Performance study of ray-based ocean acoustic tomography methods for estimating submesoscale variability in the upper ocean.

Ocean acoustic tomography (OAT) methods aim at estimating variations of sound speed profiles (SSP) based on acoustic measurements between multiple source-receiver pairs (e.g., eigenray travel times). This study investigates the estimation of range-dependent SSPs in the upper ocean over short ranges (<5 km) using the classical ray-based OAT formulation as well as iterative or adaptive OAT formulations (i.e., when the sources and receivers configuration can evolve across successive iterations of this inverse problem). A regional ocean circulation model for the DeSoto Canyon in the Gulf of Mexico is used to simulate three-dimensional sound speed variations spanning a month-long period, which exhibits significant submesoscale variability of variable intensity. OAT performance is investigated in this simulated environment in terms of (1) the selected source-receivers configuration and effective ray coverage, (2) the selected OAT estimator formulations, linearized forward model accuracy, and the parameterization of the expected SSP variability in terms of empirical orthogonal functions, and (3) the duration over which the OAT inversion is performed. Practical implications for the design of future OAT experiments for monitoring submesoscale variability in the upper ocean with moving autonomous platforms are discussed.

Machine Learning Diagnosis of Small-Bowel Crohn Disease Using T2-Weighted MRI Radiomic and Clinical Data.

BACKGROUND. Radiologists have variable diagnostic performance and considerable interreader variability when interpreting MR enterography (MRE) examinations for suspected Crohn disease (CD). OBJECTIVE. The purposes of this study were to develop a machine learning method for predicting ileal CD by use of radiomic features of ileal wall and mesenteric fat from noncontrast T2-weighted MRI and to compare the performance of the method with that of expert radiologists. METHODS. This single-institution study included retrospectively identified patients who underwent MRE for suspected ileal CD from January 1, 2020, to January 31, 2021, and prospectively enrolled participants (patients with newly diagnosed ileal CD or healthy control participants) from December 2018 to October 2021. Using axial T2-weighted SSFSE images, a radiologist selected two slices showing greatest terminal ileal wall thickening. Four ROIs were segmented, and radiomic features were extracted from each ROI. After feature selection, support-vector machine models were trained to classify the presence of ileal CD. Three fellowship-trained pediatric abdominal radiologists independently classified the presence of ileal CD on SSFSE images. The reference standard was clinical diagnosis of ileal CD based on endoscopy and biopsy results. Radiomic-only, clinical-only, and radiomic-clinical ensemble models were trained and evaluated by nested cross-validation. RESULTS. The study included 135 participants (67 female, 68 male; mean age, 15.2 ± 3.2 years); 70 were diagnosed with ileal CD. The three radiologists had accuracies of 83.7% (113/135), 88.1% (119/135), and 86.7% (117/135) for diagnosing CD; consensus accuracy was 88.1%. Interradiologist agreement was substantial (κ = 0.78). The best-performing ROI was bowel core (AUC, 0.95; accuracy, 89.6%); other ROIs had worse performance (whole-bowel AUC, 0.86; fat-core AUC, 0.70; whole-fat AUC, 0.73). For the clinical-only model, AUC was 0.85 and accuracy was 80.0%. The ensemble model combining bowel-core radiomic and clinical models had AUC of 0.98 and accuracy of 93.5%. The bowel-core radiomic-only model had significantly greater accuracy than radiologist 1 (p = .009) and radiologist 2 (p = .02) but not radiologist 3 (p > .99) or the radiologists in consensus (p = .05). The ensemble model had greater accuracy than the radiologists in consensus (p = .02). CONCLUSION. A radiomic machine learning model predicted CD diagnosis with better performance than two of three expert radiologists. Model performance improved when radiomic data were ensembled with clinical data. CLINICAL IMPACT. Deployment of a radiomic-based model including T2-weighted MRI data could decrease interradiologist variability and increase diagnostic accuracy for pediatric CD.

On the role of vertical resolution for resolving mesoscale eddy dynamics and the prediction of ocean sound speed variability.

This work investigates how vertical resolution affects the prediction of ocean sound speed through a suite of regional simulations covering the DeSoto Canyon in the Gulf of Mexico. Simulations have identical horizontal resolution of 0.5 km, partially resolving submesoscale dynamics, and vertical resolution from 30 to 200 terrain-following layers. The focus is on mesoscale eddies and how modeled sound speeds vary whenever more vertical baroclinic modes are resolved. While domain-averaged sound speed profiles do not differ substantively, the standard deviation increases for increasing resolution due to the sharper representation of mesoscale circulations underneath the mixed layer and their associated density anomalies.

Defatting of Human Livers During Long-Term e x situ Normothermic Perfusion: Novel Strategy to Rescue Discarded Organs for Transplantation.

OBJECTIVE: To develop a protocol for the defatting of steatotic liver grafts during long-term ex situ normothermic machine perfusion. BACKGROUND: Despite the alarming increase in donor organ shortage, the highly prevalent fatty liver grafts are often discarded due to the risk of primary nonfunction. Effective strategies preventing such outcomes are currently lacking. An exciting new avenue is the introduction of ex situ normothermic machine perfusion (NMP), enabling a liver to remain fully functional for up to 2 weeks and providing a unique window of opportunity for defatting before transplantation. METHODS: Over a 5-year period, 23 discarded liver grafts and 28 partial livers from our resection program were tested during ex situ normothermic machine perfusion. The steatosis degree was determined on serial biopsies by expert pathologists, and triglyceride contents were measured simultaneously. RESULTS: Of 51 liver grafts, 20 were steatotic, with up to 85% macrovesicular steatosis, and were perfused for up to 12 days. Ten livers displayed marked (5 of which almost complete) loss of fat, while the other 10 did not respond to long-term perfusion. Successful defatting was related to prolonged perfusion, automated glucose control, circadian nutrition, and L-carnitine/fenofibrate supplementation. Pseudopeliotic steatosis and the associated activation of Kupffer/stellate cells were unexpected processes that might contribute to defatting. Synthetic and metabolic functions remained preserved for most grafts until perfusion ended. CONCLUSION: Ex situ long-term perfusion effectively reduces steatosis while preserving organ viability and may in the future allow transplantation of primarily unusable high-risk grafts, significantly increasing the number of organs available for transplantation.

Novel Benchmark Values for Open Major Anatomic Liver Resection in Non-cirrhotic Patients: A Multicentric Study of 44 International Expert Centers.

OBJECTIVE: This study aims at establishing benchmark values for best achievable outcomes following open major anatomic hepatectomy for liver tumors of all dignities. BACKGROUND: Outcomes after open major hepatectomies vary widely lacking reference values for comparisons among centers, indications, types of resections, and minimally invasive procedures. METHODS: A standard benchmark methodology was used covering consecutive patients, who underwent open major anatomic hepatectomy from 44 high-volume liver centers from 5 continents over a 5-year period (2016-2020). Benchmark cases were low-risk non-cirrhotic patients without significant comorbidities treated in high-volume centers (≥30 major liver resections/year). Benchmark values were set at the 75th percentile of median values of all centers. Minimum follow-up period was 1 year in each patient. RESULTS: Of 8044 patients, 2908 (36%) qualified as benchmark (low-risk) cases. Benchmark cutoffs for all indications include R0 resection ≥78%; liver failure (grade B/C) ≤10%; bile leak (grade B/C) ≤18%; complications ≥grade 3 and CCI ® ≤46% and ≤9 at 3 months, respectively. Benchmark values differed significantly between malignant and benign conditions so that reference values must be adjusted accordingly. Extended right hepatectomy (H1, 4-8 or H4-8) disclosed a higher cutoff for liver failure, while extended left (H1-5,8 or H2-5,8) were associated with higher cutoffs for bile leaks, but had superior oncologic outcomes, when compared to formal left hepatectomy (H1-4 or H2-4). The minimal follow-up for a conclusive outcome evaluation following open anatomic major resection must be 3 months. CONCLUSION: These new benchmark cutoffs for open major hepatectomy provide a powerful tool to convincingly evaluate other approaches including parenchymal-sparing procedures, laparoscopic/robotic approaches, and alternative treatments, such as ablation therapy, irradiation, or novel chemotherapy regimens.

A Spectrofluorometric Method for Real-Time Graft Assessment and Patient Monitoring.

Biomarkers are powerful clinical diagnostics and predictors of patient outcome. However, robust measurements often require time and expensive laboratory equipment, which is insufficient to track rapid changes and limits direct use in the operating room. Here, this study presents a portable spectrophotometric device for continuous real-time measurements of fluorescent and non-fluorescent biomarkers at the point of care. This study measures the mitochondrial damage biomarker flavin mononucleotide (FMN) in 26 extended criteria human liver grafts undergoing hypothermic oxygenated perfusion to guide clinical graft assessment. Real-time data identified seven organs unsuitable for transplant that are discarded. The remaining grafts are transplanted and FMN values correlated with post-transplant indicators of liver function and patient recovery. Further, this study shows how this device can be used to monitor dialysis patients by measuring creatinine in real-time. Our approach provides a simple method to monitor biomarkers directly within biological fluids to improve organ assessment, patient care, and biomarker discovery.

Outcomes of Kidney Perfusion Techniques in Transplantation from Deceased Donors: A Systematic Review and Meta-Analysis.

The high demand for organs in kidney transplantation and the expansion of the donor pool have led to the widespread implementation of machine perfusion technologies. In this study, we aim to provide an up-to-date systematic review of the developments in this expanding field over the past 10 years, with the aim of answering the question: "which perfusion technique is the most promising technique in kidney transplantation?" A systematic review of the literature related to machine perfusion in kidney transplantation was performed. The primary outcome measure was delayed graft function (DGF), and secondary outcomes included rates of rejection, graft survival, and patient survival rates after 1 year. Based on the available data, a meta-analysis was performed. The results were compared with data from static cold storage, which is still the standard of care in many centers worldwide. A total of 56 studies conducted in humans were included, and 43 studies reported outcomes of hypothermic machine perfusion (HMP), with a DGF rate of 26.4%. A meta-analysis of 16 studies showed significantly lower DGF rates in the HMP group compared to those of static cold storage (SCS). Five studies reported outcomes of hypothermic machine perfusion + O2, with an overall DGF rate of 29.7%. Two studies explored normothermic machine perfusion (NMP). These were pilot studies, designed to assess the feasibility of this perfusion approach in the clinical setting. Six studies reported outcomes of normothermic regional perfusion (NRP). The overall incidence of DGF was 71.5%, as it was primarily used in uncontrolled DCD (Maastricht category I-II). Three studies comparing NRP to in situ cold perfusion showed a significantly lower rate of DGF with NRP. The systematic review and meta-analysis provide evidence that dynamic preservation strategies can improve outcomes following kidney transplantation. More recent approaches such as normothermic machine perfusion and hypothermic machine perfusion + O2 do show promising results but need further results from the clinical setting. This study shows that the implementation of perfusion strategies could play an important role in safely expanding the donor pool.

A multicenter randomized-controlled trial of hypothermic oxygenated perfusion (HOPE) for human liver grafts before transplantation.

BACKGROUND & AIMS: Machine perfusion is a novel method intended to optimize livers before transplantation. However, its effect on morbidity within a 1-year period after transplantation has remained unclear. METHODS: In this multicenter controlled trial, we randomly assigned livers donated after brain death (DBD) for liver transplantation (LT). Livers were either conventionally cold stored (control group), or cold stored and subsequently treated by 1-2 h hypothermic oxygenated perfusion (HOPE) before implantation (HOPE group). The primary endpoint was the occurrence of at least one post-transplant complication per patient, graded by the Clavien score of ≥III, within 1-year after LT. The comprehensive complication index (CCI), laboratory parameters, as well as duration of hospital and intensive care unit stay, graft survival, patient survival, and biliary complications served as secondary endpoints. RESULTS: Between April 2015 and August 2019, we randomized 177 livers, resulting in 170 liver transplantations (85 in the HOPE group and 85 in the control group). The number of patients with at least one Clavien ≥III complication was 46/85 (54.1%) in the control group and 44/85 (51.8%) in the HOPE group (odds ratio 0.91; 95% CI 0.50-1.66; p = 0.76). Secondary endpoints were also not significantly different between groups. A post hoc analysis revealed that liver-related Clavien ≥IIIb complications occurred less frequently in the HOPE group compared to the control group (risk ratio 0.26; 95% CI 0.07-0.77; p = 0.027). Likewise, graft failure due to liver-related complications did not occur in the HOPE group, but occurred in 7% (6 of 85) of the control group (log-rank test, p = 0.004, Gray test, p = 0.015). CONCLUSIONS: HOPE after cold storage of DBD livers resulted in similar proportions of patients with at least one Clavien ≥III complication compared to controls. Exploratory findings suggest that HOPE decreases the risk of severe liver graft-related events. IMPACT AND IMPLICATIONS: This randomized controlled phase III trial is the first to investigate the impact of hypothermic oxygenated perfusion (HOPE) on cumulative complications within a 12-month period after liver transplantation. Compared to conventional cold storage, HOPE did not have a significant effect on the number of patients with at least one Clavien ≥III complication. However, we believe that HOPE may have a beneficial effect on the quantity of complications per patient, based on its application leading to fewer severe liver graft-related complications, and to a lower risk of liver-related graft loss. The HOPE approach can be applied easily after organ transport during recipient hepatectomy. This appears fundamental for wide acceptance since concurring perfusion technologies need either perfusion at donor sites or continuous perfusion during organ transport, which are much costlier and more laborious. We conclude therefore that the post hoc findings of this trial should be further validated in future studies.

Clinical Validation of the Canada Lymph Node Score for Endobronchial Ultrasound.

BACKGROUND: The Canada Lymph Node Score (CLNS) uses 4 sonographic criteria to predict the risk of malignancy in lymph nodes during endobronchial ultrasound. The CLNS may play a role in identifying targets for biopsy or rebiopsy during invasive mediastinal staging for lung cancer. However the CLNS has not yet been prospectively validated in routine clinical practice. METHODS: CLNSs for each lymph node biopsied during endobronchial ultrasound were prospectively captured for 1 year (2019). The CLNS and the presence of malignancy in each node were compared. Univariate binary logistic regression was completed for each ultrasonographic feature and multivariate logistic regression model. RESULTS: CLNSs and diagnostic pathology results were available for 367 lymph nodes. Incidence of malignancy increased with higher scores. Scores ≥ 3 were significantly associated with malignancy (specificity, 84.4%; positive likelihood ratio, 4.0). Area under the curve was 0.76, indicating a good ability of the model to predict presence or absence of malignancy. Nodes scoring < 2 and negative on computed tomography and positron emission tomography were malignant in 10.1%. CONCLUSIONS: The CLNS correlates with the presence or absence of malignancy in thoracic lymph nodes and may serve as an adjunct to currently available methods of invasive and noninvasive mediastinal staging. The CLNS may be most helpful in selecting which nondiagnostic lymph nodes require rebiopsy. There is a significant risk of a false-negative result even with a score of 0, and using a combination of low CLNSs and negative conventional radiology to obviate the need for any initial biopsy remains to be studied in prospective trials.

Untargeted metabolomics of perfusate and their association with hypothermic machine perfusion and allograft failure.

Although hypothermic machine perfusion (HMP) is associated with improved kidney graft viability and function, the underlying biological mechanisms are unknown. Untargeted metabolomic profiling may identify potential metabolites and pathways that can help assess allograft viability and contribute to organ preservation. Therefore, in this multicenter study, we measured all detectable metabolites in perfusate collected at the beginning and end of deceased-donor kidney perfusion and evaluated their associations with graft failure. In our cohort of 190 kidney transplants, 33 (17%) had death-censored graft failure over a median follow-up of 5.0 years (IQR 3.0-6.1 years). We identified 553 known metabolites in perfusate and characterized their experimental and biological consistency through duplicate samples and unsupervised clustering. After perfusion-time adjustment and false discovery correction, six metabolites in post-HMP perfusate were significantly associated with death-censored graft failure, including alpha-ketoglutarate, 3-carboxy-4-methyl-5-propyl-2-furanpropanoate, 1-carboxyethylphenylalanine, and three glycerol-phosphatidylcholines. All six metabolites were associated with an increased risk of graft failure (Hazard Ratio per median absolute deviation range 1.04-1.45). Four of six metabolites also demonstrated significant interaction with donation after cardiac death with notably greater risk in the donation after cardiac death group (Hazard Ratios up to 1.69). Discarded kidneys did not have significantly different levels of any death-censored graft failure-associated metabolites. On interrogation of pathway analysis, production of reactive oxygen species and increased metabolism of fatty acids were upregulated in kidneys that subsequently developed death-censored graft failure. Thus, further understanding the role of these metabolites may inform the HMP process and help improve the objective evaluation of allograft offers, thereby reducing the discard of potentially viable organs.

Real-time assessment of kidney allografts during HOPE using flavin mononucleotide (FMN) - a preclinical study.

Introduction: The gap between available donor grafts and patients on the waiting lists is constantly growing. This leads to an increased utilization of high-risk and therefore more vulnerable kidney grafts. The use of high-risk organs requires further optimization of machine preservation and assessment strategies before transplantation. Hypothermic machine perfusion (HMP) is the standard of care for kidneys originating from donation after circulatory death (DCD), whereas the evidence of HMP with additional oxygen (HOPE) is still very limited. Furthermore, an objective quality assessment of HMP-perfused kidneys is lacking. Recently, the release of mitochondria derived fragments, i.e., flavin mononucleotide (FMN) of complex I during machine liver perfusion was shown to be predictive for liver graft function before implantation. Therefore, the aim of this study was to evaluate, if FMN is useful also for assessment of kidney injury before use. Methods: A porcine perfusion model was used to investigate the feasibility of assessment of kidney grafts during hypothermic oxygenated perfusion (HOPE) with either 0, 30 or 60 minutes of warm ischemia. The model with warm ischemia times (WIT) of 30 min and 60 min, was used to mimic a clinically relevant scenario. A group with no warm ischemia time (0' WIT) served as control group. The groups underwent minimal static cold storage (SCS) of 2 h followed by 2 h of end-ischemic HOPE with repeated real-time FMN measurements. In a further step, these values were related to the release of damage-associated molecular patterns (DAMPs) and to the functionality of the respiratory chain, represented by the capacity of ATP production. Results: We demonstrate, first, feasibility of perfusate FMN measurements in perfused kidneys, and secondly its correlation with donor warm ischemia time. Accordingly, FMN measurement showed significantly higher release in the 60-minute WIT group (n = 4) compared to the 30-minute WIT (n = 4) and the control group (n = 4). FMN release correlated also with DAMP signaling, such as the release of 8-OHdG and HMGB1. Finally, ATP replenishment proved to be best in control kidneys, followed by kidneys with 30 min and then by kidneys with 60 min of WIT. Discussion: This study demonstrates the feasibility of FMN measurement in kidneys during HOPE. In addition, we show a correlation between FMN quantification and pre-existing kidney graft injury. Based on this, real-time FMN measurement during HOPE may be an objective assessment tool to accept high-risk kidneys for transplantation while minimizing post-transplant dysfunction, moving away from former "gut feeling" towards objective criteria in accepting marginal kidney grafts for transplantation. Graft evaluation based on these results may close the gap between available grafts and patients on the waiting lists by increasing utilization rates without significant impact for the recipients.

Low-dose aspirin confers protection against acute cellular allograft rejection after primary liver transplantation.

This study investigated the effect of low-dose aspirin in primary adult liver transplantation (LT) on acute cellular rejection (ACR) as well as arterial patency rates. The use of low-dose aspirin after LT is practiced by many transplant centers to minimize the risk of hepatic artery thrombosis (HAT), although solid recommendations do not exist. However, aspirin also possesses potent anti-inflammatory properties and might mitigate inflammatory processes after LT, such as rejection. Therefore, we hypothesized that the use of aspirin after LT has a protective effect against ACR. This is an international, multicenter cohort study of primary adult deceased donor LT. The study included 17 high-volume LT centers and covered the 3-year period from 2013 to 2015 to allow a minimum 5-year follow-up. In this cohort of 2365 patients, prophylactic antiplatelet therapy with low-dose aspirin was administered in 1436 recipients (61%). The 1-year rejection-free survival rate was 89% in the aspirin group versus 82% in the no-aspirin group (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.63-0.94; p = 0.01). The 1-year primary arterial patency rates were 99% in the aspirin group and 96% in the no-aspirin group with an HR of 0.23 (95% CI, 0.13-0.40; p < 0.001). Low-dose aspirin was associated with a lower risk of ACR and HAT after LT, especially in the first vulnerable year after transplantation. Therefore, low-dose aspirin use after primary LT should be evaluated to protect the liver graft from ACR and to maintain arterial patency.

Transplantation of a human liver following 3 days of ex situ normothermic preservation.

Current organ preservation methods provide a narrow window (usually <12 hours) to assess, transport and implant donor grafts for human transplantation. Here we report the transplantation of a human liver discarded by all centers, which could be preserved for several days using ex situ normothermic machine perfusion. The transplanted liver exhibited normal function, with minimal reperfusion injury and the need for only a minimal immunosuppressive regimen. The patient rapidly recovered a normal quality of life without any signs of liver damage, such as rejection or injury to the bile ducts, according to a 1-year follow up. This inaugural clinical success opens new horizons in clinical research and promises an extended time window of up to 10 days for assessment of viability of donor organs as well as converting an urgent and highly demanding surgery into an elective procedure.

Machine perfusion in liver transplantation.

Although liver transplantation is a true success story, many patients still die awaiting an organ. The increasing need for liver grafts therefore remains an unsolved challenge to the transplant community. To address this, transplant donor criteria have been expanded and, for example, more liver grafts with significant steatosis or from donors with circulatory death are being used. These marginal grafts, however, carry an increased risk of graft-associated complications, such as primary nonfunction, delayed graft function, or late biliary injuries. Therefore, reliable assessment of graft viability before use is essential for further success. To achieve this, machine liver perfusion, a procedure developed more than 50 years ago but almost forgotten at the end of the last century, is again of great interest. We describe in this review the clinical most applied machine perfusion techniques, their mechanistic background, and a novel concept of combining immediate organ assessment during hypothermic oxygenated perfusion, followed by an extended phase of normothermic machine perfusion, with simultaneous ex situ treatment of the perfused liver. Such a new approach may allow the pool of usable livers to dramatically increase and improve outcomes for recipients.

Soluble immune checkpoints are dysregulated in COVID-19 and heavy alcohol users with HIV infection

Immune checkpoints (ICPs) consist of paired receptor-ligand molecules that exert inhibitory or stimulatory effects on immune defense, surveillance, regulation, and self-tolerance. ICPs exist in both membrane and soluble forms in vivo and in vitro. Imbalances between inhibitory and stimulatory membrane-bound ICPs (mICPs) in malignant cells and immune cells in the tumor immune microenvironment (TIME) have been well documented. Blockades of inhibitory mICPs have emerged as an immense breakthrough in cancer therapeutics. However, the origin, structure, production regulation, and biological significance of soluble ICPs (sICPs) in health and disease largely remains elusive. Soluble ICPs can be generated through either alternative mRNA splicing and secretion or protease-mediated shedding from mICPs. Since sICPs are found in the bloodstream, they likely form a circulating immune regulatory system. In fact, there is increasing evidence that sICPs exhibit biological functions including (1) regulation of antibacterial immunity, (2) interaction with their mICP compartments to positively or negatively regulate immune responses, and (3) competition with their mICP compartments for binding to the ICP blocking antibodies, thereby reducing the efficacy of ICP blockade therapies. Here, we summarize current data of sICPs in cancer and infectious diseases. We particularly focus on sICPs in COVID-19 and HIV infection as they are the two ongoing global pandemics and have created the worlds most serious public health challenges. A "storm" of sICPs occurs in the peripheral circulation of COVID-19 patients and is associated with the severity of COVID-19. Similarly, sICPs are highly dysregulated in people living with HIV (PLHIV) and some sICPs remain dysregulated in PLHIV on antiretroviral therapy (ART), indicating these sICPs may serve as biomarkers of incomplete immune reconstitution in PLHIV on ART. We reveal that HIV infection in the setting of alcohol abuse exacerbates sICP dysregulation as PLHIV with heavy alcohol consumption have significantly elevated plasma levels of many sICPs. Thus, both stimulatory and inhibitory sICPs are present in the bloodstream of healthy people and their balance can be disrupted under pathophysiological conditions such as cancer, COVID-19, HIV infection, and alcohol abuse. There is an urgent need to study the role of sICPs in immune regulation in health and disease.

Comparison of proteomic methods in evaluating biomarker-AKI associations in cardiac surgery patients.

Although immunoassays are the most widely used protein measurement method, aptamer-based methods such as the SomaScan platform can quantify up to 7000 proteins per biosample, creating new opportunities for unbiased discovery. However, there is limited research comparing the consistency of biomarker-disease associations between immunoassay and aptamer-based platforms. In a substudy of the TRIBE-AKI cohort, preoperative and postoperative plasma samples from 294 patients with previous immunoassay measurements were analyzed using the SomaScan platform. Inter-platform Spearman correlations (rs) and biomarker-AKI associations were compared across 30 preoperative and 34 postoperative immunoassay-aptamer pairs. Possible factors contributing to inter-platform differences were examined including target protein characteristics, immunoassay, and SomaScan coefficients of variation, other assay characteristics, and sample storage time. The median rs was 0.54 (interquartile range [IQR] 0.34-0.83) in postoperative samples and 0.41 (IQR 0.21-0.69) in preoperative samples. We observed a trend of greater rs in biomarkers with greater concentrations; the Spearman correlation between the concentration of protein and the inter-platform correlation was 0.64 in preoperative pairs and 0.53 in postoperative pairs. Of proteins measured by immunoassays, we observed significant biomarker-AKI associations for 13 proteins preop and 24 postop; of all corresponding aptamers, 8 proteins preop and 12 postop. All proteins significantly associated with AKI as measured by SomaScan were also significantly associated with AKI as measured by immunoassay. All biomarker-AKI odds ratios were significantly different (P < 0.05) between platforms in 14% of aptamer-immunoassay pairs, none of which had high (rs > 0.50) inter-platform correlations. Although similar biomarker-disease associations were observed overall, biomarkers with high physiological concentrations tended to have the highest-confidence inter-platform operability in correlations and biomarker-disease associations. Aptamer assays provide excellent precision and an unprecedented coverage and promise for disease associations but interpretation of results should keep in mind a broad range of correlations with immunoassays.

Long-term Normothermic Machine Preservation of Partial Livers: First Experience With 21 Human Hemi-livers.

OBJECTIVE: The aim of this study was to maintain long-term full function and viability of partial livers perfused ex situ for sufficient duration to enable ex situ treatment, repair, and regeneration. BACKGROUND: Organ shortage remains the single most important factor limiting the success of transplantation. Autotransplantation in patients with nonresectable liver tumors is rarely feasible due to insufficient tumor-free remnant tissue. This limitation could be solved by the availability of long-term preservation of partial livers that enables functional regeneration and subsequent transplantation. METHODS: Partial swine livers were perfused with autologous blood after being procured from healthy pigs following 70% in-vivo resection, leaving only the right lateral lobe. Partial human livers were recovered from patients undergoing anatomic right or left hepatectomies and perfused with a blood based perfusate together with various medical additives. Assessment of physiologic function during perfusion was based on markers of hepatocyte, cholangiocyte, vascular and immune compartments, as well as histology. RESULTS: Following the development phase with partial swine livers, 21 partial human livers (14 right and 7 left hemi-livers) were perfused, eventually reaching the targeted perfusion duration of 1 week with the final protocol. These partial livers disclosed a stable perfusion with normal hepatic function including bile production (5-10 mL/h), lactate clearance, and maintenance of energy exhibited by normal of adenosine triphosphate (ATP) and glycogen levels, and preserved liver architecture for up to 1 week. CONCLUSION: This pioneering research presents the inaugural evidence for long-term machine perfusion of partial livers and provides a pathway for innovative and relevant clinical applications to increase the availability of organs and provide novel approaches in hepatic oncology.

Health Disparities among Australia's Remote-Dwelling Aboriginal People: A Report from 2020.

BACKGROUND: Australia has 2 distinct indigenous groups, Torres Strait Islanders and Aborigines. The Aborigines, described in this report, first colonized the continent 65 millennia ago. Those still living in the Northern Territory (NT) retain much ancestrally derived genetic complement but also are the most health-challenged by environment and lifestyle in 21st century. Reports providing overviews of these disparities are, as yet, rare. CONTENT: This review defines the studied population and then describes and attempts to explain contemporary clinical findings among Australia's remote-dwelling Aborigines, principally in the NT. The report is structured by life stage and then by organ system. Finally, a brief synthesis is advanced concerning the disparities that Australia's Aboriginals face. SUMMARY: In 2015-2017, NT aboriginal life expectancy for people then born was 66.6 years for men and 69.9 years for women compared with 78.1 and 82.7 years, respectively, among nonindigenous Territorians. Principal causes of the reduced longevity, with nonindigenous comparisons, include adolescent pregnancy, with maternal use of alcohol and tobacco (each 7-fold greater); fetal alcohol spectrum disorder and attention deficit hyperactivity disorder; skin infections, both scabies and impetigo (50-fold greater); rheumatic heart disease (260-fold greater); premature acute myocardial infarction (9-fold greater); bronchiectasis (40-fold greater); lung cancer (2-fold greater); diabetes mellitus (10-fold greater); renal failure (30-fold greater); and suicide (2-fold greater). Some disease has genetic roots, secondary to prolonged genetic drift. Much arises from avoidable stressors and from contemporary environmental disparities in housing. The Europid diet is also not helpful.

Codes of Ethics for Laboratory Medicine: Definition, Structure and Procedures - A Narrative Review Based on Existing National Codes.

BACKGROUND: It behoves every national society of clinical laboratory medicine to have a well formulated and publicly accessible policy concerning the morally acceptable way in which its members should practise their profession; such a policy is published as a Code of Ethics.This Code assists its members in the performance of their duties in relation to the patients they share with other clinicians, within their own particular professional environment and, at large, to the rest of their national society. METHODS AND RESULT: The International Federation of Clinical Chemistry and Laboratory Medicine's (IFCC) Task Force on Ethics here examines a curated selection of extant Codes and provides guidance at the level of definition, structure and procedures to assist national societies and their clinical chemistry and laboratory medicine professionals in the task of crafting their own Ethics Code.

Controlling Drug Absorption, Release, and Erosion of Photopatterned Protein Engineered Hydrogels.

A protein-engineered triblock copolymer hydrogel composed of two self-assembling domains (SADs) has been fabricated by a photoactivatable diazirine group followed by ultraviolet (UV)-mediated crosslinking. The photocrosslinkable protein polymer CEC-D has been patterned into various features including different micrometer-scale stripes by using lithographic techniques. The patterned hydrogels are important for encapsulation of small molecules where a photopatterned fraction of 50% is optimal for maximum absorption. Stripe-patterned CEC-D100-100 exhibits slightly lower swelling ratios, an 8.9 times lower erosion profile, and a 2.6-fold higher drug release compared to the unpatterned hydrogel control, CEC-D0. Our studies demonstrate the potential of photocrosslinkable protein polymer hydrogels to be used as scaffolds for therapeutic delivery of small molecules. Through photolithographic techniques on the protein hydrogel, a variety of functionalities can be achieved by patterning different features enabling the mimicry of biological systems.