Greenland’s outlet glaciers have been a leading source of mass loss and accompanying sea‐level rise from the Greenland Ice Sheet (GrIS) over the last 25 years. The dynamic component of outlet glacier mass loss depends on both the ice flux through the terminus and the inland extent of glacier thinning, initiated at the ice‐ocean interface. Here, we find limits to the inland spread of thinning that initiates at glacier termini for 141 ocean‐terminating outlet glaciers around the GrIS. Inland diffusion of thinning is limited by steep reaches of bed topography that we call “knickpoints.” We show that knickpoints exist beneath the majority of outlet glaciers but they are less steep in regions of gentle bed topography, giving glaciers in gentle bed topography the potential to contribute to ongoing and future mass loss from the GrIS by allowing the diffusion of thinning far into the ice sheet interior. Greenland glaciers with high potential to contribute to mass loss identified using novel metricThe majority of thinning limits are set by a knickpoint, a steep drop in bed topographyGlaciers that transmit thinning far inland are preferentially in regions with gentle bed topography Negative values of Pe represent locations along glacier flow where thinning perturbations can advect upstream and, because of the particular flux‐geometry relationship that we use, this occurs where the bed slope is negative . Previous work has shown that using other typical formulations for the relationship between ice flux and geometry does not significantly affect the locations of our predicted flowline thinning limits . We then create one measure of the predicted inland thinning distance for each glacier, taking into consideration both (1) the furthest inland predicted flowline thinning limit, which accounts for the worst‐case, furthest‐inland distance over which thinning can diffuse, and (2) the spread in distances to predicted flowline thinning limits across glacier flow, which accounts for our uncertainty in the extent of thinning. We call this the “predicted glacier thinning limit,” calculated by subtracting one standard deviation of the distances to all predicted flowline thinning limits from the distance to the single furthest inland predicted flowline thinning limit. Herein, we discuss thinning limits along individual flowlines (predicted flowline thinning limits), which are used to examine spatial patterns of thinning within individual glaciers, as well as predicted glacier thinning limits, which are used to compare each glacier to one another.As an additional improvement on F17, we quantify uncertainties in both observed dynamic thinning and Pe and propagate these through our calculations of predicted glacier thinning limits. We shift values of dynamic thinning and Pe along each flowline using a systematic bias obtained from reported uncertainties in bed topography, surface DEMs, and RACMO‐estimated SMB to obtain worst‐case bounds on our calculated values of dynamic thinning and Pe (Text S9 and S10 in the supporting information). Using a Monte Carlo analysis, we randomly sample from these worst‐case calculations to examine uncertainty in our calibration of an empirical thinning limit and in the glacier thinning limits . We find that, even in this conservative uncertainty analysis, statistically, the majority of dynamic volume loss occurs downstream of Pe = 3 Figures . Thus, w3Examining predicted flowline thinning limits, we can categorize the results according to two end‐member glacier geometries: 1) those that permit thinning perturbations to diffuse very far inland and (2) those that set strong limits to the inland diffusion of thinning. We demonstrate the differences between these two geometry types through examination of two representative examples. Humboldt Gletscher (HUM) in Northwest Greenland flows over gentle bed topography from the ice sheet interior to its submarine terminus Figure . The Pe  those thKnickpoints are prevalent beneath GrIS outlet glaciers and play an important role in limiting the inland diffusion of thinning. Sixty‐eight percent of all surveyed flowlines have an identified knickpoint. To ensure that our sampling of glaciers with a variable number of flowlines does not skew this statistic, we survey one centerline per glacier and find that 65% of glacier centerlines have an identified knickpoint. Of those flowlines with an identified knickpoint, 88% have predicted flowline thinning limits within the extent of the knickpoints, indicating that knickpoints are important geometric features for mitigating the inland diffusion of terminus‐initiated thinning for the majority of outlet glaciers in Greenland. Knickpoints have a median height of hundreds of meters, relative to the median elevation of the trough, spatial extent of tens of kilometers , we find that the predicted flowline thinning limits that lie furthest inland are in regions with gentle bed topography Figure . Convers3/yr) but with thinning limits close to the ice sheet margin (<150 km). These glaciers include the well‐studied glaciers Jakobshavn Isbræ (JAK), Kangerlussuaq Gletscher (KAN), and Helheimgletscher (HEL), which are often examined in the literature due to their high flux. A second group of glaciers exists with relatively low ice flux (<10 km3/yr) but far inland thinning limits (>200 km). These glaciers do not receive much focused attention in the literature but they have the potential to be large contributors to dynamic ice mass loss as thinning perturbations diffuse hundreds of kilometers into the ice sheet interior within their catchments. The glaciers in this group are predominantly located in regions of gentle bed topography  and Cornell Gletscher (COR), where 9 of 12 neighboring glaciers have predicted glacier thinning limits >250 km from the ice sheet margin and, thus, they can collectively draw down a ∼140‐km‐wide region far into the ice sheet interior. By considering uncertainties in input datasets and our choice of Pe = 3 as the empirical thinning limit, we find that predicted glacier thinning limits are most uncertain in regions of gentle bed topography around the GrIS Figure  and we hOur results provide a mechanistic understanding for satellite observations that have measured the largest rates of dynamic thinning and mass loss along the southeast and northwest margins (Csatho et al., Although knickpoints may have a different initiation mechanism than their riverine counterparts, by drawing on ideas from fluvial geomorphology, subglacial knickpoints may also be used to reconstruct uplift rate histories (Roberts & White, 4Using a novel metric easily calculable from glacier geometry, we predict the inland extent of thinning for 141 GrIS outlet glaciers. This metric quantifies the ratio of the rate of advection to the rate of diffusion of a kinematic wave of thinning initiated at glacier termini. We find that the majority of limits on the diffusion of thinning are set by steep knickpoints in subglacial bed topography at the heads of troughs where the bed transitions from below to above sea level. Knickpoints at the heads of subglacial troughs are the locations where we would expect a large decrease in ice discharge when, sometime in the future, glacier retreat causes marine‐terminating outlets to become land‐terminating. We have shown that these same locations are already mitigating the impact of marine‐terminating outlet glaciers on dynamic ice sheet mass loss by limiting the diffusion of thinning further inland. Consequently, we find that glaciers that allow thinning to diffuse far into the interior of the GrIS are preferentially located in regions of gentle bed topography because, although knickpoints are prevalent around the entire ice sheet, they are less steep in regions of gentle bed topography. When we consider both inland thinning limits and ice flux as measures of each glacier’s potential for dynamic mass loss, we find that glaciers with low ice flux may be significant contributors because of their ability to transmit thinning far inland. We hypothesize that the low ice flux glaciers with far inland thinning limits will contribute to dynamic ice sheet mass loss over a longer timescale than high ice flux glaciers, as the rate of diffusion of thinning slows in the ice sheet interior. Of particular concern is a group of glaciers along the northwest coast of the GrIS, between Upernavik Isstrøm C and Cornell Gletscher, where 9 of 12 neighboring glaciers have the potential to lead to long‐term, diffusive thinning >250 km into the interior of the ice sheet over a ∼140‐km‐wide region. This provides a mechanistic explanation for why the northwest sector of the GrIS is the only region experiencing an ongoing increase in observed discharge.Supporting Information S1Click here for additional data file.Table S2Click here for additional data file.


Trust forms the basis of virtually all interpersonal relationships. Although significant individual differences characterize trust, the driving neuropsychological signatures behind its heterogeneity remain obscure. Here, we applied a prediction framework in two independent samples of healthy participants to examine the relationship between trust propensity and multimodal brain measures. Our multivariate prediction analyses revealed that trust propensity was predicted by gray matter volume and node strength across multiple regions. The gray matter volume of identified regions further enabled the classification of individuals from an independent sample with the propensity to trust or distrust. Our modular and functional decoding analyses showed that the contributing regions were part of three large‐scale networks implicated in calculus‐based trust strategy, cost–benefit calculation, and trustworthiness inference. These findings do not only deepen our neuropsychological understanding of individual differences in trust propensity, but also provide potential biomarkers in predicting trust impairment in neuropsychiatric disorders. We applied a prediction framework in two independent samples of healthy participants to examine the relationship between trust propensity and multimodal brain measures. Our multivariate prediction analyses revealed that trust propensity was predicted by gray matter volume and node strength across multiple regions. OverallA widely‐used quantitative and reliable measurement of trust behavior is the sequential two‐person reciprocal trust game, for which the one‐shot version measures trust propensity toward an anonymous partner  studies that associate experimental conditions or behavioral performance with neural activation. Task‐based and meta‐analytic neuroimaging  studies indicate that individual differences in intrinsic brain structures or functional connectome are closely related to individual differences in personality traits —to predict individuals' trust propensity based on two intrinsic brain features applying two task‐free neuroimaging modalities. Due to practical implications that brain morphometry can be more reliably collected than RSFC  completed the standard trust game, whereas the second sample  completed the binary trust game. Finally, we performed a modular analysis  to detect network connectivity patterns  among the identified anatomical regions as well as a functional decoding analysis to link the identified modules with psychological functions. These following‐up analyses aimed to provide data‐driven quantitative inference on psychophysiological functions of contributing regions.Based on the neuropsychoeconomic model of trust  and the second sample (playing a binary version of the trust game) included 86 college students . Although both samples were collected from the same site at Beijing Normal University; however, they were recruited in different projects. Participants gave written informed consent for this study, which was approved by the Ethics Committee of Beijing Normal University and conducted following the Declaration of Helsinki.The current study consisted of two independent samples of healthy right‐handed participants without a history of neurological or psychiatric disorders, playing two different versions of the one‐shot trust game. The first sample (playing the standard version of the trust game) included 89 college students  or distrusting (n = 51) group. The two groups did not differ in gender, age, and brain size , participants were categorized into a trusting  was unknown, participants were all paid with a fixed amount (50 RMB) about a week later. Before leaving the laboratory, participants were debriefed to examine their beliefs about the experimental setup and none of them expressed doubts about the implemented procedure.2.33; flip angle, 7°; inversion time, 1,100 ms; and field of view (FOV), 256 × 256 mm2.MRI acquisition was performed with a Siemens Trio 3‐Tesla scanner at the Beijing Normal University Imaging Center for Brain Research. High‐resolution structural images were acquired through a 3D sagittal T1‐weighted magnetization‐prepared rapid acquisition with gradient‐echo (MPRAGE) sequence, using the following parameters: sagittal slices, 144; repetition time (TR), 2,530 ms; echo time (TE), 3.39 ms; slice thickness, 1.33 mm; voxel size, 1 × 1 × 1.33 mm3; and FOV, 244 × 244 mm2. During the RS scan, participants were instructed to close their eyes, keep still, remain awake, and not to think about anything systematically. Several approaches were implemented to prevent the participants from falling asleep during the scan. They were explicitly instructed to close their eyes but not fall asleep during the scan. Experimenters communicated with each participant immediately after the scan, and they all responded promptly, indicating that they did not fall asleep.The qualities of all T1‐weighted images were good or satisfactory, and no participants were excluded . The fir2.4http://www.fil.ion.ucl.ac.uk/spm/) on a MATLAB  platform. The processing procedure consisted of the following steps. First, the original T1‐weighted image of each participant was reoriented to the center point of the anterior commissure. Second, volumetric T1‐weighted images were segmented into GM, white matter, and cerebrospinal fluid density maps using the standard unified segmentation approach  space using VBM8 implemented with Statistical Parametric Mapping  features at the most in the final model. This is problematic for a model with relatively small samples but a much larger number of features such as in our study that includes 89 samples but more than 180,000 features.To alleviate the issues of multicollinearity and overfitting, regularization methods have been frequently applied  to implement the elastic‐net regularization regression (http://scikit-learn.org/).In contrast, the L2‐norm regularization  minimizes the sum of the square of the regression coefficients and keeps all features in the model. Finally, elastic‐net regularization reflects a weighted combination of L1‐norm and L2‐norm regularization and retains the desirable property of LASSO by providing sparse solutions while overcoming the problems associated with a large number of voxel features. Specifically, the elastic‐net regularization takes the following form, which was added to the linear regressions model as a penalty term:2.6 set for the elastic‐net regularization model.For the prediction framework, nested cross‐validation was adopted with an outer leave‐one‐out cross‐validation (LOOCV) to evaluate the prediction performance and inner three‐fold cross‐validation used to select the optimal parameters Figure . First, N participants, then N − 1 participants were used for the feature selection and training for an optimal prediction model. The remaining participant was used for testing to evaluate the prediction accuracy of the model. The procedure was repeated N times, each time leaving out a different participant for testing, resulting in N predictions, and one for each participant. Estimates such as Pearson's r and mean squared error (MSE) between actual and predicted trust propensity were used to evaluate the accuracy of prediction. Within each outer loop, the optimal parameter set for the elastic‐net regularization model was determined using cross‐validations.For the outer loop, supposing the whole dataset consisted of N − 1) was further partitioned into three subsets according to their rank of the behavioral scores . Regarding the  choices, a grid search was employed: the α was chosen from 10 values in the range of  and the λ was set as λ = eγ, where γ was chosen from 20 values in the range of   parameter sets. For each set of , Pearson's r and MSE between the predicted trust propensity and the actual trust propensity were computed to quantify the accuracy of the prediction. Then, the  set with the highest inner prediction accuracy across the 200 inner three‐fold CV loops was chosen as the optimal parameter set for the final elastic‐net predictive model, which was applied to the training set of the corresponding outer LOOCV loop  were significantly better than expected by chance . Similarly, the p‐value of the MSE was the portion of permutations that showed a lower value than the actual value for the real sample.To determine whether the obtained final prediction results  with a nonzero regression coefficient/weight in the models of all outer LOOCV loops can be defined as the contributing voxels for the prediction of trust propensity  was used. The LSVC allows for finding optimal weights and bias for a discriminant function using a training data set, which is identified as a hyperplane in this multidimensional space to best separate the training data into two categories matching with the known labels . The discriminant function was, in turn, applied to predict the class of new testing samples by the output of classification scores . The LSVC was employed because (a) the predictive regression model trained on the first dataset cannot be directly used for the second dataset concerning the classification problem and (b) the LSVC is one of the most widely used supervised classification algorithms in the field of neuroscience and usually outperforms other methods  algorithm implemented in MATLAB  and LIBSVM toolbox , with the outer loop for examining the performance of the model and the inner loop for optimizing the hyperparameter in the range of  Figure . The LOOp‐value for the classification accuracy was calculated by dividing the number of models with randomly permuted targets that showed higher accuracy than that of the model with true targets by the total number of permutation .Finally, the significance of the classification accuracy and AUC was determined using a permutation test with 1,000 permutations. The algorithm was fitted to randomly permuted targets using the above‐described LOOCV procedures for a total of 1,000 permutations. In every permutation, the LOOCV approach was employed to fit the classification model to randomly permuted targets. The 2.10Each of the above prediction or classification models was validated with ten‐fold cross‐validation, which might provide more stable estimates of predictive accuracy than the LOOCV scheme  the feature selection or the elastic‐net regularization scheme was not employed, that is, all the voxels contributing to the GMV‐based prediction model were included Figure  and (b) http://www.nitrc.org/projects/gretna/)  between the time series of each pair of brain voxels in the brain mask and then converted to the Fisher's Z‐values  toolbox  were defined by building spheres with a 4 mm radius around the contributing cluster peak voxels. The mean time courses of all the voxels within each ROI were extracted to calculate the Pearson correlation coefficient matrix for representing the resting brain functional network, resulting in a symmetric connectivity matrix for each participant. These matrices were Fisher z‐transformed and averaged to obtain a mean matrix used for the following analyses.A modular analysis of the functional brain network was performed to explore the potential functionally specific relationships between these contributing clusters. Regions of interest  and remained significant after adjusting for covariates such as altruistic preferences, age, gender, brain size, and image quality , supramarginal gyrus , superior parietal lobule , precentral gyrus , postcentral gyrus , superior frontal gyrus SFG, BA 10, DMPFC), inferior frontal gyrus , middle frontal gyrus , precuneus  and middle occipital gyrus  . The prediction remained significant after adjusting for altruistic preferences, age, gender, and head motion  of brain systems—a graph‐theoretical measure of the centrality of a region computed from RSFC  to classify trusting and distrusting groups—employing only voxels identified by the prediction model from the first sample. The LSVC  accuratey Figure  and p = C Figure . ImportaC Figure .3.5Furthermore, we performed a modular analysis  to detect the connectivity patterns between the identified contributing regions. Three stable network modules were detected—DMN (blue), CEN (yellow), and APN (red)—for which the modules' partitioning maintained good consistency across different connectivity strengths Figure . For the3.6Finally, we explored the modules' psychological functions by employing a data‐driven approach to survey a broad range of fMRI studies in the Neurosynth database  and task‐independent, multimodal brain measures (as collected from sMRI and rs‐fMRI). First, our multivariate prediction analyses revealed that individual differences in trust propensity for the first sample playing the standard trust game were predicted by gray matter volume and node strength across multiple regions . Second, the gray matter volume of these regions further enabled the classification of individuals from an independent sample with the propensity to trust or distrust as measured with the binary trust game . Finally, our modular and functional decoding analyses revealed that the predicted regions were parts of three identified brain modules, of which the psychological functions have been previously associated with domain‐general large‐scale brain networks: DMN, CEN, and APN.Our findings fit well with a recently proposed neuropsychoeconomic model of trust—assuming that trust is rooted in the interplay of psychological components that engage in domain‐general large‐scale brain networks  and temporal cortex —predicted individual differences in trust propensity. The functional decoding analysis showed that the psychological functions of this module were more associated with mentalizing, awareness, memory, and emotion compared to the other two modules. As key nodes of the DMN module, the DMPFC and STG are consistently associated with mentalizing  to simulate, explain, and predict behavior of others  and PPC —predicted individual differences in trust propensity. In comparison to the other two modules, the psychological functions of the CEN module were more associated with conflict and inhibition. The cognitive control system is anchored in the LPFC  within the CEN, which has been consistently associated with high‐level cognitive functions  in regulating, integrating, and adopting goal‐directed behaviors under changing context  of the CEN module in conjunction with the pre‐motor  and primary motor , posterior parietal , and occipital  regions of the APN module enabled cost–benefit calculations. The APN module was linked with the psychological functions of action, motor, gaze, and visual‐motor compared to the other two modules. The embodied cognition framework suggests that neural systems for both action and perception are engaged in higher cognitive processes  and functional  features across multiple regions. The intrinsic structural features of these regions further enabled the classification of individuals from an independent sample with a propensity of trust or distrust as measured with the binary trust game. The predicted regions have been previously implicated as modules of domain‐general large‐scale brain networks, supporting psychological processes that determine an individual's trust propensity.A couple of limitations need to be noted. First, the current study controlled for various confound variables in a large homogeneous healthy sample. However, future studies should include additional confounding variables  with an increased sample size to fit more complex prediction models in a more heterogeneous sample. Second, future investigations have to show re‐test reliability for our findings in which the same population completes the same trust measure but at different time points—essential for characterizing trust propensity with brain functions in health and disease as the next step. Finally, although the performance of the current prediction/classification models was significantly better than the chance level, their performance was at a moderate level and could be further improved. In this regard, the current study should be considered as a proof‐of‐concept study, and future investigations should improve the accuracy of those models. For example, only voxel‐wise GMV patterns were employed in the current prediction models. Future studies might improve the performance of prediction model by including surface‐based morphometric metrics  as these metrics have been associated with human social behaviors  upon reasonable request.AppendixS1. Supporting Information.Click here for additional data file.


This study aimed to compare the standard one‐stage coloanal anastomosis (CAA) technique plus diverting ileostomy and the Turnbull–Cutait technique with delayed CAA in terms of early post‐operative morbidity in patients with low rectal cancer, and found that the two techniques did not differ in terms of early post‐operative morbidity. Thus, the Turnbull–Cutait technique may be considered in distal rectal cancer patients refusing to have a stoma and in patients in whom CAA poses technical difficulties during the initial operation. This study aimed to compare the standard one‐stage coloanal anastomosis (CAA) technique plus diverting ileostomy and the Turnbull–Cutait (T–C) technique with delayed CAA in terms of early post‐operative morbidity in patients with low rectal cancer.A total of 33 patients with non‐metastatic distal rectal cancer who were operated with one of the two different reconstruction methods (one‐stage CAA plus diverting ileostomy or two‐stage T–C technique with delayed CAA) after total mesorectal excision were included in this retrospective study. The two groups were compared for early post‐operative morbidity within 30 post‐operative days using complication frequency, Clavien–Dindo classification and Comprehensive Complication Index scores.P > 0.05 for all).The two groups did not differ in terms of morbidity parameters, including frequency of any morbidity, presence of grade 3b morbidity requiring management under general anaesthesia, as well as Comprehensive Complication Index score (Our findings suggest that the two techniques did not differ in terms of early post‐operative morbidity. Owing to its comparable morbidity and safety to CAA plus concomitant ileostomy performed at the same session, the T–C technique may be considered in distal rectal cancer patients refusing to have a temporary stoma and in patients in whom CAA poses technical difficulties during the initial operation. Although total mesorectal excision (TME) followed by coloanal anastomosis (CAA) represents a well‐established treatment modality for low rectal cancers, it still remains a challenging procedure for surgeons.In the early 1950s Turnbull in Cleveland Clinic and Cutait in Brazil simultaneously introduced the two‐stage transanal anastomosis technique in an attempt to reduce the morbidity associated with colorectal anastomosis.In recent years, we have witnessed a resurgence of the Turnbull–Cutait (T–C) technique to save patients from a permanent stoma in complicated conditions such as persistent recto‐urethral and recto‐vaginal fistula as well as chronic pelvic sepsis due to colorectal anastomotic leak or other causes.This study aimed to compare the two techniques performed after TME, that is, two‐stage T–C technique with delayed CAA and classical technique of CAA with covering ileostomy, in terms of early post‐operative morbidity.A total of 33 patients with non‐metastatic distal rectal cancer who were operated with one of the two different reconstruction methods after TME were included in this retrospective study. Patients suitable for both techniques were informed about the two procedures and were asked to choose one of them. The T–C procedure was used in patients who did not wish to have a stoma, even if temporary. Twenty‐two patients were operated with two‐stage T–C technique and the remaining 11 had CAA and simultaneous protective ileostomy. All operations were performed by two experienced colorectal surgeons. The two groups were compared for early post‐operative morbidity within 30 post‐operative days using complication frequency, Clavien–Dindo classificationIn the first stage, the patients were placed in the Lloyd–Davis position, and an abdominoperineal approach was used. In the abdominal phase, following an abdominal incision, conventional very low anterior resection with TME was carried out in accordance with the oncological principles of no‐touch technique, high vascular ligation and nerve sparing. After complete splenic flexure mobilization, the inferior mesenteric vein was ligated and divided close to the ligament of Treitz. The inferior mesenteric artery was isolated, ligated and divided 1 cm above the aorta. Dissection was advanced to the pelvic floor through the avascular plane (holy plane) between the parietal sheet of endopelvic fascia  and fascia propria encircling the mesorectum sown to the level of the levator ani musculature. A drain was placed in the pelvis. In the perineal phase, a Lone‐Star retractor  was inserted to retract the anus. Mucosa and the internal anal sphincter muscle were circumferentially incised until reaching the intersphincteric plane using a monopolar diathermy. The incision level was made depending on the location of the low rectal cancer: a 1‐cm tumour‐free distal margin was aimed for and hence the incision was made at the level of dentate line up to 1 cm above the level of the dentate line. The cranial lumen was closed with a purse string suture and dissection was continued posteriorly until the abdominal pelvic dissection plane was reached. Before pulling the colon through the anal canal, four 3/0 polyglactic acid sutures were placed at the cardinal points of the anal canal, as high as possible, taking bites of the upper edge of the divided internal sphincter thereby avoiding full‐thickness damage to the muscle. The rectum and sigmoid colon were then pulled through the anal canal and divided proximally at the level of the ligation of the left colic artery. A colonic segment of about 8–10 cm was left outside. Finally, the colonic exteriorized segment was fixed to the perianal skin with four to six 4/0 absorbable sutures  and wrapped in wet gauze. Figure The second surgical stage of delayed CAA was performed between post‐operative days 5 and 7 under sedation and epidural anaesthesia. The patient was placed in the lithotomy position. No retractors were needed, and the adhesions between the anal canal and colon were preserved. After tying off the mesocolon at the level of the anal verge, the exteriorized segment was divided with cautery. A hand‐sewn CAA was performed using 8–12 interrupted sutures at the dentate line level. Figure Patient position and abdominal phase of the operation was the same as with the T–C technique. At the perianal phase, a Lone‐Star retractor was placed in the perineum and then the mucosa and internal sphincter muscle were circumferentially incised at the dentate line with monopolar diathermy until reaching the intersphincteric plane, and continued posteriorly to reach the abdominal dissection plane. Proximal colon was divided at the level of the left colic artery and the resection specimen was removed with a pull‐through technique. CAA was done using 12 interrupted hand‐sewn 4/0 Vicryl sutures, after confirming the presence of active mucosal bleeding and absence of tension on anastomosis. A loop ileostomy was created in the right lower quadrant.After CAA plus concomitant ileostomy, oral fluid intake was initiated on the first post‐operative day. After the T–C technique, oral intake was not allowed and the patient received total parenteral nutrition  during the period between the two stages. Patients were advised to lie on their side or spread their legs when they lay in the supine position. The colonic stump viability was checked once daily. Bladder catheter was removed after the beginning of urge for urination upon clamping of the catheter. Intraoperative drain was removed when daily drainage was below 30 mL.t‐test for independent samples or Mann–Whitney U‐test was used, depending on the distribution of data. Pearson's chi‐squared test or Fisher's exact test was used for the comparison of categorical data. A P‐value of <0.05 was considered an indication of statistical significance.For statistical analysis, SPSS version 21  for windows was used. Descriptive data were presented as mean ± standard deviation or number (frequency), where appropriate. Hypothesis tests and graphical methods were used to test normality of the data. For the comparison of continuous variables, Student's P = 0.049). In addition, duration of hospitalization was significantly longer in the T–C group . Among patients who underwent the T–C operation, two patients required early colostomy or ileostomy due to complications .An early post‐operative complication within 30 days) developed in seven patients 21.2%). Table 1.2%. Tab0 days deNo serious discomfort due to the exteriorized colon segment was observed during the period between the two procedures of the T–C technique. The friction feeling at the perineum during mobilization and concerns of a possible complication that may result from movement were the most frequently encountered patient concerns. As the distal end of the exteriorized colon segment was not open, no discharge and discharge‐related complaint was seen.Formal assessment of function was not carried out in this study, but based on our observations, the most common complaints of patients who underwent the T–C procedure within the first three post‐operative months were incontinence for watery stool and fragmented defecation due to incomplete emptying of the colon. These functional problems were seen approximately in half of the patients and were managed satisfactorily in most cases with rectal enema application in the mornings.P > 0.05 for all comparisons).Table In this study, comparing two‐stage T–C technique and delayed CAA versus CAA performed in the initial operation with protective ileostomy in patients with distal rectal cancer, no differences were found with respect to early post‐operative surgical morbidity. To the best of our knowledge, ours is one of the few studies comparing these two surgical approaches in terms of early post‐operative morbidity exclusively in patients with low rectal cancer.Although manual or mechanical one‐stage CAA with prophylactic ileostomy is considered the standard of care following TME for low rectal cancer,et al. comparing the T–C technique and CAA with protective ileostomy in patients with rectal cancer should be emphasized, as it is the first study to test these two techniques versus each other.The significance of the study by Xiong et al.Among the 100 patients undergoing the T–C technique for mid or distal rectal cancer, Jarry et al. observed CCI grade 3–4 morbidity during the first post‐operative month in 20% of the 87 patients undergoing the T–C technique due to low rectal cancer.Sage et al. involving eight studies where patients underwent the T–C technique for rectal cancer, the reported rates of anastomotic leak and pelvic abscess ranged between 0–10.6% and 0–25%, respectively.In one 2019 review by Portale A study examining the long‐term oncological and functional outcomes of 13 middle and distal rectal cancer patients operated with the T–C technique following neoadjuvant chemoradiotherapy reported the 5‐year survival rate of 85% and no local recurrence during a mean follow‐up of 101.2 months.The T–C technique has also been used as a salvage procedure in several studies with encouraging results; thus, it may have a place in the management of such difficult clinical cases as well.Theoretical explanations for low rates of anastomotic leakage and pelvic septic complications in patients undergoing the T–C technique include the initially insignificant effect of the retraction on the pulled‐through colonic segment due to contracted pelvic diaphragm at the termination of surgery as there is no anastomosis as well as by the prevention of the retraction of the colonic segments due to adhesions forming between the exteriorized colonic segment and anus during the waiting period.Retrospective design not allowing proper case selection and small sample size that may be a source of low statistical power are the two main limitations of the study. Therefore, comparisons of the two groups may not represent ideal conditions and should be interpreted within this context. Another limitation is the lack of long‐term follow‐up for functional results. However, assessment of early post‐operative morbidity seems to be more relevant and crucial in our study as protective ileostomy was not created in our patients who underwent the T–C technique. We believe that our study also has certain strengths as it exclusively included patients with distal rectal cancer in both groups and a high proportion of patients (90%) received neoadjuvant chemoradiotherapy, providing a more homogeneous sample.In conclusion, no significant differences appear to exist between the two techniques (i.e. T–C versus CAA plus protective ileostomy) in terms of early post‐operative morbidity. Although stoma therapy units and staff are accessible by most patients in Turkey, we believe that a stoma is a cause of significant burden and cost. Owing to its comparable morbidity and safety to CAA plus concomitant ileostomy performed at the same session, the T–C technique may be considered by colorectal surgeons in selected distal rectal cancer patients refusing to have a stoma even though it is transient as well as in patients in whom CAA poses technical difficulties during the initial operation. Furthermore, as the technique negates the need to create a protective stoma, it may avoid complications from its closure in most cases.None declared.Osman Guner: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; supervision; writing‐original draft; writing‐review and editing. Latif Tumay: Conceptualization; data curation; methodology; validation; writing‐review and editing.


While there are many root morphology classification systems with their own distinct advantages, there are many shortcomings that come along with each system. Data Sources and Selection. An extensive literature search was conducted on PubMed and Scopus to identify the published data on root and root canal classification systems published until 1 May 2020 using keywords, root canal classification system, classification systems for root canals, and root morphology. The related literature was reviewed and then summarized. Data Synthesis. Several studies have analysed and detailed root and root canal classifications and further added new subsystems, works of Weine et al. (1969) and Vertucci et al. (1974). Besides, Sert and Bayirli (2004) added supplementary types to Vertucci's classification system. A new classification was most recently introduced by Ahmed et al. (2017) involving the use of codes for tooth numbering, number of roots, and canal configuration.  The aim of this review was to compare the various root and root canal morphology classifications, their advantages, limitations, and clinical and research implications.  Weine et al. classified only single-rooted teeth, without considering multirooted teeth and complex configurations. Vertucci's classification included complex configurations, with Sert and Bayirli adding further complex supplemental types. Ahmed et al.'s classification simplifies classifying root and canal morphology while overcoming the limitations of several previous classification systems making it beneficial for implementation in dental schools. Every clinician aims to achieve the best treatment outcomes of endodontically treated cases. To attain the best results, one must diagnose the condition very well. Therefore, complete knowledge of root canal morphology with comprehensive understanding of the root canal system complexity is particularly important in clinical practice to reach the desired treatment goals. Additionally, sound knowledge of the root canal morphology classification is important for documentation and ease of communication amongst practitioners. While there are many root morphology classification systems, there are many shortcomings that come along with each system. While some are elaborate, there are others that are concise but do not provide enough information.Apart from normal root canal morphology, a practitioner should have sound knowledge of possible root canal morphologic variations such as a single canal bifurcating into two canals that recombine to form a single canal later , 2. Thisst of July 2020 using keywords, root canal classification system, classification systems for root canals, and classification systems for root canal morphology. Several root and root canal morphology classification systems with modifications and supplemental types were identified, which are discussed in this review.A general search was carried out to identify the published data on root and root canal morphology classification systems on PubMed and Scopus until the 1Several authors have given classifications on root canal configurations. Weine et al.  were theA study was carried out by Ahmed and Dummer in 2018 to introduce a new classification system to classify tooth, root, and even accessory canal anomalies that could be used in conjunction with other systems for comprehensive analysis . In the Root canal morphology was classified by Weine et al. , 4 from Type I: a single main canal from the pulp chamber to the apex of the rootType II: two separate canals starting from the pulp chamber and joining as one, just short of the root apexType III: two separate canals starting from the pulp chamber to the root apexType IV: a single canal starting from the pulp chamber and dividing into two canals near the root apexVertucci classified root canal morphology into eight types that are described as follows :Type I: a single main canal is present starting from the pulp chamber to the root apex.Type II: two separate canals leave the pulp chamber but join to form one canal to the apex.Type III: one canal leaves the pulp chamber and divides into two smaller canals which later merge again to exit through one canal.Type IV: two separate as well as completely distinct canals run from the pulp chamber to the root apex.Type V: there is a single canal exiting the pulp chamber which divides into two canals with separate apical foramina.Type VI: two separate canals join at the middle of the root to form one canal which extends till the apex, just short of the apex, and again divides into two.Type VII: the canal starts as a single until the middle third of the root then divides into two separate canals that rejoin after some distance and then, near the apex, divides into two again.Type VIII: the pulp chamber near the coronal portion divides into three separate canals extending till the apex , 5.The authors evaluated the root canal configuration in 2800 maxillary and mandibular permanent teeth amongst Turkish population using a clearing technique. They added fourteen types to Vertucci's classification and numbered from Type IX to Type XXIII described as follows :Type IX: a single canal starts from the pulp chamber and, during its course, divides into three.Type X: a single canal starts from the pulp chamber and divides into two, out of which one canal further divides into two with two foramina.Type XI: a single canal starts from the pulp chamber and divides into two, out of which one further subdivides into two and runs as three canals and ends with four foramina.Type XII: two separate canals start from the pulp chamber, out of which one further subdivides into two and, later, all three join to form one canal with one foramen.Type XIII: a single canal starts from the pulp chamber and divides into two canal which rejoins as one and further divides into three canals with three foramina.Type XIV: four canals starts from the pulp chamber, and later, two of each will join and end with two foramina.Type XV: three canals starts from the pulp chamber, out of which two join to form one canal and end with two foramina.Type XVI: two canals start from the pulp chamber, out of which one further subdivides into two and ends with three foramina.Type XVII: a single canal starts from the pulp chamber and divides into three canals which again rejoin to form a single canal with a single foramen.Type XVIII: three canals start from the pulp chamber and rejoin to form a single canal with a single foramen.Type XIX: two canals start from the pulp chamber and join as a single canal, further again divide into two, and rejoin as one canal with a single foramen.Type XX: four canals start from the pulp chamber and end with four foramina.Type XXI: four canals start from the pulp chamber and join as a single canal with a single foramen.Type XXII: five canals start from the pulp chamber and one joins with another and ends as four canals with four foramina.Type XXIII: three canals start from the pulp chamber, out of which one further divides into two and ends with four canals with four foramina.Several studies have found root canal configurations to be highly complex and found nonclassifiable canal configurations during evaluation of internal and external anatomical canal variation using 3D imaging techniques –16. MoreAhmed et al.'s classification system provides a single code for the tooth number, number of roots (considering any division of roots as two or more roots), and the canal configuration, hence giving a logical and accurate classification. One important facet of the new system is that teeth with the same canal configuration with separate roots are described as single code which reflects their anatomy accurately. It can also describe the previous nonclassifiable root canal morphologies with a simple single code giving an exact anatomy . FurtherA new classification was introduced by Ahmed et al. . This neRTN]. The root canal configurations in each root (if more than one root) are added after the tooth number. Description of root canal configuration in each root will be given on the course of the root canal starting from the orifices [O], passing through the canal [C], and ending by the foramen [F], so it is like [TNO−C-F]. The classification for a single tooth will be written as [RTNO−C-F]  or lower lateral incisor [LLI]. The number of roots is added as a superscript before the tooth number [TNO−C-F] . Single-TNO−C-F] .Sound knowledge of the root canal morphology is important for documentation and ease of communication amongst practitioners. All the classification systems noted till date have their own advantages and limitations. While Weine et al. classified only single-rooted teeth and did not classify multirooted teeth as well as complex configurations, Vertucci's classification further detailed complex configurations, with Sert and Bayirli adding supplemental types to the latter. Ahmed et al.'s classification system provides a single code for the tooth number and number of roots considering further division of roots as two or more roots, including the canal configuration; hence, it is considered a more logical and accurate classification.


Tumor recurrence or residual tumor after targeted therapy is common in patients with advanced non‐small cell lung cancer (NSCLC). There is a lack of high‐level evidence on which type of treatment should be employed for these patients and the role of salvage surgery has not been well reported in the literature.A retrospective analysis of patients who underwent salvage surgery in our center between January 2016 and June 2019 for advanced NSCLC after targeted therapy was performed.A total number of nine patients were identified, including five males and four females, with a median age of 56 years , all diagnosed with lung adenocarcinoma stage IIIa–IVb. All patients had received targeted therapy according to individual positive mutation of driver gene(s). Salvage surgery was performed for tumor recurrence or residual tumor after a duration of 2–46 months of targeted therapy. A negative surgical margin was achieved in all cases. Postoperative complication rate was 11.1% (1/9). All patients were alive at the time of this analysis and two patients had disease progression. After a median follow‐up of 17 months (range: 5–44 months), the median event‐free survival and postoperative survival was 14 months (range: 2–44 months) and 17 months (range: 5–44 months) respectively.Salvage surgery may be a feasible and promising therapeutic option for tumor recurrence or residual tumor in advanced NSCLC in selective patients after targeted therapy.Salvage surgery is feasible in selected patients with advanced NSCLC and provides promising survival outcomes after targeted therapy failure.Salvage surgery provides precise molecular and pathological information which is most important for subsequent therapy. Lung cancer is the most common malignancy and is the first killer of cancer‐related death worldwide.In the previous two decades, targeted therapy which employs a new class of drugs that specifically target certain molecular pathways has developed remarkably and dramatically changed the treatment strategy of lung cancer.et al. a complete pathological response was found in nearly half the cases who received salvage surgery after chemotherapy/radiotherapy.Salvage surgery already plays a role in the treatment of esophageal cancer, colorectal cancer and other tumors.Here, we present our single‐center study and analyze the feasibility and efficiency of salvage surgery for advanced NSCLC after targeted therapy.All consecutive NSCLC patients receiving surgery after targeted therapy in the sixth medical center of the Chinese PLA General Hospital between January 2016 and June 2019 were collected. Patients were eligible for inclusion if they met the following criteria: (i) Pathologically identified NSCLC in clinical TNM stage of IIIa–IVb at the time of diagnosis, according to the eighth edition of the TNM staging systemDemographic and clinical data including gender, age, clinical stage, histology, driver‐gene status, targeted therapy agents, duration of targeted therapy before surgery, surgical procedure, operation time, intraoperative blood loss, postoperative complications, length of hospital stay after surgery, pathological diagnosis, postoperative therapy, and survival data were reviewed from the electronic medical records library.The study was approved by the Ethics Committee of the sixth medical center of the Chinese PLA General Hospital (No. 2019112507).Follow‐up was performed every three months for each patient, and included physical status, and contrast computed tomography (CT) of the chest and upper abdomen. Contrast magnetic resonance imaging (MRI) of the brain and nuclear bone scan were performed every six months. Positron emission tomography (PET) scan was utilized if required.Event‐free survival (EFS) was calculated from surgery to recurrence or progression, postoperative survival (POS) was calculated from surgery to death for any reason, and overall survival (OS) was calculated from first diagnosis to death for any reason.Between January 2016 and June 2019, 962 patients had undergone surgery for lung cancer. Among these, 13 patients had received preoperative targeted therapy. Four patients were ruled out of the analysis: three patients who had lost the opportunity of surgical treatment due to multiple pulmonary metastasis underwent wedge resection to secure intact histological and genomic information to enable guidance on further treatment; one patient had stage II disease at the time of first diagnosis. A total of nine patients were eventually enrolled into our study.EGFR) mutation was discovered in eight patients and anaplastic lymphoma kinase (ALK) translocation was discovered in one patient. Corresponding targeted therapy agents included EGFR‐targeted agents  and ALK‐targeted agent (Crizotinib). The duration of targeted therapy before surgery ranged from two to 46 months.The baseline demographic and clinical characteristics of eligible patients are shown in Table No other anticancer therapy was administered to these patients, with the exception of case 2, who had received six cycles of chemotherapy, and case 9 who had received gamma knife therapy for brain metastasis. After targeted therapy, partial response (PR) was reached in six patients and stable disease (SD) was achieved in three patients, according to the preoperative assessment.As shown in Table EGFR mutation. After two months of observation, there was no obvious tumor shrinkage and the patient was transferred to our center. Reassessment found that the tumor was actually resectable even at the time of first diagnosis, and therefore the patient received salvage surgery in our center. Cases 7 and 9 were two patients with resectable tumor at the time of first diagnosis who all refused surgical treatment, only receiving targeted therapy at the start of treatment. After three and two months, respectively, they changed their minds because there had been no obvious response to targeted therapy and they subsequently received salvage surgery in our center.The median duration of targeted therapy before surgery was six months . Of note, there were three cases who received targeted therapy before salvage surgery for a relatively short duration. Case 6, a 42‐year‐old male patient, was assessed with unresectable lung adenocarcinoma in a county‐level hospital and received Tarceva therapy there because of All patients were reassessed for resectability. The interval between targeted therapy and surgery ranged from 5–14 days. Lobectomy procedures plus systematic lymph node dissection were performed on all nine patients, including six who underwent video‐assisted thoracoscopic surgeries (VATS). In three cases, operations had to be transferred from VATS to open surgery due to accidental bleeding (case 1) or extensive pleural adhesion (cases 3 and 6). The median operation time and intraoperative blood loss were 110 minutes  and 120 mL , respectively.T790M (case 3 and 7). A negative surgical margin was achieved in all cases. The postoperative pathological stages of four patients  were confirmed to be different from their preoperative y‐stages, due to unexpected lymph node metastasis.As shown in Table All patients were alive at the time of the analysis. The median follow‐up time of patients in this study was 17 months . There were two patients with disease progression and the median EFS was 14 months  as shown in Figure In this case series, we retrospectively analyzed the feasibility and efficiency of salvage surgery in patients with advanced lung cancer after targeted therapy. To the best of our knowledge, this is the first case series report on this subject.In our analysis, we focused on patients with advanced (stage III or IV) NSCLC. It is our understanding that the treatment strategy for patients with early‐stage (stage I or II) NSCLC is relatively consistent  and the prognosis of patients is relatively satisfactory. By contrast, the prognosis of patients with relatively advanced NSCLC is far from satisfactory due to the complicated nature of the disease at this stage and unclarified treatment strategy. Therefore, we only included those patients with stage III or IV NSCLC and excluded those with early‐stage NSCLC.T790M mutation was identified which is related to drug‐resistance of first‐generation agents targeting EGFR mutation.et al. these postoperative findings were key information which led to consequential treatment.Salvage surgery after effective targeted therapy gives full access to the advantages of surgery and targeted therapies. This is an idea of multidisciplinary therapy and individualized therapy.Given the fact that the effect of targeted therapy is not static in one patient but will enter the plateau stage sooner or later,In terms of survival, the effect of salvage surgery is promising. All nine patients in our group were alive at the time of this analysis. After a mean follow‐up duration of 18.9 months, their median EFS reached 14 months, median POS 17 months, and OS reached 25 months. By contrast in the literature, the median progression‐free survival (PFS) of patients treated by targeted therapy with first generation drugs was only about 10.0 months and the PFS of patients who failed primary chemotherapy was only 3–6 months.Surgical trauma and risks are usually the major concerns of salvage surgery. The possible existence of lymph node metastasis, tumor invasion, pleural adhesion or destruction of hilar structures may make surgery more difficult. The physical status of patients may also deteriorate due to the side effects of preoperative treatment. However, according to our results, the process of salvage surgery is not so difficult or risky as imagined. Although pleural adhesion and fibrosis had developed in some patients in our group, radical surgery was achieved in all of them. There were six patients out of nine who received salvage surgery via minimally invasive thoracoscopic approaches. The intraoperative blood loss, operation time, postoperative hospital stay and postoperative complication rate in our group were similar to those for regular surgery. This was consistent with other reports on salvage surgery for lung cancer.Notably in our series there was a deviation between the preoperative clinical stage (y‐stage) and the postoperative pathological stage (p‐stage) in some patients, mainly due to the difference in lymph node status. The reason for this might be that preoperative targeted therapy had decreased the size and proportion of positive lymph nodes and thus the preoperative findings of PET‐CT or CT scan were not always consistent with the real status of the lymph nodes.The limitations of this study included the small sample size, its retrospective nature, the heterogeneity of baseline characteristics of enrolled patients, and the relatively short median follow‐up time. Given this, the results of our study should be interpreted with caution and it is hard to draw any definitive conclusion from our findings. However, this study highlighted salvage surgery as a feasible and promising therapeutic option for advanced NSCLC after targeted therapy in some selective fit patients. We look forward to future prospective studies to provide high‐level clinical evidence on this subject.All authors declare no conflict of interest.


The coronavirus disease 2019 (COVID‐19) pandemic has become a major public health crisis. The diagnostic and containment efforts for the disease have presented significant challenges for the global health‐care community. In this brief report, we provide perspective on the potential use of salivary specimens for detection and serial monitoring of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), based on current literature. Oral health‐care providers are at an elevated risk of exposure to COVID‐19 due to their proximity to nasopharynx of patients, and the practice involving the use of aerosol‐generating equipment. Here, we summarize the general guidelines for oral health‐care specialists for prevention of nosocomial transmission of COVID‐19, and provide specific recommendations for clinical care management. Oral health‐care providers (OHCP) are at a high risk in particular for nosocomial transmission of respiratory infectious diseases owing to their proximity to the nasopharynx and oral cavity of patients. The general consensus in dental medicine is that the greatest threat of airborne infection is from aerosols  due to their ability to stay suspended in the air and contaminate the mucous membranes of the mouth and respiratory passages.Currently there are no data available to assess the risk of transmission of SARS‐CoV‐2 in the office settings of dental and specialty practices; however, the Occupational Safety and Health Administration (OSHA) has categorized oral health‐care providers under the “very high exposure risk” category for SARS‐CoV‐2.The CDC and the American Dental Association (ADA) have recommended that all dentists and oral specialists keep their offices closed and postpone all elective procedures except for urgent and emergency care particularly those in hospital‐based practices, although new guidelines are expected for non‐urgent care.Special considerations are needed for oral and maxillofacial specialists working in an oncology practice. Initial screening of patients should be conducted via telemedicine consults, and short‐term deferment should be considered. Patients who report a recent travel history to any of the designated COVID‐19 hotspots, and the presence of any symptoms of respiratory illness should be instructed to self‐quarantine for 14 days and report to their physician for COVID‐19 testing. Patients with cancer are considered as highly vulnerable to COVID‐19 due to their immunocompromised status. The MD Anderson head and neck surgery consortium has devised guidelines for triaging patients based on site‐specific head and neck cancers.Due to the disruption of all major supply chains and increasing global demands, there is a critical shortage of PPE for health‐care personnel. Such an unprecedented situation demands for innovative ideas to address these concerns. Many academic institutions, researchers, and private organizations have come up with creative solutions such as open‐source designs for 3D‐printed respirators and face shields.COVID‐19 is now a widespread and constant presence in our community. As we adapt to this rapidly evolving situation and make adjustments based on new information, revised guidelines from the regulatory authorities will be critical in ensuring the safe reopening of oral health‐care operations. Development and implementation of a rapid COVID‐19 diagnostic test at the point‐of‐care will be vital in safeguarding the health of both patients and OHCP, and minimizing the burden of disease in our community. The American Medical Association (AMA) as of May 1, 2020 stated “as public health experts determine that it is safe to see patients and stay‐at‐home restrictions are relaxed, physician practices should strategically plan when and how best to reopen.” In parallel, the Centers for Medicare and Medicaid Services (CMS) published a Phase 1 guide for reopening facilities to provide non‐emergent, non‐COVID care. The AMA and CMS guidance include pre‐visit screening template and checklists of criteria for reopening private and hospital‐based practices.4Saliva may be a viable alternative to nasopharyngeal specimen for COVID‐19 testing. Further studies are needed to investigate the efficacy, feasibility and scalability of using salivary specimens for SARS‐CoV‐2 detection and surveillance on a nationwide basis. It is imperative that OHCP stay abreast of the latest developments surrounding the pandemic, follow guidelines from the CDC, ADA, the federal, and state governments, and make informed decisions regarding clinical care. Telemedicine efforts can be an excellent adjunct in triaging patients and determining urgency of need.


Melanoma, as for many other cancers, undergoes a selection process during progression that limits many innate and adaptive tumor control mechanisms. Immunotherapy with immune checkpoint blockade overcomes one of the escape mechanisms but if the tumor is not eliminated other escape mechanisms evolve that require new approaches for tumor control. Some of the innate mechanisms that have evolved against infections with microorganisms and viruses are proving to be active against cancer cells but require better understanding of how they are activated and what inhibitory mechanisms may need to be targeted. This is particularly so for inflammasomes which have evolved against many different organisms and which recruit a number of cytotoxic mechanisms that remain poorly understood. Equally important is understanding of where these mechanisms will fit into existing treatment strategies and whether existing strategies already involve the innate killing mechanisms. The latter is recruited to phosphotidylinosites and oligomerizes in the plasma membrane , and caspase‐1 that binds to ASC. The formation of such a complex leads to the activation of caspase‐1, which induces the cleavage and secretion of pro‐inflammatory cytokine interleukin‐1β (IL‐1β) and IL‐18  efflux and low K levels. This would be consistent with the proposed mechanism of activation by the antibiotic nigericin, which is believed to cause efflux of K+ in exchange for H+  which increases the levels of proteins in the complex. Deubiquitination of NLRP3 by deubiquitinating enzymes ‐1β and pro‐IL‐18 into the active cytokines IL‐1β and IL‐18. Caspase‐1 also cleaves a protein called gasdermin D. Gasdermin D is a member of a family of conserved proteins that includes gasdermin A, B, C, D, E, and DFNB59  with those against standard chemotherapy. The intent‐to‐treat results were negative . TMEM176B regulates CaDendritic cells (DCs) provide the essential link between innate and adaptive immunity and evidence suggests the CD141+ (cDC1) subset are of critical importance in generation of CD8 T‐cell responses  versus low (<median) levels. The forest plots shown in Figure As discussed above, the outcome of inflammasome activation may depend on whether inflammasomes are activated in immune cells or in cancer cells. TCGA analyses shown in Figure NLRP1 activation is of particular interest in that recent studies suggest that it is held in an inactive state by the serine dipeptidyl peptidases (DPP)8 and 9 and that inhibitors of these dipeptidases result in activation of NLRP1. sensor which binds a number of different gram‐negative bacteria. It can bind directly to caspase‐1 rather than through binding to ASC and can activate caspase‐8. It has also been associated with high levels of IL‐18  as anti‐tumor agents  in particular were shown to activate AIM2, and further studies are needed to examine whether cell death induced by these drugs is associated with activation of AIM2  as shown in Figure Should these interpretations prove valid a two‐pronged treatment approach might be considered that would involve selection of patients with evidence of chronic activation of inflammasomes in their tumor such as high CRP levels and treatment with agents that limit inflammation such as inhibition of circulating IL‐1β and inhibition of NF‐kB by use of BET protein inhibitors. On the other hand, should favorable outcomes depend on activation of inflammasomes in the cells of the immune system, selection of patients might be based on those not responding to ICB and treatment with agents that activate the inflammasome. There is very limited understanding of the role of inflammasomes in relation to different subsets of DCs and whether activation of different inflammasomes has different treatment outcomes. New initiatives that target inflammasomes in the immune system might include blockade of the TMEM176B checkpoint that limits activation of inflammasomes in T cells as reviewed above. There may also be scope for treatments with drugs that have selectivity for particular inflammasomes. The targeting of NLRP1 inflammasomes by DPP8/9 inhibitors or the targeting of NLRC4 inflammasomes by dabrafenib may be examples of such agents as well as the well‐known TLR9 agonists mentioned above. Blocking autophagy to increase activation of inflammasomes might also be worthy of investigation in drugs shown in past studies to have only modest benefits against melanoma.The authors have no conflict of interest in relation to this work.


Curiosity rover's exploration at Vera Rubin ridge (VRR) and summarizes the science results. VRR is a distinct geomorphic feature on lower Aeolis Mons  that was identified in orbital data based on its distinct texture, topographic expression, and association with a hematite spectral signature. Curiosity conducted extensive remote sensing observations, acquired data on dozens of contact science targets, and drilled three outcrop samples from the ridge, as well as one outcrop sample immediately below the ridge. Our observations indicate that strata composing VRR were deposited in a predominantly lacustrine setting and are part of the Murray formation. The rocks within the ridge are chemically in family with underlying Murray formation strata. Red hematite is dispersed throughout much of the VRR bedrock, and this is the source of the orbital spectral detection. Gray hematite is also present in isolated, gray‐colored patches concentrated toward the upper elevations of VRR, and these gray patches also contain small, dark Fe‐rich nodules. We propose that VRR formed when diagenetic event(s) preferentially hardened rocks, which were subsequently eroded into a ridge by wind. Diagenesis also led to enhanced crystallization and/or cementation that deepened the ferric‐related spectral absorptions on the ridge, which helped make them readily distinguishable from orbit. Results add to existing evidence of protracted aqueous environments at Gale crater and give new insight into how diagenesis shaped Mars' rock record.This paper provides an overview of the  Curiosity's campaign at Vera Rubin ridge (Sols 1726–2302) and the high‐level results from articles in this special issueWe summarize Vera Rubin ridge formed when diagenesis hardened rocks along the base of Aeolis Mons; wind subsequently etched the feature into a ridgeResults add evidence for protracted aqueous environments at Gale crater and give new insight into how diagenesis shaped Mars' rock record Although layered rocks seen from orbit could be lava flows, the lack of nearby volcanic vents, fissures, or other obvious evidence of volcanism in the area favored a sedimentary hypothesis for rocks that compose the ridge. Orbital data were not sufficient to conclude whether the sedimentary environment was lacustrine, fluvial, or eolian.Characterizing the depositional setting(s) of VRR was critical for constraining past Martian conditions and placing Understanding the stratigraphic relationship between the rocks of VRR and surrounding units was necessary to constrain when the feature formed with respect to Mount Sharp. One key question was whether the rocks exposed on VRR form part of the Mount Sharp sedimentary sequence or whether they represented a younger unconformable unit. Digital elevation models (DEMs) constructed using stereo images acquired by the HiRISE camera (1 m/post) were consistent with an interpretation that the dips of ridge layers were in family with similarly measured stratal dips of the overlying sulfate‐rich unit  acquire images of the base of VRR and study them for any evidence of gaps in the stratigraphic record or evidence for depositional hiatuses; (2) take stereo images bedding within VRR bedrock to obtain measurements of stratal strike and dip; and (3) collect high‐resolution, close‐up imaging of dust‐free surfaces to characterize grain size, sorting, and grain roundness within VRR bedrock. All three objectives were achieved using the ChemCam RMI, Mastcam, and MAHLI instruments.3.2Curiosity discovered hematite in samples drilled from Mount Sharp bedrock below VRR  were also observed in association with hematite, and these were proposed to indicate open‐system alteration of basaltic sediments with oxidation driven by periodic desiccation and migration of the water table  obtain chemical, mineralogical, and spectral reflectance measurements from the area where CRISM and long‐distance in situ spectral data showed the deepest hematite‐related spectral signatures; (2) document variations in spectral properties, chemistry, and mineralogy at numerous locations across the ridge; and (3) acquire periodic multispectral images of the terrain to search for evidence of ferric phases following or crosscutting stratigraphy. These objectives were achieved using the full suite of  obtain c3.3Curiosity's investigation of VRR that there were almost certainly minerals in VRR that are not visible to orbital instruments because of the instruments' spatial resolution and depth of sensing limitations, as well as knowledge that many minerals do not have diagnostic absorptions in CRISM wavelength's range. However, detecting and characterizing all as many components as possible within VRR by Curiosity is important for constraining the full range of primary and secondary environments preserved within the ridge. Of particular interest is evidence for a cementing phase(s) that led to the relative erosional resistance of the ridge. If a cement is present, what is its composition? Alternatively, small variations in grain size linked to depositional changes could have caused minor differences in rock strength, and these strength differences would have been emphasized by billions of years of erosion by the Martian wind.It was known in advance of Measurement objectives needed to address this goal were similar to the objectives for Goal 2. They included collecting systematic detailed textural, chemical, and mineralogical data in order to document the full diversity of rocks within VRR.4Curiosity's VRR campaign, and activities were also modified at times to respond to in situ discoveries and rover technical issues. A detailed breakdown of Curiosity's activities on VRR is shown in Table Curiosity's campaign at VRR was divided into three phases: approach, initial reconnaissance, and drilling. Rover activities during each phase are summarized below.The scientific goals presented in section 3 established the strategic planning framework for Curiosity's planned traverse in Gale crater into 1.5 km × 1.5 km (0.025°) quadrangles  for the vehicle to ascend  chemical observations on bedrock targets that were brushed beforehand using the dust removal tool (DRT) when images indicated significant dust coatings. The cadence of contact science sampling increased on Sol 1808 when Curiosity encountered a break in slope that marked the base of the ridge. The break in slope is accompanied by a lithological change where rocks are more competent and no longer dominated by the low‐angle Ca‐sulfate veins that are characteristic of the Blunts Point member. The decision to increase contact science data collection was motivated by the desire to capture chemical and textural changes that might be unique to the base of the VRR. Curiosity continued to sample VRR bedrock at <5 m elevation changes with contact science instruments as it traversed almost 1.5 km across the ridge during the next 200 sols. The rover also collected hundreds of remote sensing chemical and spectral measurements, predominantly of VRR bedrock targets, with ChemCam and Mastcam.As the rover's traverse steepened in the strata below the VRR, 4.2.1Curiosity investigated material on the edge of the fracture on Sol 1815 and compared it with material from an area far from a fracture collected on Sol 1820. Curiosity's observations included comparing the chemistry, spectral properties, and fine‐scale textures of brushed areas from both locations.The lower portion of VRR is crosscut by meter‐scale fractures that are visible in HiRISE data. Multispectral landscape images from several meters away showed that the fractures appeared to be associated with deeper ferric absorption bands at 535 and 867 nm. To assess whether the spectral differences were due to real compositional changes or an artifact caused by variable dust cover, 4.2.2Small areas on VRR appear blue‐gray relative to the surrounding terrain in stretched HiRISE false‐color images Figure . These aCuriosity reached the first of these patches on Sol 1902 and discovered that the region is distinctly different in both texture and color compared with surrounding terrain  varied as a function of lighting geometry , which involves positioning the drill bit directly over the instrument inlets and rotating the bit in reverse. Extensive testing in Curiosity's testbed on Earth showed this was safe in terms of portion amounts and particle size distribution.On Sol 1536 (December 2016), the drill feed mechanism began to exhibit intermittent failures. In response, rover engineers at the Jet Propulsion Laboratory commanded the drill to the fully extended position so that the bit would be clear of the stabilizers and remain usable in the event the feed mechanism failed entirely. They then developed new strategies for drilling and sample delivery that did not depend on the stabilizers or the sieving and portioning tool  using rotary‐only capabilities in two nearby locations within a gray bedrock target on upper VRR named “Lake Orcadie” and “Lake Orcadie 2”  Curiosity successfully drilled the target “Duluth” using the new feed‐extended drilling using percussion (FED‐uP) technique, and samples from Duluth were transferred to CheMin a few sols later using FEST  associated with the strongest CRISM hematite signature  at different elevations when the rover traversed them several hundred lateral meters apart   region, which contains rocks characterized by a strong clay signature in orbital spectroscopic data, directly to the south of VRR ,  Figures  and 2  nodules that have nearly pure FeOT (likely Fe2O3) compositions . These results are not summarized in any other papers within this special issue and so are discussed in detail here.ξabs) and H content, reported as water‐equivalent hydrogen, for the materials within this field of view were derived according to the methods described in Gabriel et al.  lateral area to a depth of ~45–75 cm  would require variations of ~10 wt % for Ni and Ti and ~5 wt % for Mn, which is well outside the range observed on the ridge by APXS and ChemCam analyses  at the meter scale and are especially variable within gray Jura bedrock patches. Additional colocations of active DAN footprints with APXS and ChemCam measurements are necessary to further pinpoint the exact source of large‐scale variability in neutron absorbers across the ridge and thus characterize the relative mobility of Cl versus Fe species in diagenetic events.5.3.32 and CIA than rocks lower on the ridge , which are not detected as crystalline phases by CheMin. Trace and/or amorphous reduced sulfur species, either iron sulfides or S‐bearing organic compounds, may also be present in the Highfield and Rock Hall samples, but at abundances far below the CheMin detection limit  and south of the ridge (Sol 2369's “Aberlady” and Sol 2384's “Kilmarie” in Glen Torridon) only required a maximum percussion level of 2. For reference, voice‐coil levels of 2, 4, and 5 correspond percussion mechanism impact energies of 0.20, 0.45, and 0.61 J, respectively  . If the ridge formed at a redox interface where dissolved Fe (II) was transported by near‐neutral, anoxic waters that were later oxidized and caused precipitation of Fe (III) phases, we would expect to see either an increase in the total measured amount of iron at the ridge compared with surrounding regions or a substantial increase in the total wt % of ferric minerals. Neither is observed, so the redox interface hypothesis in not supported by VRR in situ data.Data collected during Curiosity data also definitively confirm that the ridge is not an area that experienced extensive, top‐down oxidative weathering that would have left a lag of iron oxides and other insoluble phases, similar to a laterite deposit. If this process had occurred, APXS and ChemCam would have measured increases in iron, aluminum, and titanium with increasing elevation on VRR , meter‐scale gray patches, small variations in the distribution of trace elements. These features could have formed during multiple, separate diagenetic events, or they could represent a related continuum of products from a single event with heterogenous geochemical conditions and fluid transport pathways. Examination of crosscutting relationships of diagenetic features suggest at least one to three distinct episodes, so a combination of the above endmember scenarios may have occurred Horgan, . Sun et 6.3.1T = 100°C to 200°C)  compared to red hematite  connate water that is trapped by sediment as it is buried, (2) thermobaric water that is derived from hydrated minerals as sediments experience increased pressure and temperature, and (3) meteoric water that permeates the subsurface. Because of the evidence of late diagenesis, it is unlikely that connate water survived the burial and lithification of the Murray and overlying Stimson formations. Thermobaric water could have been derived locally from the conversion of smectite to ferripyrophyllite, opaline silica, and hematite . Gale crater lies on the Martian dichotomy boundary and is notably downslope of the highlands to the south. The crater floor is the deepest point for hundreds of surrounding kilometers, and there is ample evidence of surface flows toward and probably into Gale (Irwin et al., 7Curiosity's exploration of Vera Rubin ridge addressed all three campaign goals:Campaign Goal 1: Understand the primary depositional setting of the sedimentary rocks that make up the ridge and document their stratigraphic relationship with surrounding units. Rocks composing VRR were deposited in lacustrine and lacustrine margin settings with occasional intervals of subaqueous traction transport and are interpreted to be a continuation of the Murray formation (Edgar et al., Campaign Goal 2: Determine the source of the orbital hematite signature, understand its relationship with other hematite detections in Mount Sharp, and test the hypothesis that the hematite associated with the ridge indicated a site of past iron oxidation. The orbital spectral signature of hematite is caused by hematite associated with the bedrock of VRR. There is not a significantly greater abundance of hematite on VRR than surrounding rocks, but the ridge is associated with deeper spectral absorptions in situ that are likely due to enhanced crystallization or cementation caused by diagenesis (Fraeman et al., Campaign Goal 3: Document additional primary and secondary geochemical environments that are preserved in the ridge. There is abundant textural, mineralogical, and chemical evidence of diagenetic overprinting across multiple spatial scales on VRR (Bennett et al., Curiosity's exploration of the ridge advances our knowledge of the history and habitability of Gale crater. The discovery that VRR itself was created by diagenetic processes provides a new example of the large‐scale effects of subsurface diagenesis on the Martian rock record. The continuation of predominantly lacustrine sedimentation recorded within the ridge demonstrates that habitable lakes persisted in Gale crater even longer than previously reported (Edgar et al.,


To determine the feasibility and tissue yield of a perinatal incisionless ultrasound‐guided biopsy procedure, the INcisionless Targeted Core Tissue (INTACT) technique, in the context of minimally invasive autopsy.Cases of perinatal death in which the parents consented for minimally invasive autopsy underwent postmortem magnetic resonance imaging and an INTACT biopsy procedure, defined as needle biopsy of organs via the umbilical cord, performed under ultrasound guidance. In each case, three cores of tissue were obtained from seven target organs . Biopsy success was predefined as an adequate volume of the intended target organ for pathological analysis, as judged by a pathologist blinded to the case and biopsy procedure.Thirty fetuses underwent organ sampling. Mean gestational age was 30 weeks  and mean delivery‐to‐biopsy interval was 12 days . The overall biopsy success rate was 153/201 (76.1%) samples, with the success rates in individual organs being highest for the heart and lungs  and lowest for the spleen (11%). Excluding splenic samples, the biopsy success rate was 150/173 (86.7%). Histological abnormalities were found in 4/201 (2%) samples, all of which occurred in the lungs and kidneys of a fetus with pulmonary hypoplasia and multicystic kidney disease.Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.Incisionless ultrasound‐guided organ biopsy using the INTACT procedure is feasible, with an overall biopsy success rate of over 75%. This novel technique offers the ideal combination of an imaging‐led autopsy with organ sampling for parents who decline the conventional invasive approach. © 2019 The Authors.  What are the novel findings of this work?Ultrasound‐guided biopsy of organs through the umbilical cord using the INcisionless TArgeted Core Tissue (INTACT) procedure in cases of perinatal death provides a higher biopsy success rate than that reported previously using blinded percutaneous needle biopsy. It is feasible to obtain biopsies from several organs using this technique, avoiding incisions and multiple puncture sites.What are the clinical implications of this work?This incisionless perinatal biopsy procedure offers the ideal combination of an imaging‐led autopsy with organ sampling for parents who decline a conventional invasive perinatal autopsy approach.Non‐invasive perinatal autopsy using postmortem imaging techniques, such as postmortem magnetic resonance imaging (PM‐MRI), demonstrates high concordance rates when compared with conventional invasive autopsyMinimally invasive autopsy (MIA) methods offer a good compromise, with tissue samples obtained via smaller incisions, usually performed under laparoscopic guidanceIn this study, we aimed to improve on previous techniques by assessing the feasibility and yield of a novel technique for obtaining fetal organ tissue samples in which all samples are acquired via the umbilical cord under ultrasound guidance. This method avoids the need for any incisions, thus leaving the patient intact, as the umbilical cord is accessory tissue to the body and would be expected to harden and detach from the body in normal life. We have named this technique the ‘INcisionless TArgeted Core Tissue’ (INTACT) biopsy procedure. If this method proves successful, it could provide parents with an ideal combination of MIA with organ sampling for parents who decline the conventional invasive approach.Consecutive unselected cases of perinatal death in which the parents consented for MIA by the least invasive approach possible were included in this prospective study over a 2.5‐year period, from 1 July 2017 to 1 January 2019. Exclusion criteria included forensic death or cases without parental consent. This study was approved by a national research ethics committee (REC 09/H0713/2) and all samples were handled in accordance with the Human Tissue Act (2004). Written consent was obtained in each case.Preautopsy 1.5‐T PM‐MRI was performed in all cases according to local departmental protocolsPostmortem ultrasound was performed by a pediatric radiology research fellow (S.C.S.), according to published guidelinesThree core biopsies were acquired per organ, and the coaxial needle and trocar were repositioned for each organ. The same cutting biopsy needle was reinserted each time to obtain all tissue samples. Figure The entire procedure took approximately 20 min to complete. The performing radiologist was assisted by a mortuary assistant during each procedure, who labelled and collated the tissue samples. The samples were all fixed immediately in formalin, embedded within paraffin blocks and sectioned by histopathology laboratory staff for subsequent evaluation by in‐house pediatric pathologists. No pathologists were present during the INTACT procedures. The sampling order of organs was pseudo‐randomized for each case.If sampling of the intended organ was unsuccessful due to either tissue autolysis or failure to survive histological processing, but the preceding PM‐MRI demonstrated normal findings, no further action was taken given the low chance of pathological yieldOne of two perinatal pathologists , blinded to antenatal history and the sampled target organ, assessed the histology slides in all cases. The slides were reviewed approximately 6 months after the initial biopsy procedure had taken place to eliminate any possible recall bias from clinical reporting of the samples or possible departmental discussion of the autopsies, during either multidisciplinary meetings or professional discussions.vs pathological finding).The pathologist was asked to assess each sample for the following criteria: (1) the type of organ tissue in the sample , or whether the degree of autolysis precluded such assessment; (2) adequacy of tissue volume ; (3) presence of pathology . Biopsy failure was predefined as insufficient material for comment, tissue sample too small to undergo histological processing or target organ not sampled. Autopsy results and histological findings were analyzed according to successful organ biopsy and specific organ pathologies, using Microsoft Excel .In total, 30 fetuses underwent an INTACT biopsy procedure. Case demographics are outlined in Table During the study, there were six cases in which the intended organ for biopsy was not sampled. The reasons for this included: two cases of larger fetuses in which both lungs could not be reached by the biopsy needle, as the distance between the lungs and umbilicus was greater than the length of biopsy needle (11 cm); one case in which the heart could not be reached by the biopsy needle; two cases in which the spleen was not visible on ultrasound for targeting; and one case with bilateral renal agenesis. In the cases in which the lungs and heart could not be sampled by needle biopsy, a decision was made by the pathologist to proceed with laparoscopically assisted MIA to acquire the tissue samples. None of these subsequent samples yielded abnormal tissue.In one case, additional biopsies were obtained from a neck mass in a 25‐week fetus with known complex fetal brain malformation. These biopsies were conducted after discussion with the pathologist in charge of the case, and with parental consent. They were performed under ultrasound guidance, via a small 1‐cm incision in the skin, not using the INTACT biopsy procedure. The mass demonstrated abnormal mature tissue elements, and a differential diagnosis of a possible hamartoma or teratoma was suggested.The INTACT biopsy procedure took between 20 and 30 min in each case. In total, 201 organs were sampled. There was satisfactory sonographic biopsy needle visualization during all organ sampling , which included 36 cases in which the intended target organ was not present in the biopsy sample and 12 in which there was an insufficient volume of tissue for pathological assessment. The spleen was the target organ that was most frequently not present in the final biopsy sample . In approximately one‐third  of cases that did not contain the intended target organ tissue, the pathologist was unable to identify the tissue origin (reported ‘non‐diagnostic tissue’).en bloc. The larger volume of tissue obtained from the latter procedure allowed for better pathological assessment  showing some maceration‐related changes. A pathological finding was present in 4/153 (2.6%) biopsy samples, all of which originated from the same 20‐week fetus. This pregnancy had been terminated due to prenatal identification of bilateral enlarged cystic kidneys and pulmonary hypoplasia. There were clear abnormalities on PM‐MRI and ultrasound examination Compared with similar studies using needle biopsy methods Table , the INTAlthough we targeted seven key organs for sampling, we did not include all of the organs in the Royal College of Pathologists' autopsy guidelinesThis study has several limitations. The small sample size and lack of full autopsy correlation meant we could not calculate a robust diagnostic accuracy rate, which will be required for future studies, particularly if we are to address fully our false‐negative rates and provide a strong evidence basis with which to consent parents and define the contribution of the technique in providing a cause of death. Nevertheless, in this study, our intention was to first demonstrate feasibility of this novel biopsy technique. As the majority of our cases yielded adequate, normal tissue, we were unable to assess the adequacy of sampling for abnormal pathology in each organ. We also found that our standard biopsy needle length was too short in two larger fetuses to target the lungs and heart using the umbilical approach; thus, a range of longer needles may be required in future. Maceration affected the quality of the samples in our study, with moderate or marked maceration in two‐thirds of cases, which may have resulted in a higher inadequate sampling rate. Biopsy success rates may therefore be improved in the future by preferentially recommending non‐macerated cases for INTACT sampling or counseling parents regarding the possible lower yield in macerated fetusesWhilst we did not select our cases based on any predefined criteria other than parental consent for a minimally invasive approach, our cohort did contain a large number of stillbirths and intrauterine deaths. This may have introduced some bias, such as a potentially lower likelihood of abnormal fetal pathologies, but the final causes of death were similar to those in large unselected fetal autopsy series In conclusion, our novel incisionless biopsy procedure (INTACT procedure) is feasible and allows adequate sampling for the majority of organs. This technique offers a potential alternative approach for organ sampling when parents decline the conventional invasive approach.Table S1 Histological sampling success rates reported in adult and pediatric studies using minimally invasive tissue sampling methodsClick here for additional data file.