Background Given the association of NAFLD with metabolic risks, a name change to MAFLD is proposed. We compared the long‐term outcomes of NAFLD and MAFLD. Methods We included patients with fatty liver disease (FLD) from NHANES III and NHANES 2017–2018 (FLD defined as moderate to severe hepatic steatosis by ultrasound for NHANES III and as having a controlled attenuation parameter ≥285 dB/m for NHANES 2017–2018). NAFLD was defined as FLD without other liver diseases and excess alcohol use. Metabolic‐associated fatty liver disease (MAFLD) was defined as FLD and metabolic dysfunction per criteria. All NHANES III participants had linked mortality data through December 31, 2015. Results NHANES III participants (n = 12,878): mean age 43.1 years old; 49.5% male; 20.3% with FLD, 16.5% with NAFLD, and 18.1% with MAFLD. NHANES 2017–2018 participants (n = 4328): mean age 48.0 years old; 49.1% male; 36.8% with FLD, 34.2% with NAFLD, and 36.3% with MAFLD. Excellent concordance was noted between MAFLD and NAFLD diagnosis in both data sets (kappa coefficient = 0.83–0.94). Except for components of each definition (e.g., alcohol use for MAFLD), no other major differences in clinical characteristics were noted. During up to 27 years of follow‐up (median of 22.8 years), no differences in cumulative all‐cause and cause‐specific mortality were noted. In addition to the stage of fibrosis, insulin resistance was a predictor of liver mortality in NAFLD, and alcohol‐associated liver disease (ALD) was a predictor of mortality in MAFLD. Conclusions MAFLD and NAFLD have similar clinical profiles and long‐term outcomes. The increased liver‐related mortality among NAFLD is driven by insulin resistance, and among MAFLD is primarily driven by ALD.

We report the development of in vivo subcellular high-resolution mass spectrometry (HRMS) for proteo-metabolomic molecular systems biology in complex tissues.W ith light microscopy, we identified the left-dorsal and left-ventral animal cells in cleavage-stage non-sentient Xenopus laevis embryos.U sing precision-translated fabricated microcapillaries,t he subcellular content of each cell was double-probed, each time swiftly (< 5s/event) aspirating < 5% of cell volume ( % 10 nL). The proteins and metabolites were analyzed by home-built ultrasensitive capillary electrophoresis electrospray ionization employing orbitrap or time-of-flight HRMS.Labelfree detection of % 150 metabolites (57 identified) and 738 proteins found proteo-metabolomic networks with differential quantitative activities between the cell types.With spatially and temporally scalable sampling, the technology preserved the integrity of the analyzed cells,t he neighboring cells,a nd the embryo.95% of the analyzed embryos developed into sentient tadpoles that were indistinguishable from their wild-type siblings based on anatomy and visual function in abackground color preference assay.

We report the development of in vivo subcellular high-resolution mass spectrometry (HRMS) for proteo-metabolomic molecular systems biology in complex tissues.W ith light microscopy, we identified the left-dorsal and left-ventral animal cells in cleavage-stage non-sentient Xenopus laevis embryos.U sing precision-translated fabricated microcapillaries,t he subcellular content of each cell was double-probed, each time swiftly (< 5s/event) aspirating < 5% of cell volume ( % 10 nL). The proteins and metabolites were analyzed by home-built ultrasensitive capillary electrophoresis electrospray ionization employing orbitrap or time-of-flight HRMS.Labelfree detection of % 150 metabolites (57 identified) and 738 proteins found proteo-metabolomic networks with differential quantitative activities between the cell types.With spatially and temporally scalable sampling, the technology preserved the integrity of the analyzed cells,t he neighboring cells,a nd the embryo.95% of the analyzed embryos developed into sentient tadpoles that were indistinguishable from their wild-type siblings based on anatomy and visual function in abackground color preference assay.

We present the first example of in vivo high-resolution mass spectrometry (HRMS) for subcellular molecular systems biology of proteins and metabolites. With light microscopy, we identified the left-dorsal and left-ventral animal cells in cleavage-stage non-sentient Xenopus laevis embryos. Using precision-translated fabricated microcapillaries, the subcellular content of each cell was double-probed, each time collecting <5% of cell volume (~10 nL) swiftly (<5 s/event). The proteins and metabolites were analyzed by custom-built ultrasensitive capillary electrophoresis electrospray ionization employing Orbitrap and time-of-flight HRMS. Label-free detection of ~150 metabolites (57 identified) and 738 proteins found proteo-metabolomic networks with differential quantitative activities between the cell types. Spatially and temporally scalable sampling the technology preserved the integrity of the analyzed cells, the neighboring cells, and the embryo. 95% of the analyzed embryos developed into sentient tadpoles that were indistinguishable from their wild-type siblings based on anatomy and visual function in a background color preference assay.

Bioanalytics Single‐cell mass spectrometry was advanced by Peter Nemes et al. in their Research Article on page 12852 to enable dual characterization of proteins and metabolites in embryo cells.

21In the Drosophila lineage, both sperm and the primary female sperm storage organ, the 22 seminal receptacle (SR), may reach extraordinary lengths. In D. melanogaster, long SRs 23 bias fertilization toward long sperm during the displacement stage of sperm 24 competition. This sperm-SR interaction, together with a genetic correlation between the 25 traits, suggests that the coevolution of exaggerated sperm and SR lengths may be driven 26 by Fisherian runaway selection. To further understand the costs and benefits of long 27 sperm and SR genotypes in both sexes, we measured male and female fitness in inbred 28 lines of D. melanogaster derived from four populations previously selected for long 29 sperm, short sperm, long SRs, or short SRs. We specifically asked: do long SRs impose 30 costs or benefits on the females that bear them? Do genotypes that generate long sperm 31 in males impose a fitness cost on females sharing those genotypes? Is long sperm an 32 honest indicator of male viability and associated with increased fitness? And finally, are 33 the benefits of long sperm restricted to competitive fertilization success, or do long-34 sperm males also have increased mating success and fecundity in single matings? We 35 found that both sexes have increased longevity in long sperm and long SR genotypes, 36 with fewer reproduction-related benefits and evidence for trade-offs in males, 37 compared to females. Our results suggest that sperm length and SR length are both 38 indicators of increased viability. 39 40

W e read with great interest the article published in a recent issue of Critical Care Medicine on the prevalence of intracranial hemorrhage (ICH) in COVID-19 patients on extracorporeal membrane oxygenation (ECMO) by Seeliger et al (1).We were struck by the high prevalence of ICH in COVID-19 patients on ECMO. This retrospective article analyzes ICH occurrence rate and clinical outcomes in patients on ECMO due to COVID-19-induced acute respiratory distress syndrome (C-ARDS) compared with other viral acute respiratory distress syndrome (ARDS). The article reported ICH in 29 of 142 COVID-19 patients (20%), including 15 major bleeds.We have not observed a similar predilection to ICH in COVID-19 at our institution. We have cared for 69 COVID patients requiring venovenous ECMO support for C-ARDS, of whom 66.6% survived to hospital discharge. Of these patients, only two patients (2.9%) suffered ICH, one while on ECMO and the other following her ECMO run. Both patients recovered completely without neurologic sequelae. The reason for the discrepant rates of ICH in C-ARDS patients is unclear. Our patient population was younger, with a mean age of 43 (range, 16-68). Severity of ARDS at the time of cannulation appears similar between the groups. Our practices for screening for ICH mirror those of Seeliger et al (1). However, only 13 patients in our cohort had head imaging which is a lower percentage of imaging than the authors' report, so some subclinical bleeds could be missed. Regardless, the rate of major/fatal bleeds observed by Seeliger et al (1) still far exceeds our observed rate.Perhaps the biggest difference between cohorts is the anticoagulation strategy. Unfractionated heparin (UFH) was primarily used by Seeliger et al (1). In contrast, ~80% (n = 55) of our patients were anticoagulated with bivalirudin targeting an activated partial thromboplastin time between 50 and 80 seconds. In our patients, 14.5% (n = 10) started out with UFH and were transitioned to bivalirudin, whereas only 5.8% (n = 4) were anticoagulated with UFH exclusively.Our institutional data does not show an increased prevalence of ICH in C-ARDS patients on venovenous ECMO. Based on our experience, we postulate that bivalirudin may represent a safer strategy for anticoagulation in C-ARDS patients on VV-ECMO. Further study with prospective clinical trials is warranted to confirm these findings.

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