation and no significant change in serum markers such as CK, CK-MB, high-sensitive troponin T, NT-proBNP, CRP or D-dimer before and after the 3rd booster vaccination . As expeIn general, the assessment of both functional as well as structural CMR parameters showed highly consistent and reproducible values when the respective CMR parameters measured before and after the booster vaccination were compared. In particular, there was no change in biventricular function and volumes, in global longitudinal strain and in myocardial mass . MoreoveAlthough the pivotal approval studies, sponsored by the respective pharmaceutical companies, did not show an increased risk of myocarditis following COVID-19 vaccination , today tTo the best of our knowledge, our present study is the first one that used multi-parametric serial CMR studies prior to and after mRNA-based COVID-19 booster vaccination to carefully assess potential booster-associated cardiac effects. Our major findings can be summarized as follows:First, the present data show that no relevant myocardial changes could be observed by CMR following the 3rd booster vaccination. Our data support current recommendations regarding booster vaccinations that should not be withheld for fear of adverse cardiac events in healthy subjects aged <50 years (considering that there is no vaccination with mRNA-1273 (Moderna) in subjects <30 years since cases of peri-/myocarditis were more frequently observed after Moderna vaccination in this age group).Second, subclinical pericarditis was observed in 1 out of 40 subjects following a 3rd booster vaccination whereas no cases of myocarditis were observed in the present study. Importantly, multi-parametric CMR imaging was the only diagnostic modality that allowed to depict such a mild pattern of pericardial inflammation. In line with this findings, a large descriptive study, based on reports to the VEARS (Vaccine Adverse Event Reporting System) reported only 17% of abnormal findings based on echocardiograms (in the cohort of myocarditis patients younger than 30 years), but abnormalities were reported in >70% by CMR (Today, CMR is well-known and robust modality for the non-invasive diagnosis of myocarditis that does not only detect regional dysfunction, but allows also to depict edema and other subtle structural changes based on elevated T1- and T2-mapping values and/or characteristic patterns of LGE , 14. TheLast but not least, our present data clearly show that a 3rd booster vaccination leads to a substantial increase in the SARS CoV-2-IgG antibody titer – and interestingly to a higher increase in females compared to males. Hence, gender-based differences should be evaluated more carefully in future studies.The present serial CMR data support current recommendations regarding the safety of 3rd booster vaccinations since no functional or subtle structural changes were observed in the myocardium – as long as current vaccination recommendations are followed. However, subclinical pericarditis was observed in one case and could only be depicted by multiparametric CMR.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.Ethical approval was not provided for this study on human participants because written consent of participants were obtained and no identifiable images or data are presented in the study. The patients/participants provided their written informed consent to participate in this study.CM devised the project, performed CMR examinations, performed major analyses of the CMR data, and drafted the manuscript. DK performed the CMR analyses and participated in the interpretation of results. MB participated in the design of the study, performed CMR examinations, and statistical analyses. BC participated in the design of the study, CMR exams, and critically reviewed the manuscript. SD participated in the CMR exams and in the analysis of the CMR data. VV and PS performed CMR examinations and participated in the analysis of clinical data. AY provided the main conceptual idea, supervised the work, provided critical feedback and helped shape the research, analysis, and manuscript. 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.


To analyze data from children who were previously healthy and presented with post-varicella arterial ischemic stroke upon arrival when admitted to the emergency room, with focus on the clinical/laboratory aspects, and neurocognitive performance after four-year follow-up. Seven children presenting with arterial ischemic stroke after varicella were evaluated at pediatric emergency services in the city of São Paulo (SP), Brazil. Ischemic stroke was determined by magnetic resonance imaging/magnetic resonance angiography in a topography compatible with the areas supplied by the middle cerebral or internal carotid arteries. IgG-class antibodies against varicella zoster virus and varicella-zoster virus DNA by polymerase chain reaction in cerebrospinal fluid were tested. Patients with prothrombotic conditions were excluded. The Pediatric Stroke Outcome Measure was applied upon admission and 4-years after the stroke. All patients (age range: 1.3 to 4 years) included presented chickenpox 5.1 (±3.5) months before. All patients had analysis of anti-varicella-zoster-virus-IgG in cerebrospinal fluid, but only three (43%) had a positive result. Of the patients 43% had no vascular lesions identified in magnetic resonance angiography. All patients showed improvement in their sequela scores. After 4 years, five patients displayed good evolution in the Pediatric Stroke Outcome Measure, and only one patient presented with a score of 2 in the sensorimotor and cognition areas. No recurrence of arterial ischemic stroke was observed. We reinforced the non-progressive course of post-varicella arterial ischemic stroke after 4-year follow-up. The presence of varicella-zoster-virus-DNA detected by polymerase chain reaction, and/or intrathecal IgG antibody against varicella zoster virus, and angiopathy location in magnetic resonance angiography were not determining for the diagnosis. Invasive tests, with low sensitivity, should be well considered in the diagnosis of post-varicella arterial ischemic stroke. Transient cerebral arteriopathy affects the middle cerebral artery (MCA) or the internal carotid artery (ICA), manifesting in the basal ganglia of children with symptoms of AIS. Post-varicella AIS, although rare, accounts for approximately 30% of all AIS in children.Arteriopathy caused by viral infections is one of the most important mechanisms of arterial ischemic stroke (AIS) in the pediatric population. Several viruses were previously associated with AIS, such as the varicella-zoster virus (VZV). This is a DNA virus, like the herpes virus, which is able to remain latent in neuronal cells for months after primary infection. Therefore some complications, such as transient cerebral arteriopathy (TCA), may occur up to one year after varicella.,2-6To date, there is conflicting evidence regarding the identification of antibodies against VZV, or VZV DNA in cerebrospinal fluid for diagnosis of post-varicella AIS in children.To analyze data from children who were previously healthy and presented with post-varicella arterial ischemic stroke to emergency room, and focused on the clinical/laboratory aspects and neurocognitive performance after 4-year follow-up.Instituto da Criança, Hospital Israelita Albert Einstein, Hospital Santa Catarina, Hospital Infantil Darcy Vargas and Hospital São Camilo) in the city of São Paulo (SP), Brazil, from December 2013 to December 2017. This study was approved by the local Ethics Committee of Hospital das Clínicas of the Faculdade de Medicina of the Universidade de São Paulo (USP), CAAE: 43629315.2.1001.0068, protocol 1.036.344, and Hospital Israelita Albert Einstein (HIAE), CAAE: 43629315.2.3002.0071, protocol 1.343.515.This study reported a series of seven cases of patients admitted to the emergency room with post-varicella AIS and longitudinal follow-up. We evaluated charts of these patients from five different hospitals /magnetic resonance angiography (MRA) in a topography compatible with the areas of the MCA or ICA, cerebrospinal fluid sample collected and analyzed, and aged under 18 years. A radiologist reviewed each MRI scan to confirm the presence of AIS. Magnetic resonance imaging and MRA were performed within 24 to 72 hours after the initial visit. All participating hospitals had 1.5 Tesla MRI scanners. Individuals who presented with other risk factors for stroke, such as prothrombotic conditions, cardiopathies, trauma or other cerebral arteriopathies were excluded. Laboratory tests were used to rule out prothrombotic conditions, and two-dimensional Doppler echocardiography was performed to rule out cardiopathies or cervical arterial diseases.Results from the ELISA of cerebrospinal fluid to detect immunoglobulin G (IgG) antibodies against VZV, and polymerase chain reaction (VZV-DNA-PCR) to detect VZV virus DNA were collected up to 10 days after the onset of AIS in all patients. Patients were evaluated by physical therapy, speech therapy, and psychology services for specific follow-up, after hospital discharge.Sensorimotor, language and cognitive sequalae were accessed by the Pediatric Stroke Outcome Measure (PSOM) upon admission and 4 years after AIS.Seven children were included in this study; five of them (71.4%) were male. The median age at stroke was 3.8 years (range: 1.3 to 4), and the mean period between the clinical presentation of AIS and the episode of chickenpox was 5.1 (± 3.5) months.All patients were initially evaluated by computed tomography, and no signs of mineralizing angiopathy could be found. Four patients presented with unilateral vascular lesions in the MCA and/or ICA, while the MRI from three patients were normal. In five children, MRA was repeated after two to eight months to exclude progressive arteriopathy.deficit with slowness of function. These patients had a greater degree of sensorimotor sequelae and were supported by neurology/psychology and physical therapy groups. One of these two patients presented with a score of 2 in the sensorimotor and cognition areas after 4 years. No recurrence of AIS was observed during the 4-year follow-up.In this study we found the presence of viral DNA and/or intrathecal IgG antibodies against VZV, and angiopathy location in MRA, were not determining for diagnosis of post-varicella AIS. Our study adds to previous literature by describing sensorimotor, language and cognitive sequelae evaluated by the PSOM, in a 4-year follow-up after AIS. Therefore, the need of invasive and low-sensitivity tests should be well considered in the diagnosis of post-varicella AIS.-6Only five previous studies included at least four children each, with confirmed radiological imaging characteristic of ischemia in the territories of the MCA or ICA after an episode of varicella .(2-6),6 analyzed the cerebrospinal fluid to look for IgG antibodies against VZV; only five of ten children tested had a positive result for IgG antibodies against VZV. In our study, all patients had an analysis of IgG antibodies against VZV in cerebrospinal fluid and only three (43%) of them had a positive result. Some authors have suggested that, in location where there is universal varicella immunization, tests for IgG antibodies against VZV should be more sensitive than commercial VZV ELISA,which could help explain our anti-VZV IgG detection rates slightly lower than found in previous studies (43% versus 50%). However, given the small sample size, this difference could be explained by variance in the prevalence estimate, and further studies with larger samples are required to clarify this issue. Regarding varicella immunization, there is no association between AIS and live attenuated VZV of varicella vaccine, which has been recommended since 1996. Donahue et al. assessed 3.2 million children, and 1.14 million of them received varicella vaccine in the United States. The authors found varicella vaccine presented no association with increased risk of AIS. In our study, only one patient received one dose of VZV vaccine, probably because in Brazil it was included in the public immunization program only in 2013.Of these, only two identified previously healthy children with AIS, who had a recent history of varicella infection prior to the neurological condition. Nine out of 13 individuals tested had positive results for cerebrospinal fluid-VZV-DNA-PCR. Miravet et al. reported results similar to ours, evaluating children with and without comorbidities. These conflicting findings could be the result of the small sample sizes included; nonetheless, the absence of anti-VZV antibodies in the cerebrospinal fluid does not rule out the diagnosis in children who meet the criteria for post-varicella AIS.,6,11In our study, all children tested had negative results for VZV-DNA-PCR. Helmuth et al.The main limitation of the present study was the fact it is a series of cases based on data collection from medical records. However, there are only two reports that included more than seven patients with post-varicella AIS, confirmed by MRI and MRA. Other diagnostic techniques, such as conventional arteriography, might be more accurate, but are probably very invasive for routine practice.Our study reinforces the importance of assessing the approach to diagnose post-varicella AIS, which considers the clinical presentation, history of varicella, neuroimaging findings and, possibly, anti-VZV antibodies in the cerebrospinal fluid. It should also be noted that MRA was unable to rule out the diagnosis, since we observed three patients whose arterial lesions could not be located by MRA, a finding that had been described previously. After 4 years, the sensorimotor sequelae were more often observed than cognitive and language ones, which reflects the fact post-varicella AIS is mainly subcortical. Additionally, none of our patients presented with new ischemic or hemorrhagic episodes, reinforcing its monophasic course.Our study highlights the nonprogressive character of post-varicella arteriopathy by the PSOM, in the 4-year follow-up. It has been used to better determine the degree of neurological impairment following AIS over time, since the brain of children is still developing, unlike of adults. However, it remains unclear whether acyclovir could prevent recurrence in healthy children. Only one patient in this series received corticosteroids. Patients who were not treated with antivirals or corticosteroids showed no higher risk of neurological impairment than those who were; similar results were found by Bartolini et al.Rehabilitation therapy with neuropsychology, physical therapy and speech therapy may improve the outcomes of post-stroke patients, but these therapies have to be more structured in pediatrics. Regarding treatment, all patients received ASA, and two patients in whom intrathecal antibodies were identified received acyclovir. Treatment with acyclovir may be justified by the finding of VZV DNA in the arteries of a child, who died due to post-varicella AIS.In this study, we reinforced the nonprogressive course of post-varicella arterial ischemic stroke after 4 years of follow-up. The presence of viral DNA and/or intrathecal IgG antibodies against varicella-zoster virus, and angiopathy location in magnetic resonance angiography, were not determining for diagnosis of post-varicella arterial ischemic stroke.In addition, the necessity of invasive and low-sensitivity tests should be well considered in the diagnosis of post-varicella arterial ischemic stroke.