Rapid and automated design of two-component protein nanomaterials using ProteinMPNN.

The design of protein-protein interfaces using physics-based design methods such as Rosetta requires substantial computational resources and manual refinement by expert structural biologists. Deep learning methods promise to simplify protein-protein interface design and enable its application to a wide variety of problems by researchers from various scientific disciplines. Here, we test the ability of a deep learning method for protein sequence design, ProteinMPNN, to design two-component tetrahedral protein nanomaterials and benchmark its performance against Rosetta. ProteinMPNN had a similar success rate to Rosetta, yielding 13 new experimentally confirmed assemblies, but required orders of magnitude less computation and no manual refinement. The interfaces designed by ProteinMPNN were substantially more polar than those designed by Rosetta, which facilitated in vitro assembly of the designed nanomaterials from independently purified components. Crystal structures of several of the assemblies confirmed the accuracy of the design method at high resolution. Our results showcase the potential of deep learning-based methods to unlock the widespread application of designed protein-protein interfaces and self-assembling protein nanomaterials in biotechnology.

De novo designed ice-binding proteins from twist-constrained helices.

Attaining molecular-level control over solidification processes is a crucial aspect of materials science. To control ice formation, organisms have evolved bewildering arrays of ice-binding proteins (IBPs), but these have poorly understood structure-activity relationships. We propose that reverse engineering using de novo computational protein design can shed light on structure-activity relationships of IBPs. We hypothesized that the model alpha-helical winter flounder antifreeze protein uses an unusual undertwisting of its alpha-helix to align its putative ice-binding threonine residues in exactly the same direction. We test this hypothesis by designing a series of straight three-helix bundles with an ice-binding helix projecting threonines and two supporting helices constraining the twist of the ice-binding helix. Our findings show that ice-recrystallization inhibition by the designed proteins increases with the degree of designed undertwisting, thus validating our hypothesis, and opening up avenues for the computational design of IBPs.

Hypothermic Machine Perfusion in Liver Transplantation - A Randomized Trial.

BACKGROUND: Transplantation of livers obtained from donors after circulatory death is associated with an increased risk of nonanastomotic biliary strictures. Hypothermic oxygenated machine perfusion of livers may reduce the incidence of biliary complications, but data from prospective, controlled studies are limited. METHODS: In this multicenter, controlled trial, we randomly assigned patients who were undergoing transplantation of a liver obtained from a donor after circulatory death to receive that liver either after hypothermic oxygenated machine perfusion (machine-perfusion group) or after conventional static cold storage alone (control group). The primary end point was the incidence of nonanastomotic biliary strictures within 6 months after transplantation. Secondary end points included other graft-related and general complications. RESULTS: A total of 160 patients were enrolled, of whom 78 received a machine-perfused liver and 78 received a liver after static cold storage only (4 patients did not receive a liver in this trial). Nonanastomotic biliary strictures occurred in 6% of the patients in the machine-perfusion group and in 18% of those in the control group (risk ratio, 0.36; 95% confidence interval [CI], 0.14 to 0.94; P = 0.03). Postreperfusion syndrome occurred in 12% of the recipients of a machine-perfused liver and in 27% of those in the control group (risk ratio, 0.43; 95% CI, 0.20 to 0.91). Early allograft dysfunction occurred in 26% of the machine-perfused livers, as compared with 40% of control livers (risk ratio, 0.61; 95% CI, 0.39 to 0.96). The cumulative number of treatments for nonanastomotic biliary strictures was lower by a factor of almost 4 after machine perfusion, as compared with control. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Hypothermic oxygenated machine perfusion led to a lower risk of nonanastomotic biliary strictures following the transplantation of livers obtained from donors after circulatory death than conventional static cold storage. (Funded by Fonds NutsOhra; DHOPE-DCD ClinicalTrials.gov number, NCT02584283.).

Lesions hyper- to isointense to surrounding liver in the hepatobiliary phase of gadoxetic acid-enhanced MRI.

OBJECTIVES: Hyper- or isointensity in the hepatobiliary phase (HBP) of gadoxetic acid-enhanced MRI has high specificity for focal nodular hyperplasia (FNH) but may be present in hepatocellular adenoma and carcinoma (HCA/HCC). This study aimed to identify imaging characteristics differentiating FNH and HCA/HCC. MATERIALS AND METHODS: This multicenter retrospective cohort study included patients with pathology-proven FNH or HCA/HCC, hyper-/isointense in the HBP of gadoxetic acid-enhanced MRI between 2010 and 2020. Diagnostic performance of imaging characteristics for the differentiation between FNH and HCA/HCC were reported. Univariable analyses, multivariable logistic regression analyses, and classification and regression tree (CART) analyses were conducted. Sensitivity analyses evaluated imaging characteristics of B-catenin-activated HCA. RESULTS: In total, 124 patients (mean age 40 years, standard deviation 10 years, 108 female) with 128 hyper-/isointense lesions were included. Pathology diagnoses were FNH and HCA/HCC in 64 lesions (50%) and HCA/HCC in 64 lesions (50%). Imaging characteristics observed exclusively in HCA/HCC were raster and atoll fingerprint patterns in the HBP, sinusoidal dilatation on T2-w, hemosiderin, T1-w in-phase hyperintensity, venous washout, and nodule-in-nodule partification in the HBP and T2-w. Multivariable logistic regression and CART additionally found a T2-w scar indicating FNH, less than 50% fat, and a spherical contour indicating HCA/HCC. In our selected cohort, 14/48 (29%) of HCA were B-catenin activated, most (13/14) showed extensive hyper-/isointensity, and some had a T2-w scar (4/14, 29%). CONCLUSION: If the aforementioned characteristics typical for HCA/HCC are encountered in lesions extensively hyper- to isointense, further investigation may be warranted to exclude B-catenin-activated HCA. CLINICAL RELEVANCE: Hyper- or isointensity in the HBP of gadoxetic acid-enhanced MRI is specific for FNH, but HCA/HCC can also exhibit this feature. Therefore, we described imaging patterns to differentiate these entities. KEY POINTS: FNH and HCA/HCC have similar HBP intensities but have different malignant potentials. Six imaging patterns exclusive to HCA/HCC were identified in this lesion population. These features in liver lesions hyper- to isointense in the HBP warrant further evaluation.

No need for fasting prior to doppler ultrasound of pediatric liver transplants: A self-controlled study.

BACKGROUND: Children frequently undergo routine Doppler-ultrasound (DUS) after liver transplantation (LT) for which they are fasted, but this may cause hunger and discomfort. OBJECTIVE: To determine if DUS measurements, with focus on the portal vein (PV), are affected by prandial changes, and if this affects distress and feasibility of the DUS. MATERIALS AND METHODS: Children were prospectively included to undergo a pre- and postprandial DUS on the same day at 6 months after LT. Pre- and anastomotic PV peak systolic velocity (PSV), and hepatic artery and hepatic vein DUS measurements were obtained. Pre- and postprandial measurements, and relative postprandial change of PV velocity ratio (VR) compared to PV anastomotic PSV, were compared using paired-sample t-tests and intraclass correlation coefficients (ICC). Obscuration by bowel gas, difficulty of DUS, and impact of fasting were assessed using 5-point rating scales. RESULTS: Twenty-eight children (median age 3.5 years, IQR 1.6-10.8) were included; four were subsequently excluded because they were not fasted (N = 2) or withdrew consent for the second DUS (N = 2). Measurements between pre- and postprandial DUS, and relative postprandial change of VR compared to PV anastomotic PSV, were not significantly different (p > .05). Test consistency was good (ICC = 0.69, 95% CI = 0.29-0.67) for PV anastomotic PSV, and excellent (95% CI = 0.61-0.93) for PV VR. Obscuration by bowel gas or ease of DUS did not change after eating (p > .05). The majority (16/28, 57.2%) found fasting difficult, and several (13/28, 46.4%) got upset when fasted. CONCLUSION: Children with an LT do not need to be fasted for routine DUS, which may decrease the burden of the examination.

Algorithm-based care versus usual care for the early recognition and management of complications after pancreatic resection in the Netherlands: an open-label, nationwide, stepped-wedge cluster-randomised trial.

BACKGROUND: Early recognition and management of postoperative complications, before they become clinically relevant, can improve postoperative outcomes for patients, especially for high-risk procedures such as pancreatic resection. METHODS: We did an open-label, nationwide, stepped-wedge cluster-randomised trial that included all patients having pancreatic resection during a 22-month period in the Netherlands. In this trial design, all 17 centres that did pancreatic surgery were randomly allocated for the timing of the crossover from usual care (the control group) to treatment given in accordance with a multimodal, multidisciplinary algorithm for the early recognition and minimally invasive management of postoperative complications (the intervention group). Randomisation was done by an independent statistician using a computer-generated scheme, stratified to ensure that low-medium-volume centres alternated with high-volume centres. Patients and investigators were not masked to treatment. A smartphone app was designed that incorporated the algorithm and included the daily evaluation of clinical and biochemical markers. The algorithm determined when to do abdominal CT, radiological drainage, start antibiotic treatment, and remove abdominal drains. After crossover, clinicians were trained in how to use the algorithm during a 4-week wash-in period; analyses comparing outcomes between the control group and the intervention group included all patients other than those having pancreatic resection during this wash-in period. The primary outcome was a composite of bleeding that required invasive intervention, organ failure, and 90-day mortality, and was assessed by a masked adjudication committee. This trial was registered in the Netherlands Trial Register, NL6671. FINDINGS: From Jan 8, 2018, to Nov 9, 2019, all 1805 patients who had pancreatic resection in the Netherlands were eligible for and included in this study. 57 patients who underwent resection during the wash-in phase were excluded from the primary analysis. 1748 patients (885 receiving usual care and 863 receiving algorithm-centred care) were included. The primary outcome occurred in fewer patients in the algorithm-centred care group than in the usual care group (73 [8%] of 863 patients vs 124 [14%] of 885 patients; adjusted risk ratio [RR] 0·48, 95% CI 0·38-0·61; p<0·0001). Among patients treated according to the algorithm, compared with patients who received usual care there was a decrease in bleeding that required intervention (47 [5%] patients vs 51 [6%] patients; RR 0·65, 0·42-0·99; p=0·046), organ failure (39 [5%] patients vs 92 [10%] patients; 0·35, 0·20-0·60; p=0·0001), and 90-day mortality (23 [3%] patients vs 44 [5%] patients; 0·42, 0·19-0·92; p=0·029). INTERPRETATION: The algorithm for the early recognition and minimally invasive management of complications after pancreatic resection considerably improved clinical outcomes compared with usual care. This difference included an approximate 50% reduction in mortality at 90 days. FUNDING: The Dutch Cancer Society and UMC Utrecht.

Nonmalignant portal vein thrombi in patients with cirrhosis consist of intimal fibrosis with or without a fibrin-rich thrombus.

BACKGROUND AND AIM: Portal vein thrombosis (PVT) is a common complication of cirrhosis. The exact pathophysiology remains largely unknown, and treatment with anticoagulants does not lead to recanalization of the portal vein in all patients. A better insight into the structure and composition of portal vein thrombi may assist in developing strategies for the prevention and treatment of PVT. APPROACH AND RESULTS: Sixteen prospectively and 63 retrospectively collected nonmalignant portal vein thrombi from patients with cirrhosis who underwent liver transplantation were included. Histology, immunohistochemistry, and scanning electron microscopy were used to assess structure and composition of the thrombi. Most recent CT scans were reanalyzed for thrombus characteristics. Clinical characteristics were related to histological and radiological findings. All samples showed a thickened, fibrotic tunica intima. Fibrin-rich thrombi were present on top of the fibrotic intima in 9/16 prospective cases and in 21/63 retrospective cases. A minority of the fibrotic areas stained focally positive for fibrin/fibrinogen (16% of cases), von Willebrand factor (VWF; 10%), and CD61 (platelets, 21%), while most of the fibrin-rich areas stained positive for those markers (fibrin/fibrinogen, 100%; VWF, 77%; CD61, 100%). No associations were found between clinical characteristics including estimated thrombus age and use of anticoagulants and presence of fibrin-rich thrombi. CONCLUSION: We demonstrate that PVT in patients with cirrhosis consists of intimal fibrosis with an additional fibrin-rich thrombus in only one-third of cases. We hypothesize that our observations may explain why not all portal vein thrombi in patients with cirrhosis recanalize by anticoagulant therapy.

Evaluation of National Surgical Practice for Lateral Lymph Nodes in Rectal Cancer in an Untrained Setting.

BACKGROUND: Involved lateral lymph nodes (LLNs) have been associated with increased local recurrence (LR) and ipsi-lateral LR (LLR) rates. However, consensus regarding the indication and type of surgical treatment for suspicious LLNs is lacking. This study evaluated the surgical treatment of LLNs in an untrained setting at a national level. METHODS: Patients who underwent additional LLN surgery were selected from a national cross-sectional cohort study regarding patients undergoing rectal cancer surgery in 69 Dutch hospitals in 2016. LLN surgery consisted of either 'node-picking' (the removal of an individual LLN) or 'partial regional node dissection' (PRND; an incomplete resection of the LLN area). For all patients with primarily enlarged (≥7 mm) LLNs, those undergoing rectal surgery with an additional LLN procedure were compared to those  undergoing only rectal resection. RESULTS: Out of 3057 patients, 64 underwent additional LLN surgery, with 4-year LR and LLR rates of 26% and 15%, respectively. Forty-eight patients (75%) had enlarged LLNs, with corresponding recurrence rates of 26% and 19%, respectively. Node-picking (n = 40) resulted in a 20% 4-year LLR, and a 14% LLR after PRND (n = 8; p = 0.677). Multivariable analysis of 158 patients with enlarged LLNs undergoing additional LLN surgery (n = 48) or rectal resection alone (n = 110) showed no significant association of LLN surgery with 4-year LR or LLR, but suggested higher recurrence risks after LLN surgery (LR: hazard ratio [HR] 1.5, 95% confidence interval [CI] 0.7-3.2, p = 0.264; LLR: HR 1.9, 95% CI 0.2-2.5, p = 0.874). CONCLUSION: Evaluation of Dutch practice in 2016 revealed that approximately one-third of patients with primarily enlarged LLNs underwent surgical treatment, mostly consisting of node-picking. Recurrence rates were not significantly affected by LLN surgery, but did suggest worse outcomes. Outcomes of LLN surgery after adequate training requires further research.

Multidisciplinary management of chronic refractory pain in autosomal dominant polycystic kidney disease.

BACKGROUND: Chronic pain is often difficult to manage in autosomal dominant polycystic kidney disease (ADPKD) patients and sometimes even leads to nephrectomy. We analyzed the long-term efficacy of our innovative multidisciplinary protocol to treat chronic refractory pain that aims to preserve kidney function by applying among other sequential nerve blocks. METHODS: Patients were eligible if pain was present ≥3 months with a score of ≥50 on a visual analog scale (VAS) of 100, was negatively affecting quality of life and if there had been insufficient response to previous therapies, including opioid treatment. Treatment options were, in order, analgesics, cyst aspiration and fenestration, nerve blocks and nephrectomy. RESULTS: A total of 101 patients were assessed in our clinic (mean age 50 ± 11 years, 65.3% females). Eight patients were treated with medication, 6 by cyst aspiration or fenestration, 63 by nerve blocks and 6 received surgery as the first treatment option. Overall, 76.9% experienced a positive effect on pain complaints shortly after treatment. The VAS score was reduced from 60/100 to 20/100 (P < 0.001) and patients decreased their number of nonopioid and opioid analgesics significantly (P < 0.001, P = 0.01, respectively). A substantial number of the patients (n = 51) needed additional treatment. At the end of follow-up in only 13 patients (12.9%) was surgical intervention necessary: 11 nephrectomies (of which 10 were in patients already on kidney function replacement treatment), 1 liver transplantation and 1 partial hepatectomy. After a median follow-up of 4.5 years (interquartile range 2.5-5.3), 69.0% of the patients still had fewer pain complaints. CONCLUSIONS: These data indicate that our multidisciplinary treatment protocol appears effective in reducing pain in the majority of patients with chronic refractory pain, while postponing or even avoiding in most patients surgical interventions such as nephrectomy in most patients.

Optimal radiological gallbladder lesion characterization by combining visual assessment with CT-based radiomics.

OBJECTIVES: Differentiating benign gallbladder diseases from gallbladder cancer (GBC) remains a radiological challenge because they can appear very similar on imaging. This study aimed at investigating whether CT-based radiomic features of suspicious gallbladder lesions analyzed by machine learning algorithms could adequately discriminate benign gallbladder disease from GBC. In addition, the added value of machine learning models to radiological visual CT-scan interpretation was assessed. METHODS: Patients were retrospectively selected based on confirmed histopathological diagnosis and available contrast-enhanced portal venous phase CT-scan. The radiomic features were extracted from the entire gallbladder, then further analyzed by machine learning classifiers based on Lasso regression, Ridge regression, and XG Boosting. The results of the best-performing classifier were combined with radiological visual CT diagnosis and then compared with radiological visual CT assessment alone. RESULTS: In total, 127 patients were included: 83 patients with benign gallbladder lesions and 44 patients with GBC. Among all machine learning classifiers, XG boosting achieved the best AUC of 0.81 (95% CI 0.72-0.91) and the highest accuracy rate of 73% (95% CI 65-80%). When combining radiological visual interpretation and predictions of the XG boosting classifier, the highest diagnostic performance was achieved with an AUC of 0.98 (95% CI 0.96-1.00), a sensitivity of 91% (95% CI 86-100%), a specificity of 93% (95% CI 90-100%), and an accuracy of 92% (95% CI 90-100%). CONCLUSIONS: Machine learning analysis of CT-based radiomic features shows promising results in discriminating benign from malignant gallbladder disease. Combining CT-based radiomic analysis and radiological visual interpretation provided the most optimal strategy for GBC and benign gallbladder disease differentiation. KEY POINTS: Radiomic-based machine learning algorithms are able to differentiate benign gallbladder disease from gallbladder cancer. Combining machine learning algorithms with a radiological visual interpretation of gallbladder lesions at CT increases the specificity, compared to visual interpretation alone, from 73 to 93% and the accuracy from 85 to 92%. Combined use of machine learning algorithms and radiological visual assessment seems the most optimal strategy for GBC and benign gallbladder disease differentiation.

Doppler-ultrasound reference values after pediatric liver transplantation: a consecutive cohort study.

OBJECTIVES: Doppler ultrasound (DUS) is the main imaging modality to evaluate vascular complications of pediatric liver transplants (LT). The current study aimed to determine reference values and their change over time. METHODS: A consecutive cohort of pediatric patients undergoing an LT were retrospectively included between 2015 and 2020. Timepoints for standardized DUS were intra-operative and postoperative (day 0), days 1-7, months 1 and 3, and years 1 and 2. DUS measurements of the hepatic artery (HA), portal vein (PV), and hepatic vein(s) (HV) were included if there were no complications during 2 years follow-up. Measurements consisted of: peak systolic velocity (PSV) and resistive index (RI) for the HA, PSV for the PV, and venous pulsatility index (VPI) for the HV. Generalized estimating equations were used to analyze change over time. RESULTS: One hundred twelve pediatric patients with 123 LTs were included (median age 3.3 years, interquartile range 0.7-10.1). Ninety-five HAs, 100 PVs, and 115 HVs without complications were included. Reference values for HA PSV and RI, PV PSV, and HV VPI were obtained for all timepoints (4043 included data points in total) and presented using 5th-95th percentiles and threshold values. All reference values changed significantly over time (p = 0.032 to p < 0.001). CONCLUSIONS: DUS reference values of hepatic vessels in children after LT are presented, reference values change over time with specific vessel-dependent patterns. Timepoint-specific reference values improve the interpretation of DUS values and may help to better weigh their clinical significance. KEY POINTS: • Doppler ultrasound reference values of pediatric liver transplantations are not static but change over time. Applying the correct reference values for the specific timepoint may further improve the interpretation of the measurements. • The pattern of change over time of Doppler ultrasound measurements differs between the hepatic vessel and measurement; knowledge of these patterns may help radiologists to better understand normal postoperative hemodynamic changes.

Sonic hedgehog hepatocellular adenoma: magnetic resonance imaging features and correlation with histology.

OBJECTIVES: Sonic hedgehog hepatocellular adenoma (shHCA) is a new hepatocellular adenoma (HCA) subgroup characterized by high risk of hemorrhage. ShHCA account for below 10% of all HCA cases and are often associated with female gender, obesity, and non-alcoholic steatohepatitis. No specific MRI characteristics have been described to date. The objective of this study was to assess the value of using MRI to identify shHCA, and correlate MRI findings with histology. METHODS: We retrospectively collected MRI scans of 29 patients with shHCA from our center and from different liver referral centers to include 35 lesions. Diagnosis of shHCA was assessed by immunohistochemical overexpression of argininosuccinate synthase 1 or prostaglandin D2 synthase, then confirmed by molecular analysis of sonic hedgehog pathway activation and/or by proteomic analysis. RESULTS: In 46% (n = 16/35) of shHCA cases, we detected intralesional fluid-filled cavities defined on MR images as fluid-like foci markedly hyperintense on T2-weighted sequences, and hypointense on T1-weighted sequences, with or without delayed enhancement. Pathologically, these cavities were observed in 54% of cases as vacuoles filled with blood at different stages of degradation. Hemorrhage and/or necrosis were detected among 71% of cases by MRI analysis (n = 25/35) versus 82% pathologically. Seventeen percent of shHCA cases (n = 6/35) were completely homogeneous via MRI and pathological analysis. No MRI criteria was found in favor of focal nodular hyperplasia, HNF1A-mutated HCA, or typical inflammatory HCA. CONCLUSION: We reveal the presence of intralesional fluid-filled cavities among 46% of our shHCA cases that represent a new MRI finding possibly helpful for shHCA diagnosis. CLINICAL RELEVANCE STATEMENT: This multicenter study is the first clinical study about the radiological aspect of this new hepatocellular adenoma subgroup. This highlights a strong correlation between MRI and histological analysis, with a specific pattern emerging for diagnosis. KEY POINTS: • Sonic hedgehog hepatocellular adenoma is a new hepatocellular adenoma subgroup associated with high risk of hemorrhage, but imaging features of this subgroup remain unknown. • Analysis of MR images and correlation with pathology revealed intralesional fluid-filled cavities and necrotic-hemorrhagic changes. • Intralesional fluid-filled cavities have not yet been described in other adenoma subtypes and represent a new MRI finding for sonic hedgehog hepatocellular adenoma.

Utility of Preoperative Computed Tomography-Based Body Metrics in Relation to Postoperative Complications in Pediatric Liver Transplantation Recipients.

Computed tomography (CT)-derived body metrics such as skeletal muscle index (SMI), psoas muscle index (PMI), and subcutaneous fat area index (ScFI) are measurable components of sarcopenia, frailty, and nutrition. While these body metrics are advocated in adults for predicting postoperative outcomes after liver transplantation (LT), little is known about their value in pediatric populations. This study assessed the relation between preoperative CT-based body metrics and postoperative short-term outcomes in pediatric LT recipients. Patients aged 0-18 years who underwent a primary LT were retrospectively included (n = 101; median age 0.5 years; range 0.2-17.1). SMI, PMI, and ScFI were derived from preoperative axial CT slices. Postoperative outcomes and complications within 90 days were correlated with the CT-based body metrics. To classify postoperative infections, the Clavien-Dindo (CD) classification was used. Subgroup analyses were performed for age groups (<1, 1-10, and >10 years old). An optimal threshold for test performance was defined using Youden's J-statistic and receiver operating characteristic curve as appropriate. ScFI was significantly (P = 0.001) correlated with moderate to severe postoperative infections (CD grade 3-5) in children aged <1 year, with the optimal ScFI threshold being ≤27.1 cm2 /m2 (sensitivity 80.4% and specificity 77.8%). A weak negative correlation between SMI and the total duration of hospital stay (R = -0.3; P = 0.01) and intensive care unit (ICU) stay (R = -0.3; P = 0.01) was observed in children aged <1 year. No other associations between CT-based body metrics and postoperative outcomes were shown. In children aged <1 year with cirrhotic liver disease undergoing LT, preoperative CT-based body metrics were correlated with moderate to severe postoperative infections (ScFI) and with longer duration of hospital and ICU stay (SMI), and thus can be considered important tools for pre-LT risk assessment.

Liver fibrosis staging by deep learning: a visual-based explanation of diagnostic decisions of the model.

OBJECTIVES: Deep learning has been proven to be able to stage liver fibrosis based on contrast-enhanced CT images. However, until now, the algorithm is used as a black box and lacks transparency. This study aimed to provide a visual-based explanation of the diagnostic decisions made by deep learning. METHODS: The liver fibrosis staging network (LFS network) was developed at contrast-enhanced CT images in the portal venous phase in 252 patients with histologically proven liver fibrosis stage. To give a visual explanation of the diagnostic decisions made by the LFS network, Gradient-weighted Class Activation Mapping (Grad-cam) was used to produce location maps indicating where the LFS network focuses on when predicting liver fibrosis stage. RESULTS: The LFS network had areas under the receiver operating characteristic curve of 0.92, 0.89, and 0.88 for staging significant fibrosis (F2-F4), advanced fibrosis (F3-F4), and cirrhosis (F4), respectively, on the test set. The location maps indicated that the LFS network had more focus on the liver surface in patients without liver fibrosis (F0), while it focused more on the parenchyma of the liver and spleen in case of cirrhosis (F4). CONCLUSIONS: Deep learning methods are able to exploit CT-based information from the liver surface, liver parenchyma, and extrahepatic information to predict liver fibrosis stage. Therefore, we suggest using the entire upper abdomen on CT images when developing deep learning-based liver fibrosis staging algorithms. KEY POINTS: • Deep learning algorithms can stage liver fibrosis using contrast-enhanced CT images, but the algorithm is still used as a black box and lacks transparency. • Location maps produced by Gradient-weighted Class Activation Mapping can indicate the focus of the liver fibrosis staging network. • Deep learning methods use CT-based information from the liver surface, liver parenchyma, and extrahepatic information to predict liver fibrosis stage.

Intra-observer agreements in multidisciplinary team assessments of pancreatic cancer patients.

BACKGROUND AND METHODS: Treatment strategies for pancreatic cancer patients are made by a multidisciplinary team (MDT) board. We aimed to assess intra-observer variance at MDT boards. Participating units staged, assessed resectability, and made treatment allocations for the same patients as they did two years earlier. We disseminated clinical information and CT images of pancreatic cancer patients judged by one MDT board to have nonmetastatic pancreatic cancer to the participating units. All units were asked to re-assess the TNM stage, resectability, and treatment allocation for each patient. To assess intra-observer variance, we computed %-agreements for each participating unit, defined as low (<50%), moderate (50%-75%), and high (>75%) agreement. RESULTS: Eighteen patients were re-assessed by six MDT boards. The overall agreement was moderate for TNM-stage (ranging from 50%-70%) and resectability assessment (53%) but low for treatment allocation (46%). Agreement on resectability assessments was low to moderate. Findings were similar but more pronounced for treatment allocation. We observed a shift in treatment strategy towards increasing use of neoadjuvant chemotherapy, particularly in patients with borderline resectable and locally advanced tumors. CONCLUSIONS: We found substantial intra-observer agreement variations across six different MDT boards of 18 pancreatic cancer patients with two years between the first and second assessment.

Clinical and Radiologic Predictors of Parastomal Hernia Development After End Colostomy.

OBJECTIVE. Parastomal hernia (PSH) is a common complication that can occur after end colostomy and may result in considerable morbidity. To select the best candidates for prophylactic measures, knowledge of preoperative PSH predictors is important. This study aimed to determine the value of clinical parameters, preoperative CT-based body metrics, and size of the abdominal wall defect created during end colostomy and measured at postoperative CT for predicting PSH development. MATERIALS AND METHODS. Sixty-five patients who underwent permanent end colostomy with at least 1 year of follow-up were included. On preoperative CT, waist circumference, abdominal wall and psoas muscle indexes, rectus abdominis muscle diameter and diastasis, intra- and extraabdominal fat mass, and presence of other hernias were assessed. On postoperative CT, size of the abdominal wall defect and the presence of PSH were determined. To identify independent predictors of PSH development, univariate analysis with the Kaplan-Meier method and multivariate Cox regression analysis were performed. RESULTS. PSH developed after surgery in 30 patients (46%). Three independent risk factors were identified: chronic obstructive pulmonary disease (COPD) as a comorbidity (hazard ratio [HR], 6.4; 95% CI, 1.9-22.0; p = 0.003), operation time longer than 395 minutes (HR, 3.9; 95% CI, 1.5-10.0; p = 0.005), and maximum aperture diameter of more than 34 mm (HR, 5.2; 95% CI, 2.1-12.7; p < 0.001). PSH developed in all nine patients with a maximum abdominal wall defect diameter of more than 50 mm at the ostomy site. CONCLUSION. COPD, longer operation time, and larger abdominal wall defect at the colostomy site can predict PSH development. Intraoperative creation of an abdominal wall ostomy opening that is more than 34 mm in diameter should be avoided.

Assessment of hepatic artery anatomy in pediatric liver transplant recipients: MR angiography versus CT angiography.

During LT screening, children undergo CTA to determine hepatic artery anatomy. However, CTA imparts radiation, unlike MRA. The aim was to compare MRA to CTA in assessing hepatic artery anatomy in pediatric LT recipients. Twenty-one children (median age 8.9 years) who underwent both CTA and fl3D-ce MRA before LT were retrospectively included. Interreader variability between 2 radiologists, image quality, movement artifacts, and confidence scores, were used to compare MRA to CTA. Subgroup analyses for ages <6 years and ≥6 years were performed. Interreader variability for MRA and CTA in children <6 years was comparable (k = 0.839 and k = 0.757, respectively), while in children ≥6 years CTA was superior to MRA (k 1.000 and k 0.000, respectively). Overall image quality and confidence scores of CTA were significantly higher compared to MRA at all ages (2.8/3 vs. 2.3/3, p = .001; and 2.9/3 vs. 2.5/3, p = .003, respectively). Movement artifacts were significantly lower in CTA compared to MRA in children ≥6 years (1.0/3 vs. 1.7/3, p = .010, respectively). CTA is preferred over fl3D-ce MRA for the preoperative assessment of hepatic artery anatomy in children receiving LT, both at ages <6 years and ≥6 years.

Clinical value of diffusion-weighted MRI for differentiation between benign and malignant gallbladder disease: a systematic review and meta-analysis.

BACKGROUND: Radiological differentiation between benign and malignant gallbladder disease is important but remains challenging. Furthermore, the clinical value of diffusion-weighted imaging (DWI) remains unclear. PURPOSE: To determine the value of DWI in discriminating benign from malignant gallbladder disease by conducting a systematic review and meta-analysis. MATERIAL AND METHODS: The literature was systematically searched. Studies analyzing diagnostic value of DWI in gallbladder disease with histopathology or follow-up as reference standard were included. Study selection and data extraction were done by two reviewers independently. Methodological quality was assessed using the QUADAS-2 tool. Sensitivity and specificity were calculated and displayed in a forest plot. A sensitivity analysis was performed in case of outliers. Pooled sensitivity and specificity of DWI were plotted on a hierarchical summary receiver operating characteristic curve. If available, the added value of DWI to conventional magnetic resonance imaging (MRI) sequences was analyzed. RESULTS: Out of 2456 articles, eight studies fulfilled the inclusion criteria; 592 patients with 221 malignant lesions were included. Pooled sensitivity and specificity rates were 0.87 and 0.84, respectively. In two studies, diagnostic accuracy rates improved after adding DWI to conventional MRI (64% and 75% for conventional MRI vs. 89% and 94% after combining conventional MRI with DWI). In another study, the area under the curve increased from 0.92 to 0.95. CONCLUSION: DWI appears to be an accurate imaging technique in discriminating benign from malignant gallbladder disease. To achieve optimal patient care, it should be part of multiparametric MRI and should be combined with other imaging modalities.

Behavior and complications of hepatocellular adenoma during pregnancy and puerperium: a retrospective study and systematic review.

BACKGROUND: Hepatocellular adenomas (HCA) are benign liver tumors at risk of hemorrhage. The influence of pregnancy on HCA growth and potential bleeding remains unclear. This study investigates HCA-associated behavior and bleeding complications during or shortly after pregnancy. METHODS: (I) Single center retrospective cohort study of HCA during and after pregnancy (II) Systematic literature review. RESULTS: The retrospective study included 11 patients, of which 4 with HCA ≥5 cm. In only two patients HCA showed growth during pregnancy. In this local cohort, no HCA-related hemorrhages occurred during median follow-up of 34 months (interquartile range 19-58 months). The systematic review yielded 33 studies, totaling 90 patients with 99 pregnancies. Of 73 pregnancies without prior HCA-related intervention, 39 HCA remained stable (53.4%), 11 regressed (15.1%), and 23 (31.5%) progressed. Fifteen HCA-related hemorrhages occurred in HCA measuring 6.5-17.0 cm. Eight patients experienced bleeding during pregnancy, two during labor and five postpartum. CONCLUSION: Although hemorrhage of HCA during or shortly after pregnancy is rare and only reported in HCA ≥6.5 cm, it can be fatal. Pregnancy in women with HCA, regardless of size, warrant a close surveillance strategy. Observational studies on behavior and management of HCA ≥5 cm during and immediately after pregnancy are needed.

Kidney Infarction in Patients With COVID-19.

Coronavirus disease 2019 (COVID-19) is a contagious life-threatening infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent findings indicate an increased risk for acute kidney injury during COVID-19 infection. The pathophysiologic mechanisms leading to acute kidney injury in COVID-19 infection are unclear but may include direct cytopathic effects of the virus on kidney tubular and endothelial cells, indirect damage caused by virus-induced cytokine release, and kidney hypoperfusion due to a restrictive fluid strategy. In this report of 2 cases, we propose an additional pathophysiologic mechanism. We describe 2 cases in which patients with COVID-19 infection developed a decrease in kidney function due to kidney infarction. These patients did not have atrial fibrillation. One of these patients was treated with therapeutic doses of low-molecular-weight heparin, after which no further deterioration in kidney function was observed. Our findings implicate that the differential diagnosis of acute kidney injury in COVID-19-infected patients should include kidney infarction, which may have important preventive and therapeutic implications.