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Abstract Background Histotripsy is a novel, non-invasive, non-ionizing, and non-thermal ablation technique that disrupts tumors using acoustic cavitation. We report the first use of Histotripsy as bridging therapy prior to liver transplant for hepatocellular carcinoma (HCC) treated with histotripsy. Case presentation A 59-year-old woman presented with Metabolic-Associated Steatotic Liver Disease (MASLD) cirrhosis (labMELD = 14), hepatic encephalopathy, and a single 2 cm OPTN V lesion in the left lateral segment consistent with HCC. The patient underwent histotripsy treatment of the lesion as bridging therapy before receiving liver transplantation. Histopathology analysis of the explanted liver showed total necrosis of the treated area, with no residual viable tissue tumor. Conclusion This case demonstrates the potential utility of histotripsy as an effective bridging therapy for patients with combined cirrhosis and hepatocellular carcinoma (HCC) awaiting liver transplantation, with complete tumor necrosis on explant pathology demonstrating its therapeutic efficacy.

Abstract Approximately 8100 km2 of Alaska are leased to the oil and gas industry for exploration and extraction. According to industry estimates, subsurface expansion from these leases could cover up to 130.2 km2 per pad. As industrial oil extraction activities increase across the thawing Alaskan permafrost, impacts on the permafrost environment will include rapid thaw, increased hydrological flux, and the release of climate warming greenhouse gases. Here, we use remote sensing and field observations to provide a first-order comparison of the direct impacts to the permafrost tundra from oil well pads, and the long-term consequences of a legacy oil pads on the warming North Slope of Alaska. We find that oil well pads on the permafrost accelerate permafrost degradation and persist despite remediation.

Abstract Background Metagenomics is a powerful approach for the detection of unknown and novel pathogens. Workflows based on Illumina short-read sequencing are becoming established in diagnostic laboratories. However, high sequencing depth requirements, long turnaround times, and limited sensitivity hinder broader adoption. We investigated whether we could overcome these limitations using protocols based on untargeted sequencing with Oxford Nanopore Technologies (ONT), which offers real-time data acquisition and analysis, or a targeted panel approach, which allows the selective sequencing of known pathogens and could improve sensitivity. Methods We evaluated detection of viruses with readily available untargeted metagenomic workflows using Illumina and ONT, and an Illumina-based enrichment approach using the Twist Bioscience Comprehensive Viral Research Panel (CVRP), which targets 3153 viruses. We tested samples consisting of a dilution series of a six-virus mock community in a human DNA/RNA background, designed to resemble clinical specimens with low microbial abundance and high host content. Protocols were designed to retain the host transcriptome, since this could help confirm the absence of infectious agents. We further compared the performance of commonly used taxonomic classifiers. Results Capture with the Twist CVRP increased sensitivity by at least 10–100-fold over untargeted sequencing, making it suitable for the detection of low viral loads (60 genome copies per ml (gc/ml)), but additional methods may be needed in a diagnostic setting to detect untargeted organisms. While untargeted ONT had good sensitivity at high viral loads (60,000 gc/ml), at lower viral loads (600–6000 gc/ml), longer and more costly sequencing runs would be required to achieve sensitivities comparable to the untargeted Illumina protocol. Untargeted ONT provided better specificity than untargeted Illumina sequencing. However, the application of robust thresholds standardized results between taxonomic classifiers. Host gene expression analysis is optimal with untargeted Illumina sequencing but possible with both the CVRP and ONT. Conclusions Metagenomics has the potential to become standard-of-care in diagnostics and is a powerful tool for the discovery of emerging pathogens. Untargeted Illumina and ONT metagenomics and capture with the Twist CVRP have different advantages with respect to sensitivity, specificity, turnaround time and cost, and the optimal method will depend on the clinical context.

Background & Aims: Liver cancer-related deaths are projected to exceed one million annually by 2030. Existing therapies have significant limitations, including severe side effects and inconsistent efficacy. Innovative therapeutic approaches to address primary liver cancer (PLC) have led to the ongoing development of tumor-derived organoids. These are sophisticated three-dimensional structures capable of mimicking native tissue architecture and function in vitro, improving our ability to model in vivo homeostasis and disease. Methods: This systematic review consolidates known literature on human and mouse liver organoids across all PLC subtypes, emphasizing diagnostic precision, disease modeling, and drug screening capabilities. Results: Across all 39 included studies, organoids were most frequently patient-derived, closely followed by cancer cell line-derived. The literature concentrated on hepatocellular carcinoma and intrahepatic cholangiocarcinoma, while exploration of other subtypes was limited. These studies demonstrate a valuable role for PLC organoid cultures in biomarker discovery, disease modeling, and therapeutic exploration. Conclusions: Encouraging advances such as organoid-on-a-chip and co-culturing systems hold promise for advancing treatment regimens for PLC. Standardizing in vitro protocols is crucial to integrate research breakthroughs into practical treatment strategies for PLC. Impact and implications:: This study provides an overview of the current understanding of tumor-derived organoids in primary liver cancers, emphasizing their potential in diagnostics, disease modeling, and drug screening. The scientific foundation rests on the organoids' ability to replicate the tumor microenvironment and genetic landscape, opening new avenues for personalized therapies. These insights are crucial for both researchers and clinicians, as patient-derived organoids can help identify biomarkers and therapeutic targets. Physicians and policymakers can harness these advances to drive progress in precision medicine, while recognizing the challenges involved in standardizing organoid models for clinical implementation.

Objective: To study a surgical approach to venous vascular thrombosis after uterus transplantation (UTx). Uterus transplantation is the only treatment for uterine factor infertility when conventional therapies are not possible. One of the major limitations of UTx is the high incidence of vascular thrombosis, which in most series reaches approximately 20%. Design: A case report. Setting: Hospital. Patients: We report here a technique used in a 30-year-old woman with congenital absence of the uterus who developed intraoperative thrombosis after a UTx from a brain-dead donor. Intervention: The UTx was performed by revascularizing the graft through bilateral donor internal iliac vessels (artery and vein) anastomosed end-to-side to the external iliac vessels of the recipient. The superior uterine veins were not anastomosed and were left unreconstructed. An end-to-end graft to the recipient’s vaginal anastomosis was performed. After uterus reperfusion, congestion of the organ was noted, and bilateral venous thrombosis of the internal iliac veins of the graft was found. A “Y-shaped” venous jump graft was used to restore venous outflow of the left superior uterine vein and the internal iliac vein of the graft after thrombectomy. Main Outcome Measures: Viability and functionality of the uterus graft after intraoperative bilateral venous thrombosis. Results: The postoperative course was uneventful, and this UTx resulted in the delivery of a healthy infant. Conclusion: To our knowledge, this is the first successful rescue technique used to restore venous outflow and save the viability and functionality of a transplanted uterus. We demonstrated that a transplanted uterus from a deceased donor with a monolateral outflow could succeed in pregnancy and the delivery of a healthy infant.

Solid-organ malignancies represent a significant disease burden and remain one of the leading causes of death globally. In the past few decades, the rapid evolution of imaging modalities has shifted the paradigm towards image-based precision medicine, especially in the care of patients with solid-organ malignancies. Metabolic tumor volume (MTV) is one such semi-quantitative parameter obtained from positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose (FDG) that has been shown to have significant implications in the clinical oncology setting. Across various solid tumor malignancies, including lung cancer, head and neck cancer, breast cancer, esophageal cancer, and colorectal cancer, the current literature has demonstrated an association between MTV and various clinical outcomes. MTV may be used in conjunction with several existing and established clinical parameters to help inform risk stratification and treatment strategies and predict outcomes in cancer. Optimizing such volumetric parameters is paramount for advancing efforts to advance cancer care for our patients. While such advancements are made, it is important to investigate and address the limitations of MTV, including variability in terms of measurement methods, a lack of standardized cut-off values, and the impact of inherent tumor heterogeneity. Despite these limitations, which can precipitate challenges in standardization, MTV as a prognostic factor has great potential and opens an avenue for the future integration of technology into an image-based precision medicine model of care for cancer patients. This article serves as a narrative review and explores the utility and limitations of PET-MTV in various settings of solid-organ malignancy.

Abstract Viral clearance, antibody response and the mutagenic effect of molnupiravir has not been elucidated in at-risk populations. Non-hospitalised participants within 5 days of SARS-CoV-2 symptoms randomised to receive molnupiravir (n = 253) or Usual Care (n = 324) were recruited to study viral and antibody dynamics and the effect of molnupiravir on viral whole genome sequence from 1437 viral genomes. Molnupiravir accelerates viral load decline, but virus is detectable by Day 5 in most cases. At Day 14 (9 days post-treatment), molnupiravir is associated with significantly higher viral persistence and significantly lower anti-SARS-CoV-2 spike antibody titres compared to Usual Care. Serial sequencing reveals increased mutagenesis with molnupiravir treatment. Persistence of detectable viral RNA at Day 14 in the molnupiravir group is associated with higher transition mutations following treatment cessation. Viral viability at Day 14 is similar in both groups with post-molnupiravir treated samples cultured up to 9 days post cessation of treatment. The current 5-day molnupiravir course is too short. Longer courses should be tested to reduce the risk of potentially transmissible molnupiravir-mutated variants being generated. Trial registration: ISRCTN30448031

Abstract As the planet approaches local and global exceedance of the 1.5°C stabilization target, damages from climate change, mostly due to extremes, are growing far faster than projected. While assessment models have largely estimated high costs of mitigation, the cost of green energy is dropping faster than projected. Climate policy has assumed that damage costs are manageable while decarbonization is expensive. Both these assumptions are wrong, potentially leading to a tipping point in human behavior: scientists need to explore options aligned with this emerging reality.

Hilbert curve patterns were laser-textured on both stainless steel substrates and polytetrafluoroethylene (PTFE) thin coatings by applying 15% and 5% of the 2.3-W full laser power, respectively. The nanomechanical and tribological behavior of both smooth and laser-textured PTFE coatings on both smooth and laser-textured stainless steel substrates were studied. It was found that laser-texturing thin PTFE coatings reduced the hardness of PTFE coatings and prevented the coating from tearing under nanoindenter scratches. Furthermore, laser-texturing on both PTFE coatings and the stainless steel substrate improved the coating wear life 29 times compared to the wear life of the control sample without any laser textures.

Background. Postcapillary pulmonary hypertension (PH) can be seen in cirrhosis. Research and treatment goals exist for patients with portopulmonary hypertension but not for postcapillary PH. The aim of this study was to investigate outcomes after liver transplant (LT) for patients with postcapillary PH. Methods. This was a retrospective cohort study of 1173 patients who underwent LT at our center between 2010 and 2020. Using a propensity score matched analysis followed by multivariable Cox modeling on matched patients, we compared post-LT survival between patients with and without postcapillary PH. We also compared several post-LT outcomes between patient with different types of PH. Results. Sixty-eight patients had PH, and 50 had postcapillary PH. The median age was 59 y and the sample was 54% male. There was no significant difference in mortality between patients with postcapillary PH and patients without PH (hazard ratio, 1.72; 95% confidence interval, 0.90-3.31; P = 0.10). There was no significant difference in survival between patients with any type of PH and those without PH. There was no significance difference in post-LT survival, acute kidney injury, or pulmonary edema between patients with different types of PH. Patients with postcapillary PH who survived had a higher cardiac output than those who died (11 L/min in patients who lived, as compared with 8 L/min in patients who died; P = 0.03). Conclusions. Postcapillary PH does not appear to convey a negative impact on post-LT survival. A higher cardiac output may be protective against mortality in patients with postcapillary PH.

Abstract Gastric MALT lymphoma is a common type of non‐Hodgkin's lymphoma that has the potential for cure in patients found to have concomitant Helicobacter pylori (H. pylori) infection. This case report explores the evaluation, diagnosis, and treatment of H. pylori‐negative MALT lymphoma in a patient with a history of a RYGB.

The Los Angeles (LA) basin was responsible for approximately 20% of California’s methane emissions in 2016. Hence, curtailment of these emissions is required to meet California’s greenhouse gas emissions reduction targets. However, effective mitigation remains challenging in the presence of diverse methane sources like oil and gas production fields, refineries, landfills, wastewater treatment facilities, and natural gas infrastructure. In this study, we study the temporal variability in the surface concentrations from February 2015 to April 2022 to detect a declining trend in methane emissions. We quantify the reduction due to this declining trend through inverse modeling and show that methane emissions in the LA basin have declined by 15 Gg, or ∼7% over five years from January 2015 to May 2020.

Beaver engineering in the Arctic tundra induces hydrologic and geomorphic changes that are favorable to methane (CH _4 ) production. Beaver-mediated methane emissions are driven by inundation of existing vegetation, conversion from lotic to lentic systems, accumulation of organic rich sediments, elevated water tables, anaerobic conditions, and thawing permafrost. Ground-based measurements of CH _4 emissions from beaver ponds in permafrost landscapes are scarce, but hyperspectral remote sensing data (AVIRIS-NG) permit mapping of ‘hotspots’ thought to represent locations of high CH _4 emission. We surveyed a 429.5 km ^2 area in Northwestern Alaska using hyperspectral airborne imaging spectroscopy at ∼5 m pixel resolution (14.7 million observations) to examine spatial relationships between CH _4 hotspots and 118 beaver ponds. AVIRIS-NG CH _4 hotspots covered 0.539% (2.3 km ^2 ) of the study area, and were concentrated within 30 m of waterbodies. Comparing beaver ponds to all non-beaver waterbodies (including waterbodies >450 m from beaver-affected water), we found significantly greater CH _4 hotspot occurrences around beaver ponds, extending to a distance of 60 m. We found a 51% greater CH _4 hotspot occurrence ratio around beaver ponds relative to nearby non-beaver waterbodies. Dammed lake outlets showed no significant differences in CH _4 hotspot ratios compared to non-beaver lakes, likely due to little change in inundation extent. The enhancement in AVIRIS-NG CH _4 hotspots adjacent to beaver ponds is an example of a new disturbance regime, wrought by an ecosystem engineer, accelerating the effects of climate change in the Arctic. As beavers continue to expand into the Arctic and reshape lowland ecosystems, we expect continued wetland creation, permafrost thaw and alteration of the Arctic carbon cycle, as well as myriad physical and biological changes.

Aim: Aging and heart failure (HF) are each characterized by increased mitochondrial damage, which may contribute to further cardiac dysfunction. Mitophagy in response to mitochondrial damage can improve cardiovascular health. HF is also characterized by increased formation and consumption of ketone bodies (KBs), which may activate mitophagy and provide an endogenous mechanism to limit the adverse effects of mitochondrial damage. However, the role of KBs in activation of mitophagy in aging and HF has not been evaluated.Methods: We assessed mitophagy by measuring mitochondrial Parkin accumulation and LC3-mediated autophagosome formation in cardiomyocytes from young (2.5 months), aged (2.5 years), and aged rabbits with HF (2.5 years) induced by aortic insufficiency and stenosis. Levels of reactive oxygen species (ROS) generation and redox balance were monitored using genetically encoded sensors ORP1-roGFP2 and GRX1-roGFP2, targeted to mitochondrial or cytosolic compartments, respectively.Results: Young rabbits exhibited limited mitochondrial Parkin accumulation with small (~1 μm2) puncta. Those small Parkin puncta increased four-fold in aged rabbit hearts, accompanied by elevated LC3-mediated autophagosome formation. HF hearts exhibited fewer small puncta, but many very large Parkin-rich regions (4–5 μm2) with completely depolarized mitochondria. Parkin protein expression was barely detectable in young animals and was much higher in aged and maximal in HF hearts. Expression of mitofusin 2 (MFN2) and dynamin-related protein 1 (DRP1) was reduced by almost 50% in HF, consistent with improper fusion-fission, contributing to mitochondrial Parkin build-up. The KB β-hydroxybutyrate (β-OHB) enhanced mitophagy in young and aging myocytes, but not in HF where β-OHB further increased the number of cells with giant Parkin-rich regions. This β-OHB effect on Parkin-rich areas was prevented by cell-permeable TAT-MP1Gly peptide (thought to promote MFN2-dependent fusion). Basal levels of mitochondrial ROS were highest in HF, while cytosolic ROS was highest in aged compared to HF myocytes, suggesting that cytosolic ROS promotes Parkin recruitment to the mitochondria.Conclusion: We conclude that elevated KB levels were beneficial for mitochondrial repair in the aging heart. However, an impaired MFN2-DRP1-mediated fusion-fission process in HF reduced this benefit, as well as Parkin degradation and mitophagic signaling cascade.

We investigated whether the personal importance of objects influences utilitarian decision-making in which damaging property is necessary to produce an overall positive outcome. In Experiment 1, participants judged saving five objects by destroying a sixth object to be less acceptable when the action required destroying the sixth object directly (rather than as a side-effect) and the objects were personally important (rather than unimportant). In Experiment 2, we demonstrated that utilitarian judgments were not influenced by the objects' monetary worth. Together these findings suggest that personal importance underlies people's sensitivity to damaging property as a means for utilitarian gains.

Changes in violent crime rates implies a need for strategies to protect the population. Public safety policies should be focused on preventive security, which has the potential to reduce crime rates. The allocation of the police observation posts contributes to an increase in safety. However, given limited resources, the number of observation units has reduced in most Brazilian cities. Therefore, efficient allocation of these resources is necessary to ensure rational use of security agents. Several aspects influence decisions related to where to install these units, complicating this process. The multiple criteria approach is appropriate in this type of decision-making process, because it allows the decision maker to generate and consolidate knowledge. The results indicate that the most suitable neighborhoods are those with higher rates of violence and greater social gaps. This work presents some benefits to the area of public security, since it formalizes tacit knowledge into explicit knowledge. The information contained in this study may be made available to other public administrators who need to make this kind of decision.

The global characteristics of retrievals of the column-averaged CO2 dry air mole fraction, XCO2, from shortwave infrared observations has been studied using the expected measurement performance of the NASA Orbiting Carbon Observatory-2 (OCO-2) mission. This study focuses on XCO2 retrieval precision and averaging kernels and their sensitivity to key parameters such as solar zenith angle (SZA), surface pressure, surface type and aerosol optical depth (AOD), for both nadir and sunglint observing modes. Realistic simulations have been carried out and the single sounding retrieval errors for XCO2 have been derived from the formal retrieval error covariance matrix under the assumption that the retrieval has converged to the correct answer and that the forward model can adequately describe the measurement. Thus, the retrieval errors presented in this study represent an estimate of the retrieval precision. For nadir observations, we find single-sounding retrieval errors with values typically less than 1 part per million (ppm) over most land surfaces for SZAs less than 70° and up to 2.5 ppm for larger SZAs. Larger errors are found over snow/ice and ocean surfaces due to their low albedo in the spectral regions of the CO2 absorption bands and, for ocean, also in the O2 A band. For sunglint observations, errors over the ocean are significantly smaller than in nadir mode with values in the range of 0.3 to 0.6 ppm for small SZAs which can decrease to values as small as 0.15 for the largest SZAs. The vertical sensitivity of the retrieval that is represented by the column averaging kernel peaks near the surface and exhibits values near unity throughout most of the troposphere for most anticipated scenes. Nadir observations over dark ocean or snow/ice surfaces and observations with large AOD and large SZA show a decreased sensitivity to near-surface CO2. All simulations are carried out for a mid-latitude summer atmospheric profile, a given aerosol type and vertical distribution, a constant windspeed for ocean sunglint and by excluding the presence of thin cirrus clouds. The impact of these parameters on averaging kernels and XCO2 retrieval errors are studied with sensitivity studies. Systematic biases in retrieved XCO2, as can be introduced by uncertainties in the spectroscopic parameters, instrument calibration or deficiencies in the retrieval algorithm itself, are not included in this study. The presented error estimates will therefore only describe the true retrieval errors once systematic biases are eliminated. It is expected that it will be possible to retrieve XCO2 for cloud free observations and for low AOD (here less than 0.3 for the wavelength region of the O2 A band) with sufficient accuracy for improving CO2 surface flux estimates and we find that on average 18% to 21% of all observations are sufficiently cloud-free with only few areas suffering from the presence of persistent clouds or high AOD. This results typically in tens of useful observations per 16 day ground track repeat cycle at a 1° × 1° resolution. Averaging observations acquired along ~1° intervals for individual ground tracks will significantly reduce the random component of the errors of the XCO2 average product for ingestion into data assimilation/inverse models. If biases in the XCO2 retrieval of the order of a few tenth ppm can be successfully removed by validation or by bias-correction in the flux inversion, then it can be expected that OCO-2 XCO2 data can lead to tremendous improvements in estimates of CO2 surface-atmosphere fluxes.

Over the last 50 years, significant progress has been made in the surgical repair of thoracoabdominal aortic aneurysms (TAAA). Improvements in perioperative care and surgical techniques have resulted in reductions in complication and mortality rates. Adjunctive use of distal aortic perfusion and cerebrospinal fluid drainage has been especially helpful, reducing the incidence of neurological deficits to 2.4%. Current research is aimed at improving organ preservation. This review focuses on the current diagnosis and management of TAAA.

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