Diffusion tensor imaging (DTI) allows visualization of the main white matter tracts while intraoperative neurophysiological monitoring (IONM) represents the gold standard for surgical resection of gliomas. In recent years, the use of small craniotomies has gained popularity thanks to neuronavigation and to the low morbidity rates associated with shorter surgical procedures. The aim of this study was to review a series of patients operated for glioma using DTI, IONM, and tumor-targeted craniotomies. The retrospective analysis included patients with supratentorial glioma who met the following inclusion criteria: preoperative DTI, intraoperative IONM, tumor-targeted craniotomy, pre- and postoperative MRI, and complete clinical charts. The DTI was performed on a 3T scanner. The IONM included electroencephalography (EEG), transcranial (TC) and/or cortical motor-evoked potentials (MEP), electrocorticography (ECoG), and direct electrical stimulation (DES). Outcomes included postoperative neurological deficits, volumetric extent of resection (EOR), and overall survival (OS). One hundred and three patients  were included and presented the following WHO histologies: 65 grade IV, 19 grade III, and 19 grade II gliomas. After 3 months, only three patients had new neurological deficits. The median postoperative volume was 0cc (IQR 3). The median OS for grade IV gliomas was 15 months, while for low-grade gliomas it was not reached. In our experience, a small craniotomy and a tumor resection supported by IONM and DTI permitted to achieve satisfactory results in terms of neurological outcomes, EOR, and OS for glioma patients. Diffusion tensor imaging (DTI) is an advanced neuroimaging technique that allows the 2D and 3D reconstruction of important white matter tracts such as cortico-spinal tract (CST), superior longitudinal fascicles (SLFs), and inferior frontal-occipital (IFO) fascicles –4. PreseWhen considering brain tumor resections, intraoperative neurophysiological monitoring (IONM) and brain mapping techniques represent the gold standard for surgical management of primary CNS neoplasms , 13. TheIn this work, we present the experience of the authors in a consecutive series of 103 patients affected by astrocytoma grades I to IV operated combining DTI, IOM, and minimally invasive craniotomy. Technical aspects will be presented, together with neurological outcomes, surgical complications, the extent of resection, and patients’ survival data.A cohort of patients who received surgical treatment for supratentorial gliomas between May 2011 and February 2016 at the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milano were retrospectively assessed for inclusion in this study.The following criteria needed to be met for patient inclusion:1) age superior to 18 years;2) supratentorial gliomas;3) tumor tissue available for histological and molecular diagnoses according to the WHO 2016 CNS brain tumors’ classification;4) pre- and postoperative (obtained within 72 h) T2-weighted (w) images, T2-weighted fluid-attenuated inversion recovery (FLAIR) images, T1-weighted images before and after gadolinium intravenous administration, and diffusion-weighted images (DWI) available for radiological evaluation and volumetric analysis;5) a tailored “small-craniotomy” as a surgical approach to the tumor;6) surgical resection guided by intraoperative DTI and IONM;7) completeness of the clinical chart during the review process by the Authors;8) informed consent for participating in the study.Patients suffering from recurrent tumors were also included in this study, in case the aforementioned inclusion criteria were met. These patients were classified as revision resections.Ethical approval was waived by the local Ethics Committee of “Università degli Studi di Milano,” because of the retrospective nature of the study, and all the procedures being performed were part of routine care.Tumor samples were formalin-fixed and analyzed by dedicated neuropathologists. Tumor grade and molecular profile were reported according to both the WHO 2016 and 2021 CNS brain tumor classifications .MGMT was considered to be methylated when it showed more than 9% of promoter methylation as previously described .Baseline demographic features, preoperative KPS, length of the in-ward stay, postoperative neurological deficits, postoperative seizures’ rate—as their incidence during the in-ward stay and at follow-up (FU), destination at discharge, and neurological deficits still present at 3-month FU were collected from electronic clinical records and registers, and outpatient neuro-oncological evaluations.The occurrence of a new postoperative neurological deficit was graded according to severity (severe or mild/moderate). The following deficits were considered severe: severe muscle strength deficit , hemianopia, and aphasia. All other neurological deficits were considered mild/moderate. Deficits still present at 3-month FU were considered definitive.All patients underwent extensive pre- and postoperative neuropsychological testing using the battery of neuropsychological tests as reported previously –26.Preoperative MRI scans were performed on a 3T Philips Achieva  scanner, using a 32-channel phased-array head coil.www.horosproject.org; Horos Project) for manual segmentation which allowed us to manually delineate, slice by slice, the tumor contour, thus creating a ROI dataset from which the tumor volume (cm3) was calculated. For CE tumors , regions of interest (ROIs) contoured CE boundaries. For tumors without CE or with patchy CE, ROIs contoured FLAIR alteration areas.As part of daily care at our Institution, all patients suffering from intracranial tumors received preoperative and postoperative (within 72 h) brain MRIs. T2-weighted (w) images, T2w fluid-attenuated inversion recovery (FLAIR) images, T1w images before and after gadolinium intravenous administration, and diffusion-weighted images (DWI) were assessed for radiological feature extraction. Baseline radiological characteristics included tumor location—as affected cerebral lobe and side—contrast enhancement (CE), and preoperative and postoperative tumor volumes. Volumetric tumor measures were addressed by a trained resident neurosurgeon (G.F.) and reviewed by an experienced neurosurgeon (G.C.), both of them blinded to clinical information. We used the open-source software Horos (The extent of resection (EOR) was calculated as: [(preoperative tumor volume – postoperative tumor volume)/preoperative tumor volume] × 100 .Postoperative DWI was checked for ischemic damage and postoperative pre-contrast T1w for hyperintense blood products.2), with a sensitivity encoding reduction factor (SENSE) of 2 and a flip angle equal to 90°. Isotropic voxel dimensions of 2 × 2 × 2 mm3 were obtained by using a field of view of 225 × 225 mm2 and a matrix of 112 × 110. Seventy slices were obtained, with a thickness of 2 mm, with no gap. DTI data motion artifacts were adjusted using the installed software on the scanner. The total acquisition time was 8 min 47 s.Diffusion tensor imaging (DTI) acquisition included an axial single-shot spin-echo echo-planar imaging (EPI) sequence  with 64 diffusion-encoding directions. A diffusion gradient was applied using two b factors  was obtained by placing a cubic box region of interest (ROI) along the precentral gyrus and a second one along the anterior pons. The SLF was reconstructed by placing a first ROI on the high-anisotropy region laterally to the central part of the lateral ventricle on a coronal section; the second ROI was placed on the peri-trigonal area at the level of the descending branch of the tract . To recoFiber tracking was performed with a fractional anisotropy (FA) minimum threshold value of 0.15 (mainly 0.18–0.21), an angular threshold of 45° (not editable by the user), and a variable minimum fiber length of 30–50 mm.The armamentarium used for IONM has already been described elsewhere by our group , 31. TheThe IONM was performed by dedicated neurophysiologists and technicians . The monitoring technique was performed as described previously , 31.In all patients, a total intravenous anesthesia protocol was performed with remifentanil and propofol, as previously reported. No curare or curare-like drugs were used in this series. In the case of awake craniotomy, the surgical opening was performed in an asleep–awake fashion with a laryngeal mask , 32.The type of IONM was tailored to tumor location and patients’ characteristics, with regard to functional anatomy, as depicted by DTI-FT, and cognitive status, according to neuropsychological evaluation. EEG and EMG monitoring of motor response was used in all the cases, as described elsewhere .In the revision process, we tried to simplify our IONM choices, as reported in In our series, as “small craniotomy” we defined a craniotomy that did not extend beyond 1 cm from the maximal tumor diameters if the tumor was cortical or immediately subcortical or that did not extend beyond 1 cm of the maximal cortical tumor projections in case of a deep-seated location. In other words, no brain other than the strictly necessary to allow tumor resection was exposed. Some intraoperative pictures are available in In the case of Rolandic and peri-Rolandic gliomas (as defined by Berger in 2004 ), a smalA cortical strip with four to six platinum contacts  was placed on the motor cortex to allow monitoring of the motor function throughout the procedure. In case the motor cortex was not fully exposed, then the cortical strip was made to slide under the dura with care. After the localization of M1, then brain mapping was performed around the tumor to exclude the presence of peritumoral motor functioning areas. After the required corticectomy was performed, continuous monitoring of the motor pathway was achieved with cortical MEPs with a cortical or subdural strip. At this point, DTI was employed to help in the neurophysiological definition of the CST. Subcortical resection close to the motor pathways was performed alternating mapping with the monopolar probe and the aspiration  of tumoral/peritumoral areas as far as it was considered safe, according to brain/tumor visual appearance. Tumor resection was continued until a positive response at the intensity of 2–3 mA with the monopolar probe was obtained.In the case of gliomas located in the frontal or parietal lobe but not close to the Rolandic area, the craniotomy was placed right over the tumor , with minimal brain exposure. In this way, the motor area was not generally exposed and positioning cortical electrodes under the dura and over the motor area strip  was in most cases not possible. For this reason, before surgery, corkscrew electrodes were placed on the scalp, in the skin area that was over the projection of the motor area. Occasionally, DTI reconstruction of the CST was used to help the technician in the definition of the area and correct positioning of the corkscrew electrodes. Continuous TC MEPs were monitored during surgery. After exposure of the lesion, the resection started with a corticectomy (when necessary) and subsequent dissection of the tumor from the normal brain parenchyma using Penfield dissectors and CUSA from time to time. During the resection of the deeper part of the tumor, monopolar stimulation was used to assess the distance from the CST. During surgical resection of larger lesions, phenomena of brain shift and pneumocephalus may decrease TC MEP responses. At this point, positioning a cortical strip for cortical MEP monitoring became generally possible.In the case of gliomas located in non-dominant temporal and occipital lobes, the surgical resection was carried out similarly to what was done for frontal or parietal lobe tumors located >3 cm away from the Rolandic area. Essentially, motor monitoring was performed using TC MEP with corkscrew electrodes and monopolar DES was done subcortically. In addition to DTI for the CST, in occipital lobe tumors, the resection was planned and carried out taking into consideration the DTI reconstruction of the optic pathways, as described elsewhere .In the case of tumors, located in the dominant hemisphere affecting frontal and temporal lobes and, at times, parietal and occipital lobes, the asleep–awake technique was used for surgical resection. As extensively published, the awake technique is the most reliable and safest technique to preserve complex functions in patients with brain tumors in the dominant hemisphere. In particular, it allows intraoperative testing of the patients with specific tasks for language expression and comprehension as well as customized tasks for the preservation of other skills such as music, cognitive functions, and social recognition. The authors applied awake surgery in all the cases of LGG affecting the dominant hemisphere and in most cases of HGG. The utility of the awake technique in HGG has been extensively debated , 38, andIn the asleep–awake setting, a tumor-targeted craniotomy was performed as well Figure 2DTI was used to plan the craniotomy and to help in the definition of the lesion as it regards its relationship with the CST but also the main language fiber bundles. In particular, as described elsewhere, the IFO and the arcuate fasciculus were reconstructed using DTI and defined intraoperatively by DES.The insula is located deeply in the Sylvian fissure, and the resection of these gliomas is among the most challenging. Given these premises, it is clear that the greatest efforts were made preoperatively to get complete DTI reconstruction of the important white matter tracts and intraoperatively to obtain a reliable and complete IONM Figure 3In addition to EEG, TC MEPs were always applied. The most commonly used approach to the insular lobe was the trans-opercular approach. On the non-dominant side, this approach required cortical brain mapping (using monopolar DES) to avoid the motor area of the face, while in the dominant hemisphere awake surgery was necessary to avoid injury to the language function. The technique in the dominant hemisphere was similar to the one adopted for dominant frontal or parietal gliomas in terms of brain mapping and monitoring of language functions. Nevertheless, the technical difficulties due to perforating branches of the middle cerebral artery, the length of surgery, and the deeper location of these tumors require higher technical skills than other gliomas.Data concerning surgical procedures were retrieved from digital operative registers. The following variables of interest were collected: type of anesthesia (asleep vs. asleep–awake or asleep–awake–asleep), type of intraoperative neurophysiological monitoring (IONM), surgical procedure duration, and occurrence of intraoperative seizures.The use of the following IONM techniques was analyzed and collected: transcranial electrical stimulation (TC) with motor-evoked potentials (MEPs) and somatosensory-evoked potentials (SSEPs), electroencephalography (EEG), electrocorticography (ECoG), direct electrical stimulation (DES), monopolar stimulation for subcortical mapping, and bipolar stimulation for cortical mapping.Intraoperative seizures were classified according to their clinical manifestation—as electrical or symptomatic—and the treatment needed to stop them—cold water irrigation or drugs .In the case of recurrent tumor resection, it was recorded if an extension of the previous mini-craniotomy was required.Three outcome measures were assessed for the patients: overall survival (OS), progression-free survival (PFS), and rate of definitive neurological deficits (deficits that did not regress at the 3-month follow-up). The postoperative tumor volume and EOR were identified as the main surgical outcomes.OS was defined as the time from surgery to death. PFS was defined as the time from surgery to tumor progression. We referred to RANO criteria for gliomas to assess disease progression .Patients who did not experience death or disease progression were censored at their last scan date, during OS and PFS analyses.Variables of interest were reported and compared as follows:• Frequencies were reported as a percentage and compared by chi-square/Fisher exact test;• Continuous variables were checked for normal distribution through skewness, kurtosis, and Shapiro–Wilks normality test;• The continuous normally distributed variables were reported as mean ± standard deviation and compared through Student’s t-test or variance analyses.via Mann–Whitney U-test and Kruskal–Wallis test.• The continuous skewed distributed variables were reported as median  and compared A multiple linear regression model (using the Enter method) was settled to assess the predicting value of explanatory variables on the surgical predicted outcome (postoperative volume and EOR). The explanatory variables were chosen based on recent literature as well as on the statistical significance of the univariate analysis. Multicollinearity was assessed at each step through tolerance and the variance inflation factor (VIF). Residuals were checked for normality.OS and PFS as a function of time were calculated by the Kaplan–Meier method.Univariate analysis of risk factors influencing PFS and OS was assessed by the proportional hazard regression model. Variables associated with PFS and OS in univariate analyses (p < 0.05) were included in the multivariate Cox proportional hazard regression model. All statistical analyses were performed using IBM SPSS version 25.0, International Business Machines Corp, New York, USA.In the period between May 2011 and February 2016, 265 patients received surgical treatment for supratentorial gliomas. One hundred and three patients met the inclusion criteria for the study. Of these, 21 patients received a revision resection. The overall median follow-up was 19 months (range from 3 to 108 months). Follow-up ended in November 2021. The main variables of interest are summarized in According to WHO 2016 brain tumor classification , 65 patiThe MGMT gene promoter methylation showed superiority at 9% in 55 cases (53%).All the patients with WHO grade IV tumors received chemoradiotherapy according to the Stupp protocol except eight patients . All the patients with WHO grade III tumors received chemoradiotherapy except three patients (2 received only temozolomide and 1 did not receive any adjuvant treatment). Among patients with WHO grade II tumors, only four patients received adjuvant chemoradiotherapy.According to WHO 2021 brain tumor classification, we identified 14 patients with a molecular oligodendroglioma profile , of which 10 are WHO grade II and four WHO grade III. Nine patients showed a molecular astrocytoma profile , among which three showed WHO grade II histological features and six with WHO grade III histological characteristics. Eighty patients showed glioblastoma (GBM)-like features: IDH1 and 2 wild types (wt) and imbalance of chromosome 7 and chromosome 10q loss of heterozygosity, or telomerase reverse transcriptase (TERT) promoter mutation, or epidermal growth factor receptor (EGFR) amplification . All thePost-hoc analyses using the LSD method revealed greater age means among WHO grade IV glioma carriers (58 ± 12 years), compared to others (45 ± 15 years), and among patients with GBM and GBM-like molecular profiles (57 ± 13 years), in comparison to those with oligodendroglioma (46 ± 14 years) and astrocytoma (43 ± 16 years) molecular features.The mean age was 54 ± 14 years. Sixty-one patients (59%) were men. The mean preoperative KPS was 80. One-way ANOVA showed a statistically significant variance among age means of the different WHO tumor grades  as well as among the three molecular subtypes . Chi-square analyses revealed a higher incidence of preoperative KPS rates inferior to 80 among glioblastoma carriers (51%), in comparison to those suffering from lower-grade gliomas (7%–33%), and among patients with a GBM-like molecular profile (46%) when compared with both of those with astrocytoma (0%) and oligodendroglioma (7%).The median length of the in-ward stay was 7 (IQR 4) days. Nine patients (9%) experienced seizures during the in-ward stay, requiring an antiepileptic drug increase and/or multidrug association. All but two of these patients experienced partial epileptic events. One patient suffered from a generalized seizure, while another from a delayed postoperative awakening.Postoperative neurological deficits occurred in 31 patients, of which 14 were severe. Ten patients showed an improved neurological status at postoperative evaluations. At the 3-month FU, only three neurological deficits were still present (3%). Seventeen patients (17%) were discharged to a rehabilitation facility.Thirty-three patients underwent craniotomy under asleep–awake anesthesia. All patients underwent mini-craniotomy with at least EEG, EMG, and TC MEP as IONM. In 77 patients (75%), ECoG was used. DES was exploited in 51 patients (50%). Cortical mapping required monopolar and bipolar stimulation in 24 cases (23%). Subcortical monopolar stimulation was exploited in 33 cases (32%).Fourteen patients (13.6%) experienced intraoperative seizures, of which eight (7.7%) were only electrically evident. Seven patients  experienced intraoperative symptomatic  seizures which required cold irrigation as a unique treatment, while two patients (2%) experienced symptomatic  seizures that required pharmacological treatment.The exact Fisher chi-square test revealed a statistical correlation between the incidence of intraoperative seizures and the employment of bipolar stimulation for brain cortical mapping .Among the 21 revision resection cases, only one needed an extension of the previous craniotomy.The median preoperative volume was 24 cc (IQR 42). The median postoperative volume was 0 cc (IQR 3). The median EOR among all gliomas was 100% (IQR 10%).2 = 0.5; b = 0.15; ES = 0.03; ß = 0.5; p = 0.0001), WHO grade II IDH wt gliomas , and insular gliomas  were related to greater postoperative tumor volumes.The following explanatory variables were put in the multiple linear regression model to predict postoperative volume values: preoperative volume, WHO 2016 gliomas’ classification type, and tumor side and location . Increasing preoperative volume  and mut  gliomas and WHO grade III IDH mut , insular , and thalamic  gliomas were related to lower EOR.The same regression analysis was conducted to predict EOR: WHO grade II IDH wt , while the WHO grade III IDH1/2wt gliomas had the minimum preoperative volume median .Glioblastomas and WHO grade III IDH wt gliomas showed the lowest postoperative volume medians, equal to 0 cc, reaching statistical significance at medians’ comparison .The comparison of EOR medians among different WHO grades as well as among the three different molecular subtypes demonstrated significantly higher rates among grade IV gliomas (p = 0.038) and GBM/GBM-like gliomas (p = 0.036).The log-rank test using the Kaplan–Meier method indicated a statistically significant OS difference among all WHO grades (p = 0.0001). The median OS for WHO grade III IDH1/2mt gliomas was 74 months, for WHO grade III IDH1/2wt gliomas 20 months, and for WHO grade IV gliomas 14 months. For WHO grade II IDH1/2mt and wt gliomas, the median OS was not reached.A statistically significant difference was also demonstrated among the OS of the three molecular groups (p = 0.0001). The median OS for GBM and GBM–like gliomas was 15 months. The median OS for astrocytomas and oligodendrogliomas was not reached.The log-rank test using the Kaplan–Meier method was also employed to assess PFS, showing a statistically significant difference among all WHO grades (p = 0.0001). The median PFS for the WHO grade III IDH1/2wt gliomas was 12 months and for the WHO grade IV gliomas 10 months. For the WHO grade II IDH1/2mt and wt gliomas as well as for the WHO grade III IDH1/2mt ones, the median PFS was not reached. As for the OS, a statistically significant difference was noted among the three molecular groups (p = 0.0001). The median PFS for GBM and GBM–like gliomas was 12 months. For astrocytomas and oligodendrogliomas, the median PFS was not reached.Survival analyses were repeated on the only first resected gliomas.The log-rank test using the Kaplan–Meier method showed a statistically significant difference among the OS of all WHO grades . The median OS for WHO grade III IDH1/2mt gliomas was 74 months, for WHO grade III IDH1/2wtgliomas 15 months, and for WHO grade IV gliomas 14 months. For WHO grade II IDH1/2mtand wt gliomas, the median OS was not reached Figure 8The 1-, 2-, and 5-year OS rates were 100%, 100%, and 90% for WHO grade II IDH1/2mt gliomas, 67%, 67%, and 17% for WHO grade II IDH1/2wt gliomas, 100%, 100%, and 75% for WHO grade III IDH1/2mt gliomas, 37.5%, 12.5%, and 12.5% for WHO grade III IDH1/2wt gliomas, and 58.8%, 25%, and 4% for WHO grade IV gliomas.As for OS, the log-rank test using the Kaplan–Meier method was used to assess PFS, showing a statistically significant difference among all WHO grades . The median PFS for the WHO grade III IDH1/2wt gliomas was 12 months and for the WHO grade IV gliomas 9 months. For the WHO grade II IDH1/2mtand wt gliomas as well as for the WHO grade III IDH1/2mt ones, the median PFS was not reached The 1-, 2-, and 5-year PFS rates were respectively 100%, 100%, and 90% for WHO grade II IDH1/2mt gliomas, 67%, 67%, and 17% for WHO grade II IDH1/2wt gliomas, 100%, 100%, and 75% for WHO grade III IDH1/2mt gliomas, 37.5%, 12.5%, and 12.5% for WHO grade III IDH1/2wt gliomas, and 39%, 20%, and 4% for WHO grade IV gliomas.Concerning molecular subtypes, the log-rank test using the Kaplan–Meier method showed statistically different OS among the three molecular groups  and WHO 2016 grade II (p = 0.009) and III (p = 0.021) IDH1/2 mut gliomas confirmed a statistical correlation with the overall PFS and OS.The survival analyses through the log-rank test using the Kaplan–Meier method were not performed on the revision surgery group due to the limited sample size.The 1-, 2-, and 5-year OS rates were 100%, 100%, and 75% for WHO grade II IDH1/2mt gliomas; 100%, 100%, and 50% for WHO grade III IDH1/2mt gliomas; 100%, 0%, and 0% for WHO grade III IDH1/2wt gliomas; and 50%, 7%, and 0% for WHO grade IV gliomas.The 1-, 2-, and 5-year PFS rates were 100%, 100%, and 50% for WHO grade II IDH1/2mt gliomas, 100%, 50%, and 50% for WHO grade III IDH1/2mt gliomas, 100%, 0%, and 0% for WHO grade III IDH1/2wt gliomas, and 42%, 7%, and 0% for WHO grade IV gliomas.The 1-, 2-, and 5-year OS rates were of 53%, 7%, and 0% for GBM and GBM–like gliomas and 100%, 100%, and 67% for oligodendrogliomas.The 1-, 2-, and 5-year PFS rates were of 47%, 7%, and 0% for GBM and GBM–like gliomas and 100%, 84%, and 50% for oligodendrogliomas.In the last 20 years, the importance of white matter tracts has been rediscovered in neurosurgery , 41, 42.Nevertheless, all the DTI surgical information has to be verified by IONM and it is nowadays unacceptable to operate close to the main fiber bundles  without IONM , 45, 54.Given these premises (usefulness of DTI and need of IONM) but also the trend toward reduced invasiveness of surgical procedures, our group tried to combine IONM , DTI (useful), and small craniotomy to verify their possibility of combination and the patients’ outcomes in a large consecutive series of gliomas. Minimally invasive neurosurgery has gained popularity thanks to several technical advancements including preoperative advanced imaging , neuronavigation, intraoperative imaging techniques , and microscopic and endoscopic refinements. For brain tumors, the limited invasiveness has brought to propose even day surgery plans with doubtless advantages for patients and healthcare systems –62. OtheThe first result of our series of 103 gliomas is that, in all the cases, a tumor-targeted approach resulted to be feasible without affecting the EOR or the surgical outcomes. In particular, despite most centers using IONM performing large craniotomies to allow exposure of eloquent areas to be sure of not obtaining falsely negative brain mapping, we deliberately chose to minimize the craniotomy (without reducing the IONM) considering the expertise and trust in IONM. In other words, our confidence in IONMs and our team of neurophysiologists was so high that we were confident that a negative mapping, even without observing positive responses, was a real negative. Such confidence was supported by the extensive use of DTI which, through the reconstruction of the white matter bundles’ tridimensional architecture, allowed us to tailor the craniotomy and the type of IONM, as well as the surgical corridor, for a safer and faster surgical resection. In this paper, we were also able to summarize the type of IONM according to the location of the tumor and the distance from CST (>3 cm or less than 3 cm) to make our experience reproducible by other neurosurgical centers Table 1.Awake surgery, in our experience, was not incompatible with small craniotomies and indeed appeared to be faster and very tolerated by the patients as well. Even if the absence of positive responses may be disturbing for the surgeon, we did not recur to higher stimulation intensities or repeated stimulations to achieve positive responses, thus keeping the rates of intraoperative electric complications low. In our experience and, as already published, the use of the currents able to induce motor response was the key for having a reliable mapping.Our experience suggests that negative mapping is safe and feasible. In this view, intraoperative DTI guidance of DES allowed us to focus the cortical and subcortical mapping to the regions of strict relationship between the tumor and the main fiber bundles and increased our trust in mapping results, even for negative mapping, since we rarely experienced major discrepancies between the two localizing techniques. Nevertheless, we always kept in mind the limitations of DTI fiber reconstruction, carefully exploring by DES the regions of uncertainty, affected by peritumoral edema or marked anatomical disruption, where DTI-FT may fail to adequately reconstruct essential bundles. In doubtful cases, resection was ultimately guided by IONM results. The neurological deficits in our series, in fact, were similar to the best available literature since only 3% of patients experienced a permanent neurological worsening , 70. TheThe EOR was not affected by the small craniotomy since the median EOR was 100% among different types of gliomas. As consequent, and again in line with the literature, OS was relatively good with a median of 15 months for GBM (or GBM-like) and as it concerns LGG, median OS was not reached after a median follow-up of 19 months (range 3–108). Kaplan–Meier survival curves are available in Finally, we believe that DTI and the expertise reached by our group in the use of IONM played a major role in permitting the use of small craniotomies as well as negative mapping techniques. These latter considerations may constitute a limit of our paper and may justify the reason why limited literature is available on the topic.The effect of brain shift on preoperative DTI needs also to be discussed, even if small craniotomies are theoretically less affected by it. Since the displacement of major white matter tracts is somehow unpredictable, the authors strongly suggest checking their position during tumor resection by IONM, increasing the employment of DES mostly in the deepest part of the resection cavity, where the effects of brain shifts are likely to be amplified. Intraoperative ultrasounds and CT might be employed to correct the brain shift, as improving guidance of DES, while intraoperative MRI could even allow intraoperative DTI and fiber tracking.As last consideration, in selected cases, the small craniotomies, as defined above, could be extended a little more to nearby non-eloquent areas, as per preoperative DTI and functional assessment, to allow more extensive resection when feasible.Reduced invasiveness  and patient integrity represent surgical aims we should all try to pursue, despite technical difficulties, in the primary interest of our patients. Extensive preoperative workout, including DTI and patient cognitive assessment, allows tailoring craniotomies and IONMs to patient needs, reducing surgical invasiveness while guaranteeing optimal functional and survival outcomes. Like all surgical techniques, a learning curve is needed for relying on negative mapping as, in our experience, we found its dependability to be related to expertise, confidence, and cooperation among all the involved professionals.Other preoperative tools have gained popularity in recent years, such as the preoperative transcranial magnetic stimulation (TMS) –76. As aThe original contributions presented in the study are included in the article/Ethical review and approval were not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.GCa, GF, AC: concept and drafting. CB, LB: neurophysiological monitoring and data collection. BZ, GF: statistical analysis. GCo, FT: DTI reconstructions; data collections; imaging revision. AR, MC, GB: clinical records analysis and data collection. ML; CG; GCa: critical review of the manuscript. All authors contributed to the article and approved the submitted version.This study was supported by "Associazione Amici della Clinica Neurochirurgica" and "Università degli studi di Milano-Bicocca".The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


IntroductionIt is critical to identify asymptomatic vertebral compression fractures (VCFs) as soon as possible in order to avoid subsequent fragility fractures. The purpose of the study was to see how many vertebral compression fractures there were in patients admitted to the COVID-19 pneumonia unit in a single tertiary care hospital who underwent chest computed tomography (CT) scans.Materials and methodsSagittal reconstruction of the thoracic spine was done in around 504 patients and classified into mild, moderate, and severe categories, and we compared it with the radiological reports of the same.ResultsIn our study, the median age was 53 years (range: 31-91 years); 63% were men and 37% were women. Of the 504 patients, 76 (15%) had at least one vertebral compression fracture (VCF); 53 (10.2%) had one VCF, and 23 (4.8%) had multiple VCF, with 50 having mild fractures, 15 having moderate fractures, and 11 having severe fractures. Males (13.87%) and females (14.72%) had the same proportion of VCF (p = 0.83). Only 10% of the patients with VCFs we identified had a description in their report (eight patients).ConclusionThe reporting of VCF is insufficient. VCF detection should be included in the search patterns of radiologists and physicians, regardless of the primary reason for performing chest CT. Although many patients are unable to come to the hospital during pandemic/epidemic, careful evaluation and inclusion of mild fractures in reports, as well as an explanation of the risk of subsequent fractures and treatment accordingly, would completely eliminate the risk of subsequent fractures. Osteoporosis is a global problem that is most usually discovered by vertebral fractures, and the presence of vertebral compression fractures (VCFs) are indicators of osteoporosis in an otherwise unremarkable history and may produce non-vertebral osteoporotic fractures without additional intervention -6. AlmosAlthough computed tomography (CT) is an excellent diagnostic technique for both finding and measuring fractures, earlier research relied on midline sagittal reformatted images to diagnose fractures ,14. The This retrospective investigation was authorized by the Institutional Ethics Sub-Committee (IESC) of Dr. D. Y. Patil Medical College, Hospital & Research Centre in Pune (research permission number: IESC/FP/2021/41). We conducted this investigation on 504 patients hospitalized in the COVID-19 pneumonia unit, all of whom tested positive for SARS-CoV-2 RT-PCR. This study was conducted from January to July 2021. All patients with chest CT conducted within the aforementioned time period were included, regardless of age group, and the initial scan was evaluated in patients with numerous scans. Fresh fractures and pathological fractures, which can be detected by loss of trabeculation and step defect, thoracic spine instrumentation, and CT images without full visibility of the thoracic spine in sagittal reformats, were all eliminated.Sagittal images were created by reformatting axial images with bone windows and a section thickness of 1 mm. If needed, coronal pictures were also accessible. The CT images were examined using the Siemens software tool (PACS), which is accessible at our institution; assessors were blinded to the patients' clinical and personal data, and bone contrast windows were used. The approach of Genant et al. was used for evaluation, and patients with vertebral compression fractures were assessed by the senior author and categorized as mild (20%-25%), intermediate (25%-40%), or severe (>40%) based on vertebral height decrease .Figure Figure Figure We examined 504 individuals, the average age being 54.3 years (range: 31-91 years). In all, 317 (63%) patients were male, while 187 (37%) were female. When comparing age group variability, the age group less than 50 accounts for 42% of the population, and the age group greater than 60 accounts for 38% of the research. There were 76 (15%) individuals who had at least one vertebral fracture. In particular, 53 (10.2%) patients had a single fracture, whereas 23 (4.8%) patients had two or more VCF, for a total of 106 fractures. T11 and T12 vertebrae accounted for more than two-thirds of the accidental vertebral compression fractures.Table Table Table The column distribution among the fractures is shown in Table Figure The International Osteoporosis Foundation has concluded that one best practice standard for health institutions is the development of a VCF incidental detection methodology . Many phOur study is the first in the COVID-19 era to evaluate osteoporotic vertebral compression fractures using sagittal reformats of chest CT. Many previous studies compared the relationship between osteoporosis and COVID-19 infectivity, but none of them evaluated osteoporotic vertebral compression fractures in sagittal reformats of the vertebrae in chest CT . Our stuAlso, the proportion of compression fractures observed in the male population is higher than in the female population, and the number of multiple fractures observed in women is higher than in men, despite the fact that the value did not achieve a significant p-value. This can be ascribed to the study's huge male-dominant population, which made up over two-thirds of the population, in contrast to earlier research that found osteoporotic vertebral compression fractures to be more prevalent in female age groups . The ageOnly a 10th of the observed fractures are acknowledged in reports, with radiologists reporting only eight of the 76 fractures, all of which are severe compression fractures seen on sagittal slices of chest CT before reformatting the bone images. The clinical scenario in these cases, where radiologists are keen on giving CORADS score and also looking out for potential other causes, such as embolism and pleural effusion, can contribute to the low reporting, and many other studies showed similar underreporting, noted in patients being evaluated for cancer and terminal illness in the ICU. Many people are avoiding hospitals in these epidemic times for general diseases such as back pain, and many individuals are limiting themselves to home without sufficient physical activity and exposure to daylight, making them more prone to osteoporosis.LimitationsPrior history of trauma and the date of fracture were not determined because the present study is a retrospective study. Using a sagittal and coronal reformatting, vertebral deformities such as Scheuermann's disease cannot be ruled out, and CT concentrated on the dorsal spine and the lumbar spine is missing, which is an important factor because osteoporotic vertebral compression fractures are common at the dorso-lumbar junction.Although the study was conducted on a COVID-19-afflicted population, this cannot be considered the only constraint because the scan was completed until the L1 vertebrae, which covers almost the whole thoracolumbar junction. Age group can also be a limiting factor since vertebral compression fractures are common in the older age group and here all patients are taken into study irrespective of the age group.Underreporting of vertebral compression fractures is very evident in the above study, and radiologists should look for vertebral compression fractures regardless of their primary reason. During these pandemic/epidemic times, osteoporosis is a neglected disease, leading to underdiagnosis and undertreatment. As a result, a thorough examination of spinal compression fractures, including even mild to moderate fractures in reports, and emphasizing the danger of additional fractures are required. Treating suitably during the same hospital visit, not only in COVID-19-infected patients receiving chest CT such as in our study but also in other tests such as abdominal CT conducted during cancer staging and many others, would eliminate the danger entirely and avoid morbidity in many patients.


Knowing the degree of gastric fullness is critical in determining the potential risk of pulmonary aspiration prior to urgent or elective intubation. This study aims to investigate the role of ultrasound in predicting the gastric volume accurately.176 patients who underwent upper gastric endoscopy after 12-hour fasting were examined by gastric US. The patients were randomly divided into 6 groups according to the volume of ingested semifluid meal: (1) empty stomach (no volume), (2) 50 mL, (3) 100 mL, (4) 200 mL, (5) 300 mL, and (6) 400 mL. Antral cross-sectional area (CSA) was measured by US after each ingestion. 2 by sonographic measurement.We found a strong linear correlation between antral CSA and gastric volume up to 200 mL. The diagnostic performance of ultrasound was found to be more powerful in the supine position than in the right lateral position. A new mathematical model was established to predict gastric volume. The threshold value for antral cross-sectional area at risk of pulmonary aspiration was determined as 3.1 cmUltrasonography could be preferred to gastric endoscopy or scintigraphy in terms of non-invasiveness and easiness, although it still merits further investigation. Having a full stomach before intubation increases the risk of aspiration. This study aims to investigate the role of gastric ultrasound in predicting the gastric volume.A strong linear correlation was established between cross-sectional area (CSA) of stomach and gastric volume ingested up to 200 mL. Gastric CSA of 3.1 cm2 and above was found to be risky for aspiration.Gastric ultrasound can be used as an easy, non-invasive and bedside technique to detect the risk of gastric aspiration.−1 to be significant in terms of increased pulmonary aspiration risk.2Gastric content is one of the key causes of pulmonary aspiration risk. The critical stomach volume threshold that increases aspiration risk remains controversial. Experimental and clinical research has accepted a gastric content of ≥0.8-1.5 mL kg3 Yet, these rules can be ignored in urgent conditions requiring intubation. There is currently no easy and reliable method or a gold standard test for assessing gastric volume. Research with volunteers and certain patient groups suggests that the gastric volume can be evaluated by measuring the gastric antral cross-sectional area (CSA) using ultrasound.5Aspiration risk varies depending on the duration of the fasting period. Hence, numerous guidelines recommend certain fasting periods to reduce aspiration risk in patients.6 Previous studies investigating gastric volume using ultrasound have either failed to consider the stomach content after fasting or performed “blind” aspiration using a nasogastric tube. Besides, these studies have often evaluated stomach content after intake of liquid or solid contents.8 Here, however, gastric contents were emptied by endoscopy before ultrasound examination. We performed evaluations on a chyme-like stomach content by intake of solid–liquid mixture foods, consistent with gastric physiology, and investigated the correlation between gastric volume and antral CSA by ultrasound.After foods are taken into the stomach, they are mixed with the gastric fluid, forming a stomach content called “chyme.” Nearly 100 mL of fluid can be found in the stomach after fasting.The current study was conducted in Konya Beyhekim State Hospital in accordance with the ethical standards of Selçuk University Ethic Committee. The patients who underwent upper gastrointestinal endoscopy (UGE) under elective conditions on an outpatient basis were enrolled. Informed consent was obtained from all participants.Exclusion criteria were being aged below 18 years or above 70 years, having UGE performed at urgent conditions , having poor general condition, history of previous abdominal surgery, presence of diabetes mellitus, or pregnancy.Patients’ demographic characteristics were recorded, including age, sex, height, weight, and body mass index (BMI). Upper gastrointestinal endoscopy procedure was performed under sedation after 12 hours of fasting. During UGE, stomach contents were aspirated, if present. Once the procedure was completed, the patients were included in the study.A biscuit and clear apple juice was given to each patient to simulate “chyme,” which is a semifluid mixture of digested food and gastric juice. The patients were stratified into 6 groups regarding the amount of ingested volume: (1) no ingestion, (2) 50 mL (12.5 g biscuit and 37.5 mL fruit juice), (3) 100 mL (25 g biscuit and 75 mL fruit juice), (4) 200 mL (50 g biscuit and 150 mL fruit juice), (5) 300 mL (75 g biscuit and 225 mL fruit juice), and (6) 400 mL (100 g biscuit and 300 mL fruit juice).One minute after taking the biscuit with apple juice, ultrasonographic images of the gastric CSA were obtained in the supine position with the head raised 30° and then in the right lateral decubitus position. An appropriate view of the stomach antrum was received using real-time ultrasound .9 The gastric antrum was visualized between the left lobe of the liver anteriorly and the pancreas posteriorly at the level of the abdominal aorta or inferior vena cava /4, where DL is longitudinal diameter and DT is transverse diameter, representing the anteroposterior and craniocaudal sections, respectively.ena cava . The anaSonographic measurement of diameters was done by 2 physicians separately for each patient and the images and measurements were checked by a radiologist for every 4 patients. The mean of the 2 measurements for each diameter was used to calculate the CSA. The physicians who performed the US had an experience with 25 cases on sonographic CSA measurement. All sonographic measurements were performed blindly to ingested volume. Cross-sectional area measurements were classified according to image quality as optimal, suboptimal, or impossible. Patients whose measurements were impossible to perform were excluded from the study.−1) was evaluated using receiver operating characteristic and areas under the curve (AUC). Sensitivity and specificity were determined for cut-off values. A 5% type 1 error level was considered statistically significant for all tests. Statistical analyses were performed using the Statistical Package for the Social Sciences 22.0 statistical package software .Categorical data are expressed as percentage and frequency. Continuous parameters were investigated using the Kolmogorov–Smirnov test, histogram, probability plots, skewness, and kurtosis to determine whether they were normally distributed. Descriptive analyses are presented as mean and standard deviation for numeric data with normal distribution and as median and interquartile range for those with non-normal distribution. The relationship between the ingested volume and CSA was examined by Spearman correlation analysis. A multivariate linear regression analysis was done to detect the association between ultrasonographic CSAs and the characteristics of patients including ingested volume, age, height, weight, and BMI. A quantitative model for predicted volume was created by the equation based on the coefficients of significant factors and gastric areas. The capacity of ultrasonographic CSA in predicting the gastric volume at risk for aspiration  = 57.3+ 29.4* CSAsup (cm2) − 2.6*BMI (kg m−2) (Correlation coefficient=0.787).Predicted Volume (mL) = 63.3 + 23.4* CSAlat (cm2) − 2.4*BMI (kg m−2) (Correlation coefficient=0.659).The usCSA values corresponding to risky gastric volume for pulmonary aspiration in either position has been shown in the This study investigated the performance of sonographic measurement of antral CSA in predicting gastric volume after ingesting different volumes of a semifluid meal. Thereby, the role of US for diagnosing risky stomach for pulmonary aspiration was also studied.11 at 65% in critically ill adults. We could visualize antral gastric CSA in all patients (100%) in supine position, while it was impossible to obtain images in lateral position in 8 patients, corresponding to a 96% yield. In this single-center observational study, antral CSA could be viewed in nearly half to two-thirds of patients at optimal conditions according to patient position. This result is in concordance with the data reported by Hamada et al12 and in 65 to 73% of the time in supine and lateral positions, respectively, by Jacoby et al13 at empty stomach. However, current data support our findings with a success rate of 98%-100% in the recent literature.15 Of the 8 patients with impossible measurements, the failure to visualize the gastric antral region was documented at empty state in 4, after an ingested volume of 100 mL in 2, and after an ingested volume of 300 mL in 2. Virtually, the antrum of the stomach is displayed more clearly in lateral position because the gas and stomach contents move towards the antrum under the effect of gravity, making the antrum fuller.17 We do not know the reason for this unexpected result obtained in the 8 patients, but it may be explained by individual anatomical variations in stomach shape, which should be investigated. In early studies, stomach could be identified in up to just 60% of patients by Carp et al20 We detected a linear relationship between CSA and gastric volume up to 200 mL in both positions. However, in contrast to previous reports, the correlation coefficient was stronger in supine position compared to the right lateral position.20 We cannot explain this discrepancy, but it could be due to methodological differences in study design, including patient profile, consistency of ingested volume, and study setting. Increments in ingested volume after the threshold value of 200 mL have been shown to cause an artefactual increase in gastric CSA values, reducing the performance of ultrasound . The mathematical formula can be applicable to the nonpregnant adult population up to 200 mL gastric volume and 40 kg m−2 BMI in supine position. To the best of our knowledge, there are 2 available formulae for predicting gastric volume based on CSA measurement. Of these, the model by Perlas et al16 can predict volumes of up to 500 mL, in right lateral position with a correlation coefficient of 0.86, whereas the model by Bouvet et al7 is applicable to volumes of up to 250 mL, in semi-sitting position with a correlation coefficient of 0.72.We report a new mathematical model for each position alternative to the other models reported previously.16 . The equation proposed by Bouvet et al7 included the components of age, height, weight, and physical status [Gastric Volume (mL) = −215 + 57 * log ) − 0.78 • age − 0.16 * height (cm) − 0.25 * weight (kg) − 0.80 • American Society of Anesthesiologists Physical Status Classification (1–4) + 16 mL (in case of emergency) + 10 mL (in case of preoperative ingestion of 100 mL antacid prophylaxis)].In the model established by this study, BMI is the only demographic factor with a predictive role on determining gastric volume by CSA measurement. However, the other models were different in terms of the demographic factors affecting the predicted gastric volume. Age was the only demographic factor in the formula of Perlas et al11 The minimum gastric fluid volume to induce passive regurgitation of gastric contents and therefore pulmonary aspiration is accepted as 200 mL.22 However, according to data obtained from animal studies, a gastric volume greater than 0.8 mL kg−1 is considered the threshold value for risk of pulmonary aspiration.23 Bouvet et al7 found 3.4 cm2 to be a cut-off value for antral CSA at risk of pulmonary aspiration in preoperative setting, with a sensitivity of 91%, a specificity of 71%, and an AUC of 0.90. Another similar study by Hamada et al11 reported a cut-off value of 3.6 cm2 for risky stomach in critically ill adults with a sensitivity of 76%, a specificity of 78%, and an AUC of 0.80. We found a critical threshold of 3.1 cm2 for aspiration risk with a diagnostic accuracy of 96.2% sensitivity, 100% specificity, and 0.98 AUC in supine position. The same value with a close diagnostic performance was also obtained in lateral position.Based on the rationale that CSA measurement is correlated with gastric volume, determining a stomach at risk of pulmonary aspiration by measuring gastric CSA has been investigated in different conditions.The main limitation of this study was the research setting and patient profiles. Since the study was confined to the outpatient adult population, the results and the mathematical model cannot be generalized to other settings including critical care, emergency, or perioperative conditions, as well as to patient groups like children, pregnant women, and morbidly obese patients. However, this study was noteworthy for indicating the relationship between ingested semifluid volume and gastric CSA measured by ultrasound. Ingestion of semifluid content, has a similar consistency to gastric juice and a slower gastric emptying compared to the fluid content, which constitutes the strength of the study and its different aspect from most other studies. Also, emptying the stomach completely by endoscopic gastric aspiration before US examination can be considered a methodological advantage of the present study.Ultrasonography is a noninvasive and portable tool in predicting gastric volumes up to 200 mL. It can also be used for diagnosing a stomach at risk for pulmonary aspiration before intubation at either elective or urgent conditions. Our findings should be validated with highly qualified studies.


Several previous reports suggested that stage 4 idiopathic macular holes (IMHs) may exhibit lower rate of anatomical success and poorer functional results comparing with stage 3 IMHs, while some others showed no differences. Actually, few studies focused on comparison of prognosis between stage 3 and stage 4 IMHs. Our previous study found that IMHs of these two stages demonstrate similar preoperative characteristics, and this study aims to compare anatomical and visual outcomes of IMHs between stage 3 and stage 4, and tries to figure out the outcome-associated factors.This retrospective consecutive case series reviewed 317 eyes with IMHs of stage 3 and stage 4 from 296 patients who underwent vitrectomy with internal limiting membrane peeling. Preoperative characteristics like age, gender, and hole size, and intraoperative interventions such as combined cataract surgery were evaluated. Outcome measures included the primary closure rate (type 1), best-corrected visual acuity (BCVA), foveal retinal thickness (FRT) and prevalence of outer retinal defect (ORD) at the last visit. The pre-, intra-, and post-operative information were respectively compared between stage 3 and stage 4.P < 0.001), better postoperative BCVA , and thicker postoperative FRT  comparing with larger ones regardless of stage.The preoperative characteristics and intraoperative interventions exhibited no significant differences between stages. With comparable follow-up durations , IMHs of the two stages exhibited similar primary closure rate , BCVA , FRT , and prevalence of ORD . IMHs, either < 650 μm or larger, exhibited no significant difference in outcomes between the two stages. However, smaller IMHs (< 650 μm) demonstrated higher rate of primary closure (97.6% vs. 80.8%, IMHs of stage 3 and stage 4 exhibited considerable identity of anatomical and visual outcomes. In large IMHs, the hole size, instead of stage, may be more important for prediction of surgical outcomes and choice of surgical techniques. Idiopathic macular holes (IMHs) are defined as full-thickness dehiscence of the foveal neurosensory retina , which cIn 1995, Gass updated his classification of IMH, considering full-thickness macular holes (FTMHs) larger than 400 μm with vitreomacular separation as stage 3, and FTMHs with complete posterior vitreous detachment as stage 4 regardless of their diameters . The IntAccording to our previous study, stage 3 and stage 4 IMHs exhibited similar preoperative characteristics, including duration of symptoms, preoperative visual acuity, and size of the hole depicted by minimum linear diameter, basal diameter, etc . RegardiThe current investigation evaluates the anatomical and visual outcomes of a relatively large population, and attempts to identify whether IMHs of the two stages differ in terms of surgical prognosis.A consecutive series of patients with stage 3 or stage 4 IMHs who underwent vitrectomy together with internal limiting membrane peeling in Beijing Tongren Hospital between July 2015 and January 2019 were reviewed. Eyes with traumatic macular holes, high myopia , other fundus diseases like age-related macular degeneration, history of vitreous surgery or intravitreal injection, or treated with inverted internal limiting membrane flap were excluded. All the patients provided written informed consents after detailed explaining of surgery and follow-up examinations. This study adhered to the tenets of the Declaration of Helsinki and was approved by the ethical review committee of Beijing Tongren Hospital, Capital Medical University. Preoperative information review included a comprehensive medical history, duration of symptoms, preoperative best-corrected visual acuity (BCVA), intraocular pressure  and axial length . The anterior segment examination was performed by slit-lamp bio-microscopy, and the binocular indirect ophthalmoscope together with the fundus photography  and OCT  was utilized for fundus examination. The diagnosis of IMH was based on detailed clinical history, comprehensive ocular examination, and intraoperative observation. Stages of macular holes were identified by OCT (status of vitreomacular adhesion) image and intraoperative observation (Weiss ring presentation) according to Gass’s classification in 1995.Minimum linear diameter (MLD) was defined as the narrowest distance between the rims of the IMH paralleled to the retinal pigment epithelium (RPE) on a horizontal scan through the center of the hole, and basal diameter (BD) was the span of the broken ends of the neuroepithelium at the level of RPE. The main outcomes were the primary closure rate of IMH, the BCVA at the last visit, the foveal retinal thickness (FRT) at the last visit, and the prevalence of outer retinal defect (ORD) at the last visit. The closure of IMH was defined as type 1 closure , i.e. clAll the patients enrolled underwent the standard 3-port pars plana vitrectomy by a single surgeon with the Constellation device  by 23-gauge technique. A combined phacoemulsification and intraocular lens  implantation was performed through a 3.0-mm incision prior to the vitrectomy when necessary. After core vitrectomy, the posterior vitreous detachment was induced if necessary and the removal of vitreous was carried out to the vitreous base. The epiretinal membrane was peeled if presented, and the internal limiting membrane was removed with a diameter of approximately 2 optic disk diameters around the macular hole without staining. Before July 2016, gas tamponade (14% hexafluoroethane or 12% octafluoropropane) was injected after fluid-air exchange; since then, sterile air was retained in vitreous cavity. The three incisions closed automatically, and the intraocular pressure was kept around 20 mmHg (gas tamponade) or 25 mmHg (air tamponade). Trans-sclera suture was only performed when there was gas or air leaking. Every patient was asked to keep strict face-down position for 1 (air tamponade) or 2 weeks (gas tamponade), and further consultation was arranged as 1 week, 1 month, 4 months, 10 months after surgery, and once a year afterwards. Postoperative pharmaceutical protocol included topical antibiotics and anti-inflammatory agents.P < 0.05 was considered statistically significant.All data were presented as mean ± standard deviation. BCVA was converted to the logarithm of the minimum angle of resolution (Log MAR) for statistical analysis. Comparisons of categorical variables were carried out by Chi-square test or Fisher’s exact test; t test or Mann-Whitney test were conducted for continuous variables conformed to normal distribution or not respectively. Wilcoxon signed rank test was used to compare pre- and postoperative measurements. Pearson correlation and Spearman correlation were conducted to find out the association among MLD, FRT, ORD and postoperative BCVA. SPSS 22.0  was applied and P = 0.90). During a mean follow-up of 6.7 months (range: 1–36), three patients with stage 4 IMH were lost to follow-up with unknown closure status (one died and another two out of contact). The type 1 closure rate after first surgery was 91.4% (287/314). Among the 27 eyes with initially unclosed holes, four exhibited type 2 closure (open/flat) after surgery and remained stable during follow-up, one closed spontaneously 3 months after the initial surgery, fourteen underwent a second surgery and obtained type 1 closure, and the other eight refused the repeat operation. Eyes with gas tamponade exhibited no significant differences in the primary closure rate between stage 3 and stage 4 , so did eyes with air tamponade .A total of 317 eyes from 296 patients (61 men and 235 women) were recruited. The average age of the patients were 65 years old (ranging from 48 to 84), and the duration of symptoms ranged from 1 to 96 months with an average of 9. IMHs of stage 3 and stage 4 showed no significant difference in proportion of duration > 9 months , and no complications like retinal detachment had occurred till the last visit.Mean BCVA at last visit of all the eyes improved significantly from 0.12 ± 0.10 to 0.51 ± 0.27 , and rate of air tamponade were similar  as well.Concerning the surgical procedure, percentage of combined cataract surgery were comparable between stages  either. For postoperative parameters, IMHs of the two stages showed similar primary closure rate, postoperative BCVA, FRT, and presence of ORD  while positively correlated with postoperative BCVA .After surgery, the mean follow-up for stage 3 and stage 4 IMHs were 6.64 and 6.69 months respectively, which exhibited no significant difference (P < 0.001), better postoperative BCVA , and thicker postoperative FRT  comparing to larger ones regardless of stage.IMHs with MLD < 650 μm exhibited no significant differences in the four main outcomes between stage 3 and stage 4, neither do IMHs with MLD ≥ 650 μm (shown in Table Three representative cases were shown in Fig. It has been suggested that stage 4 IMHs seem to be associated with less satisfactory surgical outcomes comparing to stage 3 IMHs , 11. ThiAs is shown in our previous report  and confVitrectomy with internal limiting membrane peeling is considered as an efficient surgical treatment for IMHs with a primary closure rate of more than 90% according to previous reports . ConventPostoperatively, the primary closure rate exhibited no significant differences between the two stages. Eleven eyes with stage 3 IMHs and three eyes with stage 4 IMHs underwent a second operation and obtained final closure; five eyes with stage 3 IMHs and three eyes with stage 4 IMHs did not take a second operation. There seems to be no evident difference in the secondary closure rate between stages, but statistical analysis was not carried out considering the relatively small sample. The postoperative BCVA is considered to be associated with not only the preoperative minimum diameter , base diBesides closure rate and postoperative vision, the morphology of the fovea after surgery is also noteworthy. In a prospective interventional series by Apostolopoulos et al., the thickness of the fovea was manually measured and exhibited significant association with the BCVA 1 year postoperatively . TakamurThe ORD in this study, which is also referred as foveolar lucency, is a common cystic space underlying the fovea with continuous inner retina in the surgically sealed macular hole . Kang etConsidering all above, IMHs of stage 3 and stage 4 exhibited identical anatomical and visual outcomes based on comparable baseline characteristics and surgical interventions. It could be inferred that IMHs of the two stages may have an identity of the intrinsic nature in wound healing.There are quantities of parameters provided by OCT to depict the postoperative morphology of IMH, among which the integrity of the ellipsoid zone, once referred as the IS/OS junction, is frequently applied and widely considered to be associated with the vision recovery , 27. HowA previous report involving 2456 IMH eyes indicated that duration > 9 months reduced the MH closure rate . In thisThis study staged IMHs according to Gass’s classification in 1995  and all This study of stage 3 and stage 4 IMHs has a limitation of its retrospective nature. With a relatively large sample and strict inclusion criteria, the results are considerably reliable, but further studies, especially prospective ones and randomized controlled trials are still in need. Meanwhile, the mean follow-up of about 6 months seems to be relatively short, because the visual outcomes could continue to improve in the long run . HoweverIn conclusion, this study with a relatively large sample compared stage 3 and stage 4 IMHs based on the Gass’s classification in 1995, and found IMHs of the two stages exhibited considerable identity not only in preoperative characteristics, but also in anatomical and visual outcomes after vitrectomy, internal limiting membrane and other comparable intraoperative interventions. For IMHs larger than 400 μm, the size, instead of the stage, may be more valuable for outcome prediction and decision-making in proper technique for hole closure.


Thrombotic microangiopathy defines a group of pathologies characterized by microvascular dysfunction with the concurrence of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. It represents the most frequent microvascular manifestation of human immunodeficiency virus (HIV) infection. We report the case of a man in the seventh decade of life with a recent diagnosis of infection by HIV, who develops hemolytic uremic syndrome, requiring continuous renal replacement therapy and plasma replacement therapy, without response, ADAMTS13 with preserved activity, ruling out other etiologies  with successful response to eculizumab. Thrombotic microangiopathy (TMA) defines a heterogeneous group of pathologies with microvascular dysfunction characterized by the concomitance of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. It is the most frequent microvascular manifestation of human immunodeficiency virus (HIV) infection, especially in advanced stages with opportunistic infections, high viral loads, and low CD4 lymphocyte counts. The spectrum of presentation of this relationship is varied, with thrombotic thrombocytopenic purpura being the most frequent form We present the case of a 60-year-old patient with a recent diagnosis of HIV infection who was diagnosed with secondary TMA, with severe renal involvement related to hemolytic uremic syndrome (HUS), and a favorable clinical response to anti-complement therapy with eculizumab. This case highlights the unusual presentation and etiology of TMA, demonstrating the importance of recognizing therapeutic options in primary and secondary settings.A 64-year-old male patient with recent diagnosis of human immunodeficiency virus infection . He was admitted to the emergency department complaining of 15 days with intermittent fever in up to 39ºC associated with nocturnal diaphoresis, asthenia, adynamic, and progressive symmetrical edema of the lower limbs. Also, he referred chronic diarrhea that resolved before admission. He reported smoking 20 cigarettes per day for 20 years (20 pack-year smoking history). Furthermore, he received 2 months earlier the first dose SARS-CoV 2 vaccine (Sinovac) and reported an unintentional loss of 4 kg in the last 5 months. He denies any other relevant personal or family history. Physical examination revealed tachycardia, tachypnea, hypotension, without hypoxemia, severe dehydration, pallor, normal cardiopulmonary auscultation, absence of abdominal pain with grade III edema in lower limbs without any neurological focalization.+ 42 cells/µL. Due to quantitative serum cytomegalovirus (CMV) PCR level increased from 35 copies/mL - 1.54 log to 104 copies/mL – 2.04 log, ganciclovir was started.Sepsis was considered and empirical antibiotic coverage was started with Metronidazole and Ampicillin/Sulbactam . Cultures of blood, urine, lower respiratory tract, and stool were taken before antimicrobial therapy was administrated without any isolation, as well as multiple detection panels of the gastrointestinal and lower respiratory tract. Due to lack of response to crystalloids, he was transferred to the Intensive Care Unit (ICU) for high-dose vasopressor infusion. The patient developed refractory shock with subsequent multisystem failure and required ventilatory support. Blood tests reports  documentThe diagnosis considered at this time was secondary thrombotic microangiopathy/atypical hemolytic uremic syndrome. Due to persistent anemia and thrombocytopenia with multiple transfusion requirements during his stay at the ICU, plasma exchange therapy (PET) was started (negative report of Shiga-Toxin on a film array panel and a PLASMIC score of 6 points). We observed an improvement in platelet count  after 13 sessions of PET, but after anemia and severe thrombocytopenia recurred, 6 more sessions of PET were administrated. At this point the patient completed 10 days of Metronidazole + Ampicillin/Sulbactam; 14 days of Amphotericin B , and current treatment with ganciclovir (10 days so far). In the search for other causes of anemia in a critically ill patient, esophagogastroduodenoscopy was performed, and biopsy of polyps found in the gastric antrum was compatible with Kaposi's sarcoma. Bone marrow cultures, biopsy, and flow cytometry revealed preserved hematopoiesis of all three lines with no pathological findings.A cholestatic pattern was discovered so an MR cholangiography and pancreatography was performed to rule out obstruction of the bile duct and infiltrative involvement, observing findings suggestive of hepatic iron overload due to possible secondary hemosiderosis. Anti-smooth muscle antibodies, anti-mitochondrial membrane antibodies, antinuclear antibodies, and hepatotropic viruses were performed with negative results. The percentage of transferrin saturation was less than 45 % and a liver biopsy was performed in which abundant iron deposits are observed in the cells of the reticuloendothelial system in addition to findings compatible with acute lobular hepatitis with cholestasis. Since we didn’t found evidence of cirrhosis, cholangiopathy, intrinsic hepatic infectious processes, or autoimmunity, hemosiderosis was attributed to multiple blood transfusions.pneumococcus and meningococcus). We observed improvement of the hematological profile, increase in urinary volume, and decrease the creatinine value  without any clinical improvement after 14 days. Considering the requirement for PET, the ADAMTS13 of 34.8 %, and the futility of the treatment so far used, we initiated eculizumab 900 mg , who received multiple broad-spectrum antimicrobial regimens without clinical response. We consider this patient’s clinical course is compatible with Atypical Hemolytic Uremic Syndrome secondary to HIV infection. A report of genetic sequencing by Next Generation Sequencing (NGS) perform in serum was negative for pathogenic, probably pathogenic, or variants of uncertain clinical significance identified in the complement coding regions. The patient was discharged with recommendation to continue eculizumab on an outpatient basis and follow-ups by the hematology and infectious disease services. At the publication date, the patient attended to hematology’s office one month after to discharge without requiring dialysis, and with minor thrombocytopenia and anemia.Thrombotic microangiopathies (TMA) comprise a set of clinical syndromes characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. These characteristics are secondary to vascular damage manifested as capillary and arteriolar thrombosis, with characteristic changes at the endothelium and the vessel wall. Historically they have been classified as primary or secondary according to their etiology Escherichia coli and other gram-negative bacilli, Staphylococcus, pneumococcus), viral  and to a lesser extent, parasitic and fungal infections Bayer et al. published a series of 564 patients diagnosed with TMA in four French hospitals. Primary entities were identified in only 6 % of cases, while in the remaining 94 % TMA was diagnosed secondary to infections (33 %), medications (26 %), malignancy (19 %), and autoimmune diseases (9 %) as the most frequent etiologies. TMAs associated with infections constitute a diverse entity with multiple pathophysiological mechanisms depending on the pathogen involved. They have been frequently related to bacterial , low levels of CD4+ lymphocytes (median 58 cells per µL), and a higher incidence of concurrent infections at presentation, especially those caused by the complex of The absence of neurological manifestations, the severe renal involvement, and the preserved activity of ADAMTS13 led us to consider the possibility of complement-mediated TMA secondary to HIV infection therefore the use of eculizumab was proposed, with dramatic clinical results. This humanized monoclonal antibody that binds to the C5 protein, preventing its passage to C5a and C5b, blocking complement-mediated endothelial damage has been used in the past on patients with secondary TMA to HIV, with variable clinical results and a high rate of recurrence In summary, in patients with TMA associated with HIV presenting within the spectrum of HUS, combined therapy with eculizumab and initiation of ART may be beneficial. The decision to discontinue anti-complement therapy is not yet supported by clinical trials but may be considered in the context of resolution of TMA and complete virologic response to antiretroviral therapy.The manuscript and informed consent were submitted to the ethics committee of the institution La Cardio - Fundación Cardioinfantil and approval was obtained to publish the case.Studies on patients or volunteers require ethics committee approval and fully informed written consent which should be documented in the paper.Danilo E. Trujillo González: Writing, Data collection. Dagoberto Duarte Misol: Writing, Searching, Data collection. Nicolás Ariza Ordoñez: Writing, Data Collection. Fabian Andres Salgado Zamora: Writing, Others. Henry A. Millan Prada: Writing, Others. Eduardo Zuñiga R: Writing, Analysis of the case. Alejandra Molano Trivño: Writing, Analysis of the case.The authors expressly declare that there is no conflict of interest relevant to the preparation and construction of this document. The patient gave his informed consent for purely scientific purposes. The manuscript and informed consent were submitted to the ethics committee of the institution La Cardio - Fundación Cardioinfantil and approval was obtained to publish the case.


Compared with the metaphors from daily life or in literary works, scientific metaphors tend to involve both a more complicated context structure and a distinct knowledge-inferencing process. During the N400 time window (300–500 ms), English scientific metaphors elicited more negative N400s than Chinese ones at the parietal region. In the late positive component (LPC) time window (550–800 ms), English scientific metaphors elicited less positive LPCs than Chinese ones at the parietal region, and larger late negativities encompassing smaller areas of the brain. The findings might indicate that for late unbalanced bilingual speakers, L2 scientific metaphor comprehension requires more effort in information retrieval or access to the non-literal route. Altogether, the possible findings are that non-native and non-dominant language processing involves decreased automaticity of cognitive mechanisms, and decreased sensitivity to the levels of conventionality of metaphoric meanings.To study the different mechanisms of understanding figurative language in a speaker’s native language (L1) and their second language (L2), this study investigated how scientific metaphors in Chinese (L1) and English (L2) are electrophysiologically processed  The semantic integration between the daily source domain and the scientific target domain involved in scientific metaphor processing provides a perspective for exploring the similarities and differences between processing mechanisms of native language and non-native language . Howevercode) of the scientific metaphor (A mitochondrion is a code) is more frequently used in everyday contexts, while the target domain (mitochondria) is more frequently used in scientific contexts. Second, the late processing period of scientific metaphors probably involves a reasoning process from the daily concrete concept to the scientific abstract concept, so as to better comprehend the embedded scientific knowledge. The late components of ERP [the late positive component (LPC) and the late negativity] are very sensitive to this process.The processing of scientific metaphors differs from that of conventional metaphors mainly in two aspects. First, the contextual structure of scientific metaphors is more complex than that of conventional metaphors, which has been established in previous N400 experiments . For exaEvent-related potentials (ERPs) with extremely high time resolution and rich component dimensions are increasingly used in the study of metaphorical cognitive neural mechanisms. The N400 is considered to be very sensitive to semantic violations , and is The late positive component (LPC) is considered to reflect integration or reprocessing at the sentence level . Some moSo far, few studies focused on the processing mechanism of scientific metaphors for bilingual speakers. Thus, expanding a monolingual electrophysiological study on scientific metaphor processing to include a bilingual component might be insightful to enunciate conceptual integration mechanisms when processing semantically complex meanings. Some bilingual ERP studies have reported a lower N400 amplitude elicited by L2 relative to L1 stimuli , probablThe main objective of this study was to observe brain responses to scientific metaphors, conventional metaphors, and literal expressions in Chinese (L1) and English (L2). First, we aimed to observe whether scientific metaphors would evoke higher N400 amplitudes compared with conventional metaphors in both L1 and L2. That is to say, our first focus was the modulation of conventionality for the N400 effect in two languages. A linear N400 effect has been reported by two previous monolingual studies ,b, with In total, 20 participants  took part in the ERP experiment. They had either normal or corrected vision and no history of mental illness, neurological disorders, or severe brain damage. All subjects started to learn English from elementary school and have passed the CET-6. All subjects signed a consent and confidentiality agreement before the experiment and received remuneration after the experiment. Finally, the trial data of three subjects were eliminated due to failure to meet the 80% completion-rate threshold. Therefore, the final number of subjects included in our statistical analysis was 17 .The stimulus pool consisted of 120 sentences, which fell into three categories, namely, scientific metaphors, conventional metaphors, and literal sentences, with 40 sentences in each sentence category. This pool matched the one used in our previous study ,b  with 64 Ag/AgCl electrodes, monitored using the CURRY recording software and connected to a SynAmp amplifier . Amplified analog voltages were digitized at 1,000 Hz. Impedances of individual sensors were kept below 5 kΩ. Eye movements were monitored through bipolar electrodes, which were placed above and below the right eye, as well as at the left and right canthi. Electroencephalography (EEG) was measured online with reference to the left mastoid, with a ground electrode on the medial frontal aspect, and later was analyzed offline with re-reference to an average of the left and right mastoids.post-hoc multiple comparisons were carried out using Bonferroni-adjusted corrections.EEG was analyzed using the SCAN 4.5 software  and Matlab using the ERPLAB toolbox . The EEGF = 5.32, p = 0.01, p2η = 0.25. Pairwise comparisons showed that the reaction time of scientific metaphors was significantly longer than that of literal sentences (p = 0.005). There was neither significant difference between conventional metaphors and literal sentences nor between the two metaphorical conditions . For accuracy rates, a main effect between conditions was found . Pairwise comparisons showed that the accuracy rate of scientific metaphors was significantly lower than that of conventional metaphors and literal sentences . There was no significant difference between conventional metaphors and literal sentences (p = 0.569).A repeated-measures ANOVA revealed significant effects of condition for reaction time According to the Grand average ERP waveforms recorded at the nine chosen electrodes see , there wF = 12.56, p < 0.001, pη2 = 0.44]. Scientific metaphors elicited the most negative N400 , followed by conventional metaphors  and literal sentences . Pairwise comparisons revealed a significant difference between N400s elicited by scientific metaphors and conventional metaphors . Meanwhile, both scientific metaphors and conventional metaphors elicited more negative N400s than literal sentences .The condition × region × hemisphere ANOVA revealed a significant main effect of condition . The lowest LPC amplitude was registered by scientific metaphors  followed by conventional metaphors  and literal sentences . Pairwise comparisons showed that there were significant differences between LPCs elicited by scientific metaphors and conventional metaphors  and by scientific metaphors and literal sentences  but no significant difference between conventional metaphors and literal sentences .The main effect of condition was found to be significant . Scientific metaphors elicited a significantly larger late negativity  than conventional metaphors .In addition, the Grand average ERP waveforms of the differences between metaphorical and literal conditions see  showed tConsistent with our predictions, scientific metaphors elicited more negative N400 readings than conventional metaphors. The processing of scientific metaphors involves the conceptual integration between scientific-target and daily-source, while the processing of conventional metaphors involves the conceptual integration of daily-target and daily-source, resulting in the contextual complexity found in scientific metaphors. Compared with conventional metaphors, when processing scientific metaphors, it might be more difficult to search and retrieve stored conceptual knowledge due to the longer distance between the target and source domains ,b. MeanwConsistent with our predictions, both scientific metaphors and conventional metaphors elicited a late negativity partly overlapping in space and time with the LPC . The higParticipants of Experiment 2 were selected from undergraduates with similar ages, language background, and English proficiency as those of Experiment 1. Twenty participants took part in the ERP experiment. As in Experiment 1, the number of subjects included in our final statistical analysis was 17 .F = 39.72, p < 0.001, pη2 = 0.51]. The familiarity of scientific metaphors was significantly lower than that of conventional metaphors and literal sentences , while no significant difference was found between the familiarity of conventional metaphors and literal sentences (p = 0.225).The English stimuli of Experiment 2 were the English counterparts of the Chinese stimuli used in Experiment 1 see . The EngSame as Experiment 1 see .Same as Experiment 1.p = 0.48). A repeated-measures ANOVA performed on the accuracy rates yielded significant effects of condition . The difference between the accuracy rates of two metaphorical conditions was not significant (p = 0.775), but the accuracy rates of metaphorical conditions were significantly lower than that of the literal condition .Diverging from the result of Experiment 1, the main effect of condition for reaction time was not found to be significant  = 20.73, p < 0.001, pη2 = 0.56]. Scientific metaphors elicited more negative N400s  than both conventional metaphors  and literal sentences . Pairwise comparisons showed a significant difference between N400s elicited by scientific metaphors and conventional metaphors . Meanwhile, both scientific metaphors and conventional metaphors elicited significantly larger N400s than literal sentences .As with Chinese metaphor processing, the condition × region × hemisphere ANOVA revealed a significant main effect of condition , central , and parietal  regions. The difference between N400s elicited by English scientific metaphors and conventional metaphors was marginally significant at the left and middle parietal regions , significant at the right frontal and central regions , and highly significant at the right parietal region . Relative to English literal sentences, both English scientific metaphors and English conventional metaphors elicited a more negative N400 at all the three regions {scientific metaphor vs. literal sentences: frontal , central , and parietal  regions; conventional metaphors vs. literal sentences: frontal , central , and parietal  regions}.In contrast to Chinese metaphor processing, the differences between English scientific metaphors and conventional metaphors were significant at the frontal . Scientific metaphors elicited less positive LPCs  than conventional metaphors  and literal sentences . The condition × region interaction effect was significant . Pairwise comparisons showed that there was a marginally significant difference between LPCs elicited by scientific metaphors and conventional metaphors  and a significant difference between scientific metaphors and literal sentences . Between conventional metaphors and literal sentences, despite an insignificant main effect of condition , the condition × region interaction effect was significant . Post-hoc analysis showed that conventional metaphors elicited significantly lower LPCs at the parietal region .The condition × region × hemisphere ANOVA revealed a significant main effect of the condition , separate pairwise ANOVAs for the three electrodes at the parietal region  were performed. It was evident that the LPCs elicited by scientific metaphors were significantly less positive than that of conventional metaphors at P4  and marginally less significantly positive than that of conventional metaphors at P3 , whereas no such difference was observed at Pz .Since between the two metaphorical conditions, the main effect of condition was significant at the parietal region . Scientific metaphors elicited a larger late negativity  than conventional metaphors . Follow-up analysis showed that the significant effect was only found at the parietal region .Analogous to Chinese metaphor processing, English (L2) scientific metaphors and conventional metaphors also elicited a late negativity in the LPC time window see . The 2 ×F = 1.79, p = 0.46, pη2 = 0.04], but there were marginally significant condition × region interactions . Pairwise comparisons showed that English scientific metaphors elicited a significantly larger N400 than Chinese scientific metaphors at the parietal region . There were no significant effects either between Chinese and English conventional metaphors  nor between Chinese and English literal sentences .In comparing the results manifested by Chinese and English scientific metaphors see , a condiF = 1.79, p = 0.2, pη2 = 0.10], significant condition × region interactions were found . Pairwise comparisons showed that English scientific metaphors elicited a significantly lower LPC than Chinese scientific metaphors at the parietal region , and the difference between the two was highly significant at the right parietal region .For the difference between Chinese and English scientific metaphors see , a condiF = 3.08, p = 0.098, pη2 = 0.1] and significant condition × region interactions . Pairwise comparisons showed that English conventional metaphors elicited a significantly lower LPC than Chinese conventional metaphors at the parietal region , and the difference between two conditions was highly significant at the right parietal region .For the difference between Chinese and English conventional metaphors, the condition × region × hemisphere ANOVA revealed a marginally significant main effect of condition  and significant condition × region interactions . Pairwise comparisons showed that English literal sentences elicited a lower LPC than Chinese literal sentences at the parietal region , and the effect was highly significant at the right parietal region .In terms of the differences between Chinese and English literal sentences see , the conTaken together, reduced LPC amplitudes for all three English conditions were maximal over the parietal region, especially over the right parietal region, suggesting that the meanings of both L2 metaphoric and literal sentences are integrated with increased cognitive effort. This result might indicate that late speakers who master two languages asymmetrically are less sensitive to levels of conventionality of metaphoric meanings at the later stage of metaphoric language processing . MoreoveThe first aim of the current study was to observe brain responses to scientific metaphoric, conventional metaphoric, and literal sentences in Chinese (L1) and English (L2). In line with what was hypothesized, in both the Chinese and English experiments, we observed general between-condition differences, with scientific metaphors eliciting higher N400s than conventional metaphors. However, in the English experiment, more significant effects were found in larger regions over frontal, central, and parietal regions, with a slight right hemisphere bias. Importantly, this finding accords with the behavioral results drawn from the Chinese experiment, which showed lower accuracy rates and longer reaction time for scientific metaphors than with conventional metaphors. This supports the graded salience hypothesis for metaphorical expression. The unique complexity and abstraction of scientific language reduce the explicitness of language expression and have an impact on semantic integration in the later stage of processing. The longer distance between the scientific target domain and the daily source domain for scientific metaphor comprehension might increase cognitive effort in conceptual integration ,b. AccorIn both Chinese and English experiments, LPC amplitudes evoked by scientific metaphors were smaller than those elicited by conventional metaphors and literal sentences. Lower LPC amplitudes for scientific metaphors might be caused by a sustained negativity, indexing the integration process of conceptually taxing meanings. Another explanation could be due to reprocessing operations after an initial failure in meaning interpretation  or alterSecond, the current study aimed to observe whether language nativeness modulates meaning integration mechanisms of scientific metaphors, to which the N400 response is sensitive. More specifically speaking, we were interested in whether L2 scientific metaphors would elicit similar N400s as L1 equivalents for late unbalanced bilingual speakers.Between-language effects were found with English scientific metaphors eliciting more negative N400s than Chinese ones at the parietal region. Such enhanced N400 response to L2 relative to L1 stimuli is contrary to the results of some bilingual research . Within In addition, at the frontal, central, and parietal regions of the right hemisphere, English scientific metaphors elicited higher N400s than English conventional metaphors, indicating the special role of the right hemisphere in second language processing , which sThird, the current study aimed to observe the modulation of language nativeness for cognitive mechanisms involved at the later stage of meaning reintegration, which the LPC is sensitive to. In line with our predictions, within the LPC time frame, at the parietal region, we observed between-language differences with a slight right hemisphere bias, with smaller LPC responses evoked by the three English conditions than their Chinese counterparts. Reduced LPC amplitudes for scientific and conventional metaphors in the non-native language suggest more demanding cognitive effort to integrate the meaning of both novel and familiar metaphors in an L2 context. This result might indicate that late speakers who master two languages asymmetrically are less sensitive to the levels of conventionality of metaphoric meanings at the later stage of metaphoric language processing.Inconsistent with the processing of Chinese scientific metaphors, English scientific metaphors only elicited lower LPCs than English conventional metaphors at the parietal region. That is to say, the LPC distribution of L1 scientific metaphors covered a larger area than that of L2 scientific metaphors , probablThrough a comparative analysis of the ERP components elicited by scientific metaphors in English and Chinese, this study examined brain responses to scientific metaphors in L2. It was found that nativeness modulates the cognitive cost for semantic integration at an early stage and for semantic reintegration and knowledge inference at a later period, supporting the Career of Metaphor Model and the Graded Salience Hypothesis.In addition, the scalp distributions of the N400s and the late component elicited by scientific metaphors in L2 reinforce the essential role of the parietal region  in processing L2, supporting the Fine-Coarse Semantic Coding Theory. More abundant types of stimuli could be added to subsequent follow-up experiments for more comparative analysis so as to continuously verify and improve existing studies.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee in Shaanxi Normal University. The patients/participants provided their written informed consent to participate in this study.XT and WR contributed to conception and design of the study. XT, MH, YH, and SH performed the data collection. LS, MH, and PY performed the analysis. XT wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.