A US perspective on closing the carbon cycle to defossilize difficult-to-electrify segments of our economy.

Electrification to reduce or eliminate greenhouse gas emissions is essential to mitigate climate change. However, a substantial portion of our manufacturing and transportation infrastructure will be difficult to electrify and/or will continue to use carbon as a key component, including areas in aviation, heavy-duty and marine transportation, and the chemical industry. In this Roadmap, we explore how multidisciplinary approaches will enable us to close the carbon cycle and create a circular economy by defossilizing these difficult-to-electrify areas and those that will continue to need carbon. We discuss two approaches for this: developing carbon alternatives and improving our ability to reuse carbon, enabled by separations. Furthermore, we posit that co-design and use-driven fundamental science are essential to reach aggressive greenhouse gas reduction targets.

The effect of age on cerebral vasospasm and delayed cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND: The association between patient age and cerebral arterial vasospasm (CVS) and delayed cerebral ischemia (DCI) risk following aneurysmal subarachnoid hemorrhage (aSAH) remains unclear. This study aims to assess the role of age on aSAH-related complications. METHODS: Single-center retrospective study comprising aSAH patients treated between January 2009 and March 2023. Age was analyzed as continuous and categorical variables (<60yrs vs. ≥60yrs and by decade). Outcomes of interest included radiographic CVS, DCI, cerebral infarction, in-hospital mortality, length-of-stay, ventriculoperitoneal shunt placement, and modified Rankin Scale (mRS) scores at discharge and 3-month follow-up. RESULTS: 925 aSAH patients were included. Most (n=598; 64.6%) were <60yrs old (46±9.1yrs). CVS likelihood was lower in the older cohort (aOR=0.56 [0.38-0.82]). Patients ≥60yrs had higher mortality rates (aOR=2.24 [1.12-4.47]) and worse mRS scores at discharge (aOR=2.66 [1.91-3.72]) and 3-month follow-up (aOR=2.19 [1.44-3.32]). Advanced age did not have a significant effect on DCI or cerebral infarction risk. Higher in-hospital mortality was documented with increasing age (p<0.001). A significant interaction between CVS and age for the outcome of DCI was documented, with a stronger positive effect on poor outcomes (i.e., higher odds of DCI) among patients aged <60 years compared to those aged ≥60. CONCLUSION: There is an inverse relationship between patient age and CVS incidence following aSAH. Nonetheless, patients ≥60yrs had comparable DCI rates, higher in-hospital mortality, and worse functional outcomes than their younger counterparts. Routine screening and reliance on radiographic CVS as primary marker for aSAH-related complications should be reconsidered, particularly in older patients.

Contemporary cohort of cerebral cavernous malformations: natural history and utility of follow-up MRI.

OBJECTIVE: This study reports the natural history of cerebral cavernous malformations (CCMs) in a contemporary cohort with prospectively collected data from multiple sources, access to follow-up imaging, integrated electronic medical records, and detailed imaging review by study investigators. The authors aimed to define the first prospective symptomatic hemorrhage (SH) and severe SH rates, determine the risk of a second prospective SH, and identify risk factors for SH. METHODS: From a prospectively maintained database of adult patients with radiologically defined CCM, those with radiation-induced CCM, those who underwent surgery within 3 months postdiagnosis, and those with < 1 year of follow-up were excluded. The patients' medical history and radiological features of the CCM were recorded at the time of diagnosis. Follow-up annual written surveys were completed for 5 years after the initial diagnosis and then semiannually thereafter in addition to medical record and follow-up imaging review. Outcomes of interest included SH and severe SH. RESULTS: Of 315 patients, 58.7% were female and 19.7% had familial CCMs. At diagnosis, 37.1% of patients had ruptured CCMs and 28.9% of the CCMs were located in the brainstem. The 5-year cumulative rates of prospective SH and severe SH in those with ruptured CCMs at diagnosis were 41.2% and 12.8%, respectively, compared with 6.1% and 2.5% in patients with unruptured CCMs at diagnosis (p < 0.0001). Risk factors for prospective SH included a ruptured CCM at diagnosis and persistent or new hyperintensity on T1-weighted MRI performed > 3 months after baseline MRI. For those with a ruptured CCM at diagnosis, the risk of developing a second prospective SH was similar to that of developing a first SH. CONCLUSIONS: In a contemporary cohort of adult patients with CCM, the authors report 5-year SH and severe SH rates, rates of second prospective hemorrhage, and predictors of SH. Persistent or new hyperintensity on T1-weighted MRI may be a useful marker of disease activity.

Racial and Ethnic Differences in Mortality and Functional Outcomes Following Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Ischemic and hemorrhagic stroke incidence tends to be higher among minority racial and ethnic groups. The effect of race and ethnicity following an aneurysmal subarachnoid hemorrhage (aSAH) remains poorly understood. Thus, we aimed to explore the association between race and ethnicity and aSAH outcomes. METHODS: Single-center retrospective review of patients with aSAH from January 2009 to March 2023. Primary outcome was in-hospital mortality. Secondary outcomes included delayed cerebral ischemia, cerebral infarction, radiographic and symptomatic vasospasm, pulmonary complications, epileptic seizures, external ventricular drain placement, and modified Rankin Scale score at discharge and 3-month follow-up. Associations between race and ethnicity and outcomes were assessed using binary and ordinal regression models, with multivariable models adjusted for significant covariates. RESULTS: A total of 1325 patients with subarachnoid hemorrhage presented to our center. Among them, 443 cases were excluded, and data from 882 patients with radiographically confirmed aSAH were analyzed. Distribution by race and ethnicity was 40.8% (n=360) White, 31.4% (n=277) Hispanic, 22.1% (n=195) Black, and 5.7% (n=50) Asian. Based on Hunt-Hess and modified Fisher grade, aSAH severity was similar among groups (P=0.269 and P=0.469, respectively). In-hospital mortality rates were highest for Asian (14.0%) and Hispanic (11.2%) patients; however, after adjusting for patient sex, age, health insurance, smoking history, alcohol and substance abuse, and aneurysm treatment, the overall likelihood was comparable to White patients. Hispanic patients had higher risks of developing cerebral infarction (adjusted odds ratio, 2.17 [1.20-3.91]) and symptomatic vasospasm (adjusted odds ratio, 1.64 [1.05-2.56]) than White patients and significantly worse discharge modified Rankin Scale scores (adjusted odds ratio, 1.44 [1.05-1.99]). Non-White patients also demonstrated a lower likelihood of 0 to 2 discharge modified Rankin Scale scores (adjusted odds ratio, 0.71 [0.50-0.98]). No significant interactions between race and ethnicity and age or sex were found for in-hospital mortality and functional outcomes. CONCLUSIONS: Our study identified significant differences in cerebral infarction and symptomatic vasospasm risk between Hispanic and White patients following aSAH. A higher likelihood of worse functional outcomes at discharge was found among non-White patients. These findings emphasize the need to better understand predisposing risk factors that may influence aSAH outcomes. Efforts toward risk stratification and patient-centered management should be pursued.

Boston Criteria v2.0 for Cerebral Amyloid Angiopathy Without Hemorrhage: An MRI-Neuropathologic Validation Study.

BACKGROUND AND OBJECTIVES: Updated criteria for the clinical-MRI diagnosis of cerebral amyloid angiopathy (CAA) have recently been proposed. However, their performance in individuals without symptomatic intracerebral hemorrhage (ICH) presentations is less defined. We aimed to assess the diagnostic performance of the Boston criteria version 2.0 for CAA diagnosis in a cohort of individuals ranging from cognitively normal to dementia in the community and memory clinic settings. METHODS: Fifty-four participants from the Mayo Clinic Study of Aging or Alzheimer's Disease Research Center were included if they had an antemortem MRI with gradient-recall echo sequences and a brain autopsy with CAA evaluation. Performance of the Boston criteria v2.0 was compared with v1.5 using histopathologically verified CAA as the reference standard. RESULTS: The median age at MRI was 75 years (interquartile range 65-80) with 28/54 participants having histopathologically verified CAA (i.e., moderate-to-severe CAA in at least 1 lobar region). The sensitivity and specificity of the Boston criteria v2.0 were 28.6% (95% CI 13.2%-48.7%) and 65.3% (95% CI 44.3%-82.8%) for probable CAA diagnosis (area under the receiver operating characteristic curve [AUC] 0.47) and 75.0% (55.1-89.3) and 38.5% (20.2-59.4) for any CAA diagnosis (possible + probable; AUC 0.57), respectively. The v2.0 Boston criteria were not superior in performance compared with the prior v1.5 criteria for either CAA diagnostic category. DISCUSSION: The Boston criteria v2.0 have low accuracy in patients who are asymptomatic or only have cognitive symptoms. Additional biomarkers need to be explored to optimize CAA diagnosis in this population.

No Improvement in Intention-to-treat Survival and Increasing Liver Nonutilization Rate During the MELD Era.

BACKGROUND: Although post liver transplant survival rates have significantly improved during the past 2-3 decades, the trend in intention-to-treat (ITT) survival (survival from waitlist addition) has not been well studied. METHODS: We conducted a retrospective analysis of Scientific Registry of Transplant Recipients data to determine the trend in ITT survival in liver transplant candidates. Adult (age ≧ 18 y) patients who were on the waitlist between the time period of March 1, 2002, to December 31, 2019 (n = 200 816) and deceased liver donors that were registered between the same time period (n = 152 593) were analyzed. RESULTS: We found a constant increase in posttransplant survival rates; however, the ITT survival rates showed no statistically significant improvement through the study period. We observed significant linear increase in waitlist dropout rates over time. We also observed linear increase in liver nonutilization rate in both entire cases and brain-dead cases. Donor risk index increased significantly over the years; however, it was mostly driven by increase in donation after circulatory death cases; without donation after circulatory death cases, donor risk index was stable throughout the 17 y we observed. CONCLUSIONS: The reason of the increased liver nonutilization rate is unclear; however, it is possible that reluctance to use high-risk organ to maintain better posttransplant outcomes contributed to this increase, which also could have led to increase in waitlist dropout rates and no improvements in ITT survival. Further investigation is warranted on the increased nonutilization rates to improve over all contribution of liver transplant to patient care.

Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes.

INTRODUCTION/AIMS: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint. METHODS: A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty-five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale-Revised (ALSFRS-R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS-R. RESULTS: We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel-treated participants (baseline NfL, baseline latency-associated peptide/transforming growth factor beta1 [LAP/TGFß1], change galectin-1, all p < .01), with baseline NfL and LAP/TGFß1 remaining (p < .05) when disease characteristics (p < .005) were incorporated. Change from baseline to the last measurement showed debamestrocel-driven reductions in NfL were associated with less decline in ALSFRS-R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p = .037). DISCUSSION: Following debamestrocel treatment, many biomarkers showed increases (anti-inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed.

From an obliquely falling rod in a viscous fluid to the motion of suspended magnetic bead chains that are driven by a gradient magnetic field and that make an arbitrary angle with the magnetic force vector: A Stokes flow study.

In view of the growing role of magnetic particles under magnetic field influence in medical and other applications, and perforce the bead chaining, it is important to understand more generally the chain dynamics. As is well known, in the presence of a magnetic field, magnetic beads tend to form chains that are aligned with the magnetic field vector. In addition, if there is a magnetic field gradient, there will be a magnetic force acting on this chain. The main goal of the present research is to study the motion of a magnetic bead chain that makes an arbitrary angle with the magnetic force vector in the Stokes flow limit, that is, in the limit of zero Reynolds number. We used the public-domain computer program HYDRO++ to calculate the mobility matrix, which relates the magnetic force acting on the chain to the velocity of the chain, for a chain of N beads making an arbitrary angle with the magnetic force vector. Because of the presence of off-diagonal elements of the mobility matrix, as the chain is drawn in the direction of the magnetic force, it is also deflected to the side. We derived analytic solutions for this motion. Also, for bead chains moving in directions both parallel and perpendicular to their lengths, we fit three-parameter functions to solutions from HYDRO++. We found the fits to be excellent. Combining these results with the analytic solutions, we obtained expressions for the velocity components for the bead chains that provide excellent fits to HYDRO++ solutions for arbitrary angles. Finally, we apply the methodology used for the bead chain studies to the study of an obliquely falling rod in a viscous fluid and derive analytic solutions for the velocity components of the obliquely falling rod.

Reprogramming Chromosome Ends by Functional Histone Acetylation.

Cancers harness embryonic programs to evade aging and promote survival. Normally, sequences at chromosome ends called telomeres shorten with cell division, serving as a countdown clock to limit cell replication. Therefore, a crucial aspect of cancerous transformation is avoiding replicative aging by activation of telomere repair programs. Mouse embryonic stem cells (mESCs) activate a transient expression of the gene Zscan4, which correlates with chromatin de-condensation and telomere extension. Head and neck squamous cell carcinoma (HNSCC) cancers reactivate ZSCAN4, which in turn regulates the phenotype of cancer stem cells (CSCs). Our study reveals a new role for human ZSCAN4 in facilitating functional histone H3 acetylation at telomere chromatin. Next-generation sequencing indicates ZSCAN4 enrichment at telomere chromatin. These changes correlate with ZSCAN4-induced histone H3 acetylation and telomere elongation, while CRISPR/Cas9 knockout of ZSCAN4 leads to reduced H3 acetylation and telomere shortening. Our study elucidates the intricate involvement of ZSCAN4 and its significant contribution to telomere chromatin remodeling. These findings suggest that ZSCAN4 induction serves as a novel link between 'stemness' and telomere maintenance. Targeting ZSCAN4 may offer new therapeutic approaches to effectively limit or enhance the replicative lifespan of stem cells and cancer cells.

Future Therapies of Hepatic Encephalopathy.

Hepatic encephalopathy, either covert or overt, affects more than half of patients with cirrhosis and has lasting effects even after portal hypertension is corrected. Unfortunately, the current therapeutic options still result in high rates of relapse and progression, in part owing to cost barriers and side effects, leading to poor adherence. This review summarizes emerging treatment options, which could take advantage of alternative disease pathways to improve future care of those with hepatic encephalopathy.

Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.

Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.

Serum aryl hydrocarbon receptor activity is associated with survival in patients with alcohol-associated hepatitis.

BACKGROUND AND AIMS: Patients with alcohol-associated hepatitis (AH) have an altered fecal metabolome, including reduced microbiota-derived tryptophan metabolites, which function as ligands for aryl hydrocarbon receptor (AhR). The aim of this study was to assess serum AhR ligand activity in patients with AH. APPROACH AND RESULTS: The study included 74 controls without AUD, 97 patients with AUD, and 330 patients with AH from 2 different multicenter cohorts (InTeam: 134, AlcHepNet: 196). Serum AhR activity was evaluated using an AhR reporter assay with HepG2-Lucia cells incubated with serum for 24 hours. Serum AhR activity was significantly higher in patients with AH compared with both controls (1.59 vs. 0.96-fold change, p < 0.001) and patients with AUD (1.59 vs. 0.93, p < 0.001). In both AH cohorts, patients with AhR activity ≥ 2.09 had significantly lower cumulative survival rates at 30, 60, 90, and 180 days compared to those with AhR activity < 2.09. When serum AhR activity was used to further stratify patients with severe AH, the cumulative 30, 60, 90, and 180-day survival rates for patients with severe AH and the AhR activity ≥ 2.09 group were all significantly lower than those with an AhR activity < 2.09 group. CONCLUSIONS: Serum AhR activity was significantly higher in patients with AH compared with controls and individuals with AUD, and this increased activity was associated with higher mortality. Consequently, serum AhR activity holds potential as a prognostic marker.

Techno-Economic Analysis of Gas Fermentation for the Production of Single Cell Protein.

Despite the large carbon footprint of livestock production, animal protein consumption has grown over the past several decades, necessitating new approaches to sustainable animal protein production. In this techno-economic analysis, single cell protein (SCP) produced via gas fermentation of carbon dioxide, oxygen, and hydrogen is studied as an animal feed source to replace fishmeal or soybean meal. Using wind-powered water electrolysis to produce hydrogen and oxygen with carbon dioxide captured from corn ethanol, the minimum selling price (MSP) of SCP is determined to be $2070 per metric ton. An emissions comparison between SCP, fishmeal, and soybean meal shows that SCP has a carbon intensity as low as 0.73 kg CO2-equiv/kg protein, while fishmeal and soybean meal have an average carbon intensity of 2.72 kg CO2-equiv/kg protein and 0.85 kg CO2-equiv/kg protein, respectively. Moreover, SCP production would occupy 0.4% of the land per ton of protein produced compared to soybean meal and would disturb less than 0.1% of the marine ecosystem currently disturbed by fishmeal harvesting practices. These results show promise for the future economic viability of SCP as a protein source in animal feed and indicate significant environmental benefits compared to other animal feed protein sources.

Meaningful Endpoints for Idiopathic Pulmonary Fibrosis (IPF) Clinical Trials: Emphasis on 'Feels, Functions, Survives'. Report of a Collaborative Discussion in a Symposium with Direct Engagement from Representatives of Patients, Investigators, the National Institutes of Health, a Patient Advocacy Organization, and a Regulatory Agency.

Background: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. Methods: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Results: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). Conclusions: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.

DeepFreeze 3D-biofabrication for Bioengineering and Storage of Stem Cells in Thick and Large-Scale Human Tissue Analogs.

3D bioprinting holds great promise for meeting the increasing need for transplantable tissues and organs. However, slow printing, interlayer mixing, and the extended exposure of cells to non-physiological conditions in thick structures still hinder clinical applications. Here the DeepFreeze-3D (DF-3D) procedure and bioink for creating multilayered human-scale tissue mimetics is presented for the first time. The bioink is tailored to support stem cell viability, throughout the rapid freeform DF-3D biofabrication process. While the printer nozzle is warmed to room temperature, each layer solidifies at contact with the stage (-80 °C), or the subsequent layers, ensuring precise separation. After thawing, the encapsulated stem cells remain viable without interlayer mixing or delamination. The composed cell-laden constructs can be cryogenically stored and thawed when needed. Moreover, it is shown that under inductive conditions the stem cells differentiate into bone-like cells and grow for months after thawing, to form large tissue-mimetics in the scale of centimeters. This is important, as this approach allows the generation and storage of tissue mimetics in the size and thickness of human tissues. Therefore, DF-3D biofabrication opens new avenues for generating off-the-shelf human tissue analogs. It further holds the potential for regenerative treatments and for studying tissue pathologies caused by disease, tumor, or trauma.

PAD2 dysregulation and aberrant protein citrullination feature prominently in reactive astrogliosis and myelin protein aggregation in sporadic ALS.

Alteration in protein citrullination (PC), a common posttranslational modification (PTM), contributes to pathogenesis in various inflammatory disorders. We previously reported that PC and protein arginine deiminase 2 (PAD2), the predominant enzyme isoform that catalyzes this PTM in the central nervous system (CNS), are altered in mouse models of amyotrophic lateral sclerosis (ALS). We now demonstrate that PAD2 expression and PC are altered in human postmortem ALS spinal cord and motor cortex compared to controls, increasing in astrocytes while trending lower in neurons. Furthermore, PC is enriched in protein aggregates that contain the myelin proteins PLP and MBP in ALS. These results confirm our findings in ALS mouse models and suggest that altered PAD2 and PC contribute to neurodegeneration in ALS.