Novel IL-4/HB-EGF-dependent crosstalk between eosinophils and macrophages controls liver regeneration after ischaemia and reperfusion injury.

OBJECTIVE: Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair. DESIGN: Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf). RESULT: We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury. CONCLUSION: Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis.

Assessment of injuries patterns produced by a 9mm P.A.K "rubber ball" blank firing weapon: porcine model.

The use of less lethal weapons aims to mitigate civilian casualties caused by firearm use. However, due to numerous cases in which these weapons caused serious injuries, even lethal injuries, both legislation and the forensic field are interested in characterizing and regulating them better. In the forensic field, there is a lack of strong research about injury patterns of these weapons which makes it difficult to identify the type of weapon employed. In this study, the main objective was to characterize the injury pattern produced by the impact of the 9 mm P.A.K. projectile. A porcine model was used. Four different distances were studied: firm contact, 10 cm, 60 cm and 110 cm, using 3 of the more representative anatomical sites: the head, the hind leg and the ribs. The average measurement of the entrance orifice varied according to the anatomical site, being 6.67 mm wide and 6.25 mm long in the thorax, 7.3 mm wide and 8.8 mm long in the hind legs, and 7.62 mm wide and 7.54 mm long in the head. The variation in width and length measurements was not found to be directly related to the shot distance. The gunshot residues had similar characteristics to those of conventional lead projectiles, however there was more unburned powder deposit near the wounds, with a less dense soot and more dense powder tattoo. Depth varied widely regardless of tissue and firing distance, although loss of penetrating power and injury is observed as one moves away from the target.

Computational mesoscale framework for biological clustering and fractal aggregation.

Hierarchical clustering due to diffusion and reaction is a widespread occurrence in natural phenomena, displaying fractal behavior with non-integer size scaling. The study of this phenomenon has garnered interest in both biological systems such as morphogenesis and blood clotting, and synthetic systems such as colloids and polymers. The modeling of biological clustering can be difficult, as it can occur on a variety of scales and involve multiple mechanisms, necessitating the use of various methods to capture its behavior. Here, we propose a novel framework, the generalized-mesoscale-clustering (GMC), for the study of complex hierarchical clustering phenomena in biological systems. The GMC framework incorporates the effects of hydrodynamic interactions, bonding, and surface tension, and allows for the analysis of both static and dynamic states of cluster development. The framework is applied to a range of biological clustering mechanisms, with a focus on blood-related clustering from fibrin network formation to platelet aggregation. Our study highlights the importance of a comprehensive characterization of the structural properties of the cluster, including fractal dimension, pore-scale diffusion, initiation time, and consolidation time, in fully understanding the behavior of biological clustering systems. The GMC framework also provides the potential to investigate the temporal evolution and mechanical properties of the clusters by tracking bond density and including hydrodynamic interactions.

Real-life benchmarking bladder cancer care: A population-based study.

INTRODUCTION: Radical cystectomy (RC) is a complex oncological surgical procedure and population studies of routine surgical care have suggested suboptimal results compared to high-volume centers of excellence. A previous Canadian bladder cancer quality-of-care consensus led to adoption of multiple key quality-of-care indicators, with associated benchmarks created using available evidence and expert opinion to inform and measure future performance. Herein, we report real-life benchmark performance for the management of muscle-invasive bladder cancer (MIBC) relative to expert opinion guidance. METHODS: This is a population-based, retrospective, cohort study that used the Ontario Cancer Registry (OCR) to identify all incident patients who underwent RC from 2009-2013. Electronic records of treatment from 1573 patients were linked to OCR; pathology records were obtained for all cases and reviewed by a team of trained data abstractors. The primary objective was to describe benchmarks for identified indicators, first as median values obtained across hospitals or providers, as well as a "pared-mean" approach to identify a benchmark population of "top performance," as defined as the best outcome accomplished for at least 10% of the population. RESULTS: Overall, performance in Ontario across all indicators fell short of expert opinion-determined benchmarks. Annual surgical volume by each surgeon performing a RC (benchmark >6, percent of institutions meeting benchmark=20%), percent of patients with MIBC referred preoperatively to medical oncology (MO; benchmark>90%, percent of institutions meeting benchmark=2%) and radiation oncology (RO; benchmark>50%, percent of institutions meeting benchmark=0%), time to cystectomy within six weeks of transurethral resection of bladder tumor (TURBT) in patients without neoadjuvant chemotherapy (benchmark <6 weeks, percent of institutions meeting benchmark=0%), percent of patients with adequate lymph node dissection (defined as >14 nodes, benchmark>85%, percent of institutions meeting benchmark=0%), percent of patients with positive margins post-RC (benchmark <10%, percent of institutions meeting benchmark=46%), and 90-day mortality (benchmark<5%, percent of institutions meeting benchmark=37%) fell considerably short. Simply evaluating benchmarks across the province as median performance significantly underestimated benchmarks that were possible by top-performing hospitals. CONCLUSIONS: Performance through most bladder cancer quality-of-care indicators fall short of benchmarks proposed by expert opinion. Different methodologies, such as a paredmean approach of top performers, may provide more realistic benchmarking.

Transcription-Coupled Nucleotide Excision Repair and the Transcriptional Response to UV-Induced DNA Damage.

Ultraviolet (UV) irradiation and other genotoxic stresses induce bulky DNA lesions, which threaten genome stability and cell viability. Cells have evolved two main repair pathways to remove such lesions: global genome nucleotide excision repair (GG-NER) and transcription-coupled nucleotide excision repair (TC-NER). The modes by which these subpathways recognize DNA lesions are distinct, but they converge onto the same downstream steps for DNA repair. Here, we first summarize the current understanding of these repair mechanisms, specifically focusing on the roles of stalled RNA polymerase II, Cockayne syndrome protein B (CSB), CSA and UV-stimulated scaffold protein A (UVSSA) in TC-NER. We also discuss the intriguing role of protein ubiquitylation in this process. Additionally, we highlight key aspects of the effect of UV irradiation on transcription and describe the role of signaling cascades in orchestrating this response. Finally, we describe the pathogenic mechanisms underlying xeroderma pigmentosum and Cockayne syndrome, the two main diseases linked to mutations in NER factors.

The carbon footprint cost of travel to Canadian Urological Association conferences.

INTRODUCTION: Canadian Urological Association (CUA) conferences are held annually across Canada. Guests from across the world attended, contributing to the overall carbon footprint of the conference with their travel and accommodations. This study identified the carbon footprint of each of the 2016 (Vancouver), 2018 (Halifax), and 2019 (Quebec City) CUA conferences to investigate their carbon footprint and help determine the most eco-friendly location to hold future conferences. METHODS: Registrant home institution was used to estimate the distance and method of transportation of attendee travel. Carbon footprint was calculated using an online calculator in tons of CO2 equivalents (tCO2). Total attendees, number of attendees driving, number of attendees flying, mean distance travelled per attendee, total carbon footprint, and average carbon footprint per attendee were calculated for each conference. Mean carbon footprint, and mean distance travelled were compared using a Brown-Forsythe ANOVA test, with Dunnett's T3 multiple comparisons test (α=0.05). RESULTS: Vancouver had the largest number of attendees (n=473; 407 flying, 66 driving), followed by Halifax (n=382; 331 flying, 51 driving), and Quebec City (n=362; 265 flying, 97 driving). The mean distance attendees travelled was greatest for the Vancouver CUA (6041 km/roundtrip) compared to Quebec City (3096 km/roundtrip, p<0.0001) and Halifax (2985 km/roundtrip, p<0.0001). There was no difference in mean distance travelled between Halifax and Quebec City (p=0.95). The highest total carbon footprint was seen in Vancouver (tCO2=447.76), followed by Quebec City (tCO2=217.04) and Halifax (tCO2=182.22). The average footprint per attendee was significantly higher in Vancouver (mean tCO2=1.08) compared to both Quebec City (mean tCO2=0.62, p<0.0001) and Halifax (mean tCO2=0.52, p<0.0001). There was no difference in the average footprint between Halifax and Quebec City (p=0.63). CONCLUSIONS: The estimated emissions associated with the Vancouver CUA conference is greater than both the Halifax and Quebec City locations combined. In-person conferences provide several benefits to the urological community. Incorporating environmental considerations into conference planning, such as conference location, could reduce the CUA conference's overall carbon footprint, mitigating the contribution to rising temperatures and negative health outcomes.

Computational modeling of passive transport of functionalized nanoparticles.

Functionalized nanoparticles (NPs) are complex objects present in a variety of systems ranging from synthetic grafted nanoparticles to viruses. The morphology and number of the decorating groups can vary widely between systems. Thus, the modeling of functionalized NPs typically considers simplified spherical objects as a first-order approximation. At the nanoscale label, complex hydrodynamic interactions are expected to emerge as the morphological features of the particles change, and they can be further amplified when the NPs are confined or near walls. Direct estimation of these variations can be inferred via diffusion coefficients of the NPs. However, the evaluation of the coefficients requires an improved representation of the NPs morphology to reproduce important features hidden by simplified spherical models. Here, we characterize the passive transport of free and confined functionalized nanoparticles using the Rigid Multi-Blob (RMB) method. The main advantage of RMB is its versatility to approximate the mobility of complex structures at the nanoscale with significant accuracy and reduced computational cost. In particular, we investigate the effect of functional groups' distribution, size, and morphology over nanoparticle translational and rotational diffusion. We identify that the presence of functional groups significantly affects the rotational diffusion of the nanoparticles; moreover, the morphology of the groups and number induce characteristic mobility reduction compared to non-functionalized nanoparticles. Confined NPs also evidenced important alterations in their diffusivity, with distinctive signatures in the off-diagonal contributions of the rotational diffusion. These results can be exploited in various applications, including biomedical, polymer nanocomposite fabrication, drug delivery, and imaging.

Results in mediastinal lymph node staging of surgical lung cancer: Data from the prospective cohort of the Spanish Video-Assisted Thoracic Surgery Group.

OBJECTIVES: The objective of this study was to assess the diagnostic performance of combined computerised tomography (CT) and positron emission tomography (PET) in mediastinal staging of surgical lung cancer based on data obtained from the prospective cohort of the Spanish Group for Video-Assisted Thoracic Surgery (GEVATS). METHODS: A total of 2782 patients underwent surgery for primary lung carcinoma. We analysed diagnostic success in mediastinal lymph node staging (cN2) using CT and PET. Bivariate and multivariate analyses were performed of the factors involved in this success. The risk of unexpected pN2 disease was analysed for cases in which an invasive testing is recommended: cN1, the tumour centrally located or the tumour diameter >3 cm. RESULTS: The overall success of CT together with PET was 82.9% with a positive predictive value of 0.21 and negative predictive value of 0.93. If the tumour was larger than 3 cm and for each unit increase in mediastinal SUVmax, the probability of success was lower with OR 0.59 (0.44-0.79) and 0.71 (0.66-0.75), respectively. In the video-assisted thoracic surgery (VATS) approach, the probability of success was higher with OR 2.04 (1.52-2.73). The risk of unexpected pN2 increased with the risk factors cN1, the tumour centrally located or the tumour diameter >3 cm: from 4.5% (0 factors) to 18.8% (3 factors) but did not differ significantly as a function of whether invasive testing was performed. CONCLUSIONS: CT and PET together have a high negative predictive value. The overall success of the staging is lower in the case of tumours >3 cm and high mediastinal SUVmax, and it is higher when VATS is performed. The risk of unexpected pN2 is higher if the disease is cN1, the tumour centrally located or the tumour diameter >3 cm but does not vary significantly as a function of whether patients have undergone invasive testing.

A new chapter in an evolving pandemic: Successful pediatric liver transplantation with SARS-CoV-2+ donors.

BACKGROUND: Amid a viral pandemic with poorly understood transmissibility and pathogenicity in the pediatric patient, we report the first pediatric liver transplants utilizing allografts from SARS-CoV-2+ donors. METHODS: We describe the outcomes of two pediatric liver transplant recipients who received organs from SARS-CoV-2 nucleic acid test-positive (NAT+) donors. Data were obtained through the respective electronic medical record system and UNet DonorNet platform. RESULTS: The first donor was a 3-year-old boy succumbing to head trauma. One of four nasopharyngeal (NP) swabs and 1 of 3 bronchoalveolar lavage (BAL) NAT tests demonstrated SARS-CoV-2 infection before organ procurement. The second donor was a 16-month-old boy with cardiopulmonary arrest of unknown etiology. Three NAT tests (2 NP swab/1 BAL) prior to procurement failed to detect SARS-CoV-2. The diagnosis was made when the medical examiner repeated 2 NP swab NATs and an archive plasma NAT, all positive for SARS-CoV-2. Both 2-year-old recipients continue to do well 8 months post-transplant, with excellent graft function and no evidence of SARS-CoV-2 transmission. CONCLUSIONS: This is the first report to describe successful pediatric liver transplantation from SARS-CoV-2+ donors. These data reinforce the adult transplant experience and support the judicious use of SARS-CoV-2+ donors for liver transplantation in children. With SARS-CoV-2 becoming endemic, the concern for donor-derived viral transmission must now be weighed against the realized benefit of life-saving transplantation in the pediatric population as we continue to work toward donor pool maximization.

Doppler ultrasound for post-angioplasty follow-up in pediatric segmental branch renal artery stenosis: A case report.

INTRODUCTION: Segmental branch renal artery stenosis is an important cause of renovascular hypertension in the pediatric population that is often managed with angioplasty and may require imaging multiple times pre- and post-procedure. Gold standard imaging is angiography, which exposes children to radiation and intravenous contrast. There is not a clear guideline for imaging during follow-up, but patients are monitored for symptom recurrence, which could then trigger repeat imaging. The following case highlights a method of follow-up that has not been broadly studied that may offer benefits over clinical monitoring alone, and how interprofessional cooperation could offer effective surveillance and reassurance for families through a cost-effective method that minimizes potential for harm. CASE AND OUTCOMES: This report describes the clinical course of a child with hypertension secondary to segmental branch renal artery stenosis who was treated with angioplasty and who received follow-up imaging with renal Doppler ultrasound. This method allows the care team to ensure stability of the caliber of the repaired vessel and non-recurrence of stenosis at follow-ups through monitoring for intra-arterial velocity and waveform changes. DISCUSSION: Close follow-up of children with renal artery stenosis is vital following intervention due to high risk of recurrence. Clinical follow-up alone could be sufficient for some patients, however many still require CTA, sometimes even more than once, when symptoms worsen or there is evidence of end-organ damage. During follow-up, collaboration with skilled sonographers to monitor post-repair velocities and waveforms using Doppler ultrasound presents several possible advantages. This includes providing reassurance to patient families, minimizing harmful radiation and contrast exposure, and the potential for early detection of recurrence of stenosis. Especially in cooperative, older pediatric patients with a normal BMI who have a main renal artery stenosis or even in those with a segmental branch stenosis identified through CTA such as in this case. CONCLUSION: This case demonstrates how coordination with sonographers and the use of ultrasound with Doppler could improve the follow-up of pediatric patients with segmental branch renal artery stenosis post-angioplasty to provide further reassurance to families, minimize harm to patients, and ensure post-procedure stability beyond just clinical parameters.

Hydrodynamics of spike proteins dictate a transport-affinity competition for SARS-CoV-2 and other enveloped viruses.

Many viruses, such as SARS-CoV-2 or Influenza, possess envelopes decorated with surface proteins (a.k.a. spikes). Depending on the virus type, a large variability is present in the surface-proteins number, morphology and reactivity, which remains generally unexplained. Since viruses' transmissibility depends on features beyond their genetic sequence, new tools are required to discern the effects of spikes functionality, interaction, and morphology. Here, we postulate the relevance of hydrodynamic interactions in the viral infectivity of enveloped viruses and propose micro-rheological characterization as a platform for virus differentiation. To understand how the spikes affect virion mobility and infectivity, we investigate the diffusivity of spike-decorated structures using mesoscopic-hydrodynamic simulations. Furthermore, we explored the interplay between affinity and passive viral transport. Our results revealed that the diffusional mechanism of SARS-CoV-2 is strongly influenced by the size and distribution of its spikes. We propose and validate a universal mechanism to explain the link between optimal virion structure and maximal infectivity for many virus families.

Our evolution in the treatment of hepatic artery and portal vein thrombosis in pediatric liver transplantation: Success with catheter-directed therapies.

BACKGROUND: In pediatric liver transplant recipients, hepatic artery thrombosis and portal vein thrombosis are major causes of acute graft failure and mortality within 30 days of transplantation. There is, however, a strong possibility of graft salvage if flow can be re-established to reduce ischemic injury. The current standard treatment is surgical revascularization, and if unsuccessful, retransplantation. Due to our success in treating these complications with catheter-directed therapies, we sought to summarize and publish the outcomes of all patients who experienced hepatic artery thrombosis or portal vein thrombosis within 30 days of liver transplantation. METHODS: We conducted a retrospective cohort analysis of 27 pediatric liver transplant recipients who experienced hepatic artery thrombosis (n = 13), portal vein thrombosis (n = 9), or both (n = 5) between September 2012 and March 2021. We collected and tabulated data on the patients and therapies performed to treat them, including success rates, primary and secondary patency, and clinical outcomes. RESULTS: Among these patients, 6 were managed with anticoagulation and relisting for transplant and 21 had a primary revascularization attempt. Surgical recanalization was attempted in 7 patients of which 3 had successful recanalization (43%) and catheter-directed recanalization was attempted in 14 patients with 100% success in re-establishing blood flow to the graft. Additionally, patency was increased, and mortality was decreased in patients treated with catheter-directed recanalization compared to surgical revascularization or anticoagulation alone. CONCLUSION: This data illustrates the need to further investigate catheter-directed thrombolysis as a potential first-line treatment for postoperative HAT and PVT in pediatric liver transplant recipients.

COVID-19 Vaccine Efficacy and Immunogenicity in End-Stage Renal Disease Patients and Kidney Transplant Recipients.

Purpose of Review: To summarize the current literature with respect to COVID-19 vaccine efficacy patients with end-stage renal disease on dialysis and kidney transplant recipients. Recent Findings: Immunosuppressed patients are at greater risk of morbidity and mortality from COVID-19 infection. Patients with ESRD and KTR are immunosuppressed and mount a weaker antibody response to COVID-19 mRNA vaccination, and factors including immunosuppressant medications have been implicated for this weakened response. Third and fourth doses of vaccine doses have been shown to increase seropositivity and antibody production in kidney transplant recipients and patients on dialysis. Retrospective studies have demonstrated decreased mortality in vaccinated, immunosuppressed patients. Summary: ESRD and KTR patients have decreased antibody response to COVID-19 vaccines, but third and fourth doses have been shown to increase antibody production. Though a correlate of protection between antibody production and efficacy has yet to be fully established in this subset of the population, all US professional bodies who treat ESRD and KTR patients advocate for full vaccination against SARS-CoV-2 based on the data available. Studies demonstrating decreased mortality in vaccinated patients are promising on efficacy. Importantly, because KTR patients mount a weaker antibody response than ESRD patients, vaccination prior to kidney transplantation is critical.

External validation of the European Society of Thoracic Surgeons morbidity and mortality risk models.

OBJECTIVES: There is a wide variety of predictive models of postoperative risk, although some of them are specific to thoracic surgery, none of them is widely used. The European Society for Thoracic Surgery has recently updated its models of cardiopulmonary morbidity (Eurolung 1) and 30-day mortality (Eurolung 2) after anatomic lung resection. The aim of our work is to carry out the external validation of both models in a multicentre national database. METHODS: External validation of Eurolung 1 and Eurolung 2 was evaluated through calibration (calibration plot, Brier score and Hosmer-Lemeshow test) and discrimination [area under receiver operating characteristic curves (AUC ROC)], on a national multicentre database of 2858 patients undergoing anatomic lung resection between 2016 and 2018. RESULTS: For Eurolung 1, calibration plot showed suboptimal overlapping (slope = 0.921) and a Hosmer-Lemeshow test and Brier score of P = 0.353 and 0.104, respectively. In terms of discrimination, AUC ROC for Eurolung 1 was 0.653 (95% confidence interval, 0.623-0.684). In contrast, Eurolung 2 showed a good calibration (slope = 1.038) and a Hosmer-Lemeshow test and Brier score of P = 0.234 and 0.020, respectively. AUC ROC for Eurolung 2 was 0.760 (95% confidence interval, 0.701-0.819). CONCLUSIONS: Thirty-day mortality score (Eurolung 2) seems to be transportable to other anatomic lung-resected patients. On the other hand, postoperative cardiopulmonary morbidity score (Eurolung 1) seems not to have sufficient generalizability for new patients.

Surgical Risk Following Anatomic Lung Resection in Thoracic Surgery: A Prediction Model Derived from a Spanish Multicenter Database. / Riesgo quirúrgico tras resección pulmonar anatómica en cirugía torácica. Modelo predictivo a partir de una base de datos nacional multicéntrica.

INTRODUCTION: The aim of this study was to develop a surgical risk prediction model in patients undergoing anatomic lung resections from the registry of the Spanish Video-Assisted Thoracic Surgery Group (GEVATS). METHODS: Data were collected from 3,533 patients undergoing anatomic lung resection for any diagnosis between December 20, 2016 and March 20, 2018. We defined a combined outcome variable: death or Clavien Dindo grade IV complication at 90 days after surgery. Univariate and multivariate analyses were performed by logistic regression. Internal validation of the model was performed using resampling techniques. RESULTS: The incidence of the outcome variable was 4.29% (95% CI 3.6-4.9). The variables remaining in the final logistic model were: age, sex, previous lung cancer resection, dyspnea (mMRC), right pneumonectomy, and ppo DLCO. The performance parameters of the model adjusted by resampling were: C-statistic 0.712 (95% CI 0.648-0.750), Brier score 0.042 and bootstrap shrinkage 0.854. CONCLUSIONS: The risk prediction model obtained from the GEVATS database is a simple, valid, and reliable model that is a useful tool for establishing the risk of a patient undergoing anatomic lung resection.

Assessing geographic and industry-related trends in bladder cancer in Ontario: A population-based study.

INTRODUCTION: Bladder cancer (BC) is the fifth most prevalent cancer in Canada, with 9000 Canadians diagnosed each year. While smoking is the most important risk factor, environmental and occupational carcinogens have been found to significantly contribute to BC rates. As Canada is highly reliant on natural resource industries, this study seeks to identify geographical and industry-related trends of BC rates in Ontario. METHODS: The 1991 and 2001 Canadian Census Health and Environment Cohort (CanCHEC; Statistics Canada) was used, along with individual years of census data. Maps identifying hot and cold spots for BC within Ontario were generated, and the former were assessed for industry patterns between location and BC rates. Cox proportional hazards models were run for each age cohort to predict the likelihood of developing BC by industry of work. RESULTS: Significant geographical and industrial trends in BC rates were identified. For 1991-2001, hot spots included the Cochrane, Manitoulin, Parry Sound, and Sudbury (90% confidence interval [CI]), and Nipissing and Temiskaming (95% CI) regions. Toronto and York were cold spots. Concurrently, metal (p=0.039), paper and publishing (p=0.0062), and wood and furniture (p<0.0001) industries had increased rates of BC. Notably, these industries had high employment density in our hot spot areas and low density in our cold spots. CONCLUSIONS: Significant geographical and industrial BC trends were found in Northern Ontario regions reliant on heavy employment in natural resource-based industries, such as forestry, agriculture, and wood/paper. These findings may inform future screening guidelines and aid in identifying individuals at risk of BC development.

Management of Acute Portal Vein Thrombosis With Serial Mechanical Thrombectomy and tPA in a Pediatric Liver Transplant Recipient: A Case Report.

BACKGROUND: Acute portal vein thrombosis is a major cause of fulminant allograft failure in pediatric liver transplantation. Timely intervention is critical to save the graft and patient. Serial interventional radiologic management of this condition is scarcely reported in the literature. CASE SUMMARY: A recently transplanted 17-year-old male presented to the emergency department with abdominal pain. Rising liver enzymes prompted discovery of a diffuse portal thrombus, which precipitated fulminant liver failure. The adolescent developed respiratory failure, vasodilatory shock, acute kidney injury, and hepatic encephalopathy, complicating treatment. Multiple interventions attempted to clear the thrombus, including interventional radiologic and medical therapies. Uniquely, a continuous infusion catheter was placed at the thrombosis, delivering local tissue plasminogen activator during a 5-day period. Upon thrombus clearance, the patient made a full recovery with no complications during 12 months of follow-up. CONCLUSIONS: When used as a component of multidisciplinary management, continuous locally directed tissue plasminogen activator may be a useful tool for clearance of persistent portal vein thrombosis.

Chitinase 3-like-1 contributes to acetaminophen-induced liver injury by promoting hepatic platelet recruitment.

Background: Hepatic platelet accumulation contributes to acetaminophen (APAP)-induced liver injury (AILI). However, little is known about the molecular pathways involved in platelet recruitment to the liver and whether targeting such pathways could attenuate AILI. Methods: Mice were fasted overnight before intraperitoneally (i.p.) injected with APAP at a dose of 210 mg/kg for male mice and 325 mg/kg for female mice. Platelets adherent to Kupffer cells were determined in both mice and patients overdosed with APAP. The impact of α-chitinase 3-like-1 (α-Chi3l1) on alleviation of AILI was determined in a therapeutic setting, and liver injury was analyzed. Results: The present study unveiled a critical role of Chi3l1 in hepatic platelet recruitment during AILI. Increased Chi3l1 and platelets in the liver were observed in patients and mice overdosed with APAP. Compared to wild-type (WT) mice, Chil1-/- mice developed attenuated AILI with markedly reduced hepatic platelet accumulation. Mechanistic studies revealed that Chi3l1 signaled through CD44 on macrophages to induce podoplanin expression, which mediated platelet recruitment through C-type lectin-like receptor 2. Moreover, APAP treatment of Cd44-/- mice resulted in much lower numbers of hepatic platelets and liver injury than WT mice, a phenotype similar to that in Chil1-/- mice. Recombinant Chi3l1 could restore hepatic platelet accumulation and AILI in Chil1-/- mice, but not in Cd44-/- mice. Importantly, we generated anti-Chi3l1 monoclonal antibodies and demonstrated that they could effectively inhibit hepatic platelet accumulation and AILI. Conclusions: We uncovered the Chi3l1/CD44 axis as a critical pathway mediating APAP-induced hepatic platelet recruitment and tissue injury. We demonstrated the feasibility and potential of targeting Chi3l1 to treat AILI. Funding: ZS received funding from NSFC (32071129). FWL received funding from NIH (GM123261). ALFSG received funding from NIDDK (DK 058369). ZA received funding from CPRIT (RP150551 and RP190561) and the Welch Foundation (AU-0042-20030616). CJ received funding from NIH (DK122708, DK109574, DK121330, and DK122796) and support from a University of Texas System Translational STARs award. Portions of this work were supported with resources and the use of facilities of the Michael E. DeBakey VA Medical Center and funding from Department of Veterans Affairs I01 BX002551 (Equipment, Personnel, Supplies). The contents do not represent the views of the US Department of Veterans Affairs or the US Government.

Acetaminophen, also called paracetamol outside the United States, is a commonly used painkiller, with over 50 million people in the United States taking the drug weekly. While paracetamol is safe at standard doses, overdose can cause acute liver failure, which leads to 30,000 patients being admitted to emergency care in the United States each year. There is only one approved antidote to overdoses, which becomes significantly less effective if its application is delayed by more than a few hours. This has incentivized research into identify new drug targets that could lead to additional treatment options. Acetaminophen overdose triggers blood clotting and inflammation, contributing to liver injury. It also causes a decrease in cells called platelets circulating in the blood, which has been observed in both mice and humans. In mice, this occurs because platelets accumulate in the liver. Removing these excess cells appears to reduce the severity of the damage caused by acetaminophen, but it remains unclear how the drug triggers their accumulation in the liver. In 2018, researchers showed that a protein called Chi3l1 plays an important role in another form of liver damage. Shan et al. ­ including many of the researchers involved in the 2018 study ­ have examined whether the protein also contributes to acetaminophen damage in the liver. Shan et al. showed that mice lacking the gene that codes for Chi3l1 developed less severe liver injury and had fewer platelets in the liver following acetaminophen overdose. They also found that human patients with acute liver failure due to acetaminophen had high levels of Chi3l1 and significant accumulation of platelets in the liver. To test whether damage could be prevented, Shan et al. used antibodies to neutralize Chi3l1 in mice after giving them an acetaminophen overdose. This reduced platelet accumulation in the liver and the associated damage. These findings suggest that targeting Chi3l1 may be an effective strategy to prevent liver damage caused by acetaminophen overdose. Further research could help develop new treatments for acetaminophen-induced liver injury and perhaps other liver conditions.