Background: Dysregulation of lipid metabolism plays important roles in the tumorigenesis and progression of gastric cancer (GC). The present study aimed to establish a prognostic model based on the lipid metabolism–related genes in GC patients.Materials and Methods: Two GC datasets from the Gene Expression Atlas, GSE62254 (n = 300) and GSE26942 (n = 217), were used as training and validation cohorts to establish a risk predictive scoring model. The efficacy of this model was assessed by ROC analysis. The association of the risk predictive scores with patient characteristics and immune cell subtypes was evaluated. A nomogram was constructed based on the risk predictive score model and other prognostic factors.Results: A risk predictive score model was established based on the expression of 19 lipid metabolism–related genes . The time-dependent ROC analysis revealed that the risk predictive score model was stable and robust. Patients with high risk scores had significantly unfavorable overall survival compared with those with low risk scores in both the training and validation cohorts. A higher risk score was associated with more aggressive features, including a higher tumor grade, a more advanced TNM stage, and diffuse type of Lauren classification of GC. Moreover, distinct immune cell subtypes and signaling pathways were found between the high–risk and low–risk score groups. A nomogram containing patients’ age, tumor stage, adjuvant chemotherapy, and the risk predictive score could accurately predict the survival probability of patients at 1, 3, and 5 years.Conclusion: A novel 19-gene risk predictive score model was developed based on the lipid metabolism–related genes, which could be a potential prognostic indicator and therapeutic target of GC. Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide, ranking the third in males and the fifth in females . CurrentDeregulation of lipid metabolism has a critical role in the promotion of tumorigenesis and tumor progression . It alsoGC progression is closely associated with alterations of lipid metabolism. A low level of serum high-density lipoprotein predicted a high risk of GC development, a high rate of lymphatic and vascular invasion, an advanced nodal metastasis, and a poor prognosis in patients with GC . Adipocyde novo lipogenesis, lipid uptake, lipid storage, and lipolysis and generating enhanced synthesis, uptake, consumption, and storage of fatty acids  datasets, GSE62254 and GSE26942, were used for analyses. Patients eligible for analyses were as follows: 1) histologically diagnosed with gastric adenocarcinoma, 2) having available mRNA expression data, and having 3) available complete clinical and survival information. There were 300 and 217 patients in the GSE62254 and GSE26942 datasets, respectively. 17 patients were excluded from the GSE26942 dataset due to not meeting the inclusion criteria, including 12 cases of normal tissue, 3 cases of gastric stromal tumor, and 2 cases without available survival information. Finally, the 300-patient cohort from the GSE62254 dataset was used as the training cohort for our risk predictive score model development, and the 200-patient cohort from the GSE26942 dataset was used as the validation cohort. The risk predictive score was also validated in another two public GC datasets, including the TCGA dataset (n = 350) and GSE84437 dataset (n = 432).Two GEO . The 63 genes were further subjected to the LASSO Cox regression model analysis using the glmnet package, and then 19 genes were selected for construction of the risk prognostic scoring system. Calculation of risk scores was performed using the generated coefficients and corresponding expression. According to the risk scores, patients were classified into low-risk and high-risk groups with a cut-off value (risk score = −3.793587), which best stratified patients with different OS.The same model and coefficients in the training cohort were applied in the validation cohort (GSE26942 dataset). The normalized gene expression data of GSE26942 were downloaded. The efficacy of risk score prognostic classification was evaluated by ROC analysis with the timeROC package. The survival analysis was conducted as mentioned above and was also validated with another two gene sets (TCGA GC and GSE84437).The timeROC package of R software was applied to perform the time-dependent receiver-operating characteristic curve (ROC) analysis. Survival analysis with Kaplan–Meier plots and the log-rank test, and the univariate and multivariate Cox hazard model were performed. GO and KEGG functional enrichment analyses were conducted through the R package clusterProfiler.The expression matrices of GSE62254 and GSE26942 datasets were uploaded to CIBERSORT to determine the tumor-infiltrating immune cell fractions, which were calculated according to the LM22 signature with 1,000 permutations, as described previously . The genIndependent prognostic factors were identified through univariate and multivariate Cox regression analysis. The independent prognostic factors were used to construct the prognostic nomogram, which assessed the OS probability at 1, 3, and 5 years with the “rms” package in R software.t-test, the chi-squared test, and the Mann–Whitney U test were used to examine the differences between groups. Spearman analysis was adopted to assess the correlation between gene expression levels. All calculations were performed with R 3.5.3 software (http://www.R-project.org). A two-tailed p value < 0.05 was considered statistically significant.Student’s https://www.kegg.jp/) database. 13 lipid metabolism–related pathways were included for analysis . The univariate Cox regression model was used to identify genes with prognostic relevance for overall survival (OS). As a result, 63 genes were found to have statistically significant relevance with OS, and their correlations with each other were validated . The LASRisk score = (0.100 * LPL) + (−0.374 * IPMK) + (−0.122 * PLCB3) + (0.311 * CDIPT) + (0.146 * PIK3CA) + (−0.263 * DPM2) + (0.310 * PIGZ) + (−0.594 * GPD2) + (0.043 * GPX3) + (0.077 * LTC4S) + (−0.782 * CYP1A2) + (−0.102 * GALC) + (−0.189 * SGMS1) + (−0.061 * SMPD2) + (−0.184 * SMPD3) + (−0.081 * FUT6) + (0.130 * ST3GAL1) + (0.549 * B4GALNT1) + (−0.040 * ACADS).The GSE26942 dataset was adopted as the validation dataset. With a cut-off value of −3.793587, which stratified patients into two groups with the largest OS difference, patients were classified into low-risk and high-risk groups. The difference between the low-risk and high-risk groups in OS was statistically significant in the training dataset, the validation dataset, and both datasets combined. Kaplan–Meier curves are displayed in Univariate and multivariate Cox regression analysis in the combined dataset showed that the risk prognostic score model was an independent and significant prognostic factor for OS . Patientp = 0.11), so it was between males and females (p = 0.84). Tumors with more aggressive features generally had a higher risk score than those with less aggressive features. In particular, patients with a higher grade (G3) tumor had a higher risk score than those with a lower grade (G1/G2) tumor  was comparative (p = 0.007), activated CD4 memory cells (p < 0.001), follicular helper T cells (p = 0.001), and resting dendritic cells, were significantly lower in the high–risk score group (p = 0.003), while some immune cells, including naïve CD4 T cells (p = 0.005), monocytes (p < 0.001), M2 macrophages (p < 0.001), and resting mast cells, were higher in the high–risk score group (p = 0.006).We analyzed the percentage of 22 immune cell subtypes in the tumors of both datasets and compared their level between patients with low and high risk scores , cellular component (CC), and molecular function (MF) . These gFactors identified by univariate and multivariate Cox regression analysis as independent and significant prognostic factors were applied in the construction of a nomogram model . As showGC has long been recognized as a recalcitrant cancer for its high incidence, high mortality, aggressive behavior, refractory traits, and poor prognosis . IdentifIn this study, we develop a novel prognostic scoring model based on the expression of lipid metabolism–related genes in gastric cancer. We used independent datasets from GEO to construct and validate the risk predictive scoring system containing 19 lipid metabolism–related genes. This scoring system was demonstrated to be efficient in predicting patient survival by ROC analysis. Patients had a significant and remarkable difference of OS between the high–risk and low–risk score groups. We further generated a nomogram integrating the risk predictive scoring system and three other prognostic factors  that improved the efficiency of prognostic value of the nomogram and accurately predicted the 1-, 3-, and 5-year OS of GC patients in the GEO datasets.Helicobacter pylori infection  , phosphanfection . Our stuInterestingly, the present study also revealed that patients with high and low risk scores had distinct features in tumor-infiltrating immune cells. Patients with high risk scores had significantly reduced number of plasma cells, activated CD4 memory cells, follicular helper T cells, and resting dendritic cells and increased number of naïve CD4 T cells, monocytes, M2 macrophages, and resting mast cells. Activated CD4 memory cells were associated with favorable outcomes in patients with cervical cancer  and favoThe major limitation of the present study was the lack of validation in larger patient cohorts from multicenter real-world clinical practice. Thus, the risk predictive score was still far from being able to be used in clinical practice. Another important limitation was that most of the genes used to construct this risk predictive score model were scarcely investigated in cancers. In addition, we did not perform the basic experiment to validate their roles and related mechanisms in GC cells. The biological mechanism was unclear and needed further experimental validation. However, as a prognostic risk score, our model was repeatedly validated and achieved consensus results, so the conclusions of our study are still convincing despite the lack of experimental validation of each gene’s role in GC.In the present study, a novel lipid metabolism–related gene-based risk predictive score model was constructed and validated in datasets of patients with GC. This risk predictive scoring system could efficiently predict patient outcomes and had significant correlation with immune cell subtypes. A nomogram containing the risk score was generated, and it improved the prognostic predictive value of the current TNM staging system. This study will be helpful in biomarker and therapeutics development for GC patients.


Despite the modern prophylactic regimen, the preoperative DVT in patients with pelvic and acetabular fractures still draws the attention of orthopaedic surgeons. Better understanding these risk factors can help surgeons refine the risk stratification profile and perform early interdisciplinary management for patients at high risk of DVT.The objective of this study was to investigate the prevalence of preoperative deep venous thrombosis (DVT) in the pelvic cavity and lower extremities following pelvic and acetabular fractures and to identify the risk factors of the occurrence of DVT. Duplex ultrasound (DUS) screening and blood tests were conducted in patients admitted from June 2012 to December 2020 for surgical treatment of pelvic and acetabular fractures. Univariate analyses were performed on data of demographics, comorbidities, time from injury to surgery, injury mechanism, accompanied injury, and laboratory results. The optimal cutoff values of continuous variables with statistical significance were obtained by using the receiver operating characteristic (ROC) curve. A multivariate logistic regression analysis was then employed to examine the independent values in terms of predicting preoperative DVT. A total of 607 patients with pelvic and acetabular fractures were included, among whom 82 (13.5%) patients sustained preoperative DVTs. Specifically, 31.7% (26/82) were diagnosed with proximal DVTs. Fifty-two (63.4%) patients had DVT within 7 days after injury, and 67 (81.7%) patients within 10 days. The multivariate logistic regression analysis identified 6 factors independently associated with the presence of preoperative DVT, including age > 46 years (odds ratio [OR] = 2.94), BMI > 26.73 kg/m Pelvic and acetabular fractures are commonly caused by blunt high-energy potentially life-threatening injuries, and their perioperative management remains controversial and challenging , 2. TrauConsensus on the routine chemoprophylaxis for elective orthopaedic surgeries (hip or knee arthroplasty) has been reached and explicitly validated. However, the importance of thromboprophylaxis following pelvic and acetabular fractures is undervalued due to a lack of refined data of DVT, manifesting large variations in incidence, risk factors, screening methodologies, anatomic locations of clots, and optimal thrombosis –9. DVTs Taken together, the data regarding incidence and risk factors specific to the subgroup with pelvic and acetabular fractures are scarce. The objectives of this study included: (1) to investigate the incidence of DVT during the preoperative hospital stay for surgically treated pelvic and acetabular fractures, and (2) to identify the risk factors independently associated with the occurrence of DVT by employing statistical analyses.This retrospective, single-center study was performed following principles of the international guidelines for human research protections, the Declaration of Helsinki, and it was in line with Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Guidelines. All components of the study were approved by and covered under the Institutional Review Board, Faculty of Medicine, Handan Central Hospital, Handan, China. Informed consent was signed by all the participants. All the patients included in this research were admitted to our hospital from June 2012 to December 2020 for surgical treatment of pelvic and acetabular fractures. The study period started from injury to either occurrence of DVT or operation. All the data were abstracted from the radiology information system and electronic medical record system.Inclusion criteria were (1) patients admitted to our institution from June 2012 to December 2020 and received surgical treatment, (2) age of 18 years and older, and (3) definite diagnosis of pelvic and/or acetabular fractures with complete medical data. Exclusion criteria were (1) pathological (metastatic) fracture, (2) injury associated with the fracture that required immediate surgical intervention, (3) active malignant tumor, (4) a history of venous thromboembolic disease, or (5) recent use of anticoagulants for other indications within 3 months.The inpatients’ comorbidities and demographic data were retrieved from the electronic medical record system, radiographic image, and operation report system. The information included sex, age, body mass index (BMI), diabetes mellitus, chronic heart disease, hypertension, smoking habits (current smoker or not), alcohol consumption (daily drinker or not). Trauma-related data comprised the following information: (1) type of fracture: pelvic ring fractures being classified according to Young–Burgess classification  and acetOvernight fasting blood samples were drawn and measured at the central laboratory of our institution according to the manufacturers' instructions. The reference value of each inspection item was determined by the laboratory before reporting the patient's test results. Hematological indicators of interest included albumin (ALB) level, high-density lipoprotein cholesterol (HDL-C) level, low-density lipoprotein cholesterol (LDL-C) level, very-low-density lipoprotein (VLDL) level, red blood cell (RBC) count, hemoglobin (HGB) level, platelet (PLT), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB) and D-dimer level.Venography was taken as the golden standard if DVT could not be ruled out by the duplex ultrasound (DUS) screening. All the patients underwent DUS screening and monitoring on bilateral lower extremities and pelvis with Philips Affiniti50 ultrasonographic machine  after admission, every 5–7 days or when any suspected symptoms appeared, according to authors’ institutional protocol. Senior sonographers performed the scanning from the calf veins to iliac veins for positive DVTs. The diagnostic criteria included direct visualization of intraluminal thrombus, the presence of an intraluminal defect, loss of compressibility of the vein, blunted or inadequate flow augmentation, and lack of spontaneous and respirophasic flow above the knee segments . Spiral After admitted to the hospital with a negative result of DVT, all the patients were administered with intermittent pneumatic compression on lower limbs and a prophylactic dose of the low-molecular-weight heparin  within 48 h. For those with hemodynamic instability, pharmacological prophylaxis was prescribed once stable. Patients with positive DVTs were given therapeutic anticoagulants , and withheld the mechanical prophylaxis immediately. For patients with proximal DVT, preoperative placement of a retrievable vena cava filter was performed as prophylaxis against intraoperative and postoperative pulmonary embolism. Chemical prophylaxis was stopped 12 h before surgery.t test or Mann–Whitney U test, as appropriate. Variables with statistical significance (p < 0.05) were analyzed by using the receiver operating characteristic (ROC) curve to obtain the optimal cutoff values associated with the presence of DVT. Afterward, these factors were converted from continuous variables into categorical variables. A Pearson Chi-square test or Fisher's exact test was used, to evaluate the association between inter-groups, expressed as number and percentage. A multivariate logistic regression analysis was performed to examine the independent value of each significant variable from the univariable analyses in terms of predicting the outcome of preoperative DVT. Variables with a p-value less than 0.10 were retained in the final model, and the correlation strength was represented by odds ratio (OR) and 95% confidence interval (95% CI). The fitting degree of the model was evaluated by Hosmer–Lemeshow (H–L) test. Data with a p-value less than 0.05 were considered statistically significant.All the statistical analyses were employed by SPSS26.0 . Continuous variables were expressed as mean ± standard deviation (SD)/median . The Kolmogorov–Smirnov test was performed to evaluate the normality of the continuous data, and then, these data were compared between DVT group non-DVT group by using Student-In total, 607 patients with pelvic and acetabular fractures were included in this study. There were 342 males and 265 females with a mean age of 45.4 ± 14.3 years (range:18–90). According to the results of fracture classification, 291 had pelvic fractures , and 316 patients sustained acetabular fractures   and specifically, 31.7% (26/82) was diagnosed with proximal DVTs, which required placement of a vena cava filter. To be noted, in those with proximal DVTs, only 5 patients had an isolated thrombus in the thigh or pelvic vein, each of the other 21 patients had multiple thrombi in both proximal and distal veins at the first detection time of DVT. There were 13 cases of DVT in bilateral lower limbs and 69 cases in unilateral extremities. Twenty-four cases of DVT occurred in the injured limbs, 3 in uninjured limbs, and 1 in bilateral limbs. The mean time from injury to the diagnosis of DVT was 6.4 days, ranging from 1 to 16. Fifty-two (63.4%) patients had DVT within 7 days after injury, and 67 (81.7%) patients within 10 days. During the research period, no pulmonary embolism or uncontrolled bleeding was observed in patients.The comparison of continuous variables in patients with or without DVT was conducted, and the results are listed in Table 2, 9 days, 32.8 g/L, 332.5 *109/L, and 3.09 g/L, respectively (Table 2), hypertension, time from injury to surgery (> 9 days), associated injury, ASA classification (III–IV), ALB (< 32.8 g/L), PLT (> 332.5) and FIB (> 3.095 g/L) , time from injury to surgery > 9 days (OR = 5.39), associated injury (OR = 7.85), ALB < 32.8 g/L (OR = 2.71) and FIB > 3.095 g/L (OR = 3.34). The Hosmer–Lemeshow test demonstrated excellent fitness of the final model .The multivariate logistic regression analysis showed 6 factors were identified independently associated with the presence of preoperative DVT. The adjusted results are summarized in Table To the best of our knowledge, this is one of the largest retrospective studies conducted on the incidence and risk factors of preoperative DVT in patients undergoing pelvic and acetabular fractures. Despite the use of the modern prophylactic regimen, our results indicated a 13.5% incidence of DVT before surgery, with 31.7% of those being proximal veins in origin. In addition to some well-established predisposing factors such as older age or obesity, other risk factors also exhibited independent association with preoperative DVT, which was partially consistent with prior studies on population with fractures –20. Howep < 0.001), and the morbidity of DVT in patients aged older than 46 years was 67.1%, significantly higher than the rate of their counterparts . After adjusting the confounding factors, we found the patients with pelvic and acetabular fractures over 46 years old had a 2.94-fold increased risk of DVT than that of the younger ones. Similarly, Kim et al. [Increased age has been well-acknowledged as one of the principal risk factors for thromboembolic diseases, particularly in trauma patients , 20, 21,m et al.  identifim et al. . Given t2, which was determined according to the ROC analysis. It was found that obesity resulted in 3.91-time increased odds of developing DVT in this trauma group (p = 0.001). Similar findings have been reported by Morris et al. [It has been widely recognized that orthopaedic patients with elevated BMI have a higher risk of perioperative complications than patients within the normal range , 24. Hows et al.  who founs et al.  reporteds et al. . We did p < 0.001), consistent with previously published findings [In the present study, the incidence of DVT in patients with concurrent injuries was significantly higher than those with isolated pelvic and/or acetabular fractures. The regression model indicated it played an independent role in the formation of a venous clot, although pelvic and acetabular fractures themselves have been generally believed to be at high risk of thromboembolic events. It appeared to be an accumulative effect of polytrauma on amplifying the risk. Our results suggested that patients with accompanied injury demonstrated a remarkably elevated risk of DVT compared to those without other injuries  and outcome (DVT) in the certain population. Despite the numerous studies regarding FIB associations, the precise relationship between PLT count and FIB levels has yet to be fully investigated.Hypoalbuminemia is adversely associated with complications and prognosis after major orthopaedic surgeries , 31. A rWe conducted a large investigation on the incidence and risk factors of preoperative DVT in patients undergoing pelvic and acetabular fractures. However, the current study has some limitations. Firstly, this is a single-center, retrospective, case–control study, which carries some inherent weaknesses. For example, the risk factors measured in our study represent associated instead of causal relationships, which should be interpreted with clinical practice. And, some variables that potentially influence the statistical results might not be included in this study. Secondly, the main diagnostic method of DVT is color Doppler ultrasonography that may miss the venous thrombosis in the pelvis, compromising the effectiveness of the analysis results. Thirdly, to improve the internal validity, patients with certain medical conditions  were excluded, so our findings may be less applicable to patients with such features.2, time from injury to surgery > 9 days, associated injury, ALB < 32.8 g/L, and FIB > 3.095 g/L. Better understanding these risk factors can help surgeons refine the risk stratification profile and perform early interdisciplinary management for patients at high risk of DVT.In summary, the modern prophylactic regimen reduced the incidence of preoperative DVT in patients with pelvic and acetabular fractures to 13.5%, but orthopaedic surgeons’ attention should still be paid to patients with age > 46 years, BMI > 26.73 kg/m


Renewed consumer demand motivates the nutritional and sensory quality improvement of fruits and vegetables. Specialized metabolites being largely involved in nutritional and sensory quality of carrot, a better knowledge of their phenotypic variability is required. A metabolomic approach was used to evaluate phenotypic plasticity level of carrot commercial varieties, over three years and a wide range of cropping environments spread over several geographical areas in France. Seven groups of metabolites have been quantified by HPLC or GC methods: sugars, carotenoids, terpenes, phenolic compounds, phenylpropanoids and polyacetylenes. A large variation in root metabolic profiles was observed, in relation with environment, variety and variety by environment interaction effects in decreasing order of importance. Our results show a clear diversity structuration based on metabolite content. Polyacetylenes, β-pinene and α-carotene were identified mostly as relatively stable varietal markers, exhibiting static stability. Nevertheless, environment effect was substantial for a large part of carrot metabolic profile and various levels of phenotypic plasticity were observed depending on metabolites and varieties. A strong difference of environmental sensitivity between varieties was observed for several compounds, particularly myristicin, 6MM and D-germacrene, known to be involved in responses to biotic and abiotic stress. This work provides useful information about plasticity in the perspective of carrot breeding and production. A balance between constitutive content and environmental sensitivity for key metabolites should be reached for quality improvement in carrot and other vegetables. Apiaceae and other specific botanical families  [Nutritional and sensory quality is an essential attribute of fruits and vegetables  with inceraceae) . These teraceae) –9. Moreoeraceae) . In parteraceae)  while teeraceae)  and turperaceae) . Actualleraceae)  and a baeraceae)  without However, a better knowledge of the determinants of quality related metabolites is still needed to improve and master nutritional and sensorial quality in carrot. Many studies indicate that the genetic basis plays a leading part on nutritional and sensory quality related compounds , compareThe estimation of phenotypic variability extent for large range of metabolites is determinant in carrot breeding perspectives. Depicted as the organism potential to vary , phenotyThe aim of the present study is to evaluate the level of plasticity for various metabolites involved in carrot quality, in a comprehensive way through a metabolomic approach. In particular, this study aims at identifying metabolite trait stability regarding genotype by environment interaction in order to enhance nutritional and sensory carrot quality. A representative large set of varieties has been evaluated for metabolites content in multiple and contrasted environments over two years. Besides useful information for breeding, the results from this multisite study will allow to appreciate the acclimation capacity of carrot for biochemical quality traits in case of climate changes.This study is based on pluriannual and multilocation trials with randomized three-block designs. A set of 16 varieties representing the current commercial diversity of orange carrot in various types  was evalSeven types of compounds were studied: carbohydrates, acids, carotenoids, polyphenols, 6-methoxymellein, polyacetylenes and volatile compounds with terpenes, sesquiterpenes and phenylpropanoids. All compounds combined, 86 metabolites were quantified.al. (2019) [−4 N H2SO4 and elution flow rate was fixed at 0.4 mL/min. Compounds were identified and quantified using the corresponding standards . Results were expressed in grams per 100 g fresh weight.Carbohydrates and acids were extracted and analysed according to Le Clerc et . (2019)  from 10 al. (2015) [al. (2016) [Carotenoids were extracted and analysed according to Jourdan et . 2015)  and Perr15  and PPolyphenols were extracted in duplicate from 5g of freeze-fresh carrot roots grinded in methanol/water Mq  solution. After vortexing, samples were centrifuged at 1912 g during 15 min at 4°C. Supernatant was centrifuged a second time at 1912 g during 15 min at 4°C. Supernatant was then filtered on Acrodisc® 0.2 μm WWPTFE filter. 900 μL of filtrate was pipetted into a 1.5 mL glass vial and 9 μL of Biochanin A (0.08 g/mL) was added as internal standard. Metabolites were analysed by UHPLC system (Waters® Acquity H-class) coupled with a photodiode array detector. Using an auto-sampler set at 5°C, 2 μL of extract was injected into UHPLC column Waters Acquity BEH® C18 100 mm x 2.1 mm, 1.7 μm maintained at 45°C. The mobile phase solution was composed of acetonitrile/water  (solution A) and water/acetonitrile  (solution B), both with 0.5% acetic acid (v/v). The elution flow rate was 0.3 mL/min with the following gradient: B: 0−4.36 min, 100−80%; 4.36−6.95 min, 80−70%; 6.95−9.26 min, 70−50%; 9.26−11.58 min, 50−25%; 11.58−13.89 min, 25−0%; 13.89−15.00 min, 0−0%; 15.00−16.00 min, 0−100% and equilibration from 16.00–22.00 min, 100% B. UHPLC system was coupled with a Time of Flight-Mass spectrometer (Waters® Xevo G-2S) equipped with an electrospray ionization source in negative mode. The ion transfer capillary temperature was set at 350°C and needle voltage at 2.5 kV. Nitrogen was used as nebulizing gas with flow rate 25L/h. The spectra were acquired within mass ranging from 50−1200 Da, with no collision in low energy and ramp collision from 15 to 40 in high energy. Data acquisition and processing were performed using MassLynxTM and TargetLynxTM software. Results were expressed in Biochanin A equivalent in nanograms per g fresh weight.al. (2019) [al. (2017) [al. (2019) [Volatile compounds, 6-methoxymellein and polyacetylenes were extracted and analysed according to Le Clerc et . (2019)  from 10 . (2017)  from 1 μ. (2019) . The mobALS) = All statistical analyses were computed with R version 3.5.1. Permutational multivariate analysis of variance was performed by PERMANOVA on centered-scaled metabolites content. PERMANOVA was computed from Bray-Curtis dissimilarity matrix and 9999 permutations, using R vegan 2.5–6 package. In order to better understand which factor most influences the global biochemical content, a PCA was computed on all 86 biochemical compounds content scaled from means of two agronomic replications, using R FactoMineR 2.3 package. PCA area was computed according to variety coordinates on three principal components and expressed as mixt product: Area . Variety effect on identified compounds was tested thanks to one-way ANOVA, or Kruskal-Wallis test in case where parametric test conditions were not met. Post hoc tests were realized, with respectively Tukey HSD test after ANOVA and Conover test after Kruskal-Wallis, in order to determine which variety accumulates in higher proportion a given compound. To be able to compare the variation for metabolites of interest, the Environmental Variation Coefficient was computed according to Random forest algorithm was used to discriminate varieties according to their metabolic profiles. Data were pre-processed by centering and scaling, and random forest was computed using Rfpermute 2.1.81 package, using 500 trees and 2000 permutations. Out Of Bag (OOB) method was used to estimate the model prediction error. Selection of biochemical compounds was carried out based on variable importance in classification according to Mean Decrease Gini criteria and Mean Decrease Gini  and the sum of all varieties amplitudes for this compound (Srj) on the total sum of amplitudes (St): theoretical amplitude = location . The envlocation  depicts location  was compp.value <0.001)  . In compThe variation distribution was represented by principal components analysis (PCA). The first three PCA components explained only 35.89% of total variance with respectively 14.97%, 12.43% and 8.51% , due to A differential effect of locations on varieties is highlighted by area computation on PCA components . The PCAEven if results show a substantial effect of environment on metabolic profiles, the genetic background seems to play a leading part both on variety specific metabolite accumulation or metabolite content variation. Besides clear-cut discrimination of Kuroda type from other varieties, a differential effect of locations on varieties is highlighted.p.value <0.05). Polyphenol compounds were the most represented ones, with 14 compounds. Then polyacetylenes and sesquiterpenes with three compounds respectively. Finally, citrate, α-carotene and the terpene β-pinene (T2) were also involved in variety clustering. Noticeably, important quality criteria such as carbohydrates and β-carotene content were not selected and therefore not the most discriminating factors between varieties.PCA is actually an unsupervised method which lacks performance to identify the role of specific metabolites in differences between varieties and therefore to characterize variety variation for biochemical content. Random forest model was used to determine discriminant metabolites in variety characterization. Random forest model showed a high level of prediction, with only 1.04% of prediction error, only one individual being misclassified out of 96 individuals . Over 86 analysed metabolites, 24 displayed a significant and high effect on variety clustering  based onBased on the 20 most discriminating compounds (Mean Decrease in Gini >1), hierarchical clustering on Euclidean distance matrix scaled block mean shows an effective separation between varieties . MoreoveIn a comprehensive way, some compounds can characterize specifically varieties, as shown by the heatmap based on relative content and table content  and FaDOH characterize Ver variety and biochemical content is stable across environments with CV = 11.92% and 8.77%, respectively. The high level of P8.51 and α-bisabolene (S10) discriminate respectively Bol and Rod from all other varieties, even if the content may vary depending on the environment (CV = 35.26% and 18.53% respectively). Interestingly, the landrace variety Luc is distinguished by the highest and stable content in citric acid .Our results indicate that polyphenol compounds seem to play a major role in variety differentiation and deserve more attention in carrot. Polyacetylenes and terpenoids are largely involved in variety discrimination. Among terpenoids, β-pinene (T2) is the only terpene characterizing one variety from others whereas two sesquiterpenes compounds, b-elemene (S1) and α-bisabolene (S10), seem to be characteristic of a few varieties. The polyacetylenes, mainly the falcarindiol forms, are involved in several varieties. In a few cases only, the combination of compounds is useful to discriminate varieties.Considering the 51 compounds accumulated by all varieties, phenotypic plasticity was first assessed on the first-year results by measuring global amplitude response over 3 environments of diversity set varieties . The ampIn order to heighten phenotypic plasticity evaluation of compounds, a subset of five varieties , differing for the general plasticity level and carrot type, was cultivated on a large set of 20 environments (2 years and 10 locations). Pearson residuals on differences between observed and theoretical amplitudes were used to determine compounds with stronger differential of plasticity. The absolute Pearson residuals sum ranged from 4.14 to 0.96 . CompounPhenotypic plasticity pattern was characterized on a set of six key quality compounds chosen according to literature and differential plasticity level of varieties. Selected compounds presented a sum of absolute Pearson residuals  above thAs described above, accumulation for some metabolites can be highly dependent on genotype by environment interaction. It justifies a more comprehensive investigation in order to identify environments enhancing metabolite accumulation. We used AMMI model as a complementary tool to characterize metabolite patterns depending on accumulation promoting environments. Several patterns can be observed for the six studied compounds . For falThe phenotypic plasticity level differs between compounds and the extent of plasticity varies depending on varieties. Compounds with the higher differential of phenotypic plasticity level belong to terpenoids and phenolic families. The study of phenotypic plasticity must be done on a metabolite-by-metabolite basis. The use of varietal accumulation amplitude occurs as an effective approach to select compounds under both genetics and environmental determinism, facilitating such approaches. Considering environmental sensitivity for metabolites of interest is essential for prediction purposes.Metabolic profiling was used as an efficient approach to grasp phenotypic variability for various metabolites involved in carrot quality. Our results show the overall major effect of variety on carrot metabolic content, whether due to specific metabolite synthesis or differential of phenotypic plasticity level between variety according to studied compound. Two concepts are largely opposed to evaluate varietal stability: static stability and dynamic stability . ConsideStability concept allows to assess varieties fluctuations whereas adaptability considers genotype by environment interaction to depict variety ability responding positively to the environment . Widely Besides issues related to data mining for stability study applied to metabolic profiling, biomass and metabolite accumulation are not influenced in the same manner. Metabolome is strongly dynamic and plant metabolic profiles depend on various level of regulation. Kooke and Keurentjes review  highlighOur study highlighted 20 metabolites largely involved in variety discrimination under low environmental determinism, showing the constitutive ability differential of varieties to accumulate key metabolites. Corresponding varieties can be considered as statically stable for given compounds. This concept is related to biological construct of homeostasis and the corresponding index is interesting for variety selection as it is known to be repeatable in time . For theal. [al. [Alternaria dauci on chromosome four, consistently with Busta et al. [in fine pest resistance. Nevertheless, Keilwagen et al. [Among highlighted varietal markers, polyacetylenes and α-carotene have nutritional value and are recognized as health benefit molecules with large application in the medical field ,9,50–54.al.  identifial.  may alsoal. ,61. In fal.  and antial.  whereas al. . Particual. , and expal. [al.  identifia et al.  who founn et al.  highlighNevertheless, the highlighted compounds linked to stress tolerance such as polyacetylenes and β-pinene are also bitterness related . A balanal. (2010) [al. (2007) in their works on Halozetes belgicae (Michael) [More influenced by environment, compounds were characterized for the differential of phenotypic plasticity between varieties. Propensity for metabolite accumulation was evaluated thanks to environmental sensitivity of varieties corresponding to the dynamic stability concept . This la. (2010)  showed t. (2010) . D-germa. (2010) . Contrar. (2010) ,76 and e. (2010) . Several. (2010) , UV-B ir. (2010)  and cold. (2010) . A putat. (2010) . D-germa. (2010)  can help. (2010)  and promMichael) , plastical. (2013) [Globally, plants recognize environmental signals, as well as abiotic ,86 or bi. (2013)  draw up . (2013) ,91. Seve. (2013) ,93. The . (2013) , their sOur study has deepened six compounds of interest for which varieties have substantial different level of phenotypic plasticity. Depending on the compound, several strategies may be considered to improve the content: a breeding effort could be envisaged to reach the expected level as for D-germacrene, breeding could target specific classes of environments as for myristicin and 6-methoxymellein, or cultivating a variety on propitious environment where it expresses best its potential. Ensuring the highest or lowest content, according to positive or negative effect of a compound on quality, for a variety with specific adaptability requires a better knowledge of the critical environmental factors involved in accumulation.Metabolic profiling occurs as an efficient prospective approach in vegetable quality elaboration to valuate whole varietal potential, guarantee crop nutritional and resistance ability without compromising taste. This tool used in conjunction with large carrot diversity and contrasted cropping locations allows to grasp phenotypic variability and evaluate determinant factor involved on a wide range of metabolite content simultaneously. Two opposites concept at first sight, stability and environmental sensitivity, were considered in a complementary way in order to find the most suitable biochemical compounds to be selected for a breeding approach and vegetable quality improvement perspective. Our work led to the identification of compounds to target in priority, for production and breeding purposes in carrot, with adapted strategies depending on genotype-environment interaction level. Thus, variety plasticity needs to be better considered in vegetable crops and regarding quality traits, in order to raise production value and meet consumer demand. Transposable to other vegetables, this approach coupling metabolic profiling to stability and environmental sensitivity analysis offers perspectives for vegetable production improvement. Further work is underway to establish links between nutritional and sensory quality on one hand and identification of agroclimatic factors involved in key metabolites content variation on the other hand.S1 FigTrue class in line and predicted class in column. Diagonal represents proportion of individuals well ranked. Dark color represents the totality of well ranked individuals while a lighter color symbolizes a less important proportion of well predicted individuals.(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Tablex: Non applicable. CIT is expressed in grams per 100g fresh weight, polyacetylenes  are expressed in ppm 4-chlrorobenzophenone, volatiles compounds  are expressed in ppb 2-octanol equivalent, acar is expressed in milligrams per 100g fresh weight and polyphenols (P…) are expressed in nanograms per g fresh weight.(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.


Rhynocoris fuscipes (Fabricius 1787) is an important predator in China. In current study, the complete mitochondrial genome of R. fuscipes is determined. The mitogenome is 15,542 bp in size and comprises of 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and a control region. Gene arrangement is identical to that of the putative ancestral arrangement of insects. All protein-coding genes initiate with ATN codons and terminate with TAA codons except for COII, ND4, and ND5 use TA or a single T residue as the termination codons. All tRNAs have the clover-leaf structure except for the Ser(AGN)tRNA and the length of them range from 62 to 70 bp. The phylogenetic result supports the monophyly of Harpactorinae and the sister relationship between R. fuscipes and Rhynocoris incertis. Rhynocoris Hahn, 1834 belongs to the family Reduviidae, a large genus with 170 known species (Zhao Rhynocoris fuscipes (Fabricius 1787) is a common predator in China, distributed in Southeast Asia, and was massively reared in China as a biological control agent. In this study, the complete mitochondrial genome of R. fuscipes was sequenced and described. Adult specimens were collected from Xiongnan, Guangdong, China (25°9′66′′ N 114°28′45′′ E) in 18th May 2021 by Mengqing Wang and identified by Mengqing Wang. Specimens were deposited in the Natural Enemy Insects Museum (Accession Number: NI2021-19) of the Institute of Plant Protection, Chinese Academy of Agricultural Sciences (IPPCAAS) .ies Zhao . Rhynocohttp://www.bioinformatics.babraham.ac.uk/projects/fastqc). Clean reads were assembled and annotated using the MitoZ v2.4 pipeline  and stored at −20 °C until needed. The mitogenome was sequenced in BerryGenomics company used NGS. 1 μg of genomic DNA was used to generate libraries with an average insert size of 350 bp, which were sequenced using the Illumina HiSeq S6000  with 150 bp paired-end reads on one sample per flow-cell lane. A total of 17,635,709 raw paired reads were generated. The quality of all sequences was checked using FastQC  including 37 typical insect mitochondrial genes  and one control region. Gene arrangement is identical to that of the putative ancestral arrangement of insects and most assassin bugs  initiate with ATG codons, four PCGs  initiate with ATA codons, and one PCG (ND5) initiate with ATT codon. The typical termination codon TAA is assigned to ten PCGs. However, COII, ND4, and ND5 terminate with TA or a single T residue as incomplete stop codons which is common in other Reduviidae species tRNA, the dihydrouridine (DHU) arm of which forms a loop, as is a common phenomenon in Reduviidae species .There are 22 tRNA genes, ranging from 62 to 70 bp in length, and all of them can be folded into typical clover-leaf secondary structure except for R. fuscipes and Rhynocoris incertis is also highly supported. The mitogenomic data of R. fuscipes provides a basic data for future research investigating the unclear relationships within Reduviidae.Phylogenetic analyses of the available mitogenomic sequences among Reduviidae with Bayesian inference (BI) and maximum-likelihood (ML) methods using the sequences of 13 PCGs and two rRNAs resulted in identical tree topology . The BI


Cytomegalovirus (CMV) infection is amongst the most important factors complicating solid organ transplantation. In a large prospective randomized clinical trial, valganciclovir prophylaxis reduced the occurrence of CMV infection and disease compared with preemptive therapy in CMV-positive renal allograft recipients . Here, we present a subanalysis of the VIPP study, investigating single nucleotide polymorphisms (SNPs) in immune-response-related genes and their association with active CMV infection, CMV disease, graft loss or death, rejection, infections, and leukopenia.TLR4, three for IFN-γ, six for IL10, nine for IL37, and two for TNF-α. An asymptotic independence test (Cochran-Armitage trend test) was used to examine associations between SNPs and the occurrence of CMV infection or other negative outcomes. Statistical significance was defined as p<0.05 and Bonferroni correction for multiple testing was performed.Based on literature research ten SNPs were analyzed for IL37 rs2723186, an association with CMV disease (p = 0.0499), for IL10 rs1800872, with graft loss or death (p = 0.0207) and for IL10 rs3024496, with infections (p = 0.0258) was observed in all patients, however did not hold true after correction for multiple testing.SNPs were analyzed on 116 blood samples. No associations were found between the analyzed SNPs and the occurrence of CMV infection, rejection and leukopenia in all patients. For The study did not reveal significant associations between the analyzed SNPs and the occurrence of negative outcomes in CMV-positive renal transplant recipients after correction for multiple testing. The results of this association analysis may be of use in guiding future research efforts. Cytomegalovirus (CMV) infection is the most important serious viral infection that complicates solid organ transplantation . CMV infValganciclovir, a valyl ester prodrug of ganciclovir, is currently licensed for the prevention of CMV disease in high-risk (D+/R-) patients receiving a solid organ transplantation . In the IL) 10 can contribute to CMV reactivation and disease after allogeneic stem cell transplantation , the location in the coding regions of genes, their clinical relevance  as clinically associated), and PubMed records. Various criteria for the selection of SNPs which we considered in the substudy, were used: allele frequencies (>1%) extracted from the Genome Aggregation Database [gnomAD v2.1, Blood samples could be obtained at any time during the VIPP study, including at scheduled blood sampling timepoints. The samples were frozen and stored at -20°C. The SNP analysis was performed in the Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie . Genomic DNA was isolated from whole blood using the QIAamp DNA Blood BioRobot MDx Kit and the QIAamp DSP DNA Blood Mini Kit  according to the manufacturer’s protocol. DNA quality and concentration were assessed using the NanoDrop 1000 Spectrophotometer or the Qubit™ dsDNA BR Assay Kit and a Qubit Fluorometer . Genetic variants were genotyped by TaqMan technology using predesigned SNP Genotyping assays (Thermo Fisher Scientific) and the Applied Biosystems 7900HT Fast Real-Time PCR System (Thermo Fisher Scientific) according to the manufacturers’ protocols. SNPs were evaluated with Sequence Detection Software version 2.4 (SDS 2.4).The study was planned for 200 patients. Exploratory analysis was done for all patients and for subgroups of patients receiving valganciclovir prophylaxis or preemptive treatment. Statistical analyses were performed using R version 3.3.2 [Associations between SNPs and the occurrence of CMV infection, CMV disease, graft loss or death, rejection, infections, and leukopenia were examined using an asymptotic independence test (Cochran-Armitage trend test). The trend tests were envisaged for n = 30 genetic variants and 6 endpoints in the overall cohort and two subgroups (prophylaxis and preemptive treatment). For two variants (IFN-γ rs2069723 and IL10 rs3024489), no nucleotide changes were observed in our cohort. Only two events occurred for CMV disease in the prophylaxis group. The effective number of tests was therefore determined as n = 476 (= 28*17), and the corresponding Bonferroni corrected significance level consequently as α* = 0.05/476 ≈ 0.00011. Odds-Ratios (OR) and 95% confidence intervals (95% CI) were calculated using a logistic regression model as an association between genotypes and endpoints. Patients with missing data were excluded. Lower OR correspond to lower odds of seeing an event in the largest genotype group.Haplotype analyses were performed with R-library haplo.stats . HaplotyFig 1).Blood samples were collected between March 2009 and January 2014 within the VIPP study. In total, 117 of 299 patients provided blood samples for the analysis. The SNP analysis could be performed on 116 of these samples , with generally balanced demographic and clinical baseline characteristics. The mean age for all patients was 51.0 years, and more total male than female patients were included in the SNP analysis.The patient characteristics are presented in The proportion of patients with CMV infection and CMV disease was higher in the preemptive treatment group than in the valganciclovir prophylaxis group . For occurrence of graft loss or death (15 events), rejection (93 events), infections (85 events), and leukopenia (32 events), no remarkable differences were observed between both groups.TLR4, three SNPs for IFN-γ, six SNPs for IL10, nine SNPs for IL37 and two SNPs for TNF-α. Selected SNPs, genotype and allele frequencies for all patients are provided in the S2 Table. Genotype frequencies of all SNPs are in Hardy-Weinberg equilibrium.Ten SNPs were analyzed for Tables 3). For IL37 2723186, an association with CMV disease was observed . IL10 rs1800872 was associated with graft loss or death . For IL10 rs3024496, an association with infections was observed . All significant results did not hold true after Bonferroni correction.P-values were >0.05 for all analyzed SNPs and the occurrence of CMV infection, rejection and leukopenia , and IL10_rs3024496 was associated with infections  (Tables 3). Additionally, in the prophylaxis group, associations with CMV disease were observed for nearly all analyzed IL37 SNPs. However, only two CMV disease events were observed in this subgroup. In the preemptive group, we found associations with infections for TLR4 rs11536889  and with rejection for IFN-γ rs2069707 . Again, all significant results did not hold true after Bonferroni correction. For all other investigated SNPs and events, p-values were >0.05.Associations of SNPs with the occurrence of CMV infection, CMV disease, graft loss or death, rejection, infections, and leukopenia were also investigated in the prophylaxis and preemptive treatment group. In the prophylaxis group, IFN-γ (p = 0.023) as well as infections and IL10 (p = 0.017). Moreover, the association between infections and TLR4 showed a borderline effect in all patients (p = 0.051) and was nominally significant in the preemptive treatment group (p = 0.038). However, in all three cases, the differing haplotype was determined by just one variant, which we already identified in our previous per-variant analysis . In addition, in the preemptive treatment group, a nominally significant association was identified between leukopenia and IFN-γ (p = 0.049). Here, the differing haplotype was solely determined by IFN-γ rs2430561. In the corresponding per-variant analysis, the association between IFN-γ rs2430561 and leukopenia showed a borderline effect  identified were revealed for endpoint rejection and γ p = 0.03 as wellThis is the first association study of common genetic variants in patients after renal transplantation in a prospective randomized clinical trial.The characteristics of the 116 patients, from whom blood samples were analyzed, were comparable to the overall population of the VIPP study, which comprised 299 patients . The proThe selection of the SNPs which were tested in this substudy was based on various criteria. One criterium considered the allele frequencies of variants >1%. Population frequency data were obtained from the Genome Aggregation Database (gnomAD v2.1) which comprises data from more than 140,000 individuals including their ethnic background. Of note total allele frequency data of the selected variants corresponds very well with allele frequency data of European (non-Finnish) individuals .TLR4, IL10, IFN-γ, IL37 and TNF-α was observed in this largely Caucasian population. Regarding IFN-γ, our results are in line with data by Aguado et al. [IFN-γ polymorphism +874 A/T (rs2430561) with an increased risk of CMV infection in transplant recipients in a Hispanic population [IFN-γ +874 T/T genotype and CMV disease after lung transplantation, which was most striking among R+ patients. In another study, associations were found between other IL10 SNPs  and the development of CMV disease [For CMV infection, no association with the investigated SNPs in the genes o et al. , demonsto et al. –18. Thispulation  also fou disease .IL37 rs2723186 with CMV disease, for IL10 rs1800872 with the occurrence of graft loss or death, and for IL10 rs3024496 with the occurrence of infections. These results were confirmed in the prophylaxis group, however did not hold true after Bonferroni correction.For the further endpoints of interest, associations were observed in all patients for IL37 rs2723186 is located in the intronic region of the gene. Previously, it was shown that the rs2723186 allele was significantly associated with a decreased risk of Graves’disease (an autoimmune thyroid disease) in female patients [IL-37 is capable of reducing the activity of both innate and specific immune responses , 25. IL3patients . In addiIL10 rs1800872 (-592C>A) is located in the promotor region of the gene and part of the A-T-A (-1082/-819/-592) haplotype, whose impact on the production of IL10 is discussed controversially [IL10 rs3024496 is located in the 3’ untranslated region of the gene and it was previously shown to influence CD4+ T cell responses to antiretroviral therapy in patients with human immunodeficiency virus 1 infection [ersially –30. In onfection .The herein described study has the following limitations: The number of analyzed blood samples was smaller than the planned number of 200 patients, and no sample size calculation was performed in advance. The study population cannot be extended by additional patient samples since the VIPP study was a prospective randomised clinical trial. Furthermore, the study was not designed for the large number of statistical tests. Additionally, the number of events was low, particularly for CMV disease, and graft loss or death. Conversely, intensive immunosuppression may have hidden possible associations.The results of this association analysis may guide future research efforts. Based on the complexity of the immune response, research on the combined use of biomarkers and gene profiles represents a better approach than the focus on single markers. Immunity against CMV is usually defined by serology. However, a cellular immune response with potent CMV-specific T cells seems to help prevent CMV disease in CMV R+ recipients. CMV-specific T-cell responses are not measured routinely in clinics, but their potential diagnostic value has been demonstrated –34. T-ceS1 Checklist(DOC)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 File(PDF)Click here for additional data file.


For extranodal sites, a sensitivity of 80.4% and a specificity of 99.5% were found (κ 0.84). Concordance in Ann Arbor was found in 57 of 61 patients (κ 0.92). Discrepancies were due to misclassification of region and not lesion detection. In response assessment, a sensitivity of 100% and a specificity 99.9% for all sites combined were found (κ 0.92). There was a perfect agreement on Deauville scores 4 and 5 and criteria of response between the two modalities. Intraclass correlation coefficient (ICC) for SUVmax, SUVpeak, and MTV values showed excellent reliability (ICC > 0.9). FDG PET/MR is a reliable alternative to PET/CT in this patient population, both in terms of lesion detection at baseline staging and response assessment, and for quantitative prognostic imaging biomarkers.The aim of the current study was to investigate the diagnostic performance of FDG PET/MR compared to PET/CT in a patient cohort including Hodgkins lymphoma, diffuse large B-cell lymphoma, and high-grade B-cell lymphoma at baseline and response assessment. Sixty-one patients were examined with FDG PET/CT directly followed by PET/MR. Images were read by two pairs of nuclear medicine physicians and radiologists. Concordance for lymphoma involvement between PET/MR and the reference standard PET/CT was assessed at baseline and response assessment. Correlation of prognostic biomarkers Deauville score, criteria of response, SUVmax, SUVpeak, and MTV was performed between PET/MR and PET/CT. Baseline FDG PET/MR showed a sensitivity of 92.5% and a specificity 97.9% compared to the reference standard PET/CT ( The goal of treatment for Hodgkins lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), and high-grade B-cell lymphoma is most often cure. Accurate staging at baseline and response assessment is therefore essential for optimal treatment strategies. Furthermore, risk stratification and treatment decisions require reliable prognostic imaging biomarkers in addition to pretreatment clinical risk assessment scores.18F-Fluorodeoxyglucose (FDG) is the standard imaging modality for FDG-avid lymphomas. Response adaptive FDG PET/CT guided treatment approach to evaluate chemosensitivity and to guide decision of radiotherapy allows for individual treatment strategies in HL  and 20 were false negatives . An example of such a false-positive nodal site on PET/MR is shown in Fig. κ 0.84 (95% CI 0.76–0.92). Of the 16 discrepant extranodal sites, 5 were false positive on PET/MR compared with the PET/CT . An example of a false-positive extranodal site on PET/MR is shown in Fig. When comparing consensus baseline FDG PET/MR with PET/CT as the reference standard Table  for noda, pelvic , hilar (κ 0.92 (95% CI 0.85–1). When comparing limited disease, I–II versus extended disease III–IV, 59/61 was staged similar on PET/MR and PET/CT.We found concordance in disease stage (Ann Arbor 0–IV) in 57/61 patients (93%) with a weighted kappa value of Table κ 0.72 (95% CI 0.54–0.89). Difference in Deauville score grading between PET/MR and PET/CT was seen in 11 patients and only in those with complete metabolic response (Deauville score 1–3). Figure All of the 47 consensus interim and end of treatment examinations were scored similar on FDG PET/MR and PET/CT in terms of criteria of respons. Deauville score grading showed good agreement on weighted kappa, n = 236) and SUVpeak values (n = 235) from lymphoma lesions detected on both modalities. ICC estimates and their 95% confident intervals were 0.95 (0.91–0.97) for SUVmax and 0.96 (0.94–0.97) for SUVpeak, both showing excellent reliability (p < 0.001). The Bland-Altmann plot of SUVmax . A Bland-Altmann plot of MTV  for MTV, showing excellent reliability  was found in 57 of 61 patients. Three patients were understaged and one upstaged with FDG PET/MR versus PET/CT. The reason for under staging on FDG PET/MR was two patients with soft tissue or pleural involvement on PET/CT classified as nodal lesions on PET/MR, and one periaortic node with lower SUVmax on PET/MR and therefore interpreted as a reactive node. The discrepancy that led to upstaging on FDG PET/MR was a cervical lymph node with higher SUVmax on FDG PET/MR, interpreted as reactive node on PET/CT. In our cohort, this would have had clinical treatment consequences in one HL patient if staged with FDG PET/MR instead of PET/CT.In response assessment scans, we found a sensitivity of 100% and a specificity of 99.9% for FDG PET/MR on both nodal and extranodal sites combined. Seven of the 43 response assessment scans had FDG avid disease present on both modalities. Among these patients, one patient with partial metabolic response on both examinations also had an axillary node that was graded positive on FDG PET/MR due to higher SUVmax than on PET/CT. In addition, one bone marrow was graded positive on FDG PET/MR and labeled as soft tissue on PET/CT , as increased SUV is reported in lymphoma patients until 2 h after FDG injection . Previou3. When considering the scale of MTV values in our population, both the mean difference and the LoA indicate good agreement among most of the patients and no systematic bias of clinical importance. There was no misclassification in attenuation correction maps or other external explanations in the images with the largest differences. MTV has previously been compared between FDG PET/CT and PET/MR retrospectively in a lung and pancreatic cancer population [To our knowledge, this is the first study to compare MTV between FDG PET/CT and PET/MR in lymphoma patients. Our results showed excellent reliability in baseline MTV in 33 patients with aggressive NHL. MTV was slightly higher with FDG PET/CT than with PET/MR with a mean difference of 7.4 cmpulation  and the pulation . Howeverpulation , 26. Forpulation . TogetheA notable limitation of our study is that all the FDG PET/MR scans was performed after PET/CT. Future studies may scan half of the patients with PET/MR first to even out the difference in time of administration of FDG to time of imaging. Furthermore, the lack of a diagnostic contrast-enhanced CT for the radiologist to use for anatomical correlation when interpreting FDG PET/CT may have affected the interpretation of extranodal lesion localizations on the reference standard.In conclusion, our study shows an overall excellent agreement between FDG PET/MR and PET/CT in terms of lesion detection at baseline staging and response assessment for adult patients with classical HL, DLBCL, and high-grade B-cell lymphoma. The discrepancies between the modalities were mainly due to misclassification of region and not due to lesion detection. The PET-based quantitative prognostic imaging biomarkers also showed good agreement between the two modalities, demonstrating that FDG PET/MR is a reliable alternative to PET/CT in this patient population.


Depressive symptoms are globally recognized as a significant mental health problem in patients with chronic disease, particularly those with systemic lupus erythematosus (SLE). The purpose of this study was to estimate the prevalence and examine biopsychosocial factors of depressive symptoms among patients with SLE.This cross-sectional study was conducted among 185 participants diagnosed with SLE and received treatment for at least 3 months, aged 18–59 years attending the outpatient clinic of a university hospital, Bangkok, Thailand. Depressive symptoms were measured by the Thai version of the Patient Health Questionnaire-9. We assessed Demographic data, the Systemic Lupus Erythematosus Activity Index, the Systemic Lupus International Collaborating Clinics Damage Index, Numeric Rating Scale, Fatigue Severity Scale, Body Image Scale, and the ENRICHD Social Support Instrument. Data were collected from March to May 2021. Multivariable logistic regression was used to analyze the data.The proportion of the participants with depressive symptoms was 43.2%, which 8.1% of those patients presented moderate to severe depressive symptoms. In a multivariable logistic regression model, SLE patients with depressive symptoms were more likely to be severe pain , fatigue , taking prednisolone ≥15 mg daily , low satisfied of body image , and low social support . Disease flare, organ damage, and family income sufficiency did not significantly increase the risk of depressive symptoms in patients with SLE.The findings highlight depressive symptoms in patients with SLE. Therefore, the health professional should be concerned about the perception of body image, level of social support, fatigue, and pain while treating patients with SLE. Public health screening programs to identify depressive symptoms in patients with SLE are needed. In addition, a high dose of prednisolone should be considered if required, along with monitoring. Depression is the most frequent among neuropsychiatric manifestation complaints in patients with Systemic Lupus Erythematosus (SLE) , 2 that SLE is the prototypical autoimmune disease affecting multi-organ systems. A complex interaction of genetics, environment, and hormones leads to immune dysregulation and breakdown of tolerance to self-antigens, resulting in autoantibody production, inflammation, and destruction of end-organs. It is a significant disease burden across the world among different ethnic, racial, and age groups . SLE troThe nature of SLE is a complex disease that can affect the body without limitation, and the disease causes many different clinical symptoms . TypicalDepression is a profoundly impactful comorbidity for SLE patients’ health and well-being , with coMalfunction and injuries in various body organs are essential factors that cause patients to face grave disease prognoses. The severity of SLE, including active disease or disease flare and disability from organ damage , 28, andPatients with SLE are often treated with glucocorticoids as monotherapy or combination therapy with hydroxychloroquine, non-steroidal anti-inflammatory drugs (NSAIDs), and immunosuppressants. Studies show that immunosuppressants  reduce disease activity . HoweverChanging physical appearance from disease progression and its treatment leads to low self-esteem and increases the risk of depressive symptoms , 37. UnsLiving with SLE hurts partnerships, family relationships, and social life. Due to increasing disability, patients spend less overall and quality time with their partners . The unpPoor financial status or insufficiency of household income is a factor associated with depressive symptoms in patients with SLE . After 5Depressive symptoms in patients with SLE have been examined in previous studies; however, findings were with Caucasian patients  that mayThe main objective of the present study was to determine biopsychosocial factors associated with depressive symptoms among patients living with SLE in clinical settings in urban Thailand. In addition, the prevalence of depressive symptoms was estimated.A cross-sectional study was conducted in three outpatient medical clinics, including the medicine, nephrology, and rheumatology clinics of a university hospital in Bangkok, Thailand.Thailand is an upper-middle-income country located in South-East Asia. The current population of Thailand is 70,005,912 based on Worldometer elaboration of the latest United Nations data . 51.1% oData collection operations took place during the COVID-19 outbreak. The researcher and participants strictly complied with the rules for preventing the spread of infection by completing questionnaires and body temperature checks, always wearing masks, and keeping social distancing of at least 2 m.Patients with SLE were recruited at the time of their routine follow-up visit. The patients were eligible if between 18 and 59 years old, both male and female, and diagnosed according to the 1997 ACR, Revised Criteria for the classification of Systemic Lupus Erythematosus and were on medication for at least 3 months, patients observed with stable treatment. All patients were Thai, and able to read and write and give informed consent in the Thai language. Those who were unable to provide essential knowledge required in the study protocol, lacked necessary communication skills, were diagnosed with psychiatric disorders, had comorbid physical illnesses of life-threatening conditions, or need urgent treatment were excluded from the study. Inclusion and exclusion criteria were affirmed for essential information by interview and medical record.The sample size was calculated by G*Power version 3.1.9.7 program and based on the results of a study, an independent pain variable by Chang et al.  depressiPart 1: Personal information contains items about sex, age, religion, marital status, education level, occupation, rights to medical treatment, family characteristics, number of family members, average family income per month, and the sufficiency of household income.Part 2: Clinical information contains items about the duration of SLE disease, daily steroid dosage, disease flare, other congenital diseases, history of mental illness, weight, height, and body mass index.The socio-demographic and medical history questionnaire was developed by researchers and reviewed by a panel of three experts and yielded a content validity score of 1, which consisted of 19 items divided into two parts:Depressive symptoms were evaluated with the Thai version of the nine-item Patient Health Questionnaire (PHQ-9) . The ThaThe Systemic Lupus Erythematosus Activity Index (SLEDAI), developed by Bombardier et al. , was useThe Systemic Lupus International Collaborating Clinics Damage Index (SLICC Damage Index) developed by Gladman et al.  was usedThe Numeric Rating Scale (NRS) was used to assess the level of pain, with a scale developed by Jensen & Karoly  and updan = 30) obtained a Cronbach’s alpha coefficient of .89. The fatigue assessment was adjusted by self-report of participants.Fatigue Severity Scale (FSS) developed by Krupp et al.  and trann = 30) showed a Cronbach’s alpha coefficient of .89. The body image assessment was a self-report of participants.Body Image Scale (BIS) measured the level of body-image satisfaction as developed by Hopwood et al.  and was n = 30) obtained a Cronbach’s alpha coefficient of .94. The social support assessment was adjusted by self-report of participants.The ENRICHD Social Support Instrument (ESSI) measured social support as developed by Mitchell et al.  and tranEthical approval was granted by the Institutional Review Board Faculty of Nursing, Mahidol University (IRB-NS2020/42.3010), and the Institutional Review Board Faculty of Medicine, Chulalongkorn University, Thailand (IRB No. 099/64). In addition, the committee for research of the hospital approved the research project before working with human subjects. Participants completed informed consent forms. The researcher also asked subjects’ permission to use the data contained in their medical records. All procedures were performed following ethical guidelines and regulations. The study was conducted from November 2020 through July 2021, and participant recruitment took place from March 2021 to May 2021. The participants answered six questionnaires by themselves, including 48 questions, the data collection produced approximately 20 to 25 min for each participant.Data were double entered into an Excel sheet before being transferred into the SPSS program version 22.0 for analysis. Categorical and continuous data were appropriately analyzed to present the characteristics of participants by descriptive statistics. The chi-square test assessed characteristics between patients with and without depressive symptoms. Univariate logistic regression analysis was performed per each biopsychosocial variable. The complete multivariable logistic regression analysis model included all significant independent variables at a significance level of α = 0.05.The study comprised 185 Thai men and women who were diagnosed with SLE. Most of them were female (96.2%), between 36 and 59 years old (70.3%), with an average age of 42.16 years (SD = 10.78), single (52.4%), Buddhists (95.7%), and had bachelor’s degrees (42.7%). Most of the patients work (72%) and use the social security schemes to access healthcare (38.9%). Most of the patients are dwelling in single families (81.1%) with 1 to 3 of family members (57.8%), the average household monthly incomes were between 10,000 and 25,000 baht (34.1%) and had no income leftover (51.4%) (Table 2 (SD =5.77), 94 (50.9%) of patients were of abnormal weight, with 16.8% underweight and 34.1% overweight (Table Most of the patients had been diagnosed with SLE for 11 to 20 years (36.8%), took prednisolone 1 to 5 mg daily (48.1%), and had disease remission (78.4%). The result showed that 161 (87% of patients) had other congenital diseases, for instance, lupus nephritis (47%), hypertension (19.5%), and dyslipidemia (13.5%). They had an average body image index of 23.10 kg/mThe findings showed 43.2% of the participants had depressive symptoms. Classified by severity level of depressive symptoms, 2.2% of patients had severe depression, 5.9, and 35.1% had moderate or mild levels of depression. The PHQ-9 scores were between 0 and 23 points, with an average of 7.77 points (SD = 4.79) , and patients of different marital statuses tended to have different levels of depressive symptoms (p = 0.051) , disease flares especially both in the kidney system (p = 0.007) and muscles (p = 0.044), and body mass index (p = 0.008) were significantly associated with depressive symptoms in patients with SLE. Complications of avascular necrosis tended to be associated with depressive symptoms by patients (p = 0.061)  Table .p = 0.002), organ damage (p = 0.036), moderate or severe pain (p = 0.044) (p = 0.002), fatigue (p = 0.000), taking prednisolone ≥15 mg daily (p = 0.004), moderate or low satisfaction with body image (p = 0.008) (p = 0.000), moderate or low social support (p = 0.001) (p = 0.002), and leftover of income (p = 0.009) was significantly associated with depressive symptoms in patients with SLE , fatigue (p = 0.031), taking prednisolone ≥15 mg daily (p = 0.004), low satisfaction with body image (p = 0.004), and moderate or low social support (p = 0.013) (p = 0.009) was significantly associated with depressive symptoms in patients with SLE. Patients who took prednisolone, 6 to 14 mg daily (p = 0.091), tended to show an associated with depressive symptoms , inflammatory markers, and micro vasculopathy, as well as volume reduction in the white matter and grey matter of the brain . SLE’s sOn the other hand, the observation in the multivariable analysis showed extreme pain, severe fatigue, and high dosage of steroid use were strongly interwoven in physical and psychiatric disorders among patients with SLE , 29, 38.Increased body mass index scores in patients correlate with depressive symptoms, and the patients with depressive symptoms demonstrate higher levels of unemployment. Those findings could be confounding factors in depression but may also indicate the risk of depressive symptoms, which cause disease manifestations, disability, and productivity .Dissatisfaction with one’s appearance is a real problem that patients with SLE frequently face , 71. HowAmong social factors, the findings from the multivariable analysis did not show household income sufficiency was significantly associated with depressive symptoms in patients with SLE. A consistent previous examination found poverty was a significant predictor in the bivariate analysis, but not the multivariate . HoweverOur findings shed light on the need for clinical implementation to reduce depression and improve the quality of life of SLE patients. A practical approach, including medication , 79 and The strengths of this study include the use of psychological instruments, which are acceptable, reliable, and valid in the Thai populations. Moreover, independent variables were defined based on Engle’s biopsychological model. It is a practical way of understanding how patients suffer physical and mental illnesses from sociology to molecular biology , 82. RegHowever, this present study has several limitations. Participants were selected using inclusion/exclusion criteria, and the investigation was performed at a single medical center. Therefore, it may not represent patients with initial treatment, psychiatric disorders, cognitive impairment, or life-threatening conditions. Additionally, the role of inflammation and genetic susceptibility for the emergence of depressive symptoms was not assessed. Thus, more psychoanalytic research is needed to clarify the relationship between the immune system of disease activity and a patient’s psychological function.In summary, depressive symptoms are highly prevalent among Thai patients with SLE. Depressive symptoms in patients arise from various causes, including particular perceptions of individual patients. Treatments of depressive symptoms may benefit patients with extreme pain, fatigue, high prednisolone dosage, low satisfaction of body image, and low social support. Further study of biopsychosocial factors is necessary to fully address the causes and potential management of debilitating depression in patients with SLE.


Efficient cognitive tasks sensitive to longitudinal deterioration in small cohorts of Huntington’s disease (HD) patients are lacking in HD research. We thus developed and assessed the digitized arithmetic task (DAT), which combines inner language and executive functions in approximately 4 minutes.We assessed the psychometric properties of DAT in three languages, across four European sites, in 77 early-stage HD patients , and 57 controls . Forty-eight HD patients and 34 controls were followed up to one year with 96 participants who underwent MRI brain imaging (HD patients = 46) at baseline and 50 participants (HD patients = 22) at one year. Linear mixed models and Pearson correlations were used to assess associations with clinical assessment.At baseline, HD patients were less accurate (p = 0.0002) with increased response time (p<0.0001) when compared to DAT in controls. Test-retest reliability in HD patients ranged from good to excellent for response time (range: 0.63–0.79) and from questionable to acceptable for accuracy (range: r = 0.52–0.69). Only DAT, the Mattis Dementia Rating Scale, the Symbol Digit Modalities Test, and Total Functional Capacity scores were able to detect a decline within a one-year follow-up in HD patients . In contrast with all the other cognitive tasks, DAT correlated with striatal atrophy over time (p = 0.037) but not with motor impairment.DAT is fast, reliable, motor-free, applicable in several languages, and able to unmask cognitive decline correlated with striatal atrophy in small cohorts of HD patients. This likely makes it a useful endpoint in future trials for HD and other neurodegenerative diseases. Huntington’s disease (HD) is an inherited, autosomal, neurodegenerative disorder caused by a CAG repeat extension in the huntingtin gene on chromosome 4 . Thanks Executive function and language are commonly impaired in the early stages of HD –18 and ahttp://www.repair-hd.eu), which aims to establish a new protocol for assessment of innovative therapies in Huntington’s disease, 77 HD patients and 57 healthy controls matched for age  = 0.91; P = 0.34), education level  = 0.21; P = 0.64) and handedness  were included in the present study . Written informed consent was obtained from each participant.Out of the 185 patients in the European observational longitudinal study , and the task was completed on different laptops . The task lasted 2.59 ± 0.84 minutes in controls and 4.03 ± 1.51 minutes in HD patients.We adapted the paper and pencil arithmetic task  into a cWe analyzed median response time (RT) of correct responses and accuracy (percentage of correct responses) for each subject at each time of evaluation. The median was chosen for RT because of its superior reliability when using a small number of items (N = 40). Here, we provide measures combining data in the entire DAT (Arithmetic RT and Arithmetic accuracy), results for multiplication and subtraction are displayed separately in Brain MRI acquisition was performed at two centres. At Henri Mondor Hospital , participants underwent a high-resolution brain MRI scan on a Siemens Skyra including T1 3D anatomical MP-RAGE images . At the George Huntington Institute , participants underwent a high-resolution brain MRI scan on a Philips Medical Systems including T1 3D anatomical MP-RAGE images .https://surfer.nmr.mgh.harvard.edu/) [We used FreeSurfer (rd.edu/)  to calcuThe study flow chart and the demographic and clinical characteristics of participants at baseline are displayed in The motor (TMS) and functional (TFC) evaluations were only proposed at M0 and M12. Brain MRI scans were obtained for 96 participants (46 HD patients) at M1 and 50 participants (22 HD patients) at M12. Clinical, motor, cognitive evaluations and brain imaging acquisition were carried out over two days.Missing data in classic cognitive tests were imputed using the “missForest” package implemented in R using Random Forest.Linear models were performed at M0 on cognitive and DAT metrics to assess performance differences between healthy controls and HD patients. Age, sex, education level, and TMS were added as covariates. Adding TMS as a covariate allowed for limiting the motor impact on cognitive performance. Pearson correlation coefficients were used to assess associations between DAT’s measures and cognitive assessments in HD patients at M0 and to assess the reliability of these measures between M0 and M1 evaluations in all participants.We used longitudinal linear mixed models  on motor, functional, DAT, and cognitive measures using the “lme4” and “lmerTest” packages in R software . Main efAt M1, linear regression was used to compare striatal volumes between groups. We also evaluated the association between cognitive or DAT measures and the striatal volume in HD patients using striatal volume as the predictor.Least-squares linear regression was used to compare longitudinal M1-M12 change in striatal volume between groups. The association between longitudinal differences in motor, functional, DAT, and cognitive measures (delta M12 –M1) and longitudinal differences in striatal volume (delta M12 –M1) was evaluated in HD patients using linear regression with inclusion of time, striatal volume, and its interaction with time as predictors. All statistical analyses conducted with brain imaging data were adjusted for age, sex, education, and MRI centre.At M0, controls performed better than HD patients on each of the paper and pencil tasks  . Slower Arithmetic RT and higher Arithmetic IES were associated with increased striatal atrophy in the HD group . As reported in In the longitudinal subset , HD patiPerformance in controls remained stable up to M12 for each of the cognitive tests, except for the Stroop Word Reading test, in which they improved . In cont2(1) = 18.46, P<0.001). A progressive reduction in striatal volume was observed in HD patients between M1 and M12  but not in controls (P>0.05). Slower Arithmetic RT, increased Arithmetic IES and decline in TFC between M1 and M12 were associated with decrease in striatal volumes   and time  (X= 0.047) . In cont= 0.047) .We report the validity of the Digitalized Arithmetic Task (DAT) and its sensitivity to capture cognitive decline in HD patients at stages 1 and 2 of the disease. This study was conducted in the framework of the European multi-centric Repair-HD study in four centers and three languages . In approximately 4 minutes, DAT not only allowed for discrimination between groups (controls vs. HD patients), but also detected a decline in cognitive performance over one year in a relatively small cohort of HD patients (N = 48). Effect sizes were similar to those obtained in both the general cognitive assessment (MDRS) and executive (SDMT) paper and pencil tasks. In contrast with the UHDRS cognitive assessment, MDRS and HLVMT, longitudinal decline in DAT performance was associated with striatal atrophy, a major pathological hallmark of HD , and wasOur study complements the recently adopted multidomain approach to increase the sensitivity of impairment monitoring in HD. Some authors have used a composite score combining performances from several clinical and cognitive tests ,32 ratheWhen developing a cognitive test, careful consideration must be given to its psychometric validation. Following the recommendations of Mestre and collaborators , clinicaWhereas cognitive decline progresses slowly in HD, DAT has been able to show a decline over one year in a relatively small cohort of patients. Among classic cognitive tests included in our study, only the Mattis Dementia Rating Scale (MDRS) and the Symbol Digit Modalities Test (SDMT) were found to show a significant decline in this time frame. Surprisingly, despite extensive use in the 1980s and 1990s , MDRConsidering the decline in other classic paper and pencil tasks, only SDMT demonstrated a decline in our cohort in accordance with previous large and multicentric longitudinal studies, suggesting that speed processing measures are the most reliable indices of disease progression ,10. We sThis study shows that the use of DAT, a fast, cognitive, digitalized task developed for use in HD, has the potential to improve clinical practice by increasing standardization, reliability, and efficiency of cognitive assessment, as well as by automating the scoring process in longitudinal follow-up studies. By combining two key cognitive functions affected by HD, as well as the response time and accuracy through the comprehensive IES metric, DAT is sensitive to disease progression over one-year; DAT is likely to be useful in other neurodegenerative diseases. The DAT could be used to monitor cognitive status in HD patients included in clinical trials as well as in clinical follow-up. The DAT is available free of charge upon request, by writing to the corresponding author (ACBL). Thus, it also could be used in low-resource settings to assess and monitor cognitive status, when clinicians and researchers cannot access expensive assessments such as neuropsychological tests and an MRI scan. Future studies should assess whether the promising DAT has the capacity to be completed at home by HD patients, as this could reduce the financial cost and inconvenience for patients and families requiring frequent hospital and clinic visits. In addition, a longitudinal follow-up study of gene-carrier individuals on this task is important to assess whether the cognitive measures identified in this present study can be used as markers even for individuals far from predicted clinical symptom onset. This is especially crucial during the current developmental era of disease-modifying treatments for this pathology. Finally, the design of the present study did not allow for the comparison between the digitalized and paper and pencil versions of the arithmetic task used previously . To inveS1 FigTFC Total Functional Capacity, TMS Total Motor Score, SDMT Symbol Digit Modalities Test, HVLMT Hopkins Verbal Learning Memory Test, IR Immediate recall, DR Delayed Recall, MDRS Mattis Dementia Rating Scale.(DOCX)Click here for additional data file.S2 FigArithmetic IES, Arithmetic accuracy and Arithmetic RT are the score across the two conditions (subtraction and multiplication).(DOCX)Click here for additional data file.S3 FigTMS Total Motor Score, MDRS Mattis Dementia Rating Scale, SDMT Symbol Digit Modalities Test, HVLMT Hopkins Verbal Learning Memory Test, RI Immediate recall, RD Delayed Recall.(DOCX)Click here for additional data file.S4 FigTFC Total Functional capacity, TMS Total Motor Score, RT Response Time, IES Inverse Efficiency Score Arithmetic IES, Arithmetic Accuracy and Arithmetic RT are the score across the two conditions (subtraction and multiplication).(DOCX)Click here for additional data file.S5 FigMDRS Mattis Dementia Rating Scale, SDMT Symbol Digit Modalities Test, HVLMT Hopkins Verbal Learning Memory Test, RI Immediate recall, RD Delayed Recall.(DOCX)Click here for additional data file.S1 TableOn the right, the Pearson’s correlation coefficients between the two tests are shown with their p-values.(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 TableUnless otherwise specified, values are means ± standard deviations.(DOCX)Click here for additional data file.S4 TableMeans (and standard deviations) are presented for each test at each time of evaluation.(DOCX)Click here for additional data file.