Automatic hepatic tumor segmentation in intra-operative ultrasound: a supervised deep-learning approach.

Purpose: Training and evaluation of the performance of a supervised deep-learning model for the segmentation of hepatic tumors from intraoperative US (iUS) images, with the purpose of improving the accuracy of tumor margin assessment during liver surgeries and the detection of lesions during colorectal surgeries. Approach: In this retrospective study, a U-Net network was trained with the nnU-Net framework in different configurations for the segmentation of CRLM from iUS. The model was trained on B-mode intraoperative hepatic US images, hand-labeled by an expert clinician. The model was tested on an independent set of similar images. The average age of the study population was 61.9 ± 9.9 years. Ground truth for the test set was provided by a radiologist, and three extra delineation sets were used for the computation of inter-observer variability. Results: The presented model achieved a DSC of 0.84 (p=0.0037), which is comparable to the expert human raters scores. The model segmented hypoechoic and mixed lesions more accurately (DSC of 0.89 and 0.88, respectively) than hyper- and isoechoic ones (DSC of 0.70 and 0.60, respectively) only missing isoechoic or >20 mm in diameter (8% of the tumors) lesions. The inclusion of extra margins of probable tumor tissue around the lesions in the training ground truth resulted in lower DSCs of 0.75 (p=0.0022). Conclusion: The model can accurately segment hepatic tumors from iUS images and has the potential to speed up the resection margin definition during surgeries and the detection of lesion in screenings by automating iUS assessment.

Dilute gel networks vs. clumpy gels in colloidal systems with a competition between repulsive and attractive interactions.

Using Brownian dynamics simulations we study gel-forming colloidal systems. The focus of this article lies on the differences of dense and dilute gel networks in terms of structure formation both on a local and a global level. We apply reduction algorithms and observe that dilute networks and dense gels differ in the way structural properties like the thickness of strands emerge. We also analyze the percolation behavior and find that two different regimes of percolation exist which might be responsible for structural differences. In dilute networks we confirm that solidity is mainly a consequence of pentagonal bipyramids forming in the network. In dense gels, tetrahedral structures also influence solidity.

Ultrasound guidance in navigated liver surgery: toward deep-learning enhanced compensation of deformation and organ motion.

PURPOSE: Accuracy of image-guided liver surgery is challenged by deformation of the liver during the procedure. This study aims at improving navigation accuracy by using intraoperative deep learning segmentation and nonrigid registration of hepatic vasculature from ultrasound (US) images to compensate for changes in liver position and deformation. METHODS: This was a single-center prospective study of patients with liver metastases from any origin. Electromagnetic tracking was used to follow US and liver movement. A preoperative 3D model of the liver, including liver lesions, and hepatic and portal vasculature, was registered with the intraoperative organ position. Hepatic vasculature was segmented using a reduced 3D U-Net and registered to preoperative imaging after initial alignment followed by nonrigid registration. Accuracy was assessed as Euclidean distance between the tumor center imaged in the intraoperative US and the registered preoperative image. RESULTS: Median target registration error (TRE) after initial alignment was 11.6 mm in 25 procedures and improved to 6.9 mm after nonrigid registration (p = 0.0076). The number of TREs above 10 mm halved from 16 to 8 after nonrigid registration. In 9 cases, registration was performed twice after failure of the first attempt. The first registration cycle was completed in median 11 min (8:00-18:45 min) and a second in 5 min (2:30-10:20 min). CONCLUSION: This novel registration workflow using automatic vascular detection and nonrigid registration allows to accurately localize liver lesions. Further automation in the workflow is required in initial alignment and classification accuracy.

Bullous pemphigoid anti-BP180-NC16A autoantibody reactivity in healthy individuals is associated with marked hypovitaminosis D and Th2-like cytokine predominance.

Autoimmune bullous disease autoantibodies, particularly including bullous pemphigoid (BP)-related anti-BP180-NC16A IgG, have been reported in a small subset of healthy individuals, but information about associated factors is lacking. We hypothesized that an abnormal status of immunomodulatory vitamin D could play a role in anti-BP180-NC16A autoantibody reactivity in healthy persons. In addition, we aimed to evaluate the cytokine profile associated with these autoantibodies. Plasma samples from 34 anti-BP180-NC16A IgG-reactive and 85 anti-BP180-NC16A IgG-negative healthy blood donors were tested for levels of 25-hydroxyvitamin D [25(OH)D] and a wide range of cytokines (IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-21, IL-22, IFN-γ, and TNF-α). We observed that anti-BP180-NC16A IgG-reactive healthy subjects had significantly lower plasma 25(OH)D levels and about a two-fold higher rate of vitamin D deficiency (< 20 ng/ml) compared to anti-BP180-NC16A IgG-negative healthy persons. In addition, anti-BP180-NC16A IgG-positive samples were characterized by significantly higher levels of IL-2, IL-5, IL-9, IL-10, and IL-13 which were, however, not significantly associated with the vitamin D levels. Our results indicate that healthy individuals with BP autoantibody reactivity share similarities with BP patients regarding the vitamin D status and cytokine profile (i.e., marked hypovitaminosis D and Th2 predominance), which may have pathophysiologic implications.

Challenge of hepatitis B testing following intravenous immunoglobulin therapy in patients with autoimmune skin diseases.

Intravenous immunoglobulin (IVIg) contains pooled immunoglobulins from the plasma of healthy blood donors. All plasma samples are tested for HIV, hepatitis viruses (A, B, and C), and parvovirus B19. As part of this screening step, nucleic acid amplification technology (NAT) is used and allows the presence of specific antibodies targeting viral structures that are commonly used to test for infection status, such as anti-hepatitis B surface antigen (HBs) or anti-hepatitis B virus core (HBc) antibodies. For this reason, manufacturers point to the possibility of false-positive viral serological test results following IVIg treatment due to the passive transfer of antibodies. IVIg therapy is commonly used to manage patients with severe, treatment-refractory autoimmune skin diseases. The aim of this cohort study was to retrospectively quantify newly-discovered positive serological HBV test results after IVIg treatment in patients with autoimmune skin diseases. Between March 2018 and June 2021, 28 patients with autoimmune skin diseases received IVIg therapy, of whom 17 were longitudinally followed-up. None of the patients had evidence of active HBV infection prior to IVIg therapy. All patients (n = 17) had detectable anti-HBs antibodies and 12 patients had anti-HBc antibodies 4 weeks after commencing IVIg treatment. Passive antibody transfer seems the most likely interpretation. Nevertheless, complete serological hepatitis assessment should be performed to exclude a new infection. We recommend hepatitis screening before IVIg therapy to prevent diagnostic confusion which may arise due to passive antibody transfer.

Ultrasound-based navigation for open liver surgery using active liver tracking.

PURPOSE: Despite extensive preoperative imaging, intraoperative localization of liver lesions after systemic treatment can be challenging. Therefore, an image-guided navigation setup is explored that links preoperative diagnostic scans and 3D models to intraoperative ultrasound (US), enabling overlay of detailed diagnostic images on intraoperative US. Aim of this study is to assess the workflow and accuracy of such a navigation system which compensates for liver motion. METHODS: Electromagnetic (EM) tracking was used for organ tracking and movement of the transducer. After laparotomy, a sensor was attached to the liver surface while the EM-tracked US transducer enabled image acquisition and landmark digitization. Landmarks surrounding the lesion were selected during patient-specific preoperative 3D planning and identified for registration during surgery. Endpoints were accuracy and additional times of the investigative steps. Accuracy was computed at the center of the target lesion. RESULTS: In total, 22 navigated procedures were performed. Navigation provided useful visualization of preoperative 3D models and their overlay on US imaging. Landmark-based registration resulted in a mean fiducial registration error of 10.3 ± 4.3 mm, and a mean target registration error of 8.5 ± 4.2 mm. Navigation was available after an average of 12.7 min. CONCLUSION: We developed a navigation method combining ultrasound with active liver tracking for organ motion compensation, with an accuracy below 10 mm. Fixation of the liver sensor near the target lesion compensates for local movement and contributes to improved reliability during navigation. This represents an important step forward in providing surgical navigation throughout the procedure. TRIAL REGISTRATION: This study is registered in the Netherlands Trial Register (number NL7951).

On the role of softness in ionic microgel interactions.

Thermoresponsive microgels are a popular model system to study phase transitions in soft matter, because temperature directly controls their volume fraction. Ionic microgels are additionally pH-responsive and possess a rich phase diagram. Although effective interaction potentials between microgel particles have been proposed, these have never been fully tested, leading to a gap in our understanding of the link between single-particle and collective properties. To help resolve this gap, four sets of ionic microgels with varying crosslinker density were synthesised and characterised using light scattering techniques and confocal microscopy. The resultant structural and dynamical information was used to investigate how particle softness affects the phase behaviour of ionic microgels and to validate the proposed interaction potential. We find that the architecture of the microgel plays a marked role in its phase behaviour. Rather than the ionic charges, it is the dangling ends which drive phase transitions and interactions at low concentration. Comparison to theory underlines the need for a refined theoretical model which takes into consideration these close-contact interactions.

ArGSLab: a tool for analyzing experimental or simulated particle networks.

Microscopy and particle-based simulations are both powerful techniques to study aggregated particulate matter such as colloidal gels. The data provided by these techniques often contains information on a wide array of length scales, but structural analysis methods typically focus on the local particle arrangement, even though the data also contains information about the particle network on the mesoscopic length scale. In this paper, we present a MATLAB software package for quantifying mesoscopic network structures in colloidal samples. ArGSLab (Arrested and Gelated Structures Laboratory) extracts a network backbone from the input data, which is in turn transformed into a set of nodes and links for graph theory-based analysis. The routines can process both image stacks from microscopy as well as explicit coordinate data, and thus allows quantitative comparison between simulations and experiments. ArGSLab furthermore enables the accurate analysis of microscopy data where, e.g., an extended point spread function prohibits the resolution of individual particles. We demonstrate the resulting output for example datasets from both microscopy and simulation of colloidal gels, in order to showcase the capability of ArGSLab to quantitatively analyze data from various sources. The freely available software package can be used either with a provided graphical user interface or directly as a MATLAB script.

CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment.

Cytotoxic T lymphocyte (CTL) responses against tumors are maintained by stem-like memory cells that self-renew but also give rise to effector-like cells. The latter gradually lose their anti-tumor activity and acquire an epigenetically fixed, hypofunctional state, leading to tumor tolerance. Here, we show that the conversion of stem-like into effector-like CTLs involves a major chemotactic reprogramming that includes the upregulation of chemokine receptor CXCR6. This receptor positions effector-like CTLs in a discrete perivascular niche of the tumor stroma that is densely occupied by CCR7+ dendritic cells (DCs) expressing the CXCR6 ligand CXCL16. CCR7+ DCs also express and trans-present the survival cytokine interleukin-15 (IL-15). CXCR6 expression and IL-15 trans-presentation are critical for the survival and local expansion of effector-like CTLs in the tumor microenvironment to maximize their anti-tumor activity before progressing to irreversible dysfunction. These observations reveal a cellular and molecular checkpoint that determines the magnitude and outcome of anti-tumor immune responses.

Technical note: Validation of 3D ultrasound for image registration during oncological liver surgery.

PURPOSE: Registration of pre- and intraoperative images is a crucial step of surgical liver navigation, where rigid registration of vessel centerlines is currently commonly used. When using 3D ultrasound (US), accuracy during navigation might be influenced by the size of the intraoperative US volume, yet the relationship between registration accuracy and US volume size is understudied. In this study, we specify an optimal 3D US volume size for registration using varying volumes of liver vasculature. While previous studies measured accuracy at registered fiducials, in this work, accuracy is determined at the target lesion which is clinically the most relevant structure. METHODS: Three-dimensional US volumes were acquired in 14 patients after laparotomy and liver mobilization. Manual segmentation of vasculature and centerline extraction was performed. Intraoperative and preoperative vasculature centerlines were registered with coherent point drift, using different sub-volumes (sphere with radius r = 30, 40, …, 120 mm). Accuracy was measured by fiducial registration error (FRE) between vessel centerlines and target registration error (TRE) at the center of the target lesion. RESULTS: The lowest FRE for vessel registration was reached with r = 50 mm (6.5 ± 2.5 mm), the highest with r = 120 mm (7.1 ± 2.1 mm). Clinical accuracy at the target lesion, resulted most accurate (TRE = 8.8 ± 5.0 mm) in sub-volumes with a radius of 50 mm. Smaller US sub-volumes resulted in lower average TREs when compared to larger US sub-volumes (Pearson's correlation coefficient R = 0.91, p < 0.001). CONCLUSION: Our results indicate that there is a linear correlation between US volume size and registration accuracy at the tumor. Volumes with radii of 50 mm around the target lesion yield higher accuracy (p < 0.05) (Trial number IRBd18032, 11 September 2018).

T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours.

The efficacy of adoptive cell therapy for solid tumours is hampered by the poor accumulation of the transferred T cells in tumour tissue. Here, we show that forced expression of C-X-C chemokine receptor type 6 (whose ligand is highly expressed by human and murine pancreatic cancer cells and tumour-infiltrating immune cells) in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer. In mice with subcutaneous pancreatic tumours treated with T cells with either a transgenic T-cell receptor or a murine chimeric antigen receptor targeting the tumour-associated antigen epithelial cell adhesion molecule, and in mice with orthotopic pancreatic tumours or patient-derived xenografts treated with T cells expressing a chimeric antigen receptor targeting mesothelin, the T cells exhibited enhanced intratumoral accumulation, exerted sustained anti-tumoral activity and prolonged animal survival only when co-expressing C-X-C chemokine receptor type 6. Arming tumour-specific T cells with tumour-specific chemokine receptors may represent a promising strategy for the realization of adoptive cell therapy for solid tumours.

Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors.

CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (Treg) cells suppress the immune response via inhibitory factors such as transforming growth factor-ß (TGF-ß). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-ß receptor 2 (DNR) can simultaneously shield them from TGF-ß. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8+ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-ß shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.

Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop.

Foxp3+ T regulatory (Treg) cells promote immunological tumor tolerance, but how their immune-suppressive function is regulated in the tumor microenvironment (TME) remains unknown. Here, we used intravital microscopy to characterize the cellular interactions that provide tumor-infiltrating Treg cells with critical activation signals. We found that the polyclonal Treg cell repertoire is pre-enriched to recognize antigens presented by tumor-associated conventional dendritic cells (cDCs). Unstable cDC contacts sufficed to sustain Treg cell function, whereas T helper cells were activated during stable interactions. Contact instability resulted from CTLA-4-dependent downregulation of co-stimulatory B7-family proteins on cDCs, mediated by Treg cells themselves. CTLA-4-blockade triggered CD28-dependent Treg cell hyper-proliferation in the TME, and concomitant Treg cell inactivation was required to achieve tumor rejection. Therefore, Treg cells self-regulate through a CTLA-4- and CD28-dependent feedback loop that adjusts their population size to the amount of local co-stimulation. Its disruption through CTLA-4-blockade may off-set therapeutic benefits in cancer patients.

The social cost of contacts: Theory and evidence for the first wave of the COVID-19 pandemic in Germany.

Building on the epidemiological SIR model, we present an economic model with heterogeneous individuals deriving utility from social contacts creating infection risks. Focusing on social distancing of individuals susceptible to an infection we theoretically characterize the gap between private and social cost of contacts. Our main contribution is to quantify this gap by calibrating the model with unique survey data from Germany on social distancing and impure altruism from the beginning of the COVID-19 pandemic. The optimal policy is to drastically reduce contacts at the beginning to almost eradicate the epidemic and keep them at levels that contain the pandemic at a low prevalence level. We find that also in laissez faire, private protection efforts by forward-looking, risk averse individuals would have stabilized the epidemic, but at a much higher prevalence of infection than optimal. Altruistic motives increase individual protection efforts, but a substantial gap to the social optimum remains.

CBCT-based navigation system for open liver surgery: Accurate guidance toward mobile and deformable targets with a semi-rigid organ approximation and electromagnetic tracking of the liver.

PURPOSE: The surgical navigation system that provides guidance throughout the surgery can facilitate safer and more radical liver resections, but such a system should also be able to handle organ motion. This work investigates the accuracy of intraoperative surgical guidance during open liver resection, with a semi-rigid organ approximation and electromagnetic tracking of the target area. METHODS: The suggested navigation technique incorporates a preoperative 3D liver model based on diagnostic 4D MRI scan, intraoperative contrast-enhanced CBCT imaging and electromagnetic (EM) tracking of the liver surface, as well as surgical instruments, by means of six degrees-of-freedom micro-EM sensors. RESULTS: The system was evaluated during surgeries with 35 patients and resulted in an accurate and intuitive real-time visualization of liver anatomy and tumor's location, confirmed by intraoperative checks on visible anatomical landmarks. Based on accuracy measurements verified by intraoperative CBCT, the system's average accuracy was 4.0 ± 3.0 mm, while the total surgical delay due to navigation stayed below 20 min. CONCLUSIONS: The electromagnetic navigation system for open liver surgery developed in this work allows for accurate localization of liver lesions and critical anatomical structures surrounding the resection area, even when the liver was manipulated. However, further clinically integrating the method requires shortening the guidance-related surgical delay, which can be achieved by shifting to faster intraoperative imaging like ultrasound. Our approach is adaptable to navigation on other mobile and deformable organs, and therefore may benefit various clinical applications.

Crystal-to-Crystal Transitions in Binary Mixtures of Soft Colloids.

In this article, we demonstrate a method for inducing reversible crystal-to-crystal transitions in binary mixtures of soft colloidal particles. Through a controlled decrease of salinity and increasingly dominating electrostatic interactions, a single sample is shown to reversibly organize into entropic crystals, electrostatic attraction-dominated crystals, or aggregated gels, which we quantify using microscopy and image analysis. We furthermore analyze crystalline structures with bond order analysis to discern between two crystal phases. We observe the different phases using a sample holder geometry that allows both in situ salinity control and imaging through confocal laser scanning microscopy and apply a synthesis method producing particles with high resolvability in microscopy with control over particle size. The particle softness provides for an enhanced crystallization speed, while altering the re-entrant melting behavior as compared to hard sphere systems. This work thus provides several tools for use in the reproducible manufacture and analysis of binary colloidal crystals.

Quantitative assessment of metal contamination and associated pollution risk in sediments from the Mara River in Tanzania.

For most rivers in sub-Saharan Africa, information about pollution indices related to sediments is sparse. Sedimentological research of rivers that empty into Lake Victoria is highly patchy and wide apart. The present study determined the levels and associated risk of As, Cd, Cr, Hg, and Pb in sediments collected from four different sites along the Mara River that empties into Lake Victoria in Tanzania. Samples were collected in the dry and rainy months in 2019. Pollution indices, namely geo-accumulation index (Igeo), enrichment factor (EF), contamination factor (CF), modified contamination degree (mCd), pollution load index (PLI), potential ecological risk factor (Eri), and potential ecological risk index (RI) were used to evaluate the influence of heavy metal contamination in sediments. Dry month mean concentrations, in milligram per kilogram, of heavy metals were as follows: As (11.04 ± 0.13), Cr (1.02 ± 0.29), Cd (0.43 ± 0.05), and Hg (0.01) in the dry month. Respective sediment heavy metal concentrations for the rainy month were 22.22 ± 0.05 mg As/kg, 3.84 ± 0.34 mg Pb/kg, 1.53 ± 0.15 mg Cd/kg, 1.43 mg Cr/kg, and 0.03 mg Hg/kg. Generally, the risk indices showed high values in the rainy month and low values in the dry month, especially for As and Cd-an indication of anthropogenic influence. Correlation coefficient analysis for Pb and Cd showed a strong positive correlation (r = 0.99, p < 0.01)-this may suggest a similar source or similar transport behavior. Special attention needs to be paid with regard to rainy season As and Cd enrichment in the study area.

Moral Suasion and the Private Provision of Public Goods: Evidence from the COVID-19 Pandemic.

We study how moral suasion that appeals to two major ethical theories, Consequentialism and Deontology, affects individual intentions to contribute to a public good. We use the COVID-19 pandemic as an exemplary case where there is a large gap between private and social costs and where moral suasion has been widely used as a policy instrument. Based on a survey experiment with a representative sample of around 3500 Germans at the beginning of the pandemic, we study how moral appeals affect contributions with low and high opportunity costs, hand washing and social distancing, to reduce the infection externality as well as the support for governmental regulation. We find that Deontological moral suasion, appealing to individual moral duty, is effective in increasing planned social distancing and hand-washing, while a Consequentialist appeal only increases planned hand-washing. Both appeals increase support for governmental regulation. Exploring heterogeneous treatment effects reveals that younger respondents are more susceptible to Deontological appeals. Our results highlight the potential of moral appeals to induce intended private contributions to a public good or the reduction of externalities, which can help to overcome collective action problems for a range of environmental issues.

Monitoring intrapartum fetal heart rates by mothers in labour in two public hospitals: an initiative to improve maternal and neonatal healthcare in Liberia.

BACKGROUND: In low-resource settings with few health workers, Fetal Heart Rate (FHR) monitoring in labour can be inconsistent and unreliable. An initiative to improve fetal monitoring was implemented in two public hospitals in rural Liberia; the country with the second lowest number of midwives and nurses in the world (1.007 per 10,000 of the population). The initiative assessed the feasibility of educating women in labour to monitor their own FHR and alert a midwife of changes detected. METHODS: Four hundred seventy-four women admitted in labour without obstetric complications were approached. Four hundred sixty-one consented to participate (97%) and 13 declined. Those consenting were trained to monitor their FHR using a sonicaid for approximately 1 minute immediately following the end of every uterine contraction and to inform a midwife of changes. If changes were confirmed, standard clinical interventions for fetal distress (lateral tilt, intravenous fluids and oxygen) were undertaken and, when appropriate, accelerated delivery by vacuum or Caesarean section. Participants provided views on their experiences; subsequently categorized into themes. Neonatal outcomes regarding survival, need for resuscitation, presence of birth asphyxia, and treatment were recorded. RESULTS: Four hundred sixty-one out of 474 women gave consent, of whom 431 of 461 (93%) completed the monitoring themselves. Three hundred eighty-seven of 400 women who gave comments, reported positive and 13 negative experiences. FHR changes were reported in 28 participants and confirmed in 26. Twenty-four of these 26 FHR changes were first identified by mothers. Fetal death was identified on admission during training in one mother. Thirteen neonates required resuscitation, with 12 admitted to the neonatal unit. One developed temporary seizures suggesting birth asphyxia. All 26 neonates were discharged home apparently well. In 2 mothers, previously unrecognized obstetric complications (cord prolapse and Bandl's ring with obstructed labour) accompanied FHR changes. Resuscitation was needed in 8 neonates without identified FHR changes including one of birth weight 1.3 Kg who could not be resuscitated. There were no intrapartum stillbirths in participants. CONCLUSIONS: Women in labour were able to monitor and detect changes in their FHR. Most found the experience beneficial. The absence of intrapartum stillbirths after admission and the low rate of poor neonatal outcomes are promising and warrant further investigation.