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Microglia and complement can mediate neurodegeneration in Alzheimer’s disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in TauP301S synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in TauP301S hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte–synapse association and decreased astrocytic and microglial synapses engulfment in TauP301S mice and rescued synapse density. Finally, in an AD mouse model that combines β-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.

TPL2 (MAP3K8) is a central signaling node in the inflammatory response of peripheral immune cells. We find that TPL2 kinase activity modulates microglial cytokine release and is required for microglia-mediated neuron deathin vitro. In acutein vivoneuroinflammation settings, TPL2 kinase activity regulates microglia activation states and brain cytokine levels. In a tauopathy model of chronic neurodegeneration, loss of TPL2 kinase activity reduces neuroinflammation and rescues synapse loss, brain volume loss, and behavioral deficits. Single-cell RNAseq analysis indicates protection in the tauopathy model was associated with reductions in activated microglia subpopulations as well as infiltrating peripheral immune cells. Overall, using various models, we find that TPL2 kinase activity can promote multiple harmful consequences of microglial activation in the brain including cytokine release, iNOS induction, astrocyte activation, and immune cell infiltration. Consequently, inhibiting TPL2 kinase activity could represent a potential therapeutic strategy in neurodegenerative conditions.

Objective:To determine the impact of clinical decision support on guideline-concordant Clostridioides difficile infection (CDI) treatment.Design:Quasi-experimental study in >50 ambulatory clinics.Setting:Primary, specialty, and urgent-care clinics.Patients:Adult patients were eligible for inclusion if they were diagnosed with and treated for a first episode of symptomatic CDI at an ambulatory clinic between November 1, 2019, and November 30, 2020.Interventions:An outpatient best practice advisory (BPA) was implemented to notify prescribers that “vancomycin or fidaxomicin are preferred over metronidazole for C.difficile infection” when metronidazole was prescribed to a patient with CDI.Results:In total, 189 patients were included in the study: 92 before the BPA and 97 after the BPA. Their median age was 59 years; 31% were male; 75% were white; 30% had CDI-related comorbidities; 35% had healthcare exposure; 65% had antibiotic exposure; 44% had gastric acid suppression therapy within 90 days of CDI diagnosis. The BPA was accepted 23 of 26 times and was used to optimize the therapy of 16 patients in 6 months. Guideline-concordant therapy increased after implementation of the BPA (72% vs 91%; P = .001). Vancomycin prescribing increased and metronidazole prescribing decreased after the BPA. There was no difference in clinical response or unplanned encounter within 14 days after treatment initiation. Fewer patients after the BPA had CDI recurrence within 14–56 days of the initial episode (27% vs 7%; P < .001).Conclusions:Clinical decision support increased prescribing of guideline-concordant CDI therapy in the outpatient setting. A targeted BPA is an effective stewardship intervention and may be especially useful in settings with limited antimicrobial stewardship resources.

Stenotrophomonas maltophilia most often infects the lungs, where the physiologic environment is naturally slightly acidic (pH ~6.6), compared to most parts of the body (such as the bloodstream), which have neutral pH values (~7.4). Pneumonia due to S. maltophilia is often treated with the antibiotic levofloxacin, despite the activity of levofloxacin being known to be impaired at acidic pH.

BACKGROUND AND AIMS We assessed the burden of nonalcoholic fatty liver disease (NAFLD)-related acute on chronic liver failure (ACLF) among transplant candidates in the United States, along with waitlist outcomes for this population. APPROACH AND RESULTS We analyzed the United Network for Organ Sharing registry from 2005 to 2017. Patients with ACLF were identified using the European Association for the Study of the Liver/Chronic Liver Failure criteria and categorized into NAFLD, alcohol-associated liver disease (ALD), and hepatitis C virus (HCV) infection. We used linear regression and Chow's test to determine significance in trends and evaluated waitlist outcomes using Fine and Gray's competing risks regression and Cox proportional hazards regression. Between 2005 and 2017, waitlist registrants for NAFLD-ACLF rose by 331.6% from 134 to 574 candidates (P

Purpose Trachoma, the world's leading infectious cause of blindness, has been targeted by the WHO for elimination through the SAFE strategy: surgery, antibiotics, facial cleanliness, and environmental improvement. Although significant progress has been made, there remains a gap in care. This project studied the association of geographical distribution of the remaining need for trachoma intervention and its association with access to basic handwashing facilities at home, as an indicator of water/sanitation infrastructure. We hypothesized that poor water sanitation would correspond to areas where trachoma intervention is still required. Design Retrospective analysis using the WHO Global Health Observatory. Spatial, correlation, and simple and multivariable regression analyses were used. Methods Using data from the WHO Global Health Observatory, a total of 194 countries were analyzed. Two choropleth maps were created, with inset maps focused on the South Pacific region, where the top 5 countries with the greatest population proportion requiring trachoma intervention are located. Results Correlations and the simple regression model of total population with access to handwashing facilities as the only risk factor were insignificant. However, the multivariable regression models with access to handwashing facilities (total, urban, and rural) and population density as risk factors for trachoma intervention were significant. Conclusion Poor water/sanitation infrastructure correlates with trachoma burden. Therefore, water/sanitation infrastructure improvement is a worthwhile target in the efforts toward trachoma elimination, but further research on the association between these important public health indicators is warranted.

TREM2 is an Alzheimer's disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of β-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking Trem2 (PS2APP;Trem2ko) at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2ko mice, with Trem2-deficient microglia showing compromised expression of proliferation/Wnt-related genes and marked accumulation of ApoE., TREM2 is an Alzheimer's disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of β-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking Trem2 (PS2APP;Trem2ko) at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2ko mice, with Trem2-deficient microglia showing compromised expression of proliferation/Wnt-related genes and marked accumulation of ApoE. Plaque abundance was elevated in PS2APP;Trem2ko females at 6–7 months; but by 12 or 19–22 months of age, it was notably diminished in female and male PS2APP;Trem2ko mice, respectively. Across all ages, plaque morphology was more diffuse in PS2APP;Trem2ko brains, and the Aβ42:Aβ40 ratio was elevated. The amount of soluble, fibrillar Aβ oligomers also increased in PS2APP;Trem2ko hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2ko mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2ko mice also exhibited more dendritic spine loss around plaque and more neurofilament light chain in CSF. Thus, aggravated neuritic dystrophy is a more consistent outcome of Trem2 deficiency than amyloid plaque load, suggesting that the microglial packing of Aβ into dense plaque is an important neuroprotective activity. SIGNIFICANCE STATEMENT Genetic studies indicate that TREM2 gene mutations confer increased Alzheimer's disease (AD) risk. We studied the effects of Trem2 deletion in the PS2APP mouse AD model, in which overproduction of Aβ peptide leads to amyloid plaque formation and associated neuritic dystrophy. Interestingly, neuritic dystrophies were intensified in the brains of Trem2-deficient mice, despite these mice displaying reduced plaque accumulation at later ages (12–22 months). Microglial clustering around plaques was impaired, plaques were more diffuse, and the Aβ42:Aβ40 ratio and amount of soluble, fibrillar Aβ oligomers were elevated in Trem2-deficient brains. These results suggest that the Trem2-dependent compaction of Aβ into dense plaques is a protective microglial activity, limiting the exposure of neurons to toxic Aβ species.

Asphaltene deposition in petroleum refineries is known to be problematic as it reduces efficiencyand may lead to structural failure or production downtime. Though several successful approacheshave been utilized to limit deposition through the addition of dispersants and inhibitors topetroleum, these methods require constant intervention and are often expensive. In this study, wedemonstrate an innovative technique to engineer the surface chemistry of pipeline alloy steels toinhibit asphaltene deposition. Pack aluminization, a standard industrial-scale chemical vapordeposition process, is employed at a low temperature of 600 oC to aluminize API 5L X65 highstrength pipe steel substrates. The results showed deposit free steel surfaces after high-pressureand high-temperature fouling experiments. The improvement is attributed to the formation of analuminide intermetallic phase of Fe2Al5, which changes the native oxide chemistry to favoralumina over hematite. The continuous passivating oxide scale, acting as a protective barrier, mitigates asphaltene deposition and sulfidic corrosion. Since this process is based on alloying thesurface of the steel and is not a coating, it is not prone to delamination, and it can be reformedwhen damaged within the aluminized region. The combination of low-cost processing andimproved anti-fouling characteristics makes surface chemistry modification of steel a promisingpreventative approach against asphaltene deposition.

The rise in innovative digital health technologies has led a paradigm shift in health care toward personalized, patient-centric medicine that is reaching beyond traditional brick-and-mortar facilities into patients’ homes and everyday lives. Digital solutions can monitor and detect early changes in physiological data, predict disease progression and health-related outcomes based on individual risk factors, and manage disease intervention with a range of accessible telemedicine and mobile health options. In this review, we discuss the unique transformation underway in the care of patients with liver disease, specifically examining the digital transformation of diagnostics, prediction and clinical decision-making, and management. Additionally, we discuss the general considerations needed to confirm validity and oversight of new technologies, usability and acceptability of digital solutions, and equity and inclusivity of vulnerable populations.

Some protein positions play special roles in determining the magnitude of protein function: at such “rheostat” positions, varied amino acid substitutions give rise to a continuum of functional outcomes, from wild type (or enhanced), to intermediate, to loss of function. This observed range raises interesting questions about the biophysical bases by which changes at single positions have such varied outcomes. Here, we assessed variants at position 98 in human aldolase A (“I98X”). Despite being ~17 Å from the active site and far from subunit interfaces, substitutions at position 98 have rheostatic contributions to the apparent cooperativity (n ( H )) associated with fructose‐1,6‐bisphosphate substrate binding and moderately affected binding affinity. Next, we crystallized representative I98X variants to assess structural consequences. Residues smaller than the native isoleucine (cysteine and serine) were readily accommodated, and the larger phenylalanine caused only a slight separation of the two parallel helixes. However, the diffraction quality was reduced for I98F, and further reduced for I98Y. Intriguingly, the resolutions of the I98X structures correlated with their n ( H ) values. We propose that substitution effects on both n ( H ) and crystal lattice disruption arise from changes in the population of aldolase A conformations in solution. In combination with results computed for rheostat positions in other proteins, the results from this study suggest that rheostat positions accommodate a wide range of side chains and that structural consequences manifest as shifted ensemble populations and/or dynamics changes.

To determine the impact of clinical decision support on guideline-concordantQuasi-experimental study in50 ambulatory clinics.Primary, specialty, and urgent-care clinics.Adult patients were eligible for inclusion if they were diagnosed with and treated for a first episode of symptomatic CDI at an ambulatory clinic between November 1, 2019, and November 30, 2020.An outpatient best practice advisory (BPA) was implemented to notify prescribers that "vancomycin or fidaxomicin are preferred over metronidazole forIn total, 189 patients were included in the study: 92 before the BPA and 97 after the BPA. Their median age was 59 years; 31% were male; 75% were white; 30% had CDI-related comorbidities; 35% had healthcare exposure; 65% had antibiotic exposure; 44% had gastric acid suppression therapy within 90 days of CDI diagnosis. The BPA was accepted 23 of 26 times and was used to optimize the therapy of 16 patients in 6 months. Guideline-concordant therapy increased after implementation of the BPA (72% vs 91%;Clinical decision support increased prescribing of guideline-concordant CDI therapy in the outpatient setting. A targeted BPA is an effective stewardship intervention and may be especially useful in settings with limited antimicrobial stewardship resources.

Background: Vancomycin-resistant Enterococcus faecium (VRE) in particular has evolved as an important cause of hospital acquired infection, especially in immunocompromised hosts. Methods: We present a complex case of a patient with relapsed acute myeloid leukemia who underwent allogenic hematopoietic stem cell transplantation complicated by persistent VRE bacteremia and meningitis. To optimize therapy, various blood and cerebrospinal fluid (CSF) samples were sent to a research laboratory for extensive susceptibility testing, pharmacokinetic analyses, and time-kill experiments. Results: In vitro testing revealed resistance to all first-line treatment options and CSF sampling demonstrated sub-optimal central nervous system concentrations achieved by each antimicrobial agent administered in relation to their respective MIC value. Time-kill analyses at observed CSF concentrations confirmed the lack of bactericidal activity despite use of a four-drug combination regimen. Conclusions: This work is the first to report CSF concentrations of oritavancin and tedizolid in humans and adds to the limited data regarding in vitro susceptibility of new antimicrobial agents such as eravacycline, omadacycline, and lefamulin against VRE. Our study provides new insights into various aspects of treatment of extensively drug-resistant Enterococcus faecium meningitis and bacteremia and supports the continued pursuit of precision medicine for these challenging cases.

When amino acids vary during evolution, the outcome can be functionally neutral or biologically-important. We previously found that substituting a subset of nonconserved positions, "rheostat" positions, can have surprising effects on protein function. Since changes at rheostat positions can facilitate functional evolution or cause disease, more examples are needed to understand their unique biophysical characteristics. Here, we explored whether "phylogenetic" patterns of change in multiple sequence alignments (such as positions with subfamily specific conservation) predict the locations of functional rheostat positions. To that end, we experimentally tested eight phylogenetic positions in human liver pyruvate kinase (hLPYK), using 10-15 substitutions per position and biochemical assays that yielded five functional parameters. Five positions were strongly rheostatic and three were non-neutral. To test the corollary that positions with low phylogenetic scores were not rheostat positions, we combined these phylogenetic positions with previously-identified hLPYK rheostat, "toggle" (most substitution abolished function), and "neutral" (all substitutions were like wild-type) positions. Despite representing 428 variants, this set of 33 positions was poorly statistically powered. Thus, we turned to the in vivo phenotypic dataset for E. coli lactose repressor protein (LacI), which comprised 12-13 substitutions at 329 positions and could be used to identify rheostat, toggle, and neutral positions. Combined hLPYK and LacI results show that positions with strong phylogenetic patterns of change are more likely to exhibit rheostat substitution outcomes than neutral or toggle outcomes. Furthermore, phylogenetic patterns were more successful at identifying rheostat positions than were co-evolutionary or eigenvector centrality measures of evolutionary change.

To develop machine learning algorithms (MLAs) that can differentiate patients with acute cholangitis (AC) and alcohol-associated hepatitis (AH) using simple laboratory variables.A study was conducted of 459 adult patients admitted to Mayo Clinic, Rochester, with AH (n=265) or AC (n=194) from January 1, 2010, to December 31, 2019. Ten laboratory variables (white blood cell count, hemoglobin, mean corpuscular volume, platelet count, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin, albumin) were collected as input variables. Eight supervised MLAs (decision tree, naive Bayes, logistic regression, k-nearest neighbor, support vector machine, artificial neural networks, random forest, gradient boosting) were trained and tested for classification of AC vs AH. External validation was performed with patients with AC (n=213) and AH (n=92) from the MIMIC-III database. A feature selection strategy was used to choose the best 5-variable combination. There were 143 physicians who took an online quiz to distinguish AC from AH using the same 10 laboratory variables alone.The MLAs demonstrated excellent performances with accuracies up to 0.932 and area under the curve (AUC) up to 0.986. In external validation, the MLAs showed comparable accuracy up to 0.909 and AUC up to 0.970. Feature selection in terms of information-theoretic measures was effective, and the choice of the best 5-variable subset produced high performance with an AUC up to 0.994. Physicians did worse, with mean accuracy of 0.790.Using a few routine laboratory variables, MLAs can differentiate patients with AC and AH and may serve valuable adjunctive roles in cases of diagnostic uncertainty.

Chronic hepatitis C viral (HCV) infection continues to carry a high burden of disease despite recent and emerging advancements in treatment. The persistently high prevalence of HCV is attributed to the rising opioid epidemic, with a history of injection drug use as the primary risk factor for infection. As a result, the epidemiology of HCV-infected individuals is changing. Previously a disease of “Baby Boomers,” males, and non-Hispanic blacks, the new generation of patients with HCV includes younger adults from 20 to 39 years of age, both men and women similarly represented, and non-Hispanic whites. Shifting trends in these demographics may be attributed to the use of injection drugs, which also has suggested impact on fibrosis progression in infected individuals. Awareness of the changing face of HCV is necessary to expand and revise recommendations regarding screening, outreach, and care engagement of infected individuals, in order to best identify patients at-risk for infection.

Introduction The purpose of this study was to determine the correlation between a measure of physical performance, a measure of physiology and a measure of anatomy in the setting of carpal tunnel syndrome (CTS). Methods A retrospective review of 215 consecutive patients with suspected CTS was conducted. All patients were evaluated with static 2-point discrimination (2PD), ultrasound (US) measurement of the median nerve cross-sectional area (CSA), and nerve conduction studies (NCS). Correlations between 2PD and US and NCS parameters were calculated. The ability of US/NCS to predict 2PD was evaluated. Results Analysis failed to prove a statistically significant correlation between 2PD and median nerve CSA. A weak correlation was detected between 2PD and NCS parameters. When 2PD was used as a reference standard, NCS parameters combined had the greatest sensitivity, followed by US. Conclusions Currently used diagnostic tests (NCS and US) correlate poorly with 2PD. Muscle Nerve 000: 000-000, 2018 Muscle Nerve 59:236-239, 2019.

Background Liver transplantation (LT) can significantly improve mortality for severe alcoholic hepatitis (AH). However, this practice remains controversial. Our aim is to report the findings from our institution regarding outcomes for LT in severe AH and to discuss the results of a pilot program for discharging selected patients with close follow-up, in order to demonstrate sustained outpatient sobriety before listing. Methods Patient records were reviewed retrospectively from January 1, 2015 to January 17, 2018. The primary outcomes were patient and graft survival after LT. Secondary outcomes included relapse rates after LT, survival for those not transplanted, and reasons for denial among those not approved for transplant listing. Results A total of 18 patients with severe AH were considered for LT, of which 10 were transplanted and 8 were either denied transplantation or died before completing the evaluation. Patient and graft survival rates were 100% among those transplanted, and only 1 of the 10 patients (10%) returned to harmful drinking. In comparison, 6 of 8 (75%) of patients not transplanted died. Among the 10 patients transplanted, 4 were initially not approved for listing and were discharged with close follow-up, to demonstrate outpatient sobriety. All 4 of those patients demonstrated short-term abstinence and ultimately underwent transplantation, with no instances of relapse post-LT. Conclusions Liver transplantation for AH can achieve excellent outcomes with low rates of relapse. Carefully selected patients can be discharged with close monitoring to demonstrate commitment to outpatient sobriety prior to transplant listing.

The objective of this study was to evaluate the in vitro activity of aztreonam plus imipenem-relebactam against clinical and isogenic strains of Escherichia coli and Klebsiella pneumoniae co-harboring NDM and1 serine β-lactamase.Thirteen isolates were included: 4 clinical E. coli, 4 clinical K. pneumoniae, and 5 isogenic E. coli. Drugs were tested in time-kill analyses alone, in dual β-lactam combinations, and in triple drug combinations against all strains.All isolates were resistant to imipenem and imipenem-relebactam, and 85% were aztreonam-resistant. Neither imipenem nor imipenem-relebactam was bactericidal alone while aztreonam was bactericidal against 54% of isolates. The combination of aztreonam+imipenem was bactericidal and synergistic against 7/13 and 10/13 isolates. The addition of relebactam to this combination resulted in synergy against all 11 aztreonam-resistant clinical isolates.Aztreonam plus imipenem-relebactam may be a viable treatment option for aztreonam-non-susceptible NDM and serine β-lactamase-producing E. coli and K. pneumoniae.

This front-end engineering and design (FEED) study is for a carbon dioxide (CO2) capture system for Unit #2 (816 MW) at the Prairie State Generating Company’s (PSGC) Energy Campus in Marissa, IL. The capture technology used is the Advanced KM CDR Process™ from Mitsubishi Heavy Industries (MHI). The project will be the largest post-combustion capture plant in the world. In addition, it will incorporate advancements in the technology including lessons learned from past projects and a new proprietary solvent. The overall business model being developed by PSGC focuses on the generation of 45Q tax credits as a result of sequestering the captured CO2. Because the Prairie Research Institute (PRI) within the University of Illinois at Urbana-Champaign (UIUC) leads both this capture effort and the storage effort, there is close coordination and integration between the capture and storage efforts. This integration is vital to achieving the desired business targets for the project.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The production of an L1 metallo-β-lactamase and an L2 serine active-site β-lactamase precludes the use of β-lactams for the treatment of Stenotrophomonas maltophilia infections. Preclinical data suggest that cefiderocol is the first approved β-lactam with reliable activity against S. maltophilia, but data on strains resistant to current first-line agents are limited, and no studies have assessed cefiderocol-based combinations. The objective of this study was to evaluate and compare the in vitro activity of cefiderocol alone and in combination with levofloxacin, minocycline, polymyxin B, or trimethoprim-sulfamethoxazole (TMP-SMZ) against a collection of highly resistant clinical S. maltophilia isolates., The production of an L1 metallo-β-lactamase and an L2 serine active-site β-lactamase precludes the use of β-lactams for the treatment of Stenotrophomonas maltophilia infections. Preclinical data suggest that cefiderocol is the first approved β-lactam with reliable activity against S. maltophilia, but data on strains resistant to current first-line agents are limited, and no studies have assessed cefiderocol-based combinations. The objective of this study was to evaluate and compare the in vitro activity of cefiderocol alone and in combination with levofloxacin, minocycline, polymyxin B, or trimethoprim-sulfamethoxazole (TMP-SMZ) against a collection of highly resistant clinical S. maltophilia isolates. For this purpose, the MICs of cefiderocol, ceftazidime, levofloxacin, minocycline, polymyxin B, and TMP-SMZ for 37 S. maltophilia isolates not susceptible to levofloxacin and/or TMP-SMZ were determined. Nine strains with various cefiderocol MICs were then tested in time-kill experiments with cefiderocol alone and in combination with comparators. The only agents for which susceptibility rates exceeded 40% were cefiderocol (100%) and minocycline (97.3%). Cefiderocol displayed the lowest MIC50 and MIC90 values (0.125 and 0.5 mg/liter, respectively). In time-kill experiments, synergy was observed when cefiderocol was combined with levofloxacin, minocycline, polymyxin B, or TMP-SMZ against 4/9 (44.4%), 6/9 (66.7%), 5/9 (55.5%), and 6/9 (66.7%) isolates, respectively. These data suggest that cefiderocol displays potent in vitro activity against S. maltophilia, including strains resistant to currently preferred agents. Future dynamic and in vivo studies of cefiderocol alone and in combination are warranted to further define cefiderocol’s synergistic capabilities and its place in therapy for S. maltophilia infections.

PURPOSE OF REVIEW: Acute on chronic liver failure (ACLF) is a unique syndrome that afflicts patients with chronic liver disease and results in high short-term mortality, > 50% at 28 days in patients with severe ACLF (grade 3, ACLF-3). Given this prognosis, there is an urgent need to understand risk factors for this condition, as well as selection criteria for patients who may benefit from liver transplantation (LT). RECENT FINDINGS: Several studies have identified risk factors for developing ACLF, including higher model for end-stage liver disease score, anemia, and morbid obesity, as well ACLF mortality, such as infection, increasing organ failures, and higher white blood cell count. Prognostic tools are now available as online calculators. Regarding LT in ACLF, data suggest that even patients with ACLF-3 may do well after LT, with 1-year survival > 80% in several studies. Improvement in organ failures prior to LT, higher donor quality, and lack of mechanical ventilation further improve outcomes. Importantly, ACLF-3 patients may have higher short-term wait list mortality than patients listed status-1a, suggesting that increased LT prioritization may be warranted. SUMMARY: ACLF is a high-mortality condition that frequently responds well to LT. Ongoing efforts to understand the natural history of ACLF and predictors of improved post-LT survival will facilitate LT criteria for this condition, which may ultimately include increased LT prioritization for selected patients.

Habitat loss is a leading cause of species declines worldwide (1, 2). Using the Land Use Harmonization dataset (3) as the basis for ecological niche modelling, we quantify modelled changes in global suitable habitat over the past three centuries for Asian elephants, a megaherbivore representing diverse biomes. Between 1700-2015 over 60% of habitat suitable for elephants was lost, while average patch size declined 84-86%, and the largest patch decreased from 45% to 5%. Over half of the currently inhabited range is considered unsuitable for elephants, whereas suitable habitat is predicted to decline further from 2015-2099 across all six scenarios representing a range of emissions pathways and socioeconomic narratives. However, results vary by region and scenario in a non-linear manner, indicating that socioeconomic outcomes are as important as emissions pathways for the future of these habitats. Lao PDR, Thailand and Myanmar currently have lower elephant populations relative to the amount of available habitat. On the other hand, continued losses in densely settled areas such as India and Sri Lanka are expected to exacerbate human-elephant conflict. Only a few regions, notably peninsular Malaysia, Borneo, and Yunnan province, China, are predicted to have potential for habitat recovery. The most catastrophic losses across all range states occurred under a scenario of mid-range emissions but high regional inequities, leading to overexploitation of critical habitats. We conclude that steps to mitigate climate change must be taken alongside measures to ensure inter-regional social equity in order to safeguard these landscapes for elephants, humans and other species. Significance Human land-use change is a leading driver of biodiversity loss, but effects are difficult to quantify over centennial timescales. Asian elephants occupy diverse biomes that have long been impacted by human activities and are thus indicative of the fates of numerous co-existing species. Over 60% of suitable elephant habitat has been lost since the 1700s and over half of the currently inhabited range may be considered unsuitable. Declines are predicted to continue to 2099 under six scenarios of global change across the majority of elephant range states, with the worst losses corresponding to a scenario representing mid-range emissions but high global inequity. Thus climate change mitigation strategies must include measures to facilitate equitable societies to safeguard and recover elephant landscapes, together with the unique biodiversity they represent.