Ex Situ Dual Hypothermic Oxygenated Machine Perfusion for Human Split Liver Transplantation

Liver splitting allows the opportunity to share a deceased graft between 2 recipients but remains underutilized. We hypothesized that liver splitting during continuous dual hypothermic oxygenated machine perfusion (DHOPE) is feasible, with shortened total cold ischemia times and improved logistics. Here, we describe a left lateral segment (LLS) and extended right lobe (ERL) liver split procedure during continuous DHOPE preservation with subsequent transplantation at 2 different centers. Methods: After transport using static cold storage, a 51-year-old brain death donor liver underwent end-ischemic DHOPE. During DHOPE, the donor liver was maintained 106 kPa. An ex situ ERL/LLS split was performed with continuing DHOPE throughout the procedure to avoid additional ischemia time. Results: Total cold ischemia times for the LLS and ERL were 205 minutes and 468 minutes, respectively. Both partial grafts were successfully transplanted at 2 different transplant centers. Peak aspartate aminotransferase and alanine aminotransferase were 172 IU/L and 107 IU/L for the LLS graft, and 839 IU/L and 502 IU/L for the ERL graft, respectively. The recipient of the LLS experienced an episode of acute cellular rejection. The ERL transplantation was complicated by severe acute pancreatitis with jejunum perforation requiring percutaneous drainage and acute cellular rejection. No device-related adverse events were observed. Conclusions: Liver splitting during continuous DHOPE preservation is feasible, has the potential to substantially shorten cold ischemia time and may optimize transplant logistics. Therefore liver splitting with DHOPE can potentially improve utilization of split liver transplantation

Combining Radiotherapy With Anti-angiogenic Therapy and Immunotherapy; A Therapeutic Triad for Cancer?

Radiotherapy has been used for the treatment of cancer for over a century. Throughout this period, the therapeutic benefit of radiotherapy has continuously progressed due to technical developments and increased insight in the biological mechanisms underlying the cellular responses to irradiation. In order to further improve radiotherapy efficacy, there is a mounting interest in combining radiotherapy with other forms of therapy such as anti-angiogenic therapy or immunotherapy. These strategies provide different opportunities and challenges, especially with regard to dose scheduling and timing. Addressing these issues requires insight in the interaction between the different treatment modalities. In the current review, we describe the basic principles of the effects of radiotherapy on tumor vascularization and tumor immunity and vice versa. We discuss the main strategies to combine these treatment modalities and the hurdles that have to be overcome in order to maximize therapeutic effectivity. Finally, we evaluate the outstanding questions and present future prospects of a therapeutic triad for cancer

The FENIKS Survey: Spectroscopic Confirmation of Massive Quiescent Galaxies at z ~ 3-5

The measured ages of massive, quiescent galaxies at $z\sim 3-4$ imply that massive galaxies quench as early as $z\sim 6$. While the number of spectroscopic confirmations of quiescent galaxies at $z < 3$ has increased over the years, there are only a handful at $z > 3.5$. We report spectroscopic redshifts of one secure ($z=3.757$) and two tentative ($z = 3.336$, $z=4.673$) massive ($\log(M_\ast/M_\odot) > 10.3$) quiescent galaxies with 11 hours of Keck/MOSFIRE $K$-band observations. Our candidates were selected from the FENIKS survey, which uses deep Gemini/Flamingos-2 $K_b$ $K_r$ imaging optimized for increased sensitivity to the characteristic red colors of galaxies at $z > 3$ with strong Balmer/4000 \AA\ breaks. The rest-frame $UVJ$ and $(ugi)_s$ colors of 3/4 quiescent candidates are consistent with $1-2$ Gyr old stellar populations. This places these galaxies as the oldest objects at these redshifts, and challenges the notion that quiescent galaxies at $z > 3$ are all recently-quenched, "post-starburst'' galaxies. Our spectroscopy shows that the other quiescent-galaxy candidate is a broad-line AGN ($z = 3.594$) with strong, redshifted $H\beta$+[O III] emission with a velocity offset $>1000$ km/s, indicative of a powerful outflow. The star-formation history of our highest redshift candidate suggests that its progenitor was already in place by $z \sim 7-11$, reaching $\sim$ 10$^{11} M_{\odot}$ by $z \simeq 10$. These observations reveal the limit of what is possible with deep near-infrared photometry and targeted spectroscopy from the ground and demonstrate that secure spectroscopic confirmation of quiescent galaxies at $z > 4$ is only feasible with JWST.Comment: 20 pages, 11 figures, submitted to Ap

Prolonged hypothermic machine perfusion enables daytime liver transplantation - an IDEAL stage 2 prospective clinical trial

Background: Liver transplantation is traditionally performed around the clock to minimize organ ischemic time. However, the prospect of prolonging preservation times holds the potential to streamline logistics and transform liver transplantation into a semi-elective procedure, reducing the need for nighttime surgeries. Dual hypothermic oxygenated machine perfusion (DHOPE) of donor livers for 1–2 h mitigates ischemia-reperfusion injury and improves transplant outcomes. Preclinical studies have shown that DHOPE can safely extend the preservation of donor livers for up to 24 h. Methods: We conducted an IDEAL stage 2 prospective clinical trial comparing prolonged (≥4 h) DHOPE to conventional (1–2 h) DHOPE for brain-dead donor livers, enabling transplantation the following morning. Liver allocation to each group was based on donor hepatectomy end times. The primary safety endpoint was a composite of all serious adverse events (SAE) within 30 days after transplantation. The primary feasibility endpoint was defined as the number of patients assigned and successfully receiving a prolonged DHOPE-perfused liver graft. Trial registration at: WHO International Clinical Trial Registry Platform, number NL8740. Findings: Between November 1, 2020 and July 16, 2022, 24 patients were enrolled. The median preservation time was 14.5 h (interquartile range [IQR], 13.9–15.5) for the prolonged group (n = 12) and 7.9 h (IQR, 7.6–8.6) for the control group (n = 12; p = 0.01). In each group, three patients (25%; 95% CI 3.9–46%, p = 1) experienced a SAE. Markers of ischemia-reperfusion injury and oxidative stress in both perfusate and recipients were consistently low and showed no notable discrepancies between the two groups. All patients assigned to either the prolonged group or control group successfully received a liver graft perfused with either prolonged DHOPE or control DHOPE, respectively. Interpretation: This first-in-human clinical trial demonstrates the safety and feasibility of DHOPE in prolonging the preservation time of donor livers to enable daytime transplantation. The ability to extend the preservation window to up to 20 h using hypothermic oxygenated machine preservation at a 10 °C temperature has the potential to reshape the landscape of liver transplantation. Funding: University Medical Center Groningen, the Netherlands.</p

Multiscale mapping of plant functional groups and plant traits in the High Arctic using field spectroscopy, UAV imagery and Sentinel-2A data

The Arctic is warming twice as fast as the rest of the planet, leading to rapid changes in species composition and plant functional trait variation. Landscape-level maps of vegetation composition and trait distributions are required to expand spatially-limited plot studies, overcome sampling biases associated with the most accessible research areas, and create baselines from which to monitor environmental change. Unmanned aerial vehicles (UAVs) have emerged as a low-cost method to generate high-resolution imagery and bridge the gap between fine-scale field studies and lower resolution satellite analyses. Here we used field spectroscopy data (400-2500 nm) and UAV multispectral imagery to test spectral methods of species identification and plant water and chemistry retrieval near Longyearbyen, Svalbard. Using the field spectroscopy data and Random Forest analysis, we were able to distinguish eight common High Arctic plant tundra species with 74% accuracy. Using partial least squares regression (PLSR), we were able to predict corresponding water, nitrogen, phosphorus and C:N values (r (2) = 0.61-0.88, RMSEmean = 12%-64%). We developed analogous models using UAV imagery (five bands: Blue, Green, Red, Red Edge and Near-Infrared) and scaled up the results across a 450 m long nutrient gradient located underneath a seabird colony. At the UAV level, we were able to map three plant functional groups (mosses, graminoids and dwarf shrubs) at 72% accuracy and generate maps of plant chemistry. Our maps show a clear marine-derived fertility gradient, mediated by geomorphology. We used the UAV results to explore two methods of upscaling plant water content to the wider landscape using Sentinel-2A imagery. Our results are pertinent for high resolution, low-cost mapping of the Arctic.Peer reviewe

Major Publications in the Critical Care Pharmacotherapy Literature: 2020

OBJECTIVES: To summarize selected meta-analyses and trials related to critical care pharmacotherapy published in 2020. DATA SOURCES: The Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update group screened 36 journals monthly for impactful publications. STUDY SELECTION: The group reviewed a total of 119 articles during 2020 according to relevance for practice. DATA EXTRACTION: Articles were selected with consensus and importance to clinical practice from those included in the monthly Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update. The group reviewed articles according to Grading of Recommendations, Assessment, Development, and Evaluations criteria. Articles with a 1A grade were selected. DATA SYNTHESIS: Several trials were summarized, including two meta-analyses and five original research trials. Original research trials evaluating vitamin C, hydrocortisone, and thiamine versus hydrocortisone in sepsis, the use of nonsedation strategies, dexmedetomidine in cardiac surgery, remdesivir for severe acute respiratory syndrome coronavirus 2, and thrombectomy in acute ischemic stroke. Two meta-analyses determining the impact of norepinephrine initiation in patients with septic shock and the use of corticosteroids in severe acute respiratory syndrome coronavirus 2 was included. CONCLUSIONS: This clinical review provides summary and perspectives of clinical practice impact on influential critical care pharmacotherapy publications in 2020

A receptor-like protein mediates plant immune responses to herbivore-associated molecular patterns

[ENG] Herbivory is fundamental to the regulation of both global food webs and the extent of agricultural crop losses. Induced plant responses to herbivores promote resistance and often involve the perception of specific herbivore-associated molecular patterns (HAMPs); however, precisely defined receptors and elicitors associated with herbivore recognition remain elusive. Here, we show that a receptor confers signaling and defense outputs in response to a defined HAMP common in caterpillar oral secretions (OS). Staple food crops, including cowpea (Vigna unguiculata) and common bean (Phaseolus vulgaris), specifically respond to OS via recognition of proteolytic fragments of chloroplastic ATP synthase, termed inceptins. Using forward-genetic mapping of inceptin-induced plant responses, we identified a corresponding leucine-rich repeat receptor, termed INR, specific to select legume species and sufficient to confer inceptin-induced responses and enhanced defense against armyworms (Spodoptera exigua) in tobacco. Our results support the role of plant immune receptors in the perception of chewing herbivores and defenseSIGenotyping of cowpea accessions was supported by the Feed the Future Innovation Laboratory for Climate Resilient Cowpea (US Agency for International Development Cooperative Agreement AID-OAA-A-13-00070). OS analyses were supported by European Research Council Advanced Grant 788949. Research in the C.Z. laboratory was supported by The Gatsby Charitable Foundation and the Biotechnology and Biological Research Council (BB/P012574/1

Symptomatic benefit of momelotinib in patients with myelofibrosis: results from the SIMPLIFY phase III studies

Background: Myelofibrosis (MF)-associated constitutional symptoms can severely impact health-related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24-week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy. Methods: Longitudinal symptom change was evaluated using mixed-effect model repeated measure (MMRM) methodology with individual item-level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item-level odds ratios using multiple predictive imputations for missing data. Results: Momelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of <1.5 points between groups for each post-baseline visit in SIMPLIFY-1. In SIMPLIFY-2, the improvement in TSS observed in momelotinib-treated patients was consistent with that observed in SIMPLIFY-1, whereas progressive TSS deterioration was observed with control. Item-level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib-treated patients were categorized as “improved” or “stable” compared with control in SIMPLIFY-1 and SIMPLIFY-2, respectively. Odds ratios for between-group comparison ranged from 0.75 to 1.21 in SIMPLIFY-1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY-2, the likelihood of symptom improvement in each item was higher in the momelotinib arm. Conclusions: These findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor-naïve and JAK inhibitor-exposed settings

Multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci

Genome-wide association studies (GWASs) have identified hundreds of risk loci for coronary artery disease (CAD). However, non-European populations are underrepresented in GWASs, and the causal gene-regulatory mechanisms of these risk loci during atherosclerosis remain unclear. We incorporated local ancestry and haplotypes to identify quantitative trait loci for expression (eQTLs) and splicing (sQTLs) in coronary arteries from 138 ancestrally diverse Americans. Of 2,132 eQTL-associated genes (eGenes), 47% were previously unreported in coronary artery; 19% exhibited cell-type-specific expression. Colocalization revealed subgroups of eGenes unique to CAD and blood pressure GWAS. Fine-mapping highlighted additional eGenes, including TBX20 and IL5. We also identified sQTLs for 1,690 genes, among which TOR1AIP1 and ULK3 sQTLs demonstrated the importance of evaluating splicing to accurately identify disease-relevant isoform expression. Our work provides a patient-derived coronary artery eQTL resource and exemplifies the need for diverse study populations and multifaceted approaches to characterize gene regulation in disease processes.</p

Multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci

Genome-wide association studies (GWASs) have identified hundreds of risk loci for coronary artery disease (CAD). However, non-European populations are underrepresented in GWASs, and the causal gene-regulatory mechanisms of these risk loci during atherosclerosis remain unclear. We incorporated local ancestry and haplotypes to identify quantitative trait loci for expression (eQTLs) and splicing (sQTLs) in coronary arteries from 138 ancestrally diverse Americans. Of 2,132 eQTL-associated genes (eGenes), 47% were previously unreported in coronary artery; 19% exhibited cell-type-specific expression. Colocalization revealed subgroups of eGenes unique to CAD and blood pressure GWAS. Fine-mapping highlighted additional eGenes, including TBX20 and IL5. We also identified sQTLs for 1,690 genes, among which TOR1AIP1 and ULK3 sQTLs demonstrated the importance of evaluating splicing to accurately identify disease-relevant isoform expression. Our work provides a patient-derived coronary artery eQTL resource and exemplifies the need for diverse study populations and multifaceted approaches to characterize gene regulation in disease processes.</p