While converging sources of evidence point to the possibility of a large‐scale distributed network for semantic cognition, a consensus regarding the underlying subregions and their specific function in this network has not been reached. In the current study, we combined functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) methodology to investigate the neural basis of semantic cognition in Mandarin Chinese. In the fMRI experiment, strong activations were observed in left inferior frontal gyrus (IFG) and left middle temporal gyrus (MTG) for semantic judgment task. Moreover, functional connectivity was found from seed region left IFG to left MTG. Meanwhile, negative correlation between performance and extracted parameter estimates from left IFG to left MTG was detected in semantic task. Subsequent TMS stimulation over left IFG resulted in performance deficits in semantic judgment task, in contrast to other three sites: left MTG, right intraparietal sulcus (IPS) and a control site. We concluded that the neural basis of semantic processing for Mandarin Chinese closely resembled that for alphabetic languages such as English, supporting a language‐universal view on semantic cognition. Two subjects quitted the TMS experiment later for personal reasons. Thus, altogether 24 subjects participated in the TMS study . With normal or corrected‐to‐normal vision, all subjects neither had any personal or family history of neurological or psychiatric illness nor took medication in the course of the experiment. Before the formal experiment, they were all informed of the potential side effects of TMS and they offered written informed consent. All the subjects passed safety screening for TMS , word length (p = .65), and word frequency (p = .98). The numerical judgment task was also adapted from previous studies . All participants performed a semantic judgment task and a numerical judgment task .2.4.13; 43 slices. We also acquired a high‐resolution, whole‐brain structural T1‐weighted image with a magnetization‐prepared gradient echo sequence. The scanning parameters were the following: TR = 1900 ms; TE = 2.26 ms; thickness, 1 mm; sagittal field of view, 256 × 256 mm2; flip angle, 9°; matrix, 256 × 256 × 176; voxel size, 1 × 1 × 1 mm3.MRI scanning was done using a 3.0 T GE Sigma scanner at the High‐Field Magnetic Resonance Brain Imaging Key Laboratory at the University of Electronic Science and Technology of China, Chengdu, China. We acquired functional MRI images using a gradient echo planar imaging (EPI) sequence. The scanning parameters were the following: 190 EPI volumes per block; TR = 2000 ms; TE = 30 ms; FA = 90°; FOV = 240 mm; matrix size = 64 × 64; voxel size = 3.75 × 3.75 × 3 mm2.4.2http://www.restfmri.net/forum/DPARSF) and SPM12 software . For each participant, the first five volumes of each functional time series were discarded for signal stabilization. Images were corrected for head movement between scans by an affine registration. The remaining functional images were preprocessed including slice timing correction, three‐dimensional motion correction, co‐registration to individual T1 structural image, and normalization by DARTEL  reference space (3 × 3 × 3 mm3) and spatial smoothing with an 8 mm Gaussian kernel . Low‐frequency signal drifts were removed with a temporal high‐pass filter (default cutoff of 128 s). No subject had more than 2 mm of translation or 2° rotation.fMRI data analysis was performed using DPARSF version 4.1  of the experiment. The individual trial onset sequence for semantic judgment task and numerical judgment task were obtained by convolving a canonical hemodynamic response function to form regressors of the design matrix  and vice versa (number‐semantic) and between each task and the fixation blocks (semantic‐rest and control‐rest). Then, the following whole brain multi‐subject analysis was conducted by using a random effects model with a one‐sample t test on the summary statistic. The statistical contrast maps were thresholded at p < .001  to control for multiple comparison  and for left MTG at . Another region was located at parietal cortex in the right hemisphere, generally considered to be important in numerical judgment task across our subjects for right IPS .Two ROI regions were localized at the left hemisphere of the frontal and temporal cortices, which were usually considered to be important in semantic judgment task. The average MNI coordinates across our subjects for left IFG was located at  was applied at the stimuli onset to transiently disrupt the processing of semantic cognition. According to the ROIs in the fMRI experiment, online tpTMS stimulation was administered with a Magstim super rapid magnetic stimulator and a figure‐of‐eight coil (diameter 70 mm) . TMS session was conducted in accordance with the published safety guidelines . Triple‐pulse TMS was stimulated with at a pulse interval of 25 ms (40 Hz) at 100% resting motor threshold (RMT) as that used in our previous TMS studies on language comprehension  GLM. Reaction time (RT) and accuracy rate (ACC) was measured. We used repeated measures ANOVA (Bonferroni corrected) to compare RT and ACC, with stimulation sites  and tasks  as within‐subject factors. Post hoc 2.7The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the 3We combined fMRI and TMS methodology to investigate the neural basis of semantic cognition in Mandarin Chinese. First, in the fMRI experiment, participants performed semantic and numerical judgment task in Mandarin Chinese. According to each subject's fMRI data, we identified three sites for TMS stimulation: left IFG, left MTG, right IPS, and a control site Vertex. Then, we delivered online triple‐pulse TMS (tpTMS) stimulation to each of these regions on separate days.3.13.1.1p < .001 (FDR‐corrected). The clusters that exceeded 30 voxels were shown in Table The data were initially processed as a whole brain cluster analysis, comparing semantic judgment tasks with numerical judgment tasks (semantics > numbers). The statistical image was evaluated at p < .001 using FDR).Contrasting the numerical task against the semantic task , we found activation in the bilateral inferior parietal lobe, the right precuneus, the right frontal cortex (middle/superior gyrus), and the right superior occipital gyrus , a main effect of task   and a significant interaction between ROI and task   under the semantic and numerical task conditions. The results revealed that left IFG was more active during the semantic judgment task , than during numerical judgment task. Similar to left IFG, strong activation in left MTG was found in semantic judgment task, compared with that in numerical judgment task . In contrast, right IPS was more active during numerical task . Finally, although Vertex showed strong BOLD signal change in semantic and numerical judgment task, respectively, no difference of BOLD signal change was detected between the two tasks .The two‐way repeated ANOVA (Bonferroni corrected) (4 ROI × 2 task) ROI analysis showed a significant main effect of ROI   approach  = .001, cluster size = 66, t = 3.58). No other significant connectivity was detected with seed regions , respectively. For the numerical > semantic contrast, there was no significant functional connectivity detected for the four seed regions.According to the whole brain analysis, four ROIs  were taken as seed regions with a 6 mm radius sphere centered at the peak activation coordinates. To test the network of cognitive processing, two PPI contrasts were set:  and . First, for the semantic > numerical contrast, increased connectivity were only found between seed region left IFG and left MTG  in semantic task . The ANOVA model included the factors: task  and TMS site . Mean RT and ACC for the semantic and numerical judgment task at four TMS stimulation sites are listed in Table F  = 7.567, p < .05], indicating that RTs were longer when subjects made semantic judgment task compared to those in numerical judgment task. We also found an interaction between task and TMS site . Accordingly, post hoc t test, using Bonferroni corrected for multiple comparisons, was conducted to compare the RTs difference after TMS stimulation over four TMS sites within each task. For the semantic judgment task, the results showed that RTs were significantly prolonged after TMS stimulation over IFG, compared with those over MTG , IPS , and the control site, Vertex . For the numerical task, significantly increased RTs were found after TMS stimulation over right IPS, compared to similar stimulation over Vertex . No significant differences in RTs were found between IFG, MTG, and Vertex in numerical judgment task .Overall, the two‐factorial ANOVA revealed a main effect of task , indicating that ACC was significantly higher when subjects made numerical judgments compared to semantic judgments. Exploratory analyses also demonstrate a significant main effect of TMS sites  and interaction between task and TMS sites . For the semantic task, post hoc t tests revealed decreased ACC at IFG site compared with other three sites, MTG , IPS , and Vertex . No significant differences in ACC were found between MTG, IPS, and Vertex . For the numerical task, post hoc t tests revealed decreased ACC at IPS site compared with Vertex . Interestingly, we also found decreased ACC at MTG site compared with Vertex for numerical task .A two‐factorial ANOVA with task  and TMS sites  as the two within‐subject factors revealed a significant main effect of task [4The present study aimed to investigate the neural basis of semantic cognition in Mandarin Chinese and the specific functions of its underlying subregions using a combined fMRI–TMS methodology. First, in the fMRI experiment, strong activation in left IFG and left MTG were detected in semantic judgment task, coupled with significant functional connectivity between these regions. Meanwhile, functional connectivity analysis between left IFG and MTG showed strong correlation with performance in the same task. Interestingly, no significant activation was found in left MFG and superior parietal gyri, which were claimed to be unique for Chinese language processing. Moreover, TMS stimulation over left IFG largely disrupted performance in semantic task, compared to the other three sites: left MTG, right IPS, and Vertex. However, no such deficits were found at left MTG in the same task.4.1An extensive set of studies on alphabetic languages such as English have shown that left IFG plays an essential role in regulating semantic activation , with at least 100 voxels. FDR, false discovery rate.Click here for additional data file.S2 Brain activations displayed in the red color scale represent numerical > semantic judgment contrast. These contrasts are survived at the cluster level, p < .001 (FDR‐corrected), with at least 100 voxels. FDR, false discovery rate.Click here for additional data file.


Terlipressin, in general, is a vasopressor which acts via V1 receptors. Its infusion elevates mean blood pressure and can reduce bleeding which has a splanchnic origin. The primary outcome was to assess the impact of intraoperative terlipressin infusion on portal venous pressure during hepatobiliary surgery; the 2ry outcomes included effects upon systemic hemodynamics, estimated blood loss, and postoperative renal functions.This prospective randomized study involved 50 patients undergoing hepatobiliary surgery who were randomly and equally allocated into terlipressin group, or a control group. The terlipressin group received an initial bolus dose of (1 mg over 30 min) followed by a continuous infusion of 2 μg/kg/h throughout the procedure and gradually weaned over the first four postoperative hours, whereas the control group received the same volumes of normal saline. The portal venous pressure changes were measured directly through a portal vein angiocatheter.p < .001). Mean arterial blood pressure was significantly higher in the terlipressin group. Estimated blood loss was significantly higher in the control group than the terlipressin group , and the units of packed RBCs transfused were significantly higher in the control group ((0–2) versus (0–4) p = 0.003). There was no significant difference between groups as regards the incidence of acute kidney injury.Portal pressure was significantly reduced over time in the terlipressin group only (from 17.88 ± 7.32 to 15.96 ± 6.55 mmHg, Intraoperative infusion of terlipressin during hepatobiliary surgery was shown to improve intraoperative portal hemodynamics with subsequent reduction in blood loss.NCT02718599. Name of registry: ClinicalTrials.gov. URL of registry: https://clinicaltrials.gov/ct2/show/NCT02718599. Date of registration: March 2016. Date of enrolment of the first participant to the trial: April 2016.Clinical trial number and registry URL: Trial registration number:  Intraoperative blood volume loss as little as 10 to 15% could result in splanchnic hypoperfusion, which usually persists during the period of hypovolemia –4. AvoidTerlipressin is a synthetic analog of arginine vasopressin but with longer duration of action. It has been utilized in the management of circulatory dysfunction after paracentesis, hepatorenal syndrome and esophageal variceal bleeding in end-stage liver disease patients . TerliprThe primary aim of our study was to evaluate the impact of intraoperative terlipressin infusion on the hepatic hemodynamics . Secondary goals included the effects of terlipressin infusion upon intraoperative systemic hemodynamics, estimated blood loss during open hepatobiliary surgery, and the early postoperative renal function.ClinicalTrials.gov (NCT02718599). The study was carried out at Assiut University Hospitals, Al Rajhy Liver Hospital, between April 2016 and July 2017 in accordance with the Consolidating Standards of Reporting Trials (CONSORT) 2010 statement.This prospective, randomized, controlled study was approved by the Medical Ethics Committee at Assiut University (reference number IRB17200284). All participants provided written informed consent. The trial was registered prior to patient enrollment at + < 132 mmol/l), severe valvular heart disease, heart failure, symptomatic coronary heart disease, bradycardic arrhythmia (heart rate < 60/min), peripheral artery occlusive disease , uncontrolled arterial hypertension (Blood pressure > 160/100 mmHg despite intensive treatment), pregnancy and intraoperative need for Pringle maneuver. Fifty patients were randomly and equally allocated into one of two groups, control group  and terlipressin groups  by simple randomization technique  done by a study coordinator, who also encodes the drugs with matching random numbers. Surgeon, his assistants, and outcome assessing physician were kept blind to the grouping. All cases recruited to the study were done by the same surgeon.Eligible participants were adult patients aged > 18 years old with American Society of Anesthesiologists (ASA) Classification (Class I-II) undergoing major elective hepatobiliary surgery. Exclusion criteria included patients with preoperative renal failure, severe liver dysfunction (Child-Turcotte-Pugh grade C), hyponatremia (NaAll patients received standardized premedication with midazolam (0.02 mg/kg) and atropine (0.5 mg I.V). Anesthesia was induced in all patients with propofol (2 mg/kg) and fentanyl (1 μg/kg). Muscle relaxation for intubation was achieved by rocuronium (0.6–0.8 mg/kg) in both groups. Anesthesia was maintained with sevoflurane 1 MAC in medical air oxygen mixture (fraction of inspired oxygen 0.5), fentanyl infusion (1 μg/kg/hr.) and rocuronium infusion (0.01–0.012 mg/kg/min). Mechanical ventilation was controlled through a tidal volume of 6 to 8 mL/kg, and the ventilator rate (8–12/min) was adjusted to maintain an end-tidal CO2 of 35 to 40 mmHg. We used no PEEP with recruitment maneuvers repeated every 30 min after tracheal intubation. Each recruitment maneuver consisted of applying a continuous positive airway pressure of 30 cm of water for 30 s. Intraoperative normothermia was attained using warm intravenous fluids, a warm blanket, and humidifier. A 3-lm central venous catheter was placed through the right internal jugular vein, and central venous pressure (CVP) was monitored to guide fluid management during parenchymal dissection of the liver through maintaining CVP below 10 mmHg. A 22-gauge angiocatheter was inserted into the radial artery (after performing modified Allen’s test) and connected to the FloTrac/Vigileo™ monitor  for monitoring of cardiac output (COP), cardiac index (CI), stroke volume variation (SVV), and systemic vascular resistance (SVR). All blood pressure measurements were referenced to the level of the mid-axillary line. After surgical exposure of the portal vein, a 22-gauge angiocatheter was inserted into the portal vein and connected to a pressure transducer to measure the portal pressure at scheduled times, and for blood gas analysis of portal venous blood.2) after appropriate fluid administration, and the goal was to maintain CI between 2.5 and 4 l/min/m2. Ephedrine boluses (5–15 mg), or norepinephrine infusion was allowed in addition to colloid blouses to correct a fall in systolic arterial pressure < 90 mmHg, or mean arterial pressure < 65 mmHg to maintain it above 70 mmHg and the systemic vascular resistance above 600 dyn. s/cm5. Transfusion of packed RBCs was allowed if the hemoglobin level has diminished below 7 g/dl. All patients were transferred postoperatively to the post-anesthesia care unit.In a separate room, syringes containing Terlipressin for group T, and NaCl as a placebo for group C were prepared by an anesthesia technician who was not involved in the study after opening the sealed envelope and identification to which group the patient was to be enrolled. In group T, terlipressin was started just after exposure of the portal vein and obtaining a basal portal pressure reading, as an initial loading dose of 1 mg over 30 min followed by a continuous infusion of 2 μg/kg/hr. throughout the procedure and gradually weaned over the first 4 h postoperatively. In group C, patients received the same volume of normal saline. Intraoperative basal fluid replacement was attained in both groups through infusion of crystalloids (8 ml/kg/hr.), additional boluses of colloid solution in a dose of 3 ml/kg (Human Albumin 5% solution) were given when SVV was raised above 10% (a sustained rise during the previous 5 minutes) or in case of positive response (cardiac index increases above 10%) to previous fluid challenge. An infusion of dobutamine was initiated to raise the low cardiac output state conditions , mean arterial blood pressure (MAP), CVP, CI, SVV, SVR, and urine output (UOP). Fluid input , and output ) were recorded. The mean postoperative hemodynamic data  were recorded from the averaged 24 h’ measurements of the first day after surgery. Conventional renal function, hemoglobin level (Hb), sodium, and potassium levels were also reported preoperative as a baseline and daily for the first three postoperative days. The incidence of renal impairment was calculated according to AKIN criteria.p = .0001). Based on that literature [Power analysis was performed on the level of portal pressure (the 1ry outcome). A previous study showed that infusion of terlipressin was accompanied by a significant reduction of portal pressure from 25.3 ± 3.2 mmHg to 21.1 ± 3.3 mmHg  for Windows®. A A total of 50 patients were enrolled in this study and randomly allocated to the two groups as shown in the CONSORT flow-chart Fig. . There wP = 0.21). The initiation of terlipressin infusion was accompanied by a significant reduction of portal pressure from 17.88 ± 7.32 mmHg at baseline to 15.96 ± 6.55 mmHg (p < .001) in terlipressin, whereas in the control group, there was an insignificant change of portal pressure from 15.48 ± 5.92 mmHg at baseline to 16.48 ± 5.04 mmHg (p = 0.52). No significant difference was observed between both groups concerning the mean intraoperative values of portal pressure , and there was a significantly higher intraoperative SVR in terlipressin group in comparison to the control group (Table Hemodynamic changes are shown in Table . There wup Table . Three pup Table .Table 2HP = 0.002)  Table .Table 3Rp = 0.004); consequently, colloids and the units of transfused packed RBCs were significantly higher in the control group respectively   decrease of portal pressure. Terlipressin works through (V1) receptors in the vascular smooth muscle in the splanchnic blood vessels, which induces vasoconstriction and reduction in arterial blood flow to the splanchnic area with subsequent reduction in portal blood flow and thus a reduction in portal blood pressure . ElevatePrevious studies have demonstrated that intravenous injection of terlipressin improves renal function in hepatorenal syndrome patients, and at the same time can affect splanchnic and systemic circulations in cirrhotic patients , 15. HowFahrner and his colleagues reported better liver regeneration due to reduced portal venous pressure through terlipressin administration during the postoperative period . A randoWagener’s study had mentioned that vasopressin administration could decrease portal vein pressure as well as the flow in the native liver without reducing cardiac output or intestinal perfusion in liver transplant patients . MukhtarOur results as regards the improvement in SVR and the higher mean blood pressure in the terlipressin group are in agree with Hong and his colleagues’ study where they utilized terlipressin infusion in a dose of 1.0–4.0 μg/kg per hour in living donor liver transplant. They noted that terlipressin infusion was associated with increased SVR, and this offered better postoperative renal function, and shorter duration in ICU in comparison to patients who did not receive terlipressin .Many side effects to the use of terlipressin has been detected in different studies. Intestinal hypoperfusion is one of these side effects that might be noticed in patients with esophageal variceal hemorrhage, and portal hypertension who are treated with terlipressin , 23. SamIn the past, terlipressin was used to be administered by intermittent intravenous bolus injections. Recently, continuous infusion of (1.3–2.6 μg/kg/hr) of terlipressin early in distributive shock was used. This protocol significantly increased SVR with no undesirable side-effects, such as an excessive elevation in peripheral vascular resistance , 25. TheIn our study, one of the benefits of intraoperative terlipressin infusion in such major prolonged surgeries was the significant reduction of estimated blood loss in the terlipressin group which was reflected in the form of a significant reduction in the transfused packed RBCs units. This is in agreement with our previous study on liver resection surgeries  Fayed anIt has been documented that terlipressin administration can decrease plasma concentrations of renin, aldosterone, and norepinephrine. This reduction in such vasoconstrictors increases renal blood flow and improves kidney function , 28–30. It was mentioned in a retrospective study done by Yim and co-workers that the risk factors for the development of hyponatremia with terlipressin administration are young age patients, low body mass index, longer duration of terlipressin administration, and high base values of serum sodium which was not the case in our study .one limitation is that we have included patients with and without portal hypertension. Also, the use of colloid solution (Voluven) was not the ideal especially when we study renal function, but in our country, we don’t have other colloid options. One more limitation is that we did not consider the influence of terlipressin on renal tubular function through the sensitive markers, e.g., cystatin c, and urinary neutrophil gelatinase-associated lipocalin and our results about renal parameters were not correlated with postoperative fluid intake and balance. Another limitation of this study is that we didn’t document other side effects of terlipressin as limb ischemia and postoperative mortality.intraoperative infusion of terlipressin is shown to be an effective technique for reduction of portal venous pressure, and blood loss with better maintenance of systemic mean blood pressure and no significant sign of intestinal ischemia in patients undergoing major hepatobiliary surgery.


Nonocclusive mesenteric ischemia (NOMI) is a rare but life-threatening complication after cardiovascular surgery. Early diagnosis and treatment is essential for a chance to cure. The aim of this study is to identify the independent risk factors for NOMI based on the evaluation of 12 cases of NOMI after cardiovascular surgery.We retrospectively analyzed 12 patients with NOMI and 674 other patients without NOMI who underwent cardiovascular surgery in our hospital. We reviewed the clinical data on NOMI patients, including their characteristics and the clinical course. In addition, we performed a statistical comparison of each factor from both NOMI and non-NOMI groups to identify the independent risk factors for NOMI.p < 0.05), peripheral arterial disease (p < 0.001), postoperative hemodialysis (p < 0.001), intraaortic balloon pump (p < 0.05), norepinephrine (NOE) > 0.10γ (p < 0.0001), percutaneous cardiopulmonary support (p < 0.001), sepsis (p < 0.05), loss of sinus rhythm (p < 0.05), prolonged ventilation (p < 0.0001), and resternotomy for bleeding (p < 0.05) showed significant differences between NOMI and non-NOMI groups. In the multivariate logistic regression model, prolonged ventilation  and NOE > 0.10 μg/kg/min  were detected as independent risk factors for NOMI.The median duration between the cardiac surgery and the diagnosis of NOMI was 14.0 (10.3–20.3) days. The in-hospital mortality of NOMI patients was 75.0%. Age (We have identified the risk factors for NOMI based on the evaluation of the 12 cases of NOMI after cardiovascular surgery. This result may be useful in predicting NOMI, which is considered difficult in clinical practice. For the patient with suspected of NOMI who has these risk factors, early CT scan and surgical exploration should be performed without delay. Nonocclusive mesenteric ischemia (NOMI) is a rare complication after cardiovascular surgery, and its incidence rates were reported to be about 0.4 to 9.0% –4. AlthoHowever, there are few studies that have detected the risk factor of NOMI after cardiovascular surgery , 5. In tFrom March 1, 2010 to December 31, 2018, among the patients who underwent cardiovascular surgery in our institution, we conducted a retrospective case-control study for 12 (1.74%) patients who developed NOMI after surgery and 674 (98.3%) other patients. We also included emergent surgical cases and off-pump cases. Excluded cases were the patients with type A aortic dissection who had mesenteric ischemia before surgery, thoracic endovascular aortic repair, and pericardial fenestration.After cardiovascular surgery, the patients with suspected NOMI because of abdominal distension with absence of bowel sounds, acute abdominal pain, vomiting, hematochezia, or abnormal laboratory data underwent urgent abdominal CT scans. NOMI was diagnosed by the confirmation of the presence of ischemic bowel signs /mitral valve plasty (MVP), and tricuspid annulus plasty. Thoracic aortic surgery included ascending aortic replacement (AAR)/total arch replacement (TAR)/hemi-arch replacement, and aortic root replacement/remodeling. Each analyzed factor was defined using the following criteria. Norepinephrine (NOE) > 0.10 μg/kg/min was defined as using NOE more than 0.10 μg/kg/min for more than 1 h after surgery. Low output syndrome (LOS) was defined as using mechanical support, that is, intraaortic balloon pump (IABP) support and percutaneous cardiopulmonary support (PCPS). Prolonged ventilation was defined as mechanical ventilation time after surgery of more than 24 h. Loss of sinus rhythm was defined as the documented loss of sinus rhythm for at least 6 h after surgery. Hyperlactatemia was defined as having a serum lactate level of > 5.0 mmol/L.U test for continuous variables and χ2 test and Fisher’s exact test for categorical variables. Variables found associated with P < 0.05 in the univariate analysis were entered into a multivariate logistic regression analysis, using the stepwise selection method, to identify the factors independently associated with a definite risk factor of NOMI. All results were expressed as median (interquartile range). Statistical significance was set at P < 0.05 (two-sided). All data analyses were performed using the statistical program R version 3.2.1 .Statistical analysis was performed using Mann-Whitney Among patients who underwent cardiovascular surgery in our institution, 12 (1.74%) cases developed NOMI. The background of NOMI cases, including patient characteristics, surgery type, and state at the onset of NOMI, is displayed in Table NOE > 0.10 μg/kg/min was used for 7 of 12 cases within 24 h before the onset of NOMI. Cases 5 to 7 and 11 were in a state of LOS; furthermore, case 11 also had sepsis and underwent hemodialysis. Cases 5 and 7 underwent hemodialysis too, and Case 6 did not. Cases 1, 8, and 9 were not at a state of LOS and had sepsis but underwent hemodialysis while using NOE. NOE was not used for Cases 2 to 4, 10, and 12. Cases 2 and 4 had sepsis, and Case 12 was at a state of LOS and underwent hemodialysis. Cases 3 and 10 were not in any condition. As initial findings/symptoms, 7 of 12 cases showed hyperlactatemia. In others, 1 hypotension, 2 abdominal pain, 1 vomiting, and 1 hematochezia were found.p < 0.05), peripheral arterial disease , postoperative hemodialysis (p < 0.001), IABP (p < 0.01), NOE > 0.10 μg/kg/min (p < 0.0001), PCPS (p < 0.0001), sepsis (p < 0.01), loss of sinus rhythm (p < 0.01), prolonged ventilation (p < 0.0001), and resternotomy for bleeding (p < 0.01). Finally, these 10 factors were introduced for the multivariate logistic regression model as covariates and adjusted odds ratio (OR) were calculated. As a result, prolonged ventilation  and NOE > 0.10 μg/kg/min  were detected as independent risk factors for NOMI , total ventilation time (h), and index calculated from PEEP * ventilation time/body weight (BW) (cmH2O * h/kg) were statistical compared between NOMI (9 cases) and non-NOMI (108 cases) groups. As a result, all variables were higher in the NOMI group, but no significant difference was found between the two groups (Table ).Further analysis for these two variables showing significant difference in the multivariate logistic model has proceeded. Among the total 26 cases corresponding to NOE > 0.10 μg/kg/min, total quantity (μg/kg), duration (h), and maximum dose of NOE (μg/kg/min) were statistically compared between NOMI (9 cases) and non-NOMI (17 cases) groups. Similarly, among the total 117 cases corresponding to prolonged ventilation, maximum PEEP . This is because each patient status after cardiovascular surgery was individually different, and the threshold of the onset of mesenteric ischemia was varied depending on the patient’s general conditions. For example, even between patients who used the same high dose of NOE, there are several factors related to intestinal blood flow. Consequently, the actual dose that can be the cause of mesenteric ischemia for each case is not expected to be the same. If insufficient circulatory dynamics or severe arteriosclerotic change is present, mesenteric ischemia can be caused by an even lower dose of NOE. The same applies to the ventilation factor. Hence, the use of high dose of NOE and prolonged ventilation are important for the onset of NOMI; however, it is very difficult to detect the definite and detailed cutoff value.In this present study, we have further analyzed the use of NOE and prolonged ventilation as independent risk factors for NOMI, focusing on corresponding cases. This is because we considered that the definite cutoff value of NOE and ventilation factor can be further effective to predict the incidence of NOMI. For the NOE factor, total quantity, duration, and maximum dose of NOE were analyzed. For the prolonged ventilation factor, maximum PEEP, total ventilation time, and index calculated from PEEP * ventilation time/ BW were analyzed. However, between NOMI and non-NOMI groups corresponding to each factor, there were no significant differences and definite cutoff value could not be calculated in both factors Table . This isThere are several limitations to our study. Because this is a retrospective and single-center database study, the reliability of each data is insufficient. In particular, suspecting the onset of NOMI and judging to perform the CT scan and laparotomy are dependent on the surgeon’s judgment. Furthermore, we have detected the independent risk factors from the multivariate regression model, but statistical reliability does not seem to be high because of a small number of NOMI cases.There may be patients with mesenteric ischemia who were excluded from the NOMI group as we did not confirm mesenteric ischemia with surgical exploration. We confirmed no occlusion of mesenteric vessels from the CT scan findings instead of the selective mesenteric angiography. The cause of mesenteric ischemia may have been the occlusion or thrombosis.We have reviewed 12 cases who developed NOMI after cardiovascular surgery in our institution. Rapid prediction and diagnosis are essential to lower mortality. However, they are very difficult in practice because almost all patients with NOMI were under sedation and mechanical ventilated; thus, their prognosis was extremely poor.In the multivariate logistic regression model, we have detected the use of NOE > 0.10 μg/kg/min and prolonged ventilation as independent risk factors of NOMI after cardiovascular surgery. In particular, we consider that the status of NOE and the presence of the factor, which can be the reason for the use of NOE, are strongly associated with the onset of NOMI. For the patient with suspected NOMI who have these risk factors, early CT scan and surgical exploration should be performed without delay.


We analyzed the influence of anesthesia methods on surgical outcomes and renal function in retrograde intrarenal surgery (RIRS) in a prospective, randomized controlled study.Seventy patients who underwent RIRS from September 2015 to February 2017 were randomly allocated to general anesthesia (GA) or spinal anesthesia (SA) groups. Renal function was assessed using estimated glomerular filtration rate, and separate renal function was evaluated using nuclear medicine tests. Maneuverability and accessibility were evaluated after every surgery. All procedures were performed by a single experienced surgeon (SY Cho).P = 0.019) group. Pain score was higher in the GA than in the SA group on the first postoperative morning (P = 0.025), but pain scores of the two groups were similar before discharge (P = 0.560). There were no differences in the changes of serum creatinine level (P = 0.792) and changes of estimated glomerular filtration rate (P = 0.807). Differences of separate renal function between operative and contralateral site increased significantly in patients under GA than under SA at postoperative 3 months (P = 0.014). Maneuverability and accessibility were better in SA with sedation than GA (P < 0.001).Stone-free rate was higher in the GA  than the SA  (RIRS under SA showed advantages in renal function change using renogram at postoperative 3 months and in lower pain score on the first postoperative morning. Performance of operator under SA was worse than that under GA and significantly improved with sedation. RIRS under SA showed advantages in lower pain score at postoperative first day.Clinicaltrials.gov ID is NCT03957109, and registration date is 17th May 2019. This study was retrospectively registered. According to the European Association of Urology (EAU) guidelines, retrograde intrarenal surgery (RIRS) is recommended as an alternative treatment option to percutaneous nephrolithotomy (PNL) for renal stones less than 2 cm in size . RoutineRenal function abnormalities or perioperative renal dysfunction due to anesthesia, may be present even in normal patients. A previous study reported that renal dysfunction could happen even in patients who had normal renal function preoperatively . These cTherefore, this study aimed to analyze the influence of anesthesia methods on surgical outcomes and renal function in RIRS.The prospective, randomized study was conducted in compliance with Good Clinical Practices (GCP) and the Declaration of Helsinki, and the study protocol was approved by the Institutional Review Board of Seoul National University Hospital . After receiving written informed consent, 70 patients, classified as American Society of Anesthesiologists (ASA) physical status I-II, registered from September 2015 to February 2017, were recruited. Eligible patients older than 20 years with renal stones greater than 10 mm were included. The decision for active stone removal was based upon the EAU guidelines. Patients were excluded if they had urologic anatomical abnormalities. Patients with ASA status ≥ grade III, a contraindication for spinal anesthesia or RIRS, or unexpected intraoperative renal injury, were also excluded. The CONSORT Statement Extension for Randomized Controlled Trials of Nonpharmacological Trials was closely followed. Following preoperative evaluations, the enrolled patients were randomly allocated to GA or SA groups using the permuted block method. Figure All RIRS procedures were performed by a single surgeon (SY Cho) who performed over one thousand cases according to the same methods described in the same authors’ investigations , 17. UreStandard monitoring, including non-invasive blood pressure, electrocardiography, oxygen saturation, and body temperature was applied in all patients.For the GA group, 30 mg lidocaine, 1.5–2.0 mg/kg propofol, 50–100 μg fentanyl was administered to induce anesthesia. Following loss of consciousness, 0.6–0.8 mg/kg rocuronium was administered, and the patients were intubated. Patients were ventilated with a tidal volume of 6–8 ml/kg. Anesthesia was maintained using 1–4 vol% of sevoflurane in oxygen and air.The patients in the SA group were placed in a lateral decubitus position. An anesthesiologist wearing a sterile gown cleaned the skin on the patient’s back with 0.5% chlorhexidine. After the cleaned skin was dried and draped in a sterile manner, the anesthesiologist inserted a 25-gauge spinal needle into the space between 4th spinous process and 5th spinous process or between 3rd spinous process and 4th spinous process. The intrathecal position of the tip of the needle was confirmed by aspiration of clean cerebrospinal fluid, following which 10–17 mg (median: 14 mg) hyperbaric bupivacaine  and 20 μg fentanyl were administrated intrathecally considering operation site and patient’s height. After injection, the patients were placed in supine position. The anesthesiologist checked for sensory loss in the dermatome, and motor loss to ensure adequate anesthesia for RIRS. On failure of first trial of spinal anesthesia, spinal anesthesia was repeated after patient approval. If the second trial of spinal anesthesia failed, the patient was dropped from the study and general anesthesia was administered in the routine manner. For the SA group, sedation was applied with 1–3 mg of midazolam according to patient’s lead after identifying the level of spinal anesthesia.Patient characteristics included age, sex, body mass index, laboratory results, and other comorbidities. Stone characteristics included laterality, Hounsfield units, numbers, maximal size, and volume. Primary outcome was renal function change assessed by estimated glomerular filtration rate and separate renal function evaluated by nuclear medicine test. And, secondary outcome was performance of operator evaluated by one experienced surgeon. The computed tomography (CT) scans were acquired preoperatively. Information regarding the presence of hydronephrosis and infundibulopelvic angles was acquired , and theOne experienced surgeon evaluated maneuverability and accessibility after every operation. Maneuverability and accessibility were graded as ‘very poor (1-2)’, ‘poor (3–4)’, ‘so so (5-6)’, ‘good (7–8)’ and ‘very good (9-10)’. Postoperative pain was evaluated using visual analog scale scores from 1 to 10, with 10 being most severe. Postoperative complications were defined according to modified Clavien classification system .We planned a study of experimental subjects with one control(s) per experimental subject. Primary endpoint was difference of renal function recovery rate and the difference was 6.5% from previous investigation. The recovery rate was defined as the rate of changes of separate renal function into less than 10% between the two kidneys in patients who underwent according to the preoperative functional deterioration . In a prt-test or a Mann-Whitney U test between the two groups. Categorical variables were analyzed using the Chi-square and Fisher’s exact test. Statistical significance was considered at P-value < 0.05. Statistical analyses were performed with IBM SPSS Statistics version 20  and R version 3.0.1 (http://www.r-project.org).All parameters were represented as the mean value ± standard deviation or frequency (percentage). Comparative results were analyzed by using an independent P = 0.035). There were no significant differences between the two groups in terms of age, gender, stone laterality, and incidence of comorbidities, and mean number of stones, mean maximal stone size, mean Hounsfield unit, and distribution of S-ReSC scores.Patient demographics and stone characteristics are shown in Table P = 0.019) group. Changes in serum creatinine after surgery were not significantly different between the two groups (P = 0.792). Pain score of the GA group was higher than that of the SA group on the first postoperative morning ; however, pain scores of the two groups were similar before discharge  1 or 2 days postoperatively. There were no differences in postoperative complications between the two groups (P = 0.841), and there were no complications of Clavien classification grade III or higher.Table P = 0.792) and changes in estimated glomerular filtration rate (P = 0.807) between the GA and SA groups. The preoperative DTPA renal scan was performed in 65 of 70 patients, and 26 (40%) showed a difference greater than 10% in separate renal function. After 3 months, 11 of 12 patients (91.7%) in the SA group showed improvement in separate renal function, whereas 10 of 14 patients (71.4%) in the GA group showed improvement in separate renal function (P = 0.330). The difference in separate renal function increased significantly in the GA group than in the SA group (P = 0.014).Considering parameters of renal function after surgery, there were no differences in changes in serum creatinine level (P = 0.726) and accessibility  during procedures were not different (Table P < 0.001). In addition, accessibility was ‘so so’ (5.50 ± 0.00) in GA, ‘very good’ (9.19 ± 0.75) in SA with sedation, and ‘poor’ (2.72 ± 1.83) in SA without sedation (P < 0.001).Between GA and SA, scores of maneuverability  than those under GA –4. In geP = 0.01 and 0.001, respectively), and patients reported better satisfaction (P = 0.001) and lower pain scores (P = 0.001) after spinal-epidural anesthesia. Kuzgunbay and colleagues compared surgical outcomes of PNL between GA and SA . The tidal volume during GA was independently chosen by the anesthesiologist, and sedation during SA was decided by patients just before surgery. Further studies comparing GA with low tidal volume and SA with sedation would be helpful to determine a better anesthetic strategy. Maneuverability and accessibility were measured subjectively by the operator, but all measurements were carried out by one experienced operator (SY Cho).There were no significant differences in changes in serum creatinine level and estimated glomerular filtration rate between GA and SA groups immediately. Also, operator performance was better under GA than under SA in general. However, RIRS under SA showed advantages in renal function change using renogram at postoperative 3 months and in lower pain score on the first postoperative morning. In addition, the performance of operator was significantly improved under SA with sedation. Hence, this topic warrants further investigations to evaluate safer and more convenient analgesic settings during RIRS.


Raw bioelectrical values can be used to assess physiological outcomes, though limited information is available concerning the relationships between changes in these values and changes in other variables of interest.n = 31, body mass index: 22.8 ± 2.6 kg/m2, body fat: 28 ± 6%) completed eight weeks of supervised resistance training. Before and after the intervention, body composition was assessed via dual-energy x-ray absorptiometry (GE® Lunar Prodigy), and raw bioelectrical variables were assessed via 8-point multi-frequency bioelectrical impedance analysis (Seca® mBCA 515/514) at 19 frequencies ranging from 1 to 1000 kHz.This investigation quantified the relationships between total and segmental changes in raw bioelectrical variables  and corresponding whole-body and segmental changes in independently assessed body composition. Resistance-trained females  were found between changes in lean soft tissue and changes in resistance for the whole body, trunk, and arms. No significant correlations were identified between changes in fat mass or bone mineral content and changes in any bioelectrical variable.Lean soft tissue of the whole body  and each body segment (+ 2.8 to 6.3%) increased as a result of the intervention. Group-level changes in total  and segmental fat mass were not statistically significant. Significant decreases in total resistance  and increases in phase angle  were observed, with minimal changes in reactance and varying changes in segmental values. Moderate to strong negative correlations  and body composition variables . Measurement frequency and body segment appeared to influence the presence and strength relationships between bioelectrical and body composition variables. These findings suggest that researchers and practitioners utilizing bioimpedance technology may benefit from examining raw resistance values to enhance detection of physiological adaptations to exercise interventions. Bioimpedance devices are commonly used to estimate body composition and fluid status due to their low cost, portability, and ease of use , 2. ThesTo date, a variety of investigations have supported the prognostic utility of raw bioelectrical parameters in patients with Human Immunodeficiency Virus infection, cancer, conditions requiring hemodialysis, malnutrition, and anorexia nervosa, suggesting that these measures may be useful for clinicians , 6. Varin = 31, age: 22 ± 3 y, height: 165.9 ± 6.6 cm; body mass: 62.8 ± 7.9 kg; body mass index [BMI]: 22.8 ± 2.6 kg/m2, body fat: 28 ± 6%) were included in this analysis. These participants were primarily Non-Hispanic Caucasians (n = 23), and the remaining participants were Hispanic Caucasians (n = 6), Black (n = 1), and Asian (n = 1). All participants completed the same RT program and had comparable dietary intakes and physical activity levels throughout the intervention as previously described [The present analysis utilized data collected during a supervised RT intervention in resistance-trained females . Healthyescribed .Participants reported to the laboratory in athletic clothing after an overnight (≥ 8 h) abstention from eating, drinking, exercising, and consuming caffeine. Metal and accessories were removed, and each participant voided her bladder prior to testing. Urine specific gravity (USG) was assessed via digital refractometer . USG was 1.022 ± 0.005 at the baseline assessment and 1.021 ± 0.005 at the final assessment. After voiding, height was determined via mechanical stadiometer.An 8-point MFBIA device  with contact electrodes for both hands and both feet was utilized in the present study. This device utilizes 19 frequencies ranging from 1 to 1000 kHz [DXA scans were performed on a Lunar Prodigy scanner  with enCORE software (v. 16.2). The scanner was calibrated using a quality control block each morning prior to use, and positioning of participants was conducted according to manufacturer recommendations. Each participant was able to fit within the scanning dimensions. A trained operator manually adjusted the analysis lines to demarcate body regions . In the lower body, all tissue distal to the line placed perpendicular to the femoral neck was designated as the leg region. In the upper body, all tissue distal to the line placed through the glenohumeral joint was designated as the arm region. The trunk region consisted of all tissue inferior to the mandible that was not included in the leg or arm regions. For the whole body and each body region, estimates of lean soft tissue (LST), fat mass (FM), soft tissue , and bone mineral content (BMC) were obtained. Previous reliability assessment in our laboratory with the specific device used in the present investigation produced SEM values of 0.7% for total LST, 2.1% for total FM, and 0.9% for BMC in a sample of 10 resistance-trained females, although reliability may be higher with the positioning procedures utilized in the present study .All participants completed eight weeks of supervised RT coupled with protein supplementation, and data from all participants completing the intervention were included in the present analysis. Training took place three times per week within the research laboratories under direct researcher supervision. Upper- and lower-body sessions were alternated, with the following exercises included in the overall program at least weekly: barbell deadlift, barbell back squat, hip sled, stiff-leg deadlift, lunges with dumbbells, leg curl machine, leg extension machine, barbell bench press, bent-over dumbbell rows, barbell shoulder press, dumbbell flyes, barbell preacher curls, dumbbell triceps extensions, “skull crushers,” dumbbell curls, and inverted rows  and a significance level of p ≤ 0.004 for each bioelectrical parameters . Pearson correlation coefficients (r) between percent changes in raw bioelectrical parameters and percent changes in DXA variables were calculated for the entire body and each body region. For example, ΔR, ΔXc, and Δφ for the leg region were correlated with DXA ΔST, ΔLST, ΔFM, and ΔLST for the leg region. The accepted statistical significance level for all correlations was adjusted for multiple comparisons using the Bonferroni method for each bioelectrical parameter , yielding a significance level of p ≤ 0.001. Correlations with p-values below this threshold were considered statistically significant, and correlations with p-values > 0.001 and <  0.05  were noted as correlations potentially worthy of further exploration. All correlation coefficients were classified as weak (|r| ≤ 0.35), moderate (0.36 ≤ |r| ≤ 0.67), or strong (0.68 ≤ |r| ≤ 1.0) [Changes in raw bioelectrical parameters  and DXA variables  were expressed as changes between baseline and final values relative to the baseline value , and the associated ranges and 95% confidence intervals were generated. Changes in R, Xc, and φ were quantified for the entire body and each body region at each measurement frequency , although results from the standard 50 kHz frequency, along with a representative low frequency (1 kHz) and high frequency (1000 kHz), are presented in the main body of this manuscript. Results from all 19 frequencies are presented in Additional file | ≤ 1.0) . Data wep <  0.001) increases in total and segmental LST in all body segments were observed across the eight-week RT intervention. Segmental values for ST increased in the arms only (p <  0.0001). No statistically significant group-level changes in FM were detected, although the majority of the 95% confidence intervals were negative, indicative of fat loss, for total, trunk, and leg FM (p: 0.05 to 0.12). Similarly, no group-level changes in BMC were detected. Significant decreases in total R and increases in whole-body φ were detected at the 50 kHz frequency, with no changes in total Xc. Decreases in arm R, an increase in trunk Xc, and increases in trunk and arm φ were also observed at the 50 kHz frequency. At the 1 kHz frequency, only a significant increase in arm φ was detected. At the 1000 kHz frequency, total and arm R, as well as arm Xc, decreased.Pre-testing and post-testing values for raw bioelectrical and DXA variables, as well as mean percent changes and the associated ranges and confidence intervals, are displayed in Table r| ≤ 0.62, p ≤ 0.001) were detected between changes in both total and segmental ST and the corresponding ΔR values at all three measurement frequencies of interest  were found between ΔLST and ΔR for total and segmental changes to the trunk and arms at all three frequencies of interest , total ΔLST was negatively correlated with ΔXc at 50 kHz (r = − 0.56), and arm ΔLST was negatively correlated with ΔXc at 1000 kHz (r = − 0.69). No significant correlations were identified between ΔFM or ΔBMC and ΔXc. Correlations between Δφ and DXA variables generally did not reach the threshold of statistical significance, although arm Δφ exhibited a moderate negative correlation with arm ΔLST (r = − 0.67) at the 1000 kHz frequency only. Additional file Moderate negative correlations  as well as between changes in DXA-derived skeletal muscle mass and Δφ (r = 0.54). However, it is important to note that, in contrast to the college-aged resistance-trained females recruited in the present investigation, the participants recruited by Tomeleri and colleagues [The findings of this investigation suggest that total and segmental changes in LST resulting from a RT intervention are more consistently correlated with corresponding changes in R rather than changes in Xc and φ in young, resistance-trained females. Significant negative correlations were identified between ΔLST and ΔR at multiple frequencies, suggesting that as participants gained LST, the resistance of their body tissues to electrical current decreased. Slightly weaker correlations were also identified between ΔST and ΔR at the same frequencies, and no significant correlations were found between ΔFM and ΔR. Together, these findings indicate that the relationship between ΔST and ΔR was primarily driven by ΔLST. Fewer significant correlations were identified between ΔXc and ΔST or ΔLST. Finally, only one statistically significant correlation was identified between any Δφ variable and DXA body composition change, specifically between changes in arm φ and ΔLST at the 1000 kHz frequency only. The lack of correlation between changes in body composition and Δφ at the 50 kHz frequency is somewhat contrary to the report of Tomeleri et al. , who idelleagues  were inaThe results of the present study have several important implications for researchers and practitioners who employ raw bioelectrical variables to evaluate physiological changes resulting from lifestyle interventions. First, because disparities in the correlations between specific bioelectrical variables and body composition changes were observed, it is recommended that relationships between all available raw bioelectrical parameters  and outcome variables of interest be fully explored. In the present investigation, changes in R were more consistently correlated with changes in body composition compared to changes in other bioelectrical parameters. However, the majority of investigations which have examined changes in raw bioelectrical parameters following an exercise training intervention have employed φ as the primary, or only, bioelectrical outcome , 23, 25.Several key strengths of the present investigation should be noted. The lifestyle intervention was rigorously controlled. All participants were fully supervised during the RT sessions and were provided with sufficient supplemental protein to support hallmark RT-induced adaptations such as increases in muscle size. The body composition and bioelectrical assessments were well-standardized to reduce confounding factors such as exercise, caffeine, pre-testing dietary intake, and changes in hydration status. However, it is important to note that menstrual phase was not controlled, although the absence of a regular menstrual cycle in 20–30% of participants precluded this control measure . Though This investigation identified relationships between changes in raw bioelectrical parameters and changes in body composition resulting from a RT intervention in young, resistance-trained females. The most consistent relationships were identified between changes in LST and changes in R, rather than with other raw bioelectrical parameters such as φ or Xc. These findings suggest that researchers and practitioners utilizing bioimpedance technology may benefit from examining raw R values to enhance detection of physiological adaptations to exercise interventions. In addition, the strength and presence of relationships between raw bioimpedance values and body composition varied to some extent based on measurement frequency and body region, although the results also generally support the continued use of the standard whole-body evaluation of bioelectrical parameters at the 50 kHz frequency. Nonetheless, evaluation of segmental bioimpedance variables can potentially be employed by researchers, clinicians, and practitioners who wish to more comprehensively assess changes in various physiological variables in response to an intervention or biological process.Additional file 1: Table S1. Resistance training programAdditional file 2: Table S2. Pearson correlations between changes in bioelectrical resistance and changes in dual-energy x-ray absorptiometry body compositionAdditional file 3: Table S3. Pearson correlations between changes in bioelectrical reactance and changes in dual-energy x-ray absorptiometry body compositionAdditional file 4: Table S4. Pearson correlations between changes in bioelectrical phase angle and changes in dual-energy x-ray absorptiometry body composition


The clinically silent, symptom‐free T‐cell prolymphocytic leukemia case that we report here confirms the major interest of the analysis of the blood smear as usual care of any emergent lymphocytosis. It also brings out the issue of the monitoring and follow‐up of this uncommon presentation. T‐cell prolymphocytic leukemia (T‐PLL) is a rare and severe mature lymphoid malignancy characterized by a clonal proliferation of a mature T‐cell population, classically associated with a serious vital prognosis. The clinical presentation usually includes hepatosplenomegaly, associated with peripheral adenopathy, asthenia, but also skin lesions and peritoneal or pleural effusion in some advanced cases. The disease occurs essentially in elderly patients with an average age of 70 at time of diagnosis, and the median survival is estimated to be <1 year. Indeed, T‐PLL is usually resistant to classic antineoplastic therapies.Blood counts typically reveal a progressive lymphocytosis with the typical morphology consisting of prolymphocytes of small to medium size with oval or markedly irregular nuclei, condensed nuclear chromatin, a single prominent nucleolus, and intensely basophilic nongranular cytoplasm with cytoplasmic protrusions or “blebs.” In 25% of cases, the cell size is smaller and the nucleolus may not be visible by light microscopy . In 5%, the nuclear outline is markedly irregular and can even be cerebriform, mimicking Sezary cells, or can remind a “flower cell” aspect as well in 5% of cases.α or β chains. 60% of the clones are CD4+ CD8−, 25% coexpress CD4 and CD8, and only 15% are CD4− CD8+ The phenotypic profile of these clonal T cells has been described: leukemic T cells are CD2+, CD3+, CD4+, CD5+, CD7+ with a strong expression of CD7, CD52, and TCR Here, we report the unusual case of a 75‐year‐old patient in whom a T‐PLL was discovered during the biological exploration of a chronic and particularly clinically silent lymphocytosis, fortuitously revealed by a routine checkup.μmol/L), as well as calcium (2.66 mmol/L). Renal function as well as liver function tests were normal. Serum protein electrophoresis was normal but immunofixation showed a low‐key oligoclonal profile of IgG and IgM.A 75‐year‐old patient was referred to internal medicine consultation in June 2016 for exploration of a stable moderate lymphocytosis, first documented in 2014 with 7.17 G/L. Two years later, lymphocyte counts rose to 10.1 G/L. Past history included diabetes, a right partial nephrectomy for malformation, a heavy smoking of 40 years generating leukoplakia on the vocal cords, and high blood pressure. His treatment included insulin, gliclazide, perindopril, bisoprolol, nicardipine, indapamide, urapidil, pravastatin, aspirin, and oral potassium. Blood analysis found a slightly increased uric acid , whereas TCR‐β of CD8+ cells and TCR‐α relative proportions were normal. NK‐cells and B‐cells populations were qualitatively normal.The analysis of blood smear showed a monomorphic lymphocytic population composed of small mature cells, with high nuclear/cytoplasmic ratio, with mature chromatin and prominent nucleoli, presenting regularly basophilic expansion of the cytoplasm. Cytoplasmic expansions (blebs) were present Fig. A. PeriphThe diagnosis of a lymphoid neoplasm and a T‐prolymphocytic leukemia (T‐PLL) was suspected. On clinical examination, the patient was in good general health with stable body weight at 100 kg. His temperature was of 37°C, and blood pressure was 154/84 mmHg. TEP scan confirmed the lack of hepatosplenomegaly.The marrow aspirate revealed the presence of 40% of atypical lymphocytes of small size, with high nuclear/cytoplasmic ratio, uniform mature chromatin with a single nucleolus in most of them. Bone marrow karyotype showed a complex karyotype with inversion on chromosome 14 (impacting on locus 14q11) and deletion on the chromosome 11 long arm , isochromosomes 6p and 8q, causing partial trisomy and monosomy, respectively on its long and short arm. Furthermore, these abnormal nuclei could be subdivided in two different type, as a first one carried an additional monosomy of chromosome 15, and a second carried a rearrangement in both long arms of chromosomes 1 and 3, suggesting a potential translocation t  CJ: performed the cytologic and phenotypic analysis for diagnosis, synthesized the medical record, and wrote the paper. JF: supervised the laboratory steps for cytological diagnosis and follow‐up. CB: performed cytogenetics analyses and provided references and wrote the paper. EL: performed the clinical care of the patient in the in‐and outpatient setting. AB‐G: provided the scientific and bibliographic features. AGT: provided the scientific and bibliographic features and wrote the paper. CA: supervised the cytological analyses, synthesized the entire clinical history and wrote the paper.None declared.


Isocitrate dehydrogenase 1 (IDH1) has been proven as a prognostic and predictive marker in glioblastoma (GBM) patients. The purpose was to preoperatively predict IDH mutation status in GBM using multiregional radiomics features from multiparametric magnetic resonance imaging (MRI).In this retrospective multicenter study, 225 patients were included. A total of 1614 multiregional features were extracted from enhancement area, non‐enhancement area, necrosis, edema, tumor core, and whole tumor in multiparametric MRI. Three multiregional radiomics models were built from tumor core, whole tumor, and all regions using an all‐relevant feature selection and a random forest classification for predicting IDH1. Four single‐region models and a model combining all‐region features with clinical factors  were also built. All models were built from a training cohort (118 patients) and tested on an independent validation cohort (107 patients).Among the four single‐region radiomics models, the edema model achieved the best accuracy of 96% and the best F1‐score of 0.75 while the non‐enhancement model achieved the best area under the receiver operating characteristic curve (AUC) of 0.88 in the validation cohort. The overall performance of the tumor‐core model  and the whole‐tumor model  was slightly better than the single‐regional models. The 8‐feature all‐region radiomics model achieved an improved overall performance of an accuracy 96%, an AUC 0.90, and an F1‐score 0.78. Among all models, the model combining all‐region imaging features with age achieved the best performance of an accuracy 97%, an AUC 0.96, and an F1‐score 0.84.The radiomics model built with multiregional features from multiparametric MRI has the potential to preoperatively detect the IDH1 mutation status in GBM patients. The multiregional model built with all‐region features performed better than the single‐region models, while combining age with all‐region features achieved the best performance. However, biopsy‐based approach has been controversial due to its invasiveness, potential complications, and possible incomplete sampling caused by intratumor genetic heterogeneity.Several radiomics models associated with IDH1 mutations in low‐ (grade I and II)In this retrospective multicenter study, we aimed to develop a radiomics model with a minimal set of imaging features from multiple tumor subregions in multiparametric MRI for pretreatment prediction of IDH1 status in GBM patients.22.1www.cancerimagingarchive.net) and three local institutions between January 2013 and July 2017 were analyzed. The inclusion criteria were that patients with (a) newly diagnosed histologically‐confirmed GBM and (b) pretreatment MRI including axial T1‐weighted, axial T1‐weighted Gadolinium contrast‐enhanced, axial T2‐weighted, and T2‐weighted fluid attenuation inversion recovery images , and (c) known IDH1 genotype determined from tumor tissue and (d) known clinical data including age, sex, and Karnofsky performance status (KPS). Exclusion criteria were that (a) patients without confirmed IDH1 data and (b) MRI with motion artifact. Finally, 225 patients were included in this study, consisting of a training cohort of 118 patients and an independent validation cohort of 107 patients. The training cohort comprised 58 patients from TCIA and 60 patients from Sun Yat‐sen University Cancer Center. The validation cohort comprised 45 patients from The 3rd Affiliated Hospital of Sun Yat‐sen University and 62 patients from Guangzhou General Hospital of Guangzhou Military Command. The study was approved by the Ethics Committee of Sun Yat‐sen University Cancer Center, the Ethics Committee of The 3rd Affiliated Hospital of Sun Yat‐sen University, and the Ethics Committee of Guangzhou General Hospital of Guangzhou Military Command. Because the data in TCIA was deidentified, Institutional Review Board approval for TCIA data was not required. Informed consent for the patients in three local institutions was waved. Patient and tumor characteristics were summarized in Table In this retrospective study, 651 patients from The Cancer Imaging Archive (TCIA) publicly‐available dataset . The scanning sequences and parameters were: (a) T1‐weighted sequences at repetition time milliseconds, 210‐720; echo time milliseconds, 4‐20; section thickness, 2.0‐5.0 mm; (b) T1‐weighted Gadolinium contrast‐enhanced images at repetition time milliseconds, 260‐950; echo time milliseconds, 4‐20; section thickness, 2.0‐5.0 mm; (c) T2‐weighted images at repetition time milliseconds, 2137‐10 000; echo time milliseconds, 80‐140; section thickness, 3.0‐5.0 mm; (d) T2‐weighted fluid attenuation inversion recovery images at repetition time milliseconds, 6000‐11 000; echo time milliseconds, 85‐155; section thickness, 2.5‐6.0 mm.2.3For the TCIA patients, IDH1 mutation data were obtained from The Cancer Genome Atlas (TCGA) publicly‐available dataset corresponding to the TCIA patients. For patients from the three local institutions, IDH1 status was assessed by pyrosequencing approach. The DNA was isolated from paraffin sections of tumor tissue using QIAamp DNA FFPE Tissue Kit . Pyrosequencing analysis was performed using the PyroMark Q96 system (Qiagen) with polymerase chain reaction (PCR) products of exon 4 of IDH1 containing R132 coding region.2.43. With the ITK software (https://itk.org/), rigid body registration was performed with the mutual information similarity metric using T1c as a template. To standardize the intensity variation between MRI acquisitions across multicenter study, an efficient landmark‐based piecewise intensity mapping was used for histogram matching.Image preprocessing was critical for extracting stable features and achieving reproducible results in this multicenter study where MRI data were acquired from multiple scanners. All images were preprocessed to standardize the intensity and geometric variations of the MRI data. First, a N4ITK correction was used to correct the bias field distortion.2.5From the segmented subregions, high‐throughput imaging features were extracted, including location features, geometry features, intensity features, and texture features. To fully characterize the tumor heterogeneity, we extracted in total 1614 image features from multiple tumor subregions, including necrosis, enhancement area, non‐enhancement area, edema, solid core (the whole tumor except edema), and whole tumor. The radiomics features extracted were summarized in Table The location features indicating the tumor geographic epicenter were defined by two features  were not equally represented, as shown in Table 2.7The feature selection was assumed to discover a minimal set of features relevant to IDH1 mutation. A random forest‐based wrapper method, named Boruta, was used for relevant feature selection.To compare radiomics features from different tumor subregions, four single‐region models and three multiregional models were built. The four single‐region models were built based on imaging features from the enhancement area, non‐enhancement area, necrosis, and edema, respectively. The three multiregional models were built with imaging features extracted from the tumor core, the whole tumor, and all six regions (as introduced in the feature extraction subsection). Furthermore, a combined model was built based on all‐region radiomics features and clinical factors . When building the seven radiomics models and the combined model, Boruta was used for feature selection and random forest model was used for predicting IDH1 mutation. A clinical model based on clinical factors alone was also built using random forest. After a set of testing, the tree number of all random forest models was set to 300, as increasing the tree number did not bring significant performance gain. Gini index was used as an importance measure. The R package randomForest was used for model building.2.8https://www.r-project.org/). Two‐sided P value of <0.05 was considered significant. The differences in sex, age, KPS, and IDH1 mutation status between the training and validation data sets were assessed. According to the guideline in ref. [The statistical analysis was done with R software, version 3.4.3 . To further reveal the relevance of the selected eight multiregional features with the IDH1 mutation status, the feature maps were presented in Figure No difference was found between the training dataset and the validation dataset in sex, age, KPS, and IDH1 mutation status  and F1‐score (0.75), while the model built of non‐enhancement area reached the highest AUC (0.88). It indicated that the imaging phenotypes within distinct tumor subregions may contribute differently to the outcome. The work in ref.  has demoPrevious genomics study has revealed that IDH1 mutations are much more common in younger GBM patients.There were several limitations to our study. First, although this study was based on multicenter cohorts, larger prospective cohorts from more institutes should be involved to demonstrate the potential clinical utility of our model. Larger multicenter cohorts also have great potential to improve the performance of the machined learning‐based radiomics approach, especially for this imbalanced learning problem. Second, our model made use of four MR modalities. Recent studies have shown that MR spectroscopy, diffusion‐weighted imaging (DWI), diffusion tensor imaging (DTI), and arterial spin labeling (ASL) perfusion MR imaging are promising in predicting IDH1 mutation status in glioma.In conclusion, the radiomics‐based model with a minimal set of multiregional features from multiparametric MRI has the potential to noninvasively detect the IDH1 status in preoperative GBM patients. The multiregional radiomics models performed better than the single‐region models, while combining age with multiregional features achieved the best prediction performance.


MET p.Y1234C mutation to be responsible for arthrogryposis in this pedigree. MET p.Y1234C mutation caused the failure of activation of MET tyrosine kinase. A Met p.Y1232C mutant mouse model was established. The phenotypes of homozygous mice included embryonic lethality and complete loss of muscles that originated from migratory precursors. Heterozygous mice were born alive and showed reduction of the number of myofibers in both appendicular and axial muscles. Defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts were proven to be responsible for the skeletal muscle dysplasia of mutant mice. Overall, our study shows MET to be a causative gene of arthrogryposis and MET mutation could cause skeletal muscle dysplasia in human beings.Arthrogryposis is a group of phenotypically and genetically heterogeneous disorders characterized by congenital contractures of two or more parts of the body; the pathogenesis and the causative genes of arthrogryposis remain undetermined. We examined a four‐generation arthrogryposis pedigree characterized by camptodactyly, limited forearm supination, and loss of myofibers in the forearms and hands. By using whole‐exome sequencing, we confirmed  The biological effects exerted by MET are triggered by the stimulation of its only ligand, hepatocyte growth factor  mutation to be responsible for the pathogenesis of arthrogryposis in this pedigree. MET p.Y1234C mutation was shown to cause the dysfunction of phosphorylation and tyrosine kinase activity of MET in vitro. We established a Met c.A3695G  mutant mouse model, and the defective migration of myogenic progenitor cells and impaired proliferation of secondary myoblasts were demonstrated to be responsible for the disturbed muscle development.Herein, we recruited a rare four‐generation Chinese arthrogryposis pedigree with only upper limb involvement, and we found the A four‐generation Chinese family presented with completely penetrant, autosomal dominant arthrogryposis characterized mainly by camptodactyly Fig A. All paSubject IV:7 is a patient with unilateral camptodactyly, absent flexion crease, and limited forearm supination. Severe pronator quadratus aplasia of affected forearm was observed through magnetic resonance imaging MRI; Fig C. For thet al, MET; c.G2074A (Refseq NM_006019) in TCIRG1 (MIM:604592). By using Sanger sequencing, we excluded the SNV on TCIRG1 because MET c.A3701G turned out to be the only one which co‐segregated with disease phenotypes in this family  mutant mouse model was constructed. No homozygous newborns were found. The ratio of homozygous embryos started to decline since E14.5, and E16.5 was the latest time that homozygous embryos could survive, which was consistent with Met null mutants  and Met was assessed in embryonic limbs and dermomyotome at the end of migration (E10.5). In dermomyotome, heterozygous and homozygous embryos showed more Pax3‐positive (Pax3+) and Met‐positive (Met+) cells than wild types  homozygous embryos were lower than that of wild types  were studied. The body size and weight of E16.5 embryos decreased in heterozygotes and homozygotes  in European and North American populations . Sequences were generated on a HiSeq PE150 (Illumina). Base calling was performed, and raw sequencing read files were generated in FASTQ format. Subsequently, the sequenced reads were aligned to the reference human genome . SeattleSeq Annotation 150 (version 9.10) was used to perform the annotation. Various databases, including dbSNP database, 1000 genomes, Mutation Taster, Polyphen‐2, and SIFT, were used to predict and filter mutations. Data analysis was performed as given below: Exome capture was performed using an Agilent SureSelect Human All Exon Kit and sequences were generated on HiSeq PE150. After mapping to the human reference genome , an average of 99.3% of reads were mapped and a sequencing depth per target base of 168 times on average was provided, with at least 20 times for 99% of bases. More than 154,876 SNVs per individual were identified. We first chose variants that were shared by the four affected individuals but not present in the unaffected individual. We found 5,350 such variants. Next, to identify potentially pathogenic variants, we annotated those variants and filtered out synonymous variants, non‐coding variants, intergenic variants, and variants located in introns, retaining those affecting splice sites. We then parsed a total of 1,441 variants and kept only those that were novel in dbSNP.Mut), and Vector plasmids were expressed in a 293T cell expression system. Forty‐eight hours post‐transfection, cells were treated with 10 ng/ml recombinant human HGF  for 1 h. As previously reported . Lysates were incubated with 20 μl anti‐Flag affinity agarose  overnight at 4°C. Beads containing affinity‐bound proteins were washed seven times with 5 ml wash buffer  and collected by centrifugation. Samples were subjected to SDS–PAGE and immunoblotting analysis after the addition of 30 μl of sample buffer  and denaturation. The following antibodies were used: 1:1,000 dilution of anti‐Phospho‐Met (Tyr1234/1235) antibody , 1:1,000 dilution of anti‐Phospho‐Met (Tyr1349) antibody , 1:500 dilution of anti‐Phospho‐Met (Tyr1356) antibody , 1:2,000 dilution of anti‐GAPDH antibody , and 1:1,000 dilution of anti‐FLAG antibody .Flag‐tagged MET, p.Y1234C mutant MET .Flag‐tagged MET/METMet gene  is located on mouse chromosome 6, and human MET c. A3701G is identical to Met c.A3695G in mouse gene. Twenty‐two exons have been identified, with the ATG start codon in exon 3 and TGA stop codon in exon 22. The Tyr1232 is located on exon 20. Exon 20 was selected as a target site. MET gRNA targeting sequencing 5′‐GCTTGGCACCCGTCTTGTTGTGG‐3′ and donor oligo were designed. The Tyr1232Cys (TAC to TGC) mutation sites in donor oligo were introduced into exon 20 using homology‐directed repair. A silent mutation (GTC to GTA or ACG to ACT) was also introduced to prevent the binding and recutting of the sequence by gRNA after homology‐directed repair. Cas9 mRNA, gRNA generated by in vitro transcription, and donor oligo were co‐injected into fertilized eggs for KI mouse production.The mouse Tissues from E14.5, E16.5, and P0 mice were dissected and fixed in 4% paraformaldehyde overnight, dehydrated, and embedded in paraffin. Sections for histological analysis were rehydrated and stained with hematoxylin‐eosin. Immunofluorescence was performed with Histostain‐Plus Kit . Primary antibodies included: 1:400 dilution of anti‐myosin antibody ; 1:200 dilution of anti‐Ki67 antibody . Detection was conducted using 1:1,000 dilution of anti‐mouse IgG fragment, Alexa Fluor 555 conjugate , and 1:1,000 dilution of anti‐rabbit fragment, Alexa Fluor 555 conjugate . Nucleus was stained by DAPI in a final concentration of 0.1 μg/ml . TUNEL assay was performed according to the manufacturer's instructions . Quantification of Ki67‐positive rate and TUNEL‐positive rate was conducted using ImageJ (version 1.51) software.Transmission electron microscope analysis was performed on the gastrocnemius in standard fashion. Ultra‐thin sections were stained with uranyl acetate and lead citrate, and then examined using a Tecnai transmission electron microscope (FEI) operated at 80 kV.In situ hybridization using RNAscope probes was performed on E10.5 mouse embryos. Embryos were fixed with 4% paraformaldehyde for 24 h at 4°C, dehydrated, and embedded in paraffin. Tissue sections were washed twice with PBS for 5 min, followed by incubation in hydrogen peroxide  for 10 min at room temperature, boiling in target retrieval  for 15 min. After target retrieval, slides were briefly washed with distilled water and incubated for 30 min at 40°C with Protease Plus . Following all pretreatments, the manufacturer's protocol for RNAscope 2.5 HD Detection Kit‐Brown  was followed to hybridize probes and detect the signals. The following probes were used: RNAscope Probe‐Mm‐Pax3 ; RNAscope Probe‐Mm‐Met ; RNAscope Negative Control Probe‐DapB ; and RNAscope Positive Control Probe‐Mm‐Ppib .post hoc test for multiple comparisons. The positive rates of Ki67‐ and TUNEL‐labeled cells were analyzed using the chi‐square test (χ2 test). All statistical analyses were conducted with the SPSS (version 19.0) statistical software. The level of statistical significance was set at P < 0.05. See P‐value in each experiment.All quantitative data are here presented as mean ± standard deviation (SD). Statistical analysis of body weight of transgenic mice was performed using one‐way ANOVA followed by Dunnett's Written informed consent was obtained from all subjects or, in the case of children under 16 years of age, their parents. Collection and usage of patient samples for this study were approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat‐sen University. All procedures in studies involving human participants were performed in accordance with the principles set out in the WMA Declaration of Helsinki and the Department of Health and Human Services Belmont Report. Transgenic mice were raised in the laboratory animal center of Sun Yat‐sen University, and all animal experiments, housing, and husbandry followed the operating procedures approved by the Institutional Animal Care and Use Committee of Sun Yat‐sen University.PS designed the experiments. HZ, CL, XY, SZ, ZL, TZ, CX, and XH conducted the experiments. TW, DS, XQ, XW, YL, BG, and YC raised transgenic mice. HZ and CL analyzed the data and wrote the manuscript. DH, GY, QF, and CG helped with the replication studies.The authors declare that they have no conflict of interest.Arthrogryposis is a group of disorders characterized by congenital contractures of two or more joints, and it affects about 1/3,000 newborns. As a group of phenotypically and genetically heterogeneous disorders, the underlying molecular etiology and mechanism remain unknown in a large number of cases of arthrogryposis.MET p.Y1234C mutation was found to be responsible for arthrogryposis in a four‐generation pedigree. In vitro study showed that MET p.Y1234C mutation caused dysfunction of the phosphorylation and tyrosine kinase activity of MET protein. A Met p.Y1232C mutant (corresponding to MET p.Y1234C mutation in human beings) mouse model was constructed, and the phenotype of homozygotes was identical to Met null mutant mice, including embryonic lethality and complete loss of muscles that originate from migratory precursors. Heterozygous mice were born alive and showed reduction of myofibers in both appendicular and axial muscles. Further study demonstrated that the defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts were responsible for the muscular dysplasia in mutant mice.In the present study, MET mutation and skeletal muscle dysplasia in human beings.This is the first study to report MET to be a disease‐causing gene of arthrogryposis. We showed that arthrogryposis could be caused by the reduction of myofibers around the affected joints. Our study is also first to demonstrate a direct relationship between The URLs for data presented in this article are as follows:(i)http://www.omim.org/OMIM, (ii)http://www.ncbi.nlm.nih.gov/projects/SNP/dbSNP, (iii)http://snp.gs.washington.edu/SeattleSeq Annotation 150, (iv)http://genome.ucsc.edu/NCBI Build 37, hg19, (v)http://www.1000genomes.org/1000 genomes, (vi)http://www.mutationtaster.orgMutation Taster, (vii)http://genetics.bwh.harvard.edu/pph2Polyphen‐2, (viii)http://sift.jcvi.org.SIFT, (ix)https://www.ncbi.nlm.nih.gov/clinvar/Clinvar dataset, AppendixClick here for additional data file.Expanded View Figures PDFClick here for additional data file.Table EV1Click here for additional data file.Source Data for Expanded ViewClick here for additional data file.Review Process FileClick here for additional data file.Source Data for Figure 1JClick here for additional data file.


Emotions are considered distractions that often prompt subsequent actions. In this way, the aim of this work was to examine the role of distracting stimuli on the relationship of RT and accuracy. In order to do that, a word recognition task was carried out in which emotional valence was manipulated. More precisely, a mediational model, testing how changes in distracting stimuli mediate RT predicting accuracy across emotional conditions, was carried out. The results suggest that changes in task demands should distract from the secondary task to the extent that these task demands implicate and affect accuracy. Moreover, the distracting task seems to mediate between accuracy and the target task under emotional stimuli, showing the negative distracting condition to be the most remarkable effect. Furthermore, neutral distracting latencies did not affect accuracy. Understanding the mechanisms by which emotion impairs cognitive functions has important implications in several fields, such as affective disorders. However, the effects of emotion on goal-directed cognitive processing remain unclear. How emotion affects memory is a subject of interest for several areas such as clinical or even the forensic fields. In this way, the effect of emotional valence on word recognition has been described in both theoretical and empirical research. This is an effect that has been reported as a robust one on several aspects of cognition, as well as on behavior . In terms of inclusion criteria, all the participants had normal or corrected to normal vision, were native Spanish speakers and did not report cognitive or neurological disorders after a personal interview.Busca Palabras database  was first calculated on the mediational M variable (and its inherent a and b paths), the X independent variable on the dependent variable without the inclusion of moderator (c’ path) and the X independent variable on the dependent variable after the mediator was included (c path). Figure A repeated measure design was employed where a classical analysis of variance (ANOVA) explored the impact of stimulus identity (target or distractor) and emotional valence on response latency and accuracy. The statistical analysis was performed using SPSS 20. We conducted a mediational analysis using process macro for SPSS Hayes  to test The RTs were longer for negative stimuli than positive and neutral ones. Table F = 2.94; MSE = 16,329.33; η2 = 0.03; p = 0.055. Bonferroni’s pairwise comparison approached but did not reached the statistically significant for negative versus positive stimuli (p = 0.06). In the case of distracting and target conditions, target stimuli were processed faster than distractors, and this difference reached statistical significance: F = 61.25; MSE = 1,131,718.40; η2 = 0.39; p < 0.01. Any interaction or error differences did not reach statistical significance (F < 1).The ANOVA of RT showed that differences in emotional valence (where negative stimuli was recognized slower) were close to but did not reach statistical significant: F = 8.33; MSE = 0.015; η2 = 0.081; p < 0.01. In the case of distracting and target conditions, target stimuli were processed faster than distractors, and this difference reached the statistical significance: F = 5.38; MSE = 0.434; η2 = 0.054; p < 0.05. All Bonferroni’s pairwise comparison between negative versus positive/neutral stimuli were statistically significant for emotion (p < 0.05), but neutral versus positive differences did not reach the statistical level. An interaction (emotion*presentation) was found across variables: F = 6.99; MSE = 0.016; η2 = 0.069; p < 0.01.On the other hand, the ANOVA of on accuracy showed that differences in emotional valence (where positive stimuli was recognized slower) reached the statistical significant, F = 53.07; MSE = 0.6435; R2 = .36; p < 0.001), the neutral  = 47.83; MSE = 0.6675; R2 = .34; p < 0.001) and the positive one  = 40.85; MSE = 0.7022; R2 = .31; p < 0.001). Figure Finally, a mediational model was tested. Previously, any relationship between variables was examined through Pearson correlation coefficient Fig. . As depiF,93 = 53.Emotions are considered distractions that often prompt subsequent actions. The aim of this work was to examine the role of distracting stimuli on the relationship of RT and accuracy. Understanding the mechanisms by which emotion impairs cognitive functions has important implications in several fields, such as affective disorders. Moreover, and according to Dolcos and McCarthy , the neuThe results could be described as follows: (i) First of all, changes in task demands should distract from the secondary task to the extent that these task demands implicate and affect accuracy, (ii) the distracting task mediates between the target task and accuracy under emotional stimuli, (iii) negative distracting stimuli seem to have a higher mediational effect than neutral or positive distracting stimuli, and (iv) positive distracting stimuli seem to have a higher mediational effect than neutral distracting stimuli.As expected from the literature, latencies to distracting words presented higher RT. This indicates a cognitive cost in rejecting the second demand in a task. Moreover, and as it was hypothesized, RTs were inversely correlated to accuracy in most of the cases, in particular, under emotional conditions (as expected from previous literature (León Gordillo et al. In sum, our results showed that distraction should be intermediate under emotional conditions. Moreover, a stronger prediction from the negative stimuli was found. This hypothesis has received strong empirical support that negative stimuli generally hold more attention than neutral or positive stimuli, even for mood-congruent cognitions (Van Dillen & Koole


Drosophila melanogaster lines that have been maintained under direct selection for postponed reproduction and indirect selection for longevity, relative to unselected control lines, for over 35 years. We identified many candidate loci shaped by selection for longevity and late‐life fertility, but – contrary to expectation – we did not find overrepresentation of canonical longevity genes. Instead, we found an enrichment of immunity genes, particularly in the Toll pathway, suggesting that evolutionary changes in immune function might underpin – in part – the evolution of late‐life fertility and longevity. To test whether this genomic signature is causative, we performed functional experiments. In contrast to control flies, long‐lived flies tended to downregulate the expression of antimicrobial peptides upon infection with age yet survived fungal, bacterial, and viral infections significantly better, consistent with alleviated immunosenescence. To examine whether genes of the Toll pathway directly affect longevity, we employed conditional knockdown using in vivo RNAi. In adults, RNAi against the Toll receptor extended lifespan, whereas silencing the pathway antagonist cactus‐–causing immune hyperactivation – dramatically shortened lifespan. Together, our results suggest that genetic changes in the age‐dependent regulation of immune homeostasis might contribute to the evolution of longer life.Much has been learned about the genetics of aging from studies in model organisms, but still little is known about naturally occurring alleles that contribute to variation in longevity. For example, analysis of mutants and transgenes has identified insulin signaling as a major regulator of longevity, yet whether standing variation in this pathway underlies microevolutionary changes in lifespan and correlated fitness traits remains largely unclear. Here, we have analyzed the genomes of a set of  D. melanogaster populations that have been undergoing selection for late‐life reproduction and postponed senescence, relative to unselected controls, for over 35 years. Instead of an enrichment of evolutionary changes in previously identified “canonical” longevity genes, we found an enrichment of genetically diverged immunity genes, suggesting that variation in immune function contributes to the evolution of lifespan and late‐life fertility. To test this hypothesis, we employed immunity assays: long‐lived flies survived infections better and showed altered age‐dependent immune gene expression as compared to control flies. Using in vivo RNAi we confirmed that reduced expression of immune genes extends lifespan while immune overactivation is strongly detrimental.Despite much progress in our understanding of the genetic basis of aging, mainly from studying large‐effect mutants, little is known about natural variants that contribute to the evolution of lifespan and related fitness traits. To identify the mechanisms by which longevity evolves, we sequenced a set of C. elegans, Drosophila, and mice , have been identified using analyses of large‐effect mutants and transgenes in the laboratory  > 0.9; Bonferroni‐corrected Fisher's exact test: P < 10−9)  that this large number of candidate SNPs arose by chance  (Schlötterer −9) Fig. . To furtet al.et al.et al.et al.While some mechanisms of longevity are evolutionarily conserved (“shared”) among species and thus “public,” for example insulin/insulin‐like growth factor 1 signaling (IIS), most others are likely to be lineage‐specific and thus ‘private’ , and age‐specific fecundity , the receptor Toll (Tl), the Toll inhibitor cactus (cact), the NFκB transcription factors Dorsal‐related immunity factor (Dif) and dorsal (dl), the upstream serine proteases persephone (psh) and sphinx2, and two regulators of cactus, scalloped (sd) and cactin  and the antimicrobial peptide Cecropin A1 (CecA1)  analysis  Fig. .et al.et al. , Attacin A (AttA), and Diptericin (Dpt). Drs and AttA are regulated by both Toll and Imd signaling, whereas Dpt is mainly regulated by the Imd pathway . Systemic infections with this bacterium induce the expression of all three AMPs assayed here , the major effectors of the innate immune response. We used three AMPs as readouts of Toll and Imd signaling activity, et al.et al.et al.et al.et al.Without pricking, control flies upregulated AMP baseline expression with age Fig. A – a patet al.et al.et al.et al.AMP expression also differed substantially between control and selected flies upon infection: at young age, the AMP response was slightly stronger in long‐lived flies than in control flies, whereas at old age long‐lived flies tended to downregulate AMP induction Fig. b. Thus, et al.et al.Our results therefore suggest that long‐lived flies might have evolved improved age‐dependent immune homeostasis and alleviated immunosenescence , with the Gram‐negative bacterium Ecc15 and with the Gram‐positive bacterium Enterococcus faecalis (Ef) overall markedly better than control flies . This assay was carried out only with young, not aged flies, but we again found that long‐lived flies survived infection with DCV much better than control flies  infections over a 6‐day period postinfection. The ability of control flies to clear an infection was higher than that of long‐lived flies at young age but declined at old age; in contrast, clearance was overall lower in long‐lived flies yet did not change with age ‐GeneSwitch(GS)‐GAL4 driver , whereas overactivation of this pathway strongly shortens life.Downregulation of the pan Fig. A,B,C,D, les Fig. G and malles Fig. H. In agret al.AttacinC (AttC) and Diptericin B (DiptB) are downregulated in the fat body , including details of selection and control lines, next‐generation sequencing, bioinformatic, and statistical analyses, gene expression analyses, immunity assays, transgenic RNAi, and lifespan assays.The authors declare no conflict of interest.Associate Editor: Rhonda SnookSupplementary methods (pdf). Description of all methods, including details of selection and control lines, next‐generation sequencing, bioinformatic and statistical analyses, gene expression analyses, immunity assays, transgenic RNAi and lifespan assays.Click here for additional data file.Table S1. (xls). Longevity candidate SNPs and candidate genes.Click here for additional data file.Table S2. (xls). Shared candidate genes across three independent studies.Click here for additional data file.Table S3. (xls). Gene ontology (GO) analysis of longevity candidate genes.Click here for additional data file.Table S4. (xls). Immunity genes implicated in lifespan and aging.Click here for additional data file.Table S5. (xls). Full statistical details of data analyses shown in the main text.Click here for additional data file.