What Is Hot and New in Basic and Translational Science in Liver Transplantation in 2023? Report of the Basic and Translational Research Committee of the International Liver Transplantation Society.

The 2023 Joint Annual Congress of the International Liver Transplantation Society, European Liver and Intestine Transplant Association, and Liver Intensive Care Group of Europe were held in Rotterdam, the Netherlands, from May 3 to 6, 2023. This year, all speakers were invited to attend the Congress in person for the first time since the COVID-19 pandemic. The congress was attended by 1159 registered delegates from 54 countries representing 5 continents, with the 10 countries comprising the bulk of the delegates. Of the 647 abstracts initially submitted, 542 were eventually presented at the meeting, coming from 38 countries (mainly North America, Europe, and Asia) and 85% of them (462 abstracts) came from only 10 countries. Fifty-three (9.8%) abstracts, originated from 17 countries, were submitted under the Basic/Translational Scientific Research category, a similar percentage as in 2022. Abstracts presented at the meeting were classified as (1) ischemia and reperfusion injury, (2) machine perfusion, (3) bioengineering and liver regeneration, (4) transplant oncology, (5) novel biomarkers in liver transplantation, (6) liver immunology (rejection and tolerance), and (7) artificial intelligence and machine learning. Finally, we evaluated the number of abstracts commented in the Basic and Translational Research Committee-International Liver Transplantation Society annual reports over the past 5 y that resulted in publications in peer-reviewed journals to measure their scientific impact in the field of liver transplantation.

Portal vein thrombosis and liver transplantation: management, matching, and outcomes. A retrospective multicenter cohort study.

BACKGROUND AND AIMS: Besides the increased risk of perioperative morbidity, graft failure, and mortality, the majority of PVT are diagnosed at liver transplantation (LT). Improving preoperative management and patient selection may lead to better short-term and long-term outcomes and reduce the risk of a futile LT. The authors aimed to identify predictors of adverse outcomes after LT in patients with nonmalignant portal vein thrombosis (PVT) and improve donor to recipient matching by analyzing the results of the Italian cohort of LT recipients. METHODS: Adult patients who underwent LT in Italy between January 2000 and February 2020 diagnosed with PVT pre-LT or at time of LT were considered eligible for inclusion. Based on a survey encompassing all 26 surgeons participating in the study, a binary composite outcome was defined. Patients were classified as having the composite event if at least one of these conditions occurred: operative time more than 600 min, estimated blood loss greater than 5000 ml, more than 20 ICU days, 90 days mortality, 90 days retransplant. RESULTS: Seven hundred fourteen patients were screened and 698 met the inclusion criteria. The analysis reports the results of 568 patients that fulfilled the criteria to enter the composite outcome analysis.Overall, 156 patients (27.5%) developed the composite outcome. PVT stage 3/4 at transplant and need for any surgical correction of PVT are independent predictors of the composite outcome occurrence. When stratified by PVT grade, overall survival at 1-year ranges from 89.0% with PVT grade 0/1 to 67.4% in patients with PVT grade 3/4 at LT ( P <0.001). Nevertheless, patients with severe PVT can improve their survival when identified risk factors are not present. CONCLUSIONS: Potential LT candidates affected by PVT have a benefit from LT that should be adequately balanced on liver function and type of inflow reconstruction needed to mitigate the incidence of adverse events. Nonetheless, the absence of specific risk factors may improve the outcomes even in patients with PVT grades 3-4.

Recipient hepatectomy technique may affect oncological outcomes of liver transplantation for hepatocellular carcinoma.

To date, caval sparing (CS) and total caval replacement (TCR) for recipient hepatectomy in liver transplantation (LT) have been compared only in terms of surgical morbidity. Nonetheless, the CS technique is inherently associated with an increased manipulation of the native liver and later exclusion of the venous outflow, which may increase the risk of intraoperative shedding of tumor cells when LT is performed for HCC. A multicenter, retrospective study was performed to assess the impact of recipient hepatectomy (CS vs. TCR) on the risk of posttransplant HCC recurrence among 16 European transplant centers that used either TCR or CS recipient hepatectomy as an elective protocol technique. Exclusion criteria comprised cases of non-center-protocol recipient hepatectomy technique, living-donor LT, HCC diagnosis suspected on preoperative imaging but not confirmed at the pathological examination of the explanted liver, HCC in close contact with the IVC, and previous liver resection for HCC. In 2420 patients, CS and TCR approaches were used in 1452 (60%) and 968 (40%) cases, respectively. Group adjustment with inverse probability weighting was performed for high-volume center, recipient age, alcohol abuse, viral hepatitis, Child-Pugh class C, Model for End-Stage Liver Disease score, cold ischemia time, clinical HCC stage within Milan criteria, pre-LT downstaging/bridging therapies, pre-LT alphafetoprotein serum levels, number and size of tumor nodules, microvascular invasion, and complete necrosis of all tumor nodules (matched cohort, TCR, n = 938; CS, n = 935). In a multivariate cause-specific hazard model, CS was associated with a higher risk of HCC recurrence (HR: 1.536, p = 0.007). In conclusion, TCR recipient hepatectomy, compared to the CS approach, may be associated with some protective effect against post-LT tumor recurrence.

Twelve-hour normothermic liver perfusion in a rat model: characterization of the changes in the ex-situ bio-molecular phenotype and metabolism.

The partial understanding of the biological events that occur during normothermic machine perfusion (NMP) and particularly during prolonged perfusion might hinder its deployment in clinical transplantation. The aim of our study was to implement a rat model of prolonged NMP to characterize the bio-molecular phenotype and metabolism of the perfused organs. Livers (n = 5/group) were procured and underwent 4 h (NMP4h) or 12 h (NMP12h) NMP, respectively, using a perfusion fluid supplemented with an acellular oxygen carrier. Organs that were not exposed to any procedure served as controls (Native). All perfused organs met clinically derived viability criteria at the end of NMP. Factors related to stress-response and survival were increased after prolonged perfusion. No signs of oxidative damage were detected in both NMP groups. Evaluation of metabolite profiles showed preserved mitochondrial function, activation of Cori cycle, induction of lipolysis, acetogenesis and ketogenesis in livers exposed to 12 h-NMP. Increased concentrations of metabolites involved in glycogen synthesis, glucuronidation, bile acid conjugation, and antioxidant response were likewise observed. In conclusion, our NMP12h model was able to sustain liver viability and function, thereby deeply changing cell homeostasis to maintain a newly developed equilibrium. Our findings provide valuable information for the implementation of optimized protocols for prolonged NMP.

Impact of Pre-Liver Transplant Treatments on the Imaging Accuracy of HCC Staging and Their Influence on Outcomes.

The outcome of liver transplantation (LT) for hepatocarcinoma (HCC) is strongly influenced by HCC staging, which is based on radiological examinations in a pre-LT setting; concordance between pre-LT radiological and definitive pathological staging remains controversial. To address this issue, we retrospectively analyzed our LT series to assess concordance between radiology and pathology and to explore the factors associated with poor concordance and outcomes. We included all LTs with an HCC diagnosis performed between 2013 and 2018. Concordance (Co group) was defined as a comparable tumor burden in preoperative imaging and post-transplant pathology; otherwise, non-concordance was diagnosed (nCo group). Concordance between radiology and pathology was observed in 32/134 patients (Co group, 24%). The number and diameter of the nodules were higher when nCo was diagnosed, as was the number of pre-LT treatments. Although concordance did not affect survival, more than three pre-LT treatments led to a lower disease-free survival. Patients who met the Milan Criteria (Milan-in patients) were more likely to receive ≥three prior treatments, leading to a lower survival in multi-treated Milan-in patients than in other Milan-in patients. In conclusion, the concordance rate between the pre-LT imaging and histopathological results was low in patients with a high number of nodules. Multiple bridging therapies reduce the accuracy of pre-LT imaging in predicting HCC stages and negatively affect outcomes after LT.

Portal hypertension-like pattern in coronavirus disease 2019 acute respiratory distress syndrome.

OBJECTIVES: Although respiratory failure is the most common feature in coronavirus disease 2019 (COVID-19), abdominal organ involvement is likewise frequently observed. To investigate visceral and thoracic circulation and abdominal organ damage in COVID-19 patients. MATERIALS AND METHODS: A monocentric observational study was carried on. In COVID-19 patients affected by acute respiratory distress syndrome (ARDS) (n = 31) or mild pneumonia (n = 60) thoracoabdominal circulation was evaluated using Doppler-ultrasound and computed tomography. The study also included non-COVID-19 patients affected by ARDS (n = 10) or portal hypertension (n = 10) for comparison of the main circulatory changes. RESULTS: Patients affected by COVID-19 ARDS showed hyperdynamic visceral flow and increased portal velocity, hepatic artery resistance-index, and spleen diameter relative to those with mild-pneumonia (p = 0.001). Splanchnic circulatory parameters significantly correlated with the main respiratory indexes (p < 0.001) and pulmonary artery diameter (p = 0.02). The chest and abdominal vascular remodeling pattern of COVID-19 ARDS patients resembled the picture observed in the PH group, while differed from that of the non-COVID ARDS group. A more severe COVID-19 presentation was associated with worse liver dysfunction and enhanced inflammatory activation; these parameters both correlated with abdominal (p = 0.04) and chest imaging measures (p = 0.03). CONCLUSION: In COVID-19 ARDS patients there are abdominal and lung vascular modifications that depict a portal hypertension-like pattern. The correlation between visceral vascular remodeling, pulmonary artery enlargement, and organ damage in these critically ill patients is consistent with a portal hyperlfow-like syndrome that could contribute to the peculiar characteristics of respiratory failure in these patients. CLINICAL RELEVANCE STATEMENT: our data suggest that the severity of COVID-19 lung involvement is directly related to the development of a portal hyperflow-like syndrome. These observations should help in defining the need for a closer monitoring, but also to develop dedicated therapeutic strategies.

Machine perfusion of the liver and in vivo animal models: A systematic review of the preclinical research landscape.

Machine perfusion (MP) is often referred to as one of the most promising advancements in liver transplantation research of the last few decades, with various techniques and modalities being evaluated in preclinical studies using animal models. However, low scientific rigor and subpar reporting standards lead to limited reproducibility and translational potential, hindering progress. This pre-registered systematic review (PROSPERO: CRD42021234667) aimed to provide a thematic overview of the preclinical research landscape on MP in liver transplantation using in vivo transplantation models and to explore methodological and reporting standards, using the ARRIVE (Animal Research: Reporting of In Vivo Experiments) score. In total 56 articles were included. Studies were evenly distributed across Asia, Europe, and the Americas. Porcine models were used in 57.1% of the studies, followed by rats (39.3%) and dogs (3.6%). In terms of graft type, 55.4% of the studies used donation after cardiac death grafts, while donation after brain death grafts accounted for 37.5%. Regarding MP modalities, the distribution was as follows: 41.5% of articles utilized hypothermic MP, 21.5% normothermic MP, 13.8% subnormothermic MP, and 16.9% utilized hypothermic oxygenated MP. The stringent documentation of ARRIVE elements concerning precise experimental execution, group size and selection, the choice of statistical methods, as well as adherence to the principles of the 3Rs, was notably lacking in the majority of publications, with less than 30% providing comprehensive details. Postoperative analgesia and antibiotics treatment were not documented in 82.1% of all included studies. None of the analyzed studies fully adhered to the ARRIVE Guidelines. In conclusion, the present study emphasizes the importance of adhering to reporting standards to promote reproducibility and adequate animal welfare in preclinical studies in machine perfusion. At the same time, it highlights a clear deficiency in this field, underscoring the need for further investigations into animal welfare-related topics.

Mitochondrial injury during normothermic regional perfusion (NRP) and hypothermic oxygenated perfusion (HOPE) in a rodent model of DCD liver transplantation.

BACKGROUND: Normothermic regional perfusion (NRP) and hypothermic-oxygenated-perfusion (HOPE), were both shown to improve outcomes after liver transplantation from donors after circulatory death (DCD). Comparative clinical and mechanistical studies are however lacking. METHODS: A rodent model of NRP and HOPE, both in the donor, was developed. Following asystolic donor warm ischemia time (DWIT), the abdominal compartment was perfused either with a donor-blood-based-perfusate at 37 °C (NRP) or with oxygenated Belzer-MPS at 10 °C (donor-HOPE) for 2 h. Livers were then procured and underwent 5 h static cold storage (CS), followed by transplantation. Un-perfused and HOPE-treated DCD-livers (after CS) and healthy livers (DBD) with direct implantation after NRP served as controls. Endpoints included the entire spectrum of ischemia-reperfusion-injury. FINDINGS: Healthy control livers (DBD) showed minimal signs of inflammation during 2 h NRP and achieved 100% posttransplant recipient survival. In contrast, DCD livers with 30 and 60 min DWIT suffered from greater mitochondrial injury and inflammation as measured by increased perfusate Lactate, FMN- and HMGB-1-levels with subsequent Toll-like-receptor activation during NRP. In contrast, donor-HOPE (instead of NRP) led to significantly less mitochondrial-complex-I-injury and inflammation. Results after donor-HOPE were comparable to ex-situ HOPE after CS. Most DCD-liver recipients survived when treated with one HOPE-technique (86%), compared to only 40% after NRP (p = 0.0053). Following a reduction of DWIT (15 min), DCD liver recipients achieved comparable survivals with NRP (80%). INTERPRETATION: High-risk DCD livers benefit more from HOPE-treatment, either immediately in the donor or after cold storage. Comparative prospective clinical studies are required to translate the results. FUNDING: Funding was provided by the Swiss National Science Foundation (grant no: 32003B-140776/1, 3200B-153012/1, 320030-189055/1, and 31IC30-166909) and supported by University Careggi (grant no 32003B-140776/1) and the OTT (grant No.: DRGT641/2019, cod.prog. 19CT03) and the Max Planck Society. Work in the A.G. laboratory was partially supported by the NIH R01NS112381 and R21NS125466 grants.

Interaction between estrogen receptor-α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women.

Fatty liver disease (FLD) caused by metabolic dysfunction is the leading cause of liver disease and the prevalence is rising, especially in women. Although during reproductive age women are protected against FLD, for still unknown and understudied reasons some develop rapidly progressive disease at the menopause. The patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M variant accounts for the largest fraction of inherited FLD variability. In the present study, we show that there is a specific multiplicative interaction between female sex and PNPLA3 p.I148M in determining FLD in at-risk individuals (steatosis and fibrosis, P < 10-10; advanced fibrosis/hepatocellular carcinoma, P = 0.034) and in the general population (P < 10-7 for alanine transaminase levels). In individuals with obesity, hepatic PNPLA3 expression was higher in women than in men (P = 0.007) and in mice correlated with estrogen levels. In human hepatocytes and liver organoids, PNPLA3 was induced by estrogen receptor-α (ER-α) agonists. By chromatin immunoprecipitation and luciferase assays, we identified and characterized an ER-α-binding site within a PNPLA3 enhancer and demonstrated via CRISPR-Cas9 genome editing that this sequence drives PNPLA3 p.I148M upregulation, leading to lipid droplet accumulation and fibrogenesis in three-dimensional multilineage spheroids with stellate cells. These data suggest that a functional interaction between ER-α and PNPLA3 p.I148M variant contributes to FLD in women.

Perfusion fluid-related infections in liver transplant recipients: A 5-year, single-center, retrospective study.

BACKGROUND: Perfusion fluid (PRF) is employed in liver transplantation (LTx) to maintain graft viability. Still, it represents a new potential way of infection transmission in LTx recipients (LTRs). Currently, no systematic research has investigated this topic. METHODS: Five-year single-center retrospective study conducted on LTRs from January 2017 to December 2021. We analyzed the incidence of positive PRF culture (PRF+) and perfusion fluid-related infections (PRF-RI) and their associated factors. We also assessed 1-year mortality, both overall and infection-related. RESULTS: Overall, 234 LTx were included. PRF+ were found in 31/234 (13.2%) LTx for a total of 37 isolates, with >1 isolate identified in 5 (2.1%) cases. High-risk microorganisms (Enterobacterales 13/37, Enterococcus spp. 4/37, S. aureus 3/37, P. aeruginosa 2/37) were isolated in 25/37 (67.6%) LTRs, the remaining being coagulase-negative staphylococci (12/37, 32.4%). Antimicrobial prophylaxis was administered to all LTRs, always active against the isolate even if suboptimal in 19 cases (61.3%). PRF-RI developed in 4/234 LTx (1.7%), and prophylaxis was considered suboptimal in 2/4 of them. The isolation of >1 microorganism in PRF culture was associated with an increased risk of developing PRF-RI (OR 37.5 [95%CI 2.6-548.4], p = .01). PRF-RI were associated with longer ICU stays (p = .005) and higher 1-year mortality, both overall and related to infections (p = .001). CONCLUSION: Despite PRF+ being infrequent, only a minority of patients develops PRF-RI. Nonetheless, once occurred, PRF-RI seems to increase morbidity and mortality rates.

Trends and Obstacles to Implement Dynamic Perfusion Concepts for Clinical Liver Transplantation: Results from a Global Web-Based Survey.

BACKGROUND: Organ perfusion technology is increasingly used in many countries, with a focus, however, on the Western world. This study investigates the current international trends and obstacles to the broader routine implementation of dynamic perfusion concepts in liver transplantation. METHODS: A web-based anonymous survey was launched in 2021. Experts of all involved specializations from 70 centers in 34 countries were contacted, based on the published literature and experience in the field of abdominal organ perfusion. RESULTS: Overall, 143 participants from 23 countries completed the survey. Most respondents were male (67.8%) and transplant surgeons (64.3%) working at university hospitals (67.9%). The majority had experience with organ perfusion (82%), applying mainly hypothermic machine perfusion (HMP; 38%) and other concepts. While most (94.4%) expect a higher utilization of marginal organs with machine perfusion, the majority considers HMP the best technique to reduce liver discard-rates. While most respondents (90%) believed machine perfusion should be fully commissioned, the lack of funding (34%) and knowledge (16%) as well as limited staff (19%) were the three main obstacles to a routine clinical implementation. CONCLUSION: Although dynamic preservation concepts are increasingly used in clinical practice, significant challenges remain. Specific financial pathways, uniform regulations, and tight collaborations among involved experts are needed to achieve wider global clinical use.

Machine perfusion techniques for liver transplantation - A meta-analysis of the first seven randomized-controlled trials.

BACKGROUND & AIMS: Machine perfusion is increasingly being tested in clinical transplantation. Despite this, the number of large prospective clinical trials remains limited. The aim of this study was to compare the impact of machine perfusion vs. static cold storage (SCS) on outcomes after liver transplantation. METHODS: A systematic search of MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted to identify randomized-controlled trials (RCTs) comparing "post-transplant" outcomes following machine perfusion vs. SCS. Data were pooled using random effect models. Risk ratios (RRs) were calculated for relevant outcomes. The quality of evidence was rated using the GRADE-framework. RESULTS: Seven RCTs were identified (four on hypothermic oxygenated [HOPE] and three on normothermic machine perfusion [NMP]), including a total number of 1,017 patients. Both techniques were associated with significantly lower rates of early allograft dysfunction (NMP: n = 41/282, SCS: n = 74/253, RR 0.50, 95% CI 0.30-0.86, p = 0.01, I2 = 39%; HOPE: n = 45/241, SCS: n = 97/241, RR 0.48, 95% CI 0.35-0.65, p < 0.00001, I2 = 5%). The HOPE approach led to a significant reduction in major complications (Clavien Grade ≥IIIb; HOPE: n = 90/241; SCS: n = 117/241, RR 0.76, 95% CI 0.63-0.93, p = 0.006, I2 = 0%), "re-transplantation" (HOPE: n = 1/163; SCS: n = 11/163; RR 0.21, 95% CI 0.04-0.96, p = 0.04; I2 = 0%) and graft loss (HOPE: n = 7/163; SCS: n = 19/163; RR 0.40, 95% CI 0.17-0.95, p = 0.04; I2 = 0%). Both perfusion techniques were found to 'likely' reduce overall biliary complications and non-anastomotic strictures. CONCLUSIONS: Although this study provides the highest current evidence on the role of machine perfusion, outcomes remain limited to a 1-year follow-up after liver transplantation. Comparative RCTs and large real-world cohort studies with longer follow-up are required to enhance the robustness of the data further, thereby supporting the introduction of perfusion technologies into routine clinical practice. PROSPERO-REGISTRATION: CRD42022355252. IMPACT AND IMPLICATIONS: For a decade, two dynamic perfusion concepts have increasingly been tested in several transplant centres worldwide. We undertook the first systematic review and meta-analysis and identified seven published RCTs, including 1,017 patients, evaluating the effect of machine perfusion (hypothermic and normothermic perfusion techniques) compared to static cold storage in liver transplantation. Both perfusion techniques were associated with lower rates of early allograft dysfunction in the first week after liver transplantation. Hypothermic oxygenated perfusion led to a reduction in major complications, lower "re-transplantation" rates and better graft survival. Both perfusion strategies were found to 'likely' reduce overall biliary complications and non-anastomotic biliary strictures. This study provides the highest current evidence on the role of machine perfusion. Outcomes remain limited to a 1-year post-transplant follow-up. Larger cohort studies with longer follow-up and clinical trials comparing the perfusion techniques are required. This is especially relevant to provide clarity and optimise implementation processes further to support the commissioning of this technology worldwide.

Enhanced extracorporeal carbon dioxide removal by acidification and metabolic control.

BACKGROUND: Extracorporeal carbon dioxide removal (ECCO2R) promotes protective ventilation in patients with acute respiratory failure, but devices with high CO2 extraction capacity are required for clinically relevant impact. This study evaluates three novel low-flow techniques based on dialysate acidification, also combined with renal replacement therapy, and metabolic control. METHODS: Eight swine were connected to a low-flow (350 mL/min) extracorporeal circuit including a dialyzer with a closed-loop dialysate circuit, and two membrane lungs on blood (MLb) and dialysate (MLd), respectively. The following 2-hour steps were performed: 1) MLb-start (MLb ventilated); 2) MLbd-start (MLb and MLd ventilated); 3) HLac (lactic acid infusion before MLd); 4) HCl-NaLac (hydrochloric acid infusion before MLd combined with renal replacement therapy and reinfusion of sodium lactate); 5) HCl-ßHB-NaLac (hydrochloric acid infusion before MLd combined with renal replacement therapy and reinfusion of sodium lactate and sodium 3-hydroxybutyrate). Caloric and fluid inputs, temperature, blood glucose and arterial carbon dioxide pressure were kept constant. RESULTS: The total MLs CO2 removal in HLac (130±25 mL/min), HCl-NaLac (130±21 mL/min) and HCl-ßHB-NaLac (124±18 mL/min) were higher compared with MLbd-start (81±15 mL/min, P<0.05) and MLb-start (55±7 mL/min, P<0.05). Minute ventilation in HLac (4.3±0.9 L/min), HCl-NaLac (3.6±0.8 L/min) and HCl-ßHB-NaLac (3.6±0.8 L/min) were lower compared to MLb-start (6.2±1.1 L/min, P<0.05) and MLbd-start (5.8±2.1 L/min, P<0.05). Arterial pH was 7.40±0.03 at MLb-start and decreased only during HCl-ßHB-NaLac (7.35±0.03, P<0.05). No relevant changes in electrolyte concentrations, hemodynamics and significant adverse events were detected. CONCLUSIONS: The three techniques achieved a significant extracorporeal CO2 removal allowing a relevant reduction in minute ventilation with a sufficient safety profile.

Utilization of livers donated after circulatory death for transplantation - An international comparison.

BACKGROUND & AIMS: Liver graft utilization rates are a hot topic due to the worldwide organ shortage and the increasing number of transplant candidates on waiting lists. Liver perfusion techniques have been introduced in several countries, and may help to increase the organ supply, as they potentially enable the assessment of livers before use. METHODS: Liver offers were counted from donation after circulatory death (DCD) donors (Maastricht type III) arising during the past decade in eight countries, including Belgium, France, Italy, the Netherlands, Spain, Switzerland, the UK, and the US. Initial type-III DCD liver offers were correlated with accepted, recovered and implanted livers. RESULTS: A total number of 34,269 DCD livers were offered, resulting in 9,780 liver transplants (28.5%). The discard rates were highest in the UK and US, ranging between 70 and 80%. In contrast, much lower DCD liver discard rates, e.g. between 30-40%, were found in Belgium, France, Italy, Spain and Switzerland. In addition, we observed large differences in the use of various machine perfusion techniques, as well as in graft and donor risk factors. For example, the median donor age and functional donor warm ischemia time were highest in Italy, e.g. >40 min, followed by Switzerland, France, and the Netherlands. Importantly, such varying risk profiles of accepted DCD livers between countries did not translate into large differences in 5-year graft survival rates, which ranged between 60-82% in this analysis. CONCLUSIONS: Overall, DCD liver discard rates across the eight countries were high, although this primarily reflects the situation in the Netherlands, the UK and the US. Countries where in situ and ex situ machine perfusion strategies were used routinely had better DCD utilization rates without compromised outcomes. IMPACT AND IMPLICATIONS: A significant number of Maastricht type III DCD livers are discarded across Europe and North America today. The overall utilization rate among eight Western countries is 28.5% but varies significantly between 18.9% and 74.2%. For example, the median DCD-III liver utilization in five countries, e.g. Belgium, France, Italy, Switzerland, and Spain is 65%, in contrast to 24% in the Netherlands, UK and US. Despite this, and despite different rules and strategies for organ acceptance and preservation, 1- and 5-year graft survival rates remain fairly similar among all participating countries. A highly varying experience with modern machine perfusion technology was observed. In situ and ex situ liver perfusion concepts, and application of assessment tools for type-III DCD livers before transplantation, may be a key explanation for the observed differences in DCD-III utilization.

Comprehensive management of paranasal sinus fungus balls: A Young-IFOS consensus statement.

BACKGROUND: Paranasal sinus fungus balls (PSFB) are a common form of surgically treatable, noninvasive mycosis. To date, no guidelines have standardized PSFB treatment or management of difficult cases (eg, immunocompromised or fragile patients). The clinical consensus statement presented herein aims to provide a comprehensive management guide to PSFB based on current evidence. METHODS: A multidisciplinary, international panel of 19 specialists judged statements in 3 rounds of a modified Delphi method survey. Statements encompassed the following PSFB management issues: definition, diagnostic workup; treatment indications and modalities; and follow-up. Otolaryngologists, maxillofacial surgeons, infectious disease specialists, and transplant physicians were considered the target audience. RESULTS: Among the 23 statements, 7 reached strong consensus and 16 reached consensus. Consensus was reached on the definition, diagnosis, and treatment modalities for PSFB. Postoperative follow-up modalities and scenarios with bacterial superinfection were the most debated issues. CONCLUSION: Until further data are available, these points provide a framework for the management of PSFB. Moreover, PSFB should be considered a noninvasive mycosis that is not necessarily symptomatic or related to odontogenic conditions. Although diagnosis may be incidental, endoscopy and single imaging (computed tomography or magnetic resonance imaging, with distinctive features) are required for diagnosis, whereas contrast medium would allow for differential diagnosis. Although treatment of PSFB should be considered mandatory before sinus augmentation and is recommended for symptomatic patients, immunosuppressed patients, or patients with planned immunosuppression, watchful waiting could be considered for asymptomatic patients with chronic rhinosinusitis who are provided with appropriate advice and assessment.

Methodology for clinical research.

A clinical research requires a systematic approach with diligent planning, execution and sampling in order to obtain reliable and validated results, as well as an understanding of each research methodology is essential for researchers. Indeed, selecting an inappropriate study type, an error that cannot be corrected after the beginning of a study, results in flawed methodology. The results of clinical research studies enhance the repertoire of knowledge regarding a disease pathogenicity, an existing or newly discovered medication, surgical or diagnostic procedure or medical device. Medical research can be divided into primary and secondary research, where primary research involves conducting studies and collecting raw data, which is then analysed and evaluated in secondary research. The successful deployment of clinical research methodology depends upon several factors. These include the type of study, the objectives, the population, study design, methodology/techniques and the sampling and statistical procedures used. Among the different types of clinical studies, we can recognize descriptive or analytical studies, which can be further categorized in observational and experimental. Finally, also pre-clinical studies are of outmost importance, representing the steppingstone of clinical trials. It is therefore important to understand the types of method for clinical research. Thus, this review focused on various aspects of the methodology and describes the crucial steps of the conceptual and executive stages.