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It is increasingly clear that cellular metabolic function varies not just between cells of different tissues, but also within tissues and cell types. In this essay, we envision how differences in central carbon metabolism arise from multiple sources, including the cell cycle, circadian rhythms, intrinsic metabolic cycles, and others. We also discuss and compare methods that enable such variation to be detected, including single-cell metabolomics and RNA-sequencing. We pay particular attention to biosensors for AMPK and central carbon metabolites, which when used in combination with metabolic perturbations, provide clear evidence of cellular variance in metabolic function.

INTRODUCTION: Personalized and tumor-informed circulating tumor DNA (ctDNA) testing is feasible and allows for molecular residual disease (MRD) identification in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: In this retrospective analysis of commercial cases from multiple US institutions, personalized, tumor-informed, whole-exome sequenced, and germline-controlled ctDNA levels were quantified and analyzed in patients with PDAC. Plasma samples (n = 1329) from 298 clinically validated patients were collected at diagnosis, perioperatively (MRD-window; within 2-12 weeks after surgery, before therapy), and during surveillance (>12 weeks post-surgery if no ACT or starting 4 weeks post-ACT) from November 2019 to March 2023. RESULTS: Of the initially diagnosed patients with stages I-III PDAC who went for resection, the median follow-up time from surgery was 13 months (range 0.1-214). Positive ctDNA detection rates were 29% (29/100) and 29.6% (45/152) during the MRD and surveillance windows, respectively. Positive ctDNA detection was significantly associated with shorter DFS within the MRD window (median DFS of 6.37 months for ctDNA-positive vs 33.31 months for ctDNA-negative patients; HR: 5.45, P

Abstract: The local scale of rotating convection, ℓ, is a fundamental parameter in many turbulent geophysical and astrophysical fluid systems, yet it is often poorly constrained. Here we conduct rotating convection laboratory experiments analogous to convecting flows in planetary cores and subsurface oceans to obtain measurements of the local scales of motion. Utilizing silicone oil as the working fluid, we employ shadowgraph imagery to visualize the flow, from which we extract values of the characteristic cross‐axial scale of convective columns and plumes. These measurements are compared to the theoretical values of the critical onset length scale, ℓcrit, and the turbulent length scale, ℓturb. Our experimentally obtained length scale measurements simultaneously agree with both the onset and turbulent scale predictions across three orders of magnitude in convective supercriticality , a correlation that is consistent with inferences made in prior studies. We further explore the nature of this correlation and its implications for geophysical and astrophysical systems.

The term "metaverse" first appeared in Neal Stephenson's 1992 science fiction novel Snow Crash. It was defined as a virtual environment shared through the Internet in which avatars represent people in three dimensions, and users can build what they wish. Since the publication of Stephenson's novel, technological advances have enabled the creation of several metaverses for widespread usages, such as virtual world platforms like World of Warcraft and Second Life. This paper aims to review studies on the metaverse using bibliometric analysis. The findings include a summary of the most important scientific articles and journals in the subject area and the most prolific and prominent authors, organisations, and nations. Furthermore, keyword co-occurrence analysis revealed the core research clusters and their sub-themes, allowing for more pertinent debates and viewpoints on crucial areas for future research. Finally, the implications for theory and practice have been addressed, offering a comprehensive overview of expected metaverse impacts on industry and society.

Abstract Open-lung ventilation during cardiopulmonary bypass (CPB) in patients undergoing heart transplantation (HTx) is a potential strategy to mitigate postoperative acute respiratory distress syndrome (ARDS). We utilized an ovine HTx model to investigate whether open-lung ventilation during CPB reduces postoperative lung damage and complications. Eighteen sheep from an ovine HTx model were included, with ventilatory interventions randomly assigned during CPB: the OPENVENT group received low tidal volume (VT) of 3 mL/kg and positive end-expiratory pressure (PEEP) of 8 cm H20, while no ventilation was provided in the NOVENT group as per standard of care. The recipient sheep were monitored for 6 h post-surgery. The primary outcome was histological lung damage, scored at the end of the study. Secondary outcomes included pulmonary shunt, driving pressure, hemodynamics and inflammatory lung infiltration. All animals completed the study. The OPENVENT group showed significantly lower histological lung damage versus the NOVENT group (0.22 vs 0.27, p = 0.042) and lower pulmonary shunt (19.2 vs 32.1%, p = 0.001). In addition, the OPENVENT group exhibited a reduced driving pressure (9.6 cm H2O vs. 12.8 cm H2O, p = 0.039), lower neutrophil (5.25% vs 7.97%, p ≤ 0.001) and macrophage infiltrations (11.1% vs 19.6%, p

Abstract Background Escherichia coli is the most common cause of human bloodstream infections and bacterial sepsis/septic shock. However, translation of preclinical septic shock resuscitative therapies remains limited mainly due to low-fidelity of available models in mimicking clinical illness. To overcome the translational barrier, we sought to replicate sepsis complexity by creating an acutely critically-ill preclinical bacterial septic shock model undergoing active 48-h intensive care management. Aim To develop a clinically relevant large-animal (ovine) live-bacterial infusion model for septic shock. Methods Septic shock was induced by intravenous infusion of the live antibiotic resistant extra-intestinal pathogenic E. coli sequence type 131 strain EC958 in eight anesthetised and mechanically ventilated sheep. A bacterial dose range of 2 × 105–2 × 109 cfu/mL was used for the dose optimisation phase (n = 4) and upon dose confirmation the model was developed (n = 5). Post-shock the animals underwent an early-vasopressor and volume-restriction resuscitation strategy with active haemodynamic management and monitoring over 48 h. Serial blood samples were collected for testing of pro-inflammatory (IL-6, IL-8, VEGFA) and anti-inflammatory (IL-10) cytokines and hyaluronan assay to assess endothelial integrity. Tissue samples were collected for histopathology and transmission electron microscopy. Results The 2 × 107 cfu/mL bacterial dose led to a reproducible distributive shock within a pre-determined 12-h period. Five sheep were used to demonstrate consistency of the model. Bacterial infusion led to development of septic shock in all animals. The baseline mean arterial blood pressure reduced from a median of 91 mmHg (71, 102) to 50 mmHg (48, 57) (p = 0.004) and lactate levels increased from a median of 0.5 mM (0.3, 0.8) to 2.1 mM (2.0, 2.3) (p = 0.02) post-shock. The baseline median hyaluronan levels increased significantly from 25 ng/mL (18, 86) to 168 ng/mL (86, 569), p = 0.05 but not the median vasopressor dependency index which increased within 1 h of resuscitation from zero to 0.39 mmHg−1 (0.06, 5.13), p = 0.065, and. Over the 48 h, there was a significant decrease in the systemic vascular resistance index (F = 7.46, p = 0.01) and increase in the pro-inflammatory cytokines [IL-6 (F = 8.90, p = 0.02), IL-8 (F = 5.28, p = 0.03), and VEGFA (F = 6.47, p = 0.02)]. Conclusions This critically ill large-animal model was consistent in reproducing septic shock and will be applied in investigating advanced resuscitation and therapeutic interventions.

Abstract Through their involvement in cancer metabolism, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), γ-glutamyltransferase (GGT) and lactate dehydrogenase (LDH) reflect the tumor burden and thus could have a prognostic potential for patients treated with immune checkpoint inhibitors (CPI). Therefore, this study investigated the prognostic potential of these parameters in a real-world cohort of patients with metastatic renal cell cancer (mRCC) under first-line CPI-based therapy. The retrospective study cohort included 82 mRCC patients treated with CPI-based first-line therapy between 2019 and 2023. Progression-free survival (PFS), overall survival (OS) and response rates were evaluated according to baseline levels and early dynamic changes of ALAT, ASAT, GGT and LDH. Multivariate Cox proportional hazard regression models were generated to identify independent prognosticators for PFS and OS. High baseline levels and non-normalized kinetics of ALAT, ASAT, GGT and LDH were significantly associated with shorter PFS and OS (p

The initial conditions for the simulation of a seismically induced tsunami for a rapid, assumed-to-be-instantaneous vertical seafloor displacement is given by the Kajiura low-pass filter integral. This work proposes a new, efficient, and accurate approach for its numerical evaluation, valid when the seafloor displacement is discretized as a set of rectangular contributions over variable bathymetry. We compare several truncated quadrature formulae, selecting the optimal one. The reconstruction of the initial sea level perturbation as a linear combination of pre-computed elementary sea surface displacements is tested on the tsunamigenic Kuril earthquake doublet – a megathrust and an outer rise – that occurred in the central Kuril Islands in late 2006 and early 2007. We also confirm the importance of the horizontal contribution to tsunami generation, and we consider a simple model of the inelastic deformation of the wedge on realistic bathymetry. The proposed approach results are accurate and fast enough to be considered relevant for practical applications. A tool to build a tsunami source database for a specific region of interest is provided.

Abstract Background Transient erythroblastopenia of childhood (TEC) is an acquired, self-limited pure red cell aplasia that usually occurs in children 4 years old and younger. This clinical condition has been priorly described to be linked to numerous viral and immunologic mechanisms. COVID-19, caused by the coronavirus SARS-CoV-2, was initially discovered in China in December 2019. The disease quickly spread worldwide, resulting in pandemic. Case Presentation This manuscript reports a new clinically relevant condition associated to COVID-19, describing a child with clinical and biochemical signs of Pure Red Blood cells aplasia and complete absence of erythroblasts at the bone marrow needle aspiration with signs of erythrophagocytosis, resembling morphological signs such as in hemophagocytic lymphohistiocytosis (HLH), temporally associated to SARS-CoV-2 infection. Conclusion This report highlights a newly described continuum laboratory and clinical spectrum of immune/hematological dysregulations secondary to SARS-CoV-2. SARS-CoV‐2 infection-linked TEC has never been described in literature, but, according to our findings, should be considered in all the patients with transient erythroblastopenia without congenital red blood cell abnormalities and serology negative for major infections associated with TEC. This condition must be considered in the same spectrum of MIS-C and the inter-links among the two clinical manifestations, as well as a potential interdependence among them, should be considered in the future.

Lower extremity lymphedema (LEL) is a common complication following surgical staging of endometrial cancer. LEL is a chronic condition associated with significant impact on patient morbidity and quality of life (QoL). This review aimed to report the current evidence in the literature on secondary LEL after surgical staging for endometrial cancer, focusing on the incidence based on different approaches to lymph node staging, diagnosis, risk factors, and the impact on QoL. Due to the absence of a standardized agreement regarding the methodology for evaluating LEL, the documented frequency of occurrence fluctuates across different studies, ranging from 0% to 50%. Systematic pelvic lymphadenectomy appears to be the primary determinant associated with the emergence of LEL, whereas the implementation of sentinel lymph node biopsy has notably diminished the occurrence of this lymphatic complication after endometrial cancer staging. LEL is strongly associated with decreased QoL, lower limb function, and negative body image, and has a detrimental impact on cancer-related distress reported by survivors. Standardization of lymphedema assessment is needed, along with cross-cultural adaptation of subjective outcome measures for self-reported LEL. The advent of sentinel lymph node mapping represents the ideal approach for accurate nodal assessment with less short- and long-term morbidity. Further research is needed to definitively assess the prevalence and risk factors of LEL and to identify strategies to improve limb function and QoL in cancer survivors with this chronic condition.

In recent years, the global market for novel psychoactive substances (NPS) has continued to grow rapidly, presenting significant challenges for analytical toxicologists. Indeed, the constant emergence and the evolving nature of NPS requires their rapid detection and identification; studies on their pharmacokinetics; and ideally the prediction of future analogues to try and stay ahead of the competition with illicit NPS manufacturers. This presentation will provide an overview, from the analytical toxicologists’ point of view, of the current challenges and future outlooks for detecting, identifying, and predicting NPS. It will explore both recent efforts in my group, and what we plan to do in the near future to tackle the emergence of NPS using multidisciplinary approaches. I will discuss the importance of both emerging analytical tools and techniques, including portable instruments, for the rapid and on-site detection and identification of NPS. Finally, I will briefly mention how computational methods could simplify substance identification and aid in predicting the emergence of NPS. It is hoped that some of the described approaches will have positive implications for public health and safety and will create opportunities to promote exchange between various stakeholders, including basic scientists/toxicologists, clinicians, and policy makers.

Ambient ionisation has recently become an attractive addition to toxicology workflows, as it provides rapid analysis of drugs of abuse compared with traditional chromatographic techniques such as LC-MS. Based on electrospray ionisation mechanisms, paper spray ionisation (PSI) generates ions directly from a sample spotted onto a paper substrate, minimising the cost and time of analysis. PSI uses dried matrix spots (DMS), a well-established but evolving trend in toxicology providing an alternative to collection of venous blood samples. DMS also offer improved matrix and analyte stability due to fewer enzymatic processes taking place as a result of matrix dehydration. Using DMS and PSI combined introduces the possibility of less invasive sample collection for the patient, no sample extraction or chromatography required facilitating lower cost per analysis, and quicker turnaround with earlier results available to clinicians. Emergency department (ED) presentations due to acute drug toxicity can be life-threatening; currently clinicians rely on self-report and clinical patterns of toxicity to determine the drug(s) likely to be involved. The use of PSI for identification and quantitation of NPS/other drugs can provide results on drugs present to inform patient care early in the patients’ ED presentation. With the NPS market continually expanding, PSI coupled to MS has the potential for a wide-reaching benefit to ED care, ultimately enabling clinicians to tailor patient care based on analytically confirmed NPS use. This presentation will illustrate our preliminary work using a VeriSpray PSI-MS.